A method for preparing an injectable β-blocker

Abstract

This application discloses a method for preparing an injectable β-blocker, comprising the following steps: 1) Solution preparation: mixing the prescribed amount of landiolol hydrochloride, the prescribed amount of lyophilization protectant, and a portion of solvent, stirring to dissolve, adjusting the pH value of the solution with sodium hydroxide solution, and adjusting the volume to a predetermined volume with solvent to obtain landiolol hydrochloride solution; 2) Filtration; 3) Filling; 4) Semi-stopping; 5) Lyophilization: performing lyophilization on the landiolol hydrochloride product through pre-freezing, one drying, and two analytical drying processes; 6) Nitrogen filling, stopping, and unpacking; 7) Capping to obtain the final landiolol hydrochloride product; The injectable landiolol obtained by this application has good stability and a short reconstitution time.

Description

Technical Field

[0001] This application belongs to the field of pharmaceutical formulation technology, and specifically relates to a method for preparing an injectable β-blocker. Background Technology

[0002] Landilol hydrochloride for injection is an injectable drug developed by Ono Pharmaceutical Co., Ltd. of Japan for the treatment of tachyarrhythmias. It is a novel ultra-short-acting beta-adrenergic receptor blocker. Due to its rapid onset of action, rapid metabolism, and rapid disappearance of beta-receptor blocking effect after discontinuation, ultra-short-acting beta-adrenergic receptor blockers play an important and irreplaceable role in the treatment of newly occurring tachyarrhythmias. Clinically, it is indicated for: 1. Emergency treatment of the following tachyarrhythmias occurring during surgery: atrial fibrillation, atrial flutter, sinus tachycardia; 2. Emergency treatment of tachyarrhythmias occurring during dynamic monitoring of the circulatory system after surgery: atrial fibrillation, atrial flutter, sinus tachycardia; 3. Treatment of the following tachyarrhythmias in patients with heart failure: atrial fibrillation, atrial flutter.

[0003] Patent CN101732319B discloses an injectable pharmaceutical composition containing the active ingredient landilol hydrochloride and its preparation method, which obtains the lyophilized landilol hydrochloride injectable formulation through freeze drying.

[0004] Patent CN102475706A discloses a pharmaceutical composition for injectable landilol hydrochloride and its preparation method. The method involves mixing landilol, sodium edetate, and lactose, and preparing an injectable lyophilized dosage form of landilol hydrochloride using freeze-drying technology.

[0005] CN102232930A discloses a drug composition of landiolol hydrochloride and its preparation method, which obtains a lyophilized formulation of landiolol hydrochloride by using amino acids as excipients and controlling the temperature of water for injection and the pH value of the solution.

[0006] The contents described in the above patents are all aimed at solving the stability problem of injectable landilol hydrochloride, but the effect they can achieve is limited. Summary of the Invention

[0007] To address the problems existing in the prior art, the present invention provides a method for preparing an injectable β-blocker, comprising the following steps:

[0008] 1) Solution preparation: Mix the prescribed amount of landiolol hydrochloride, the prescribed amount of lyophilization protectant and part of the solvent, stir to dissolve, adjust the pH value of the solution with sodium hydroxide solution, and make up to the predetermined volume with the solvent to obtain landiolol hydrochloride solution;

[0009] 2) Filtration: Filter the landiol hydrochloride solution obtained in step 1) using a filter membrane;

[0010] 3) Filling: Fill the filtered landiol hydrochloride solution from step 2) into injection vials to obtain landiol hydrochloride product 1;

[0011] 4) Semi-stopping: The brandyl hydrochloride product 1 is subjected to semi-stopping treatment to obtain brandyl hydrochloride product 2;

[0012] 5) Freeze-drying: The brandyl hydrochloride product 2 is freeze-dried through pre-freezing, one drying and two desorption drying processes to obtain brandyl hydrochloride product 3;

[0013] 6) Nitrogen filling, plugging, and unpacking: The brandyl hydrochloride product 3 is subjected to nitrogen filling under vacuum, and then plugged in a freeze dryer before being unpacked.

[0014] 7) Capping: The product obtained in step 6) is capped to obtain the final brandyl hydrochloride product 4.

[0015] Further, the pre-freezing process in step 5) is as follows: the brandylore hydrochloride product 2 is placed in a freeze dryer, the temperature of the heat transfer fluid is set to -30°C, and the temperature of the brandylore hydrochloride product 2 is reduced to -30°C ± 5°C within 60 minutes, and then maintained within this temperature range for 60 to 120 minutes.

