A method for preparing high temperature resistant adenosylmethionine butanedisulfonate for injection

Abstract

The present invention relates to a method for preparing a high temperature resistant succinate methionine for injection, and relates to the technical field of pharmaceutical and freeze drying. The preparation method comprises the following steps: obtaining a succinate methionine raw material drug aqueous solution; transferring the succinate methionine raw material drug aqueous solution into an injection bottle, and then half-pressing the stopper to obtain an injection bottle containing a succinate methionine raw material drug aqueous solution; transferring the injection bottle containing the succinate methionine raw material drug aqueous solution into a freeze drying chamber for freeze drying to obtain the high temperature resistant succinate methionine for injection; wherein the freeze drying sequentially comprises pre-freezing, pre-vacuuming, primary drying, analytical drying and press-stopping. The present invention adopts freeze drying under specific conditions, and the prepared succinate methionine for injection has a low total growth of impurities under high temperature conditions, and has high safety for clinical use.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceuticals and freeze drying, and in particular to a method for preparing high-temperature resistant adenosylmethionine butanedisulfonate for injection. Background Art

[0002] Adenosylmethionine butanedisulfonate has demonstrated extensive and significant therapeutic effects in the field of clinical application, especially in the treatment of various liver diseases, where its value has been fully verified. Specifically, adenosylmethionine butanedisulfonate has been successfully used in the treatment of alcoholic cirrhosis, effectively alleviating the symptoms and pain of patients. At the same time, in the treatment of diseases such as cholestatic hepatitis, acute icteric hepatitis, and chronic hepatitis B, adenosylmethionine butanedisulfonate has also shown good therapeutic effects. What is more worth mentioning is that this drug can also play a positive therapeutic role in hyperbilirubinemia associated with patients with post-hepatitis cirrhosis.

[0003] In addition to being used alone, adenosylmethionine butadisulfonate also shows the potential for combined use with other drugs. Clinical studies have shown that the combination of this drug with glycyrrhizic acid compound, glycyrrhizin, ursodeoxycholic acid, and reduced glutathione can further enhance the therapeutic effect and bring more significant hope of recovery to patients. This combination drug strategy not only broadens the clinical application scope of adenosylmethionine butadisulfonate, but also provides new ideas and methods for the treatment of liver diseases.

[0004] However, in the process of formulating and developing the process of injectable adenosylmethionine butane disulfonate, researchers also encountered certain challenges. Especially under high temperature conditions, the drug showed certain instability and was prone to the problem of increased total impurity content, which may have an adverse effect on the efficacy and safety of the drug. Therefore, how to optimize the formula process and improve the stability of injectable adenosylmethionine butane disulfonate under high temperature conditions has become an important direction of current research. Summary of the invention

[0005] In order to solve the above problems, the present invention provides a method for preparing high temperature resistant adenosylmethionine butanedisulfonate for injection.

[0006] The present invention provides a method for preparing adenosylmethionine butanedisulfonate for high temperature resistant injection, the preparation method comprising the following steps:

[0007] Obtaining adenosylmethionine butanedisulfonate raw material drug aqueous solution;

[0008] The aqueous solution of the adenosylmethionine butanedisulfonate raw material drug is transferred into an injection bottle, and the back half is plugged to obtain an injection bottle containing the aqueous solution of the adenosylmethionine butanedisulfonate raw material drug;

[0009] The injection bottle containing the aqueous solution of the raw material drug of adenosyl methionine butanedisulfonate is transferred to a freeze-drying chamber for freeze drying to obtain the high temperature resistant adenosyl methionine butanedisulfonate for injection;

[0010] The freeze drying process includes pre-freezing, pre-vacuuming, primary drying, analytical drying and tamponing in sequence;

[0011] The pre-freezing step includes the following process: keeping warm at 5°C for 30 minutes, cooling at a rate of 1°C / (18-22)min to -10--6°C and maintaining for 8-12 minutes, then heating at a rate of 1°C / (18-22)min to -3--1°C and maintaining for 118-122 minutes, and finally cooling at full speed at a rate of 3-5°C / min to -52--48°C and maintaining for 238-242 minutes.

[0012] Furthermore, the pre-freezing step includes the following process: keeping warm at 5°C for 30 minutes, cooling to -8°C at a rate of 1°C / 20min and maintaining for 10 minutes, then heating to -2°C at a rate of 1°C / 20min and maintaining for 120 minutes, and finally cooling at full speed at a rate of 4°C / min to -50°C and maintaining for 240 minutes.