[0016] Further, the drying process described in step 5) is as follows: after the pre-freezing process is completed, when the vacuum degree in the freeze-drying chamber should reach 0.15 mbar, the temperature is raised to slowly raise the temperature of the heat transfer fluid to 10-15°C, and the heating time is controlled within 60 minutes. Then, the temperature is maintained at this temperature for 180-720 minutes.

[0017] Further, the two analytical drying processes in step 5) are as follows: First analytical drying: After the first drying process is completed, the heat transfer system is started to raise the temperature of the heat transfer fluid to 30-40°C, and the heating time is controlled within 60 minutes. Then, the temperature is maintained at this temperature for 60-120 minutes, while the vacuum degree in the freeze-drying chamber is maintained at 0.1 mbar; Second analytical drying: After the first analytical drying is completed, the vacuum degree in the freeze-drying chamber is gradually adjusted to 0 mbar. While adjusting the vacuum degree, the temperature of the heat transfer fluid is maintained at 30-40°C and held for 60-120 minutes.

[0018] Furthermore, the temperature of the heat transfer fluid in the first analytical drying process is the same as the temperature of the heat transfer fluid in the second analytical drying process.

[0019] Furthermore, the pH value of the landiol hydrochloride solution is 5.5–6.5.

[0020] Furthermore, the composition of the injectable β-blocker includes: 50-55 parts of landilol hydrochloride, 50-55 parts of lyophilization protectant, an appropriate amount of sodium hydroxide, and an appropriate amount of solvent.

[0021] Furthermore, the freeze-drying protectant is D-mannitol.

[0022] Furthermore, the solvent is used to bring the mixture of brandylol hydrochloride and the lyophilization protectant to a predetermined volume for each vial of formulation.

[0023] On the other hand, the present invention provides an injectable β-blocker prepared according to the above method, wherein the injectable β-blocker is preferably injectable landiolol hydrochloride, and the dosage form is a sterile powder for injection.

[0024] Compared with the prior art, the preparation method of the β-blocker for injection (hereinafter referred to as "landilolol hydrochloride for injection") of the present invention has the following advantages:

[0025] (1) By improving the freeze-drying process, the preparation method of the present invention can significantly improve the stability of landilol hydrochloride injection. During the freeze-drying process, by precisely controlling parameters such as temperature and time, the structural changes of drug molecules during the freeze-drying process are reduced, thereby maintaining its efficacy.

[0026] (2) The optimized freeze-drying process results in a longer shelf life for the prepared injections. This is due to the removal of moisture and the stabilization treatment of the drug during freeze-drying, which reduces the degradation rate of the drug during storage.

[0027] (3) The improved freeze-drying process significantly enhances the solubility of landilol hydrochloride in water or other solvents. The freeze-dried drug exhibits a loose and porous structure, which greatly increases the contact area between the drug and the solvent, thereby greatly promoting the rapid and complete dissolution of the drug. Thanks to this, the landilol hydrochloride injection prepared by the method of this invention can achieve rapid reconstitution, which is particularly important in emergency situations, ensuring the high efficiency and timeliness of treatment. Detailed Implementation

[0028] The technical solutions in the embodiments of this application will be clearly described below. Obviously, the described embodiments are only some, not all, of the embodiments of this application. All other embodiments obtained by those skilled in the art based on the embodiments of this application are within the scope of protection of this application.

[0029] The terms "first," "second," etc., used in the specification and claims of this application are used to distinguish similar objects and not to describe a specific order or sequence. It should be understood that such use of data can be interchanged where appropriate so that embodiments of this application can be implemented in orders other than those described herein, and the objects distinguished by "first," "second," etc., are generally of the same class and the number of objects is not limited; for example, a first object can be one or more. Furthermore, in the specification and claims, "and / or" indicates at least one of the connected objects, and the character " / " generally indicates that the preceding and following objects are in an "or" relationship.

[0030] The inventors of this application have discovered that by controlling the key processes in the preparation method of landiolol hydrochloride for injection, the stability of landiolol hydrochloride injection can be significantly improved, and the shelf life of the drug can be extended. The entire process includes the following main steps:

[0031] 1) Solution preparation: Mix the prescribed amount of landiolol hydrochloride, the prescribed amount of lyophilization protectant and part of the solvent, stir to dissolve, adjust the pH value of the solution with sodium hydroxide solution, and make up to the predetermined volume with the solvent to obtain landiolol hydrochloride solution;

[0032] In one embodiment of the present invention, the amount of landiolol hydrochloride and the amount of lyophilization protectant are 50-55 parts; in one embodiment of the present invention, the lyophilization protectant is D-mannitol; in one embodiment of the present invention, the pH value of the landiolol hydrochloride solution is 5.5-6.5, for example 5.5, 5.9, 6.0, 6.1 or 6.5, but not limited to the listed values, other unlisted values ​​within this range are also applicable;

[0033] 2) Filtration: Filter the landiol hydrochloride solution obtained in step 1) using a filter membrane;

[0034] 3) Filling: Fill the filtered landiol hydrochloride solution from step 2) into injection vials to obtain landiol hydrochloride product 1;

[0035] 4) Semi-stopping: The brandyl hydrochloride product 1 is semi-stopped to obtain brandyl hydrochloride product 2; the semi-stopping is mainly used to ensure the stability of the freeze-dried product during the drying process and the quality of the final product. The operation is to gently push the stopper into the bottle mouth, but not completely seal it.

[0036] 5) Freeze-drying: The brandyl hydrochloride product 2 is freeze-dried through pre-freezing, one drying and two desorption drying processes to obtain brandyl hydrochloride product 3;

[0037] Specifically, it includes the following processes:

[0038] A. Pre-freezing: Place the brandyl hydrochloride product 2 into a freeze dryer, set the temperature of the heat transfer fluid to -30℃, and lower the temperature of the brandyl hydrochloride product 2 to -30℃±5℃ within 60 minutes. Then maintain this temperature range for 60 to 120 minutes, for example, 60 minutes, 90 minutes or 120 minutes, but not limited to the listed values. Other unlisted values ​​within this range are also applicable.

[0039] B. Single drying: When the vacuum degree inside the freeze dryer reaches 0.15 mbar, start heating, allowing the temperature of the heat transfer fluid to slowly rise to 10-15°C, such as 10°C, 11°C, 12°C, 13°C, 14°C, or 15°C, but not limited to the listed values; other unlisted values ​​within this range are also applicable. The heating time should be controlled within 60 minutes, followed by holding at this temperature for 180-720 minutes, such as 180 minutes, 240 minutes, 300 minutes, 360 minutes, 420 minutes, 480 minutes, 540 minutes, 600 minutes, 660 minutes, or 720 minutes, but not limited to the listed values; other unlisted values ​​within this range are also applicable.

[0040] C. First Drying: After step B is completed, start the heat transfer system to raise the temperature of the heat transfer fluid to 30-40℃, such as 30℃, 31℃, 32℃, 33℃, 34℃, 35℃, 36℃, 37℃, 38℃, 39℃ or 40℃, but not limited to the listed values, other unlisted values ​​within this range are also applicable; the heating time is controlled within 60 minutes, and then the temperature is maintained at 60-120 minutes, such as 60 minutes, 90 minutes or 120 minutes, but not limited to the listed values, other unlisted values ​​within this range are also applicable, while maintaining the vacuum degree in the freeze-drying chamber at 0.1 mbar;

[0041] D. Second drying step: After step C, gradually adjust the vacuum level in the freeze-drying chamber to 0 mbar. While adjusting the vacuum level, maintain the temperature of the heat transfer fluid at 30-40℃, such as 30℃, 31℃, 32℃, 33℃, 34℃, 35℃, 36℃, 37℃, 38℃, 39℃ or 40℃, but not limited to the listed values. Other unlisted values ​​within this range are also applicable. Keep warm for 60-120 minutes.

[0042] Temperature and time control during the lyophilization process are crucial for preserving the active ingredients of a drug. Precise control of temperature and time during lyophilization can reduce structural changes in drug molecules, thereby maintaining their efficacy and ensuring the stability of landiolol hydrochloride for injection. Simultaneously, temperature and time control during lyophilization also affect drug solubility; appropriate temperature and time help form a loose, porous lyophilized structure, thus improving the solubility of landiolol hydrochloride for injection in water or other solvents.

[0043] 6) Nitrogen filling, stoppering, and unpacking: The brandyl hydrochloride product 3 is subjected to nitrogen filling under vacuum, and then stoppering is performed in a freeze dryer before unpacking; stoppering refers to completely sealing the stopper at the bottle mouth.

[0044] 7) Capping: The product obtained in step 6) is capped to obtain the final brandyl hydrochloride product 4.

[0045] The specific embodiments and comparative examples of the present invention are listed below, but the present invention is not limited to the following examples.