[0013] Furthermore, the pre-vacuum step includes the following process: turning on the vacuum pump to make the vacuum degree in the freeze-drying chamber 13-17 Pa, preferably 15 Pa; the filling volume of a single injection bottle is 3 mL.

[0014] Furthermore, the primary drying step includes the following processes: heating to -27~-23°C at a rate of 1°C / (4.5~5.0)min at a vacuum degree of 13Pa~25Pa and maintaining for 2350~2450min; then heating to -17~-13°C at a rate of 1°C / (2~4)min at a vacuum degree of 13Pa~25Pa and maintaining for 115~125min; finally heating to 0°C at a rate of 1°C / (1~3)min at a vacuum degree of 13~25Pa and maintaining for 55~65min.

[0015] Furthermore, the primary drying step includes the following processes: heating to -25°C at a rate of 1°C / 4.8min and maintaining for 2400min at a vacuum degree of 13Pa~25Pa; then heating to -15°C at a rate of 1°C / 3min and maintaining for 120min at a vacuum degree of 13Pa~25Pa; finally heating to 0°C at a rate of 1°C / 2min and maintaining for 60min at a vacuum degree of 13~25Pa.

[0016] Furthermore, the analytical drying step includes the following process: heating to (38~42)°C at a rate of 1°C / (1~2)min at a vacuum degree of 7Pa~18Pa and maintaining for 55~65min; then adjusting the vacuum fluctuation to 3~12Pa and maintaining at a temperature of (38~42)°C for 115~125min.

[0017] Furthermore, the analytical drying step includes the following process: heating to 40°C at a rate of 1°C / 1.5min and maintaining for 60min at a vacuum degree of 7Pa~18Pa; then adjusting the vacuum fluctuation to 3~12Pa and maintaining at 40°C for 120min.

[0018] Furthermore, the plugging step includes the following process: after the analytical drying is completed, nitrogen is filled until the pressure of the freeze-drying chamber is 800-850 Pa, and then it is sealed by full plugging to obtain the high temperature resistant adenosylmethionine butanedisulfonate for injection.

[0019] Furthermore, the preparation method further comprises the following steps:

[0020] After the plugging is completed, the air inlet valve is opened to restore the pressure in the freeze-drying chamber to normal pressure, and the capping is performed for sealing.

[0021] Furthermore, measured by mass fraction, the total amount of impurities in the high temperature resistant adenosylmethionine butanedisulfonate for injection after being stored at 60°C for 30 days is ≤3.0%; the diameter of the adenosylmethionine butanedisulfonate ice crystals in the high temperature resistant adenosylmethionine butanedisulfonate for injection is 80~260μm.

[0022] The above technical solution provided by the embodiment of the present invention has at least the following advantages compared with the prior art:

[0023] The embodiment of the present invention provides a method for preparing high temperature resistant adenosylmethionine butane disulfonate for injection, taking the pharmaceutical properties, moisture, related substances and isomers of adenosylmethionine butane disulfonate for injection as evaluation indicators, exploring the processes such as temperature, rate and time in the drug solution prescription, pre-freezing and sublimation process, and optimizing the freeze-drying process after enlargement. The results show that the prescription and freeze-drying process provided by the present invention can significantly reduce the growth of the total impurities of the product under high temperature conditions. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate embodiments consistent with the invention and, together with the description, serve to explain the principles of the invention.

[0025] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, for ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative labor.

[0026] Figure 1 A schematic flow chart of a method for preparing a high temperature resistant adenosylmethionine butanedisulfonate for injection provided in an embodiment of the present invention.

[0027] Figure 2 This is a particle size diagram of the product obtained in Example 1 of the present invention.

[0028] Figure 3 This is a particle size diagram of the product obtained in Example 2 of the present invention.

[0029] Figure 4 This is a particle size diagram of the product obtained in Example 3 of the present invention.

[0030] Figure 5 This is a particle size diagram of the product obtained in Example 4 of the present invention.

[0031] Figure 6 This is a particle size diagram of the product obtained in Example 5 of the present invention.

[0032] Figure 7 This is a particle size diagram of the product obtained in Example 6 of the present invention.

[0033] Figure 8 This is a particle size diagram of the product obtained in Example 7 of the present invention. DETAILED DESCRIPTION

[0034] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution in the embodiments of the present invention will be clearly and completely described below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. 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.