[0046] The sources of raw materials for the examples and comparative examples are as follows:

[0047] Product Name batch number Manufacturer Landilol Hydrochloride 231110 Beijing Sunshine Novo Pharmaceutical Research Co., Ltd. D-Mannitol F835E Guangxi Nanning Chemical Pharmaceutical Co., Ltd. Sodium hydroxide 100920211214 Hunan Ercon Pharmaceutical Co., Ltd. Watsons Water 20220609R Guangzhou Watsons Food and Beverage Co., Ltd.

[0048] The production equipment for the examples and comparative examples is as follows:

[0049] Equipment Name Device Model Equipment manufacturers freeze dryer LYO-0.5 Dongfulong Technology Co., Ltd. Pneumatic capping machine SUS304-8 Foshan Lianxing Yongsheng Steel Pipe Co., Ltd.

[0050] Example 1

[0051] Prescription composition:

[0052] Raw material names unit dose 600 effect Landilol Hydrochloride 50mg 30.04g Active substances D-Mannitol 50mg 30g Lyophilization protectant Sodium hydroxide solution Appropriate amount / pH adjuster Watsons Water Adjust the volume to 1ml 600ml solvent

[0053] Preparation process:

[0054] 1) Solution preparation: 0.1M sodium hydroxide solution preparation: Add 2.0g of sodium hydroxide to 500ml of water for injection and stir well. Measure 70% of the prescribed amount of Watson's water and add it to a beaker. Add the prescribed amount of D-mannitol while stirring, and stir until the mannitol dissolves. Then add the prescribed amount of brandylol hydrochloride and dissolve. Adjust the pH to 5.5-6.5 with sodium hydroxide solution. Transfer the solution to a graduated cylinder, rinse the beaker several times with Watson's water, and bring the volume to 600ml. Then stir for 10 minutes.

[0055] 2) Filtration: Filter the landiol hydrochloride solution obtained in step 1) using a 0.22μm PES filter membrane for later use.

[0056] 3) Filling: Fill the filtered landiol hydrochloride solution from step 2) into injection vials to obtain landiol hydrochloride product 1.

[0057] 4) Semi-stopping: The brandyl hydrochloride product 1 is subjected to semi-stopping treatment to obtain brandyl hydrochloride product 2.

[0058] 5) Freeze-drying: Freeze-dry the brandyl hydrochloride product 2 according to the following parameters.

[0059]

[0060] The specific steps are as follows:

[0061] Pre-freezing: Place brandylol hydrochloride product 2 into a freeze-drying chamber and set the temperature of the heat transfer fluid to -30℃ according to the freeze-drying process, so that the temperature of brandylol hydrochloride product 2 is reduced to -30℃±5℃ within 60 minutes, and then maintained within this temperature range for 60 minutes.

[0062] One-time drying (freeze drying): After the pre-freezing process is completed, when the vacuum degree in the freeze drying chamber should reach 0.15 mbar, start heating to slowly raise the temperature of the heat transfer fluid to 10°C. The heating time should be controlled within 60 minutes, and then the temperature should be maintained at that temperature for 720 minutes.

[0063] First drying step: After the first drying step, the heat transfer system is activated to raise the temperature of the heat transfer fluid to 40°C, with the heating time controlled within 60 minutes. This temperature is then maintained for 120 minutes. During this period, the vacuum level inside the freeze-drying chamber is maintained at 0.1 mbar.

[0064] Second analytical drying: After the first analytical drying is completed, the vacuum degree in the freeze-drying chamber is gradually adjusted to 0 mbar. While adjusting the vacuum degree, the temperature of the heat transfer fluid is kept constant at 40℃ and kept at this temperature for 60 minutes to obtain brandylol hydrochloride product 3.

[0065] 6) Nitrogen filling, plugging, and unpacking: Under vacuum conditions, the freeze-dried brandyl hydrochloride product 3 is filled with nitrogen to a capacity of 100%. After plugging in the freeze dryer, it is unpacked.

[0066] 7) Capping: The product obtained in step 6) is used to cap the aluminum-plastic combination cap of the antibiotic bottle using a pneumatic capping machine to obtain the final brandyl hydrochloride product 4.

[0067] Example 2

[0068] Adjust the temperature of the two lyophilization drying steps in step 5). The specific freeze-drying parameters are shown in the table below. The specific operation, formulation composition and other process steps and conditions are the same as in Example 1.

[0069]

[0070] Example 3

[0071] Adjust the pre-freezing duration in step 5). The specific freeze-drying parameters are shown in the table below. The specific operation, formulation composition and other process steps and conditions are the same as in Example 1.