[0035] Unless otherwise specified, various raw materials, reagents, instruments and equipment used in the present invention can be purchased from the market or prepared by existing methods.

[0036] The present invention provides a method for preparing adenosylmethionine butanedisulfonate for high temperature resistant injection, such as Figure 1 As shown, the preparation method comprises the following steps:

[0037] Obtaining adenosylmethionine butanedisulfonate raw material drug aqueous solution;

[0038] The aqueous solution of the adenosylmethionine butanedisulfonate raw material drug is transferred into an injection bottle, and the back half is plugged to obtain an injection bottle containing the aqueous solution of the adenosylmethionine butanedisulfonate raw material drug;

[0039] The injection bottle containing the aqueous solution of the raw material drug of adenosyl methionine butanedisulfonate is transferred to a freeze-drying chamber for freeze drying to obtain the high temperature resistant adenosyl methionine butanedisulfonate for injection;

[0040] The freeze drying process includes pre-freezing, pre-vacuuming, primary drying, analytical drying and tamponing in sequence;

[0041] The pre-freezing step includes the following process: keeping warm at 5°C for 30 minutes, cooling at a rate of 1°C / (18-22)min to -10--6°C and maintaining for 8-12 minutes, then heating at a rate of 1°C / (18-22)min to -3--1°C and maintaining for 118-122 minutes, and finally cooling at full speed at a rate of 3-5°C / min to -52--48°C and maintaining for 238-242 minutes.

[0042] The embodiment of the present invention provides a method for preparing high temperature resistant adenosylmethionine butane disulfonate for injection, taking the pharmaceutical properties, moisture, related substances and isomers of adenosylmethionine butane disulfonate for injection as evaluation indicators, exploring the processes such as temperature, rate and time in the drug solution prescription, pre-freezing and sublimation process, and optimizing the freeze-drying process after enlargement. The results show that the prescription and freeze-drying process provided by the present invention can significantly reduce the growth of the total impurities of the product under high temperature conditions.

[0043] In some specific embodiments, the aqueous solution of succinyl butanedisulfonate raw material drug can be prepared by the following method: take 60wt% of the total amount of water for injection, add the prescribed amount of succinyl butanedisulfonate raw material drug, stir to obtain the initial solution, and add water for injection to the full amount; the obtained liquid is sterilized and filtered through a 0.22-micron PES microporous filter, the standard volume per bottle is 3ml, and the succinyl butanedisulfonate content is 0.949g.

[0044] In some specific embodiments, the pre-freezing step includes the following process: keeping warm at 5°C for 30 minutes, cooling to -8°C at a rate of 1°C / 20min and maintaining for 10 minutes, then heating to -2°C at a rate of 1°C / 20min and maintaining for 120 minutes, and finally cooling at full speed at a rate of 4°C / min to -50°C and maintaining for 240 minutes.

[0045] In some specific embodiments, the pre-vacuum step includes the following process: turning on the vacuum pump to make the vacuum degree in the freeze-drying chamber 13-17 Pa, preferably 15 Pa; the filling volume of a single bottle of the injection bottle is 3 mL.

[0046] In some specific embodiments, the primary drying step includes the following process: heating to -27~-23°C at a rate of 1°C / (4.5~5.0)min at a vacuum degree of 13Pa~25Pa and maintaining for 2350~2450min; then heating to -17~-13°C at a rate of 1°C / (2~4)min at a vacuum degree of 13Pa~25Pa and maintaining for 115~125min; finally heating to 0°C at a rate of 1°C / (1~3)min at a vacuum degree of 13~25Pa and maintaining for 55~65min.

[0047] In some specific embodiments, the primary drying step includes the following process: heating to -25°C at a rate of 1°C / 4.8min and maintaining for 2400min at a vacuum degree of 13Pa~25Pa; then heating to -15°C at a rate of 1°C / 3min and maintaining for 120min at a vacuum degree of 13Pa~25Pa; finally heating to 0°C at a rate of 1°C / 2min and maintaining for 60min at a vacuum degree of 13~25Pa.

[0048] In some specific embodiments, the analytical drying step includes the following process: heating to (38~42)°C at a rate of 1°C / (1~2)min at a vacuum degree of 7Pa~18Pa and maintaining for 55~65min; then adjusting the vacuum fluctuation to 3~12Pa and maintaining at (38~42)°C for 115~125min.