[0072]

[0073] Example 4

[0074] Adjust the duration of the drying cycle in step 5). The specific freeze-drying parameters are shown in the table below. The specific operation, formulation composition and other process steps and conditions are the same as in Example 1.

[0075]

[0076] Example 5

[0077] Adjust the duration of the drying cycle in step 5). The specific freeze-drying parameters are shown in the table below. The specific operation, formulation composition and other process steps and conditions are the same as in Example 1.

[0078]

[0079] Example 6

[0080] Adjust the duration of the first analysis drying in step 5). The specific freeze-drying parameters are shown in the table below. The specific operation, formulation composition and other process steps and conditions are the same as in Example 1.

[0081]

[0082]

[0083] Comparative Example 1

[0084] Step 5) There is only one analysis and drying process. The specific freeze-drying parameters are shown in the table below. The specific operation, formulation composition and other process steps and conditions are the same as in Example 1.

[0085]

[0086] Comparative Example 2

[0087] Adjust the temperature of the two lyophilization drying steps in step 5). The specific freeze-drying parameters are shown in the table below. The specific operation, formulation composition and other process steps and conditions are the same as in Example 1.

[0088]

[0089] Comparative Example 3

[0090] Adjust the pre-freezing duration in step 5). The specific freeze-drying parameters are shown in the table below. The specific operation, formulation composition and other process steps and conditions are the same as in Example 1.

[0091]

[0092] Comparative Example 4

[0093] Adjust the drying duration in step 5). The specific freeze-drying parameters are shown in the table below. The specific operation, formulation composition and other process steps and conditions are the same as in Example 1.

[0094]

[0095] Comparative Example 5

[0096] Adjust the drying duration in step 5). The specific freeze-drying parameters are shown in the table below. The specific operation, formulation composition and other process steps and conditions are the same as in Example 1.

[0097]

[0098] Comparative Example 6

[0099] Adjust the duration of the first desorption drying in step 5). The specific freeze-drying parameters are shown in the table below. The specific operation, formulation composition and other process steps and conditions are the same as in Example 1.

[0100]

[0101] Comparative Example 7

[0102] Adjust the temperature of the first drying and the two desorption drying in step 5). The specific freeze-drying parameters are shown in the table below. The specific operation, formulation composition and other process steps and conditions are the same as in Example 1.

[0103]

[0104]

[0105] Comparative Example 8

[0106] Step 5) The freeze-drying process is the same as in Example 1, referring to patent CN102232930A, with the same formulation and other process steps and conditions. The specific freeze-drying process is as follows:

[0107] Place the product in a freeze-drying chamber, close the door, turn on the refrigeration unit, and use the heat transfer oil to lower the product temperature. When the product temperature reaches below the eutectic point, continue freezing for 2 hours. When the product temperature reaches -45℃, stop the heat transfer oil and turn on the condenser. When the condenser temperature reaches -50℃, turn on the vacuum system and heat up the product at a rate of 2-4℃ per hour for sublimation drying. The final drying temperature is 45℃, and this temperature is maintained for 4 hours.

[0108] Tests were performed on Examples 1-6, Comparative Examples 1-8, and commercially available injectable landilol hydrochloride (manufactured by Ono Pharmaceutical Co., Ltd.). (Batch: 168YA) Related substances of the product on day 0 and after being placed under strong light (5000 lux), high temperature (60°C) and high humidity (RH90%) for 10 days.

[0109] Related substances determination methods

[0110] The determination was performed according to high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512).

[0111] Solvent: Water-acetonitrile (9:1)

[0112] Test Solution: Dissolve and dilute the sample in solvent to prepare a solution containing approximately 1.0 mg of brandylol hydrochloride per ml. Control Solution: Accurately measure an appropriate amount of the test solution and dilute with solvent to prepare a solution containing approximately 2.0 μg per ml.

[0113] For system suitability solution, take appropriate amounts of impurity standards YLDZ-SM-B, YLDZ-IM-A, YLDZ-IM-B, YLDZ-IM-C, and YLDZ-IM-H, and landiolol hydrochloride, dissolve and dilute with solvent to prepare a mixed solution containing approximately 2.0 μg each of YLDZ-SM-B, YLDZ-IM-A, YLDZ-IM-B, YLDZ-IM-C, and YLDZ-IM-H, and approximately 1.0 mg of landiolol hydrochloride per 1 ml.

[0114] For the sensitivity solution, accurately measure an appropriate amount of the reference solution and dilute it with a solvent to prepare a solution containing approximately 0.2 μg per ml.