[0049] In some specific embodiments, the analytical drying step includes the following process: heating to 40°C at a rate of 1°C / 1.5min and maintaining for 60min at a vacuum degree of 7Pa~18Pa; then adjusting the vacuum fluctuation to 3~12Pa and maintaining at 40°C for 120min.

[0050] In some specific embodiments, the plugging step includes the following process: after the analytical drying is completed, nitrogen is filled until the freeze-drying chamber pressure is 800~850Pa, and then it is sealed by full plugging to obtain the high temperature resistant adenosylmethionine butanedisulfonate for injection.

[0051] In some specific embodiments, the preparation method further comprises the following steps:

[0052] After the plugging is completed, the air inlet valve is opened to restore the pressure in the freeze-drying chamber to normal pressure, and the capping is performed for sealing.

[0053] In some specific embodiments, the total amount of impurities in the high temperature resistant adenosylmethionine butane disulfonate for injection after being stored at 60°C for 30 days is ≤3.0% by mass fraction; the diameter of the adenosylmethionine butane disulfonate ice crystals in the high temperature resistant adenosylmethionine butane disulfonate for injection is 80~260μm.

[0054] In the present invention, the vacuum degree in primary drying and subsequent analytical drying refers to the vacuum degree in the freeze-drying chamber.

[0055] It should be noted that the component raw materials involved in the preparation method of the high temperature resistant adenosylmethionine butanedisulfonate for injection provided by the embodiment of the present invention, unless otherwise specified or specified, can be directly commercially available products or homemade using the existing public preparation method; at the same time, the steps and parameters involved, unless otherwise specified or specified, can be carried out according to the existing processing technology of adenosylmethionine butanedisulfonate for injection or directly carried out using existing equipment, and the present invention document will not repeat them one by one.

[0056] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended only to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples that do not specify specific conditions are usually measured according to national standards. If there is no corresponding national standard, then the conditions recommended by the manufacturer are followed.

[0057] Example 1

[0058] This example provides a high temperature resistant adenosylmethionine butanedisulfonate for injection, and the preparation method of the high temperature resistant adenosylmethionine butanedisulfonate for injection comprises the following steps:

[0059] Step (1): add 60% of the prescribed amount of water for injection into the liquid preparation tank, start stirring, and add the prescribed amount of adenosylmethionine butane disulfonate (18.98 kg); add water for injection to the full amount (60 L), start stirring, and stop stirring after complete dissolution; sterilize and filter through a 0.22 μm filter to obtain adenosylmethionine butane disulfonate raw material aqueous solution, and wait for filling;

[0060] Step (2): the aqueous solution of succinyl methionine disulfonate raw material drug is divided into 20 ml vials by a filling machine, with a standard filling volume of 3 ml per bottle and a succinyl methionine disulfonate content of 0.949 g, and the vials are stoppered and half-stoppered to obtain injection bottles containing the aqueous solution of succinyl methionine disulfonate raw material drug;

[0061] Step (3): transferring the injection bottle containing the aqueous solution of the raw material drug of adenosyl methionine butane disulfonate to a freeze-drying chamber for freeze drying to obtain the high temperature resistant adenosyl methionine butane disulfonate for injection;

[0062] The freeze drying process includes pre-freezing, pre-vacuuming, primary drying, analytical drying and tamponing in sequence;

[0063] Pre-freezing: keep at 5℃ for 30min, then cool to -8℃ at a rate of 1℃ / 20min and maintain for 10min, heat to -2℃ at a rate of 1℃ / 20min and maintain for 120min, cool to -50℃ at a full speed of 4℃ / min and maintain for 240min;

[0064] Pre-vacuum: Turn on the vacuum pump to make the vacuum degree of the freeze-drying chamber where the drug solution is located to 15Pa;

[0065] Primary drying: vacuum degree is 20Pa, temperature is increased to -25℃ at a rate of 1℃ / 4.8min and maintained for 2400min; vacuum degree is 20Pa, temperature is increased to -15℃ at a rate of 1℃ / 3min and maintained for 120min; vacuum degree is 20Pa, temperature is increased to 0℃ at a rate of 1℃ / 2min and maintained for 60min;

[0066] Analytical drying: vacuum degree is 10Pa, temperature is raised to 40℃ at a rate of 1℃ / 1.5min and maintained for 60min; vacuum degree is adjusted to 5Pa and maintained at 40℃ for 120min;

[0067] Pressure plugging: After the analytical drying is completed, nitrogen is filled until the cavity pressure is 820Pa, and the pressure plugging is performed to obtain adenosylmethionine butanedisulfonate for injection;

[0068] Step (4): Open the air inlet valve to return the pressure in the cavity to normal pressure, take the product out of the box, and perform capping and sealing, which is recorded as the product of Example 1.

[0069] The product of Example 1 has no appearance of collapse or remelting, the detected moisture content is less than 2.0%, the re-dissolution time is less than 30s, and the total impurity content is ≤1.0%. 500 vials of adenosylmethionine butanedisulfonate for injection of the product of Example 1 were tested for high temperature influence factors. The results are shown in Table 1, and the particle size is shown in the attached Figure 2 , the particle size in the figure is about 160μm.

[0070] Example 2

[0071] This example provides a high temperature resistant adenosylmethionine butanedisulfonate for injection, and the preparation method of the high temperature resistant adenosylmethionine butanedisulfonate for injection comprises the following steps:

[0072] Step (1): Add 60% of the prescribed amount of water for injection into the liquid preparation tank, start stirring, add the prescribed amount of adenosylmethionine disulfonate (28.47 kg); add water for injection to the full amount (90 L), start stirring, and stop stirring after it is completely dissolved. Sterile filter through a 0.22 μm filter to obtain adenosylmethionine disulfonate raw material aqueous solution, waiting for filling;

[0073] Step (2): the aqueous solution of succinyl methionine disulfonate raw material drug is divided into 10 ml vials by a filling machine, with a standard filling volume of 3 ml per bottle and a succinyl methionine disulfonate content of 0.949 g, and the vials are stoppered and half stoppered to obtain injection bottles containing the aqueous solution of succinyl methionine disulfonate raw material drug;

[0074] Step (3): transferring the injection bottle containing the aqueous solution of the raw material drug of adenosyl methionine butane disulfonate to a freeze-drying chamber for freeze drying to obtain the high temperature resistant adenosyl methionine butane disulfonate for injection;

[0075] The freeze drying process includes pre-freezing, pre-vacuuming, primary drying, analytical drying and tamponing in sequence;

[0076] Pre-freezing: keep at 5℃ for 30min, then cool to -6℃ at a rate of 1℃ / 18min and maintain for 12min, heat to -1℃ at a rate of 1℃ / 18min and maintain for 122min, cool to -52℃ at a full speed of 3℃ / min and maintain for 238min;

[0077] Pre-vacuuming: Turn on the vacuum pump to make the vacuum degree of the freeze-drying chamber where the drug solution is located to 13Pa;

[0078] Primary drying: vacuum degree is 13Pa, temperature is increased to -23℃ at a rate of 1℃ / 4.5min and maintained for 2450min; vacuum degree is 13Pa, temperature is increased to -13℃ at a rate of 1℃ / 2min and maintained for 125min; vacuum degree is 13Pa, temperature is increased to 0℃ at a rate of 1℃ / 1min and maintained for 55min;

[0079] Analytical drying: vacuum degree is 7Pa, temperature is raised to 38℃ at a rate of 1℃ / 1.5min and maintained for 65min; vacuum degree is adjusted to 5Pa and maintained at 38℃ for 125min;

[0080] Pressure plugging: After the analytical drying is completed, nitrogen is filled until the cavity pressure is 800Pa, and pressure plugging is performed to obtain adenosylmethionine butanedisulfonate for injection;

[0081] Step (4): Open the air inlet valve to return the pressure in the cavity to normal pressure, take the product out of the box, and perform capping and sealing, which is recorded as the product of Example 2.

[0082] The product of Example 2 has no appearance collapse or remelting, the detected moisture content is less than 2.0%, the re-dissolution time is less than 30s, and the total impurities are ≤1.0%. 500 vials of adenosylmethionine butanedisulfonate for injection of the product of Example 2 were tested for high temperature influence factors. The results are shown in Table 1, and the particle size is shown in the attached Figure 3 , the particle size in the figure is about 100μm.