[0115] Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the stationary phase (YMC-Pack ODS-AQ, 4.6 mm × 250 mm, 5 μm or equivalent column); mobile phase A was 0.05 mol / L sodium dihydrogen phosphate (pH adjusted to 4.8 with 1 mol / L sodium hydroxide)-acetonitrile (90:10), and mobile phase B was 0.05 mol / L sodium dihydrogen phosphate (pH adjusted to 4.8 with 1 mol / L sodium hydroxide)-acetonitrile (30:70); flow rate was 1.0 mL / min; column temperature was 30 °C; detection wavelength was 220 nm; injection volume was 20 μL. Elution was performed according to the following gradient.

[0116] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 100 0 5 100 0 10 70 30 35 20 80 40 20 80 45 100 0 55 100 0

[0117] For system suitability requirements, in the chromatogram of the solution, the elution order should be impurity YLDZ-IM-A, YLDZ-IM-B, YLDZ-IM-H, brandyvolol hydrochloride, YLDZ-SM-B, and YLDZ-IM-C. The resolution between the main peak and adjacent peaks should be no less than 1.5. The theoretical plate number, calculated based on brandyvolol, should be no less than 5000. In the chromatogram of the solution, the signal-to-noise ratio of the main component peak should be no less than 10.

[0118] Assay: Accurately measure the test solution and control solution, inject them into the liquid chromatograph, and record the chromatograms.

[0119] If impurity peaks are present in the chromatogram of the limit test solution, after subtracting the blank solvent peak, the area of ​​each known impurity peak, calculated according to the self-comparison method, should not exceed 3 times (0.3%) the area of ​​the main peak of the control solution, and the area of ​​any other individual impurity peak should not exceed 2.0 times (0.2%) the area of ​​the main peak of the control solution. The sum of the areas of all impurity peaks should not exceed 10 times (1.0%) the area of ​​the main peak of the control solution. Impurity peaks smaller than the area of ​​the Pembavertine peak in the sensitivity solution (0.02%) can be ignored.

[0120] The following information is available regarding impurities in landiolol hydrochloride for injection:

[0121]

[0122]

[0123] The results of related substance detection in the examples and comparative examples are as follows:

[0124]

[0125]

[0126]

[0127]

[0128] The results of related substance testing in the examples and comparative examples show that the impurity content in Examples 1 to 6 is similar to, or even lower than, the impurity content in commercially available products.

[0129] Examples 1-6 involve two analytical drying processes, while Comparative Example 1 involves only one analytical drying process. The content of impurity YLDZ-IM-B in the injectable brandylol hydrochloride obtained in Comparative Example 1 on day 0 is 0.28%, which is too high compared to the contents of the examples and commercially available products. Furthermore, the total impurity content of Comparative Example 1 after being placed at high temperature (60°C) for 10 days is 0.92%, which is also too high compared to Examples 1-6.

[0130] In Examples 1-6, the temperatures for the first and second drying analyses were 30-40°C. In Comparative Example 2, the temperatures for the first and second drying analyses were increased to 45°C. In Comparative Example 7, the temperatures for the first and second drying analyses were decreased to 25°C. The YLDZ-IM-B impurity content in the injectable brandylol hydrochloride obtained in Comparative Example 2 was 0.3% on day 0, reaching the limit value. After being placed under different conditions for 10 days, the YLDZ-IM-B impurity content exceeded the limit of 0.3%. Meanwhile, the total impurity content was 1.08% after being placed at high temperature (60°C) for 10 days, which was too high compared to the content in Examples 1-6 and exceeded the limit of 1.0%. The content of other single impurities was 0.37% after being placed at high temperature (60°C) for 10 days, exceeding the limit value of 0.2%. The total impurities in the injectable landiolol hydrochloride obtained in Comparative Example 7 were 1.02% after being stored at high temperature (60°C) for 10 days. This was significantly higher than that in Examples 1-6, exceeding the limit of 1.0%. Meanwhile, the impurity YLDZ-IM-B had already reached 0.3% on day 0, which was also the limit. Furthermore, after being stored under different conditions for 10 days, the impurity YLDZ-IM-B content exceeded the limit of 0.3%.

[0131] In Examples 1-6, the pre-freezing duration was 60-120 minutes. In Comparative Example 3, the pre-freezing duration was adjusted to 180 minutes. According to the relevant material data, the total impurity content of the injectable brandylol hydrochloride obtained in Comparative Example 3 was 1.06% after being placed at high temperature (60°C) for 10 days, exceeding the limit of 1.0%. At the same time, the impurity YLDZ-IM-B reached 0.31% on day 0, reaching the limit value. Furthermore, after being placed under different conditions for 10 days, the impurity YLDZ-IM-B content exceeded the limit of 0.3%.