[0083] Example 3

[0084] This example provides a high temperature resistant adenosylmethionine butanedisulfonate for injection, and the preparation method of the high temperature resistant adenosylmethionine butanedisulfonate for injection comprises the following steps:

[0085] Step (1): Add 60% of the prescribed amount of water for injection into the liquid preparation tank, start stirring, add the prescribed amount of adenosylmethionine disulfonate (11.388 kg); add water for injection to the full amount (60 L), start stirring, and stop stirring after it is completely dissolved. Sterile filter through a 0.22 μm filter to obtain adenosylmethionine disulfonate raw material aqueous solution, waiting for filling;

[0086] Step (2): filling the aqueous solution of succinyl methionine disulfonate raw material drug into 10 ml vials through a filling machine, with a standard filling volume of 5 ml per bottle and a content of succinyl methionine disulfonate of 0.949 g; stoppering and half stoppering to obtain injection bottles containing the aqueous solution of succinyl methionine disulfonate raw material drug;

[0087] Step (3): transferring the injection bottle containing the aqueous solution of the raw material drug of adenosyl methionine butane disulfonate to a freeze-drying chamber for freeze drying to obtain the high temperature resistant adenosyl methionine butane disulfonate for injection;

[0088] The freeze drying process includes pre-freezing, pre-vacuuming, primary drying, analytical drying and tamponing in sequence;

[0089] Pre-freezing: keep at 5℃ for 30min, then cool to -10℃ at a rate of 1℃ / 22min and maintain for 8min, heat to -3℃ at a rate of 1℃ / 22min and maintain for 118min, cool to -48℃ at a full speed of 5℃ / min and maintain for 242min;

[0090] Pre-vacuum: Turn on the vacuum pump to make the vacuum degree of the freeze-drying chamber where the drug solution is located to 17Pa;

[0091] Primary drying: vacuum degree is 25Pa, temperature is increased to -27℃ at a rate of 1℃ / 5min and maintained for 2450min; vacuum degree is 25Pa, temperature is increased to -17℃ at a rate of 1℃ / 4min and maintained for 115min; vacuum degree is 25Pa, temperature is increased to 0℃ at a rate of 1℃ / 1min and maintained for 65min;

[0092] Analytical drying: vacuum degree is 18Pa, temperature is raised to 42℃ at a rate of 1℃ / 1.5min and maintained for 55min; vacuum degree is adjusted to 12Pa and maintained at 42℃ for 115min;

[0093] Pressure plugging: After the analytical drying is completed, nitrogen is filled until the cavity pressure is 850Pa, and the pressure plugging is performed to obtain adenosylmethionine butanedisulfonate for injection;

[0094] Step (4): Open the air inlet valve to return the pressure in the cavity to normal pressure, take the product out of the box, and perform capping and sealing, which is recorded as the product of Example 3.

[0095] The product obtained in this example was tested for high temperature factors. The results are shown in Table 1 and the particle size is shown in Appendix Figure 4 , the particle size in the figure is about 60μm.

[0096] Example 4

[0097] This example provides a method for preparing high temperature resistant adenosylmethionine butanedisulfonate for injection, which differs from Example 1 only in that the pre-freezing adopts a quick freezing process: the whole process is cooled to -50°C at a full speed of 4°C / min and maintained for 240 minutes; the remaining steps and parameters are the same.

[0098] The product obtained in this example was tested for high temperature factors. The results are shown in Table 1 and the particle size is shown in Appendix Figure 5 , the particle size in the figure is about 40μm.

[0099] Example 5

[0100] This example provides a method for preparing high temperature resistant adenosylmethionine butanedisulfonate for injection, which differs from Example 1 only in that the pre-freezing adopts a slow freezing process: the temperature is lowered to -50°C at a rate of 1°C / 10min and maintained for 240min throughout the process; the remaining steps and parameters are the same.

[0101] The product obtained in this example was tested for high temperature factors. The results are shown in Table 1 and the particle size is shown in Appendix Figure 6 , the particle size in the figure is about 40μm.

[0102] Example 6

[0103] This example provides a method for preparing high-temperature resistant adenosylmethionine butanedisulfonate for injection, which differs from Example 1 only in that a slow freezing process is used for pre-freezing: cooling to -20°C at a rate of 1°C / 10min and maintaining for 120min, and cooling to -50°C at a rate of 1°C / 10min and maintaining for 240min; the remaining steps and parameters are the same.

[0104] The product obtained in this example was tested for high temperature factors. The results are shown in Table 1 and the particle size is shown in Appendix Figure 7 , the particle size in the figure is about 45μm.

[0105] Example 7

[0106] This example provides a method for preparing high-temperature resistant adenosylmethionine butanedisulfonate for injection, which differs from Example 1 only in that the pre-freezing adopts a slow freezing and annealing process: cooling to -50°C at a rate of 1°C / 10min and maintaining for 120min, heating to 10°C at a rate of 1°C / 5min and maintaining for 90min, and then cooling to -50°C at a full speed of 4°C / min and maintaining for 240min; the remaining steps and parameters are the same.

[0107] The product obtained in this example was tested for high temperature factors. The results are shown in Table 1 and the particle size is shown in Appendix Figure 8 , the particle size in the figure is about 25μm.

[0108] Table 1

[0109]

[0110]

[0111] Various embodiments of the present invention may be presented in the form of a range; it should be understood that the description in the form of a range is only for convenience and brevity, and should not be understood as a rigid limitation on the scope of the present invention; therefore, the range description should be considered to have specifically disclosed all possible sub-ranges and single numerical values ​​within the range. For example, the range description from 1 to 6 should be considered to have specifically disclosed sub-ranges, such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc., as well as single numbers within the range, such as 1, 2, 3, 4, 5 and 6, which apply regardless of the range. In addition, whenever a numerical range is indicated herein, it is meant to include any cited number (fractional or integer) within the indicated range.

[0112] The foregoing is merely a specific embodiment of the present invention, which enables those skilled in the art to understand or implement the present invention. Various modifications to these embodiments will be apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention will not be limited to the embodiments shown herein, but rather to the widest scope consistent with the principles and novel features claimed herein.

Claims

1. A method for preparing high temperature resistant adenosylmethionine butanedisulfonate for injection, characterized in that: The preparation method comprises the following steps: Obtaining adenosylmethionine butanedisulfonate raw material drug aqueous solution; The aqueous solution of the adenosylmethionine butanedisulfonate raw material drug is transferred into an injection bottle, and the back half is plugged to obtain an injection bottle containing the aqueous solution of the adenosylmethionine butanedisulfonate raw material drug; The injection bottle containing the aqueous solution of the raw material drug of adenosyl methionine butanedisulfonate is transferred to a freeze-drying chamber for freeze drying to obtain the high temperature resistant adenosyl methionine butanedisulfonate for injection; The freeze drying process includes pre-freezing, pre-vacuuming, primary drying, analytical drying and tamponing in sequence; The pre-freezing step includes the following processes: keeping at 5°C for 30 minutes, cooling to -8°C at a rate of 1°C / 20min and maintaining for 10 minutes, then heating to -2°C at a rate of 1°C / 20min and maintaining for 120 minutes, and finally cooling at full speed at a rate of 4°C / min to -50°C and maintaining for 240 minutes; The pre-vacuuming step includes the following processes: turning on the vacuum pump to make the vacuum degree in the freeze-drying chamber 13-17 Pa; the filling volume of a single injection bottle is 3 mL; The primary drying step comprises the following processes: heating to -25°C at a rate of 1°C / 4.8min at a vacuum degree of 13Pa-25Pa and maintaining for 2400min; then heating to -15°C at a rate of 1°C / 3min at a vacuum degree of 13Pa-25Pa and maintaining for 120min; finally heating to 0°C at a rate of 1°C / 2min at a vacuum degree of 13-25Pa and maintaining for 60min; The analytical drying step includes the following process: heating to 40°C at a rate of 1°C / 1.5min at a vacuum degree of 7Pa-18Pa and maintaining for 60min; then adjusting the vacuum fluctuation to 3-12Pa and maintaining at 40°C for 120min; The plugging step includes the following process: after the analytical drying is completed, nitrogen is filled until the pressure of the freeze-drying chamber is 800-850 Pa, and then the chamber is sealed by full plugging to obtain the high temperature resistant adenosylmethionine disulfonate for injection; Measured by mass fraction, the total amount of impurities in the high temperature resistant adenosylmethionine butanedisulfonate for injection is ≤3.0% after being stored at 60° C. for 30 days.

2. The method for preparing high temperature resistant adenosylmethionine butanedisulfonate for injection according to claim 1, characterized in that: The preparation method further comprises the following steps: After the plugging is completed, the air inlet valve is opened to restore the pressure in the freeze-drying chamber to normal pressure, and the capping is performed for sealing.

3. The method for preparing high temperature resistant adenosylmethionine butanedisulfonate for injection according to claim 2, characterized in that: The diameter of the ice crystals of succinyl methionine butane disulfonate in the high temperature resistant succinyl methionine butane disulfonate for injection is 80-260 μm.

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