[0132] In Examples 1-6, the drying time for one cycle was 180-720 minutes. In Comparative Example 4, the drying time for one cycle was adjusted to 120 minutes, and in Comparative Example 5, the drying time for one cycle was adjusted to 780 minutes. Based on the relevant material data, in Comparative Example 4, the content of impurity YLDZ-IM-B reached 0.3% on day 0, exceeding the limit. Furthermore, after 10 days under different conditions, the content of impurity YLDZ-IM-B exceeded the limit of 0.3%. Simultaneously, the total impurity content after 10 days at high temperature (60°C) was 0.97%, which is excessively high compared to Examples 1-6. In Comparative Example 5, the content of impurity YLDZ-IM-B reached 0.31% on day 0, exceeding the limit. Furthermore, after 10 days under different conditions, the content of impurity YLDZ-IM-B exceeded the limit of 0.3%. The total impurity content after 10 days at high temperature (60°C) was 0.95%, which is excessively high compared to Examples 1-6.

[0133] In Examples 1-6, the duration of the first desorption drying was 60-120 minutes. In Comparative Example 6, the duration of the first desorption drying was extended to 180 minutes. According to the relevant material data, the content of other single impurities in the injectable brandylol hydrochloride obtained in Comparative Example 6 after being placed at high temperature (60°C) for 10 days was 0.33%, which exceeded the limit value of 0.2%. The content of total impurities after being placed at high temperature (60°C) for 10 days was 0.93%, which was too high compared to Examples 1-6.

[0134] Meanwhile, using the freeze-drying process of the existing patent CN102232930A as Comparative Example 8, the inventors further investigated the effects of different freeze-drying processes on related substances. Under the same conditions as Example 1, the total impurities in the injectable brandylol hydrochloride obtained in Comparative Example 8 were 1.07% after being placed at high temperature (60°C) for 10 days, which exceeded the limit of 1.0%. The content of other single impurities was 0.32% after being placed at high temperature (60°C) for 10 days, which exceeded the limit of 0.2%. The content of impurity YLDZ-IM-B reached 0.29% on day 0. After being placed under different conditions for 10 days, the content of impurity YLDZ-IM-B exceeded the limit of 0.3%.

[0135] Therefore, to ensure the excellent stability of the obtained injectable brandylol hydrochloride, each step of the lyophilization process—pre-freezing, primary drying, first analytical drying, and second analytical drying—is indispensable. Furthermore, the parameters at each step must be maintained within specific ranges.

[0136] Tests were performed on Examples 1-6, Comparative Examples 1-8, and commercially available injectable landilol hydrochloride (manufactured by Ono Pharmaceutical Co., Ltd.). (Batch: 168YA) Reconstitution time.

[0137] Determination method Add sterile water for injection at 20-25°C according to the indicated amount, shake gently, and it should be completely dissolved within 15 minutes.

[0138] The reconstitution time test results for the examples and comparative examples are as follows:

[0139] batch Reconstitution time Commercially available products 43 seconds Example 1 38 seconds Example 2 37 seconds Example 3 44 seconds Example 4 42 seconds Example 5 41 seconds Example 6 39 seconds Comparative Example 1 1 minute 58 seconds Comparative Example 2 2 minutes and 5 seconds Comparative Example 3 2 minutes and 21 seconds Comparative Example 4 2 minutes and 15 seconds Comparative Example 5 1 minute 45 seconds Comparative Example 6 2 minutes and 22 seconds Comparative Example 7 2 minutes and 19 seconds Comparative Example 8 2 minutes and 31 seconds

[0140] The reconstitution time test results of the examples and comparative examples show that the reconstitution time of Examples 1 to 6 is similar to that of commercially available products, while the reconstitution time of the comparative examples is longer than that of the examples and commercially available products. For emergency drugs such as injectable landiolol hydrochloride, reconstitution time is directly related to life safety and is an extremely critical influencing factor.

[0141] Freeze-drying is widely used in the pharmaceutical industry and typically involves pre-freezing, primary drying (sublimation drying), and secondary drying (desorption drying). However, because injectable landilol hydrochloride is an ultra-short-acting β-adrenergic receptor blocker with rapid onset of action and rapid metabolism, it places higher demands on the freeze-drying process.

[0142] The inventors of this application have discovered that rapid freezing is necessary in the pre-freezing stage of the lyophilization process to reduce ice crystal size and prevent cell death, thereby ensuring the activity and stability of the product. The pre-freezing temperature and holding time are crucial. In the primary drying stage (sublimation drying), due to the extremely high selectivity of landilolol hydrochloride for β1 receptors, precise control of temperature, time, and vacuum is required to ensure the preservation of drug activity. In the secondary drying stage (desorption drying), temperature and vacuum need to be carefully controlled to further remove residual moisture while avoiding damage to the drug structure, ensuring drug stability and reconstitution. Only by simultaneously controlling multiple parameters in the lyophilization process within specific ranges can injectable landilolol hydrochloride with good stability and rapid reconstitution be obtained.

[0143] The embodiments of this application have been described above, but this application is not limited to the specific embodiments described above. The specific embodiments described above are merely illustrative and not restrictive. Those skilled in the art can make many other forms under the guidance of this application without departing from the spirit and scope of the claims, and all of these forms are within the protection scope of this application.

Claims

1. A method for preparing an injectable β-blocker, characterized in that, The steps include: 1) Solution preparation: Mix the prescribed amount of landiolol hydrochloride, the prescribed amount of lyophilization protectant and part of the solvent, stir to dissolve, adjust the pH value of the solution with sodium hydroxide solution, and make up to the predetermined volume with the solvent to obtain landiolol hydrochloride solution; 2) Filtration: Filter the landiol hydrochloride solution obtained in step 1) using a filter membrane; 3) Filling: Fill the filtered landiol hydrochloride solution from step 2) into injection vials to obtain landiol hydrochloride product 1; 4) Semi-stopping: The brandyl hydrochloride product 1 is subjected to semi-stopping treatment to obtain brandyl hydrochloride product 2; 5) Freeze-drying: The brandyl hydrochloride product 2 is freeze-dried through pre-freezing, one drying and two desorption drying processes to obtain brandyl hydrochloride product 3; 6) Nitrogen filling, plugging, and unpacking: The brandyl hydrochloride product 3 is subjected to nitrogen filling under vacuum, and then plugged in a freeze dryer before being unpacked. 7) Capping: The product obtained in step 6) is capped to obtain the final brandylol hydrochloride product 4; The two analytical drying processes mentioned in step 5) are as follows: First analytical drying: After the first drying process is completed, the heat transfer system is started to raise the temperature of the heat transfer fluid to 30~40℃, and the heating time is controlled within 60 minutes. Then, the temperature is maintained at this temperature for 60~120 minutes, while maintaining the vacuum degree in the freeze-drying chamber at 0.1mbar; Second analytical drying: After the first analytical drying is completed, the vacuum degree in the freeze-drying chamber is gradually adjusted to 0mbar. While adjusting the vacuum degree, the temperature of the heat transfer fluid is maintained at 30~40℃ and held for 60~120 minutes. The composition of the injectable β-blocker includes: 50-55 parts of landiolol hydrochloride, 50-55 parts of lyophilization protectant, appropriate amount of sodium hydroxide, and appropriate amount of solvent. The freeze-drying protectant is D-mannitol.

2. The method for preparing the injectable β-blocker according to claim 1, characterized in that, The pre-freezing process described in step 5) is as follows: place the brandylore hydrochloride product 2 into a freeze dryer, set the temperature of the heat transfer fluid to -30°C, so that the temperature of the brandylore hydrochloride product 2 is reduced to -30°C±5°C within 60 minutes, and then maintain it within this temperature range for 60~120 minutes.

3. The method for preparing the injectable β-blocker according to claim 2, characterized in that, The drying process described in step 5) is as follows: After the pre-freezing process is completed, when the vacuum degree in the freeze-drying chamber should reach 0.15 mbar, the temperature is raised to slowly raise the temperature of the heat transfer fluid to 10-15°C. The heating time is controlled within 60 minutes, and then the temperature is maintained at that temperature for 180-720 minutes.

4. The method for preparing the injectable β-blocker according to claim 3, characterized in that, The temperature of the heat transfer fluid in the first analytical drying process is the same as the temperature of the heat transfer fluid in the second analytical drying process.

5. The method for preparing the injectable β-blocker according to claim 4, characterized in that, The pH value of the landilol hydrochloride solution is 5.5~6.

5.

6. The method for preparing the injectable β-blocker according to claim 5, characterized in that, The solvent is used to bring the mixture of brandylol hydrochloride and the lyophilization protectant to a predetermined volume for each vial of formulation.

7. The β-blocker for injection prepared by the method according to any one of claims 1 to 6, wherein the β-blocker for injection is landiolol hydrochloride for injection, and the dosage form is sterile powder for injection.

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