Butanedisulfonic acid adenosyl methionine for injection and preparation method thereof

Abstract

The invention provides butanedisulfonic acid adenosyl methionine for injection and a preparation method thereof, and relates to the technical field of medicine preparation. The preparation method comprises the following steps: filtering a butanedisulfonic acid ademetionine liquid medicine, sub-packaging and semi-plugging to obtain a sample, freeze-drying the sample, and carrying out nitrogen charging and plug pressing and re-pressing and capping to obtain butanedisulfonic acid ademetionine for injection; the freeze drying sequentially comprises pretreatment, pre-freezing, sublimation drying and desorption drying; the pretreatment comprises the steps that the temperature is set to be-5 DEG C to 0 DEG C, the holding time is set to be 1-2 h, then the vacuum degree is set to be 80-150 pa, and the holding time is 0.5-2 min; the sublimation drying is one-time sublimation. According to the invention, the sample can be rapidly nucleated and uniformly form large ice crystals at a relatively high supercooling temperature, so that the uniformity in batches is ensured, the one-time sublimation drying time can be shortened, the moisture of the obtained freeze-dried preparation is lower, meanwhile, the shelf life of the product can be effectively ensured to meet the quality standard, and the clinical safety effectiveness is improved.

Description

Technical Field

[0001] The present invention relates to the technical field of drug preparation, in particular to a kind of adenosylmethionine butanedisulfonate for injection and a preparation method thereof. Background Art

[0002] Adenosylmethionine is a physiologically active molecule that is ubiquitous in human tissues and body fluids. It participates in important biochemical reactions in the body as a methyl donor and a precursor of physiological sulfhydryl compounds. In the liver, it regulates the fluidity of liver cell membranes by methylating plasma membrane phospholipids, and promotes the synthesis of sulfide products in the detoxification process through transsulfurization reactions. As long as the bioavailability of intrahepatic adenosylmethionine is within the normal range, these reactions help prevent intrahepatic cholestasis.

[0003] Adenosylmethionine butadisulfonate for injection was first launched in Italy in 1993 and imported into China in 1996. It is currently a commonly used drug for intrahepatic cholestasis of pregnancy in China. Adenosylmethionine butadisulfonate for injection is composed of a freeze-dried powder containing only adenosylmethionine butadisulfonate and a special solvent L-lysine aqueous solution. The freeze-dried powder has differences in sample appearance during the shelf life, and some samples are yellow in color, the clarity and color of the solution are unqualified, and related substances are unqualified. Studies have shown that these phenomena are mainly affected by the difference in moisture content of the freeze-dried powder. Because the solid content of adenosylmethionine butadisulfonate is high during the preparation process and the product moisture level requirement is low, the freeze-drying process in the existing technology can easily lead to the inability to control the product moisture at a low level, and there are intra-batch differences, which in turn leads to a rapid increase in related substances and yellow color during the shelf life of the product. Summary of the invention

[0004] One of the purposes of the present invention is to provide a method for preparing adenosylmethionine butanedisulfonate for injection, which enables the sample to form uniform large ice crystals in the pre-freezing stage, improves the sublimation efficiency, shortens the sublimation time, obtains low-moisture and uniform lyophilized powder, ensures that the product meets the quality standards during the shelf life, and improves clinical safety and effectiveness.

[0005] Another object of the present invention is to provide adenosylmethionine butanedisulfonate for injection, which is prepared by the above preparation method.

[0006] The technical solution adopted by the present invention is as follows:

[0007] A preparation method of succinate adenosylmethionine for injection comprises the following steps: dissolving succinate adenosylmethionine in injection water to prepare a medicine liquid; filtering the medicine liquid, subpackaging and half-stoppering to obtain a sample; freeze-drying the sample, and then performing nitrogen-filled stoppering and re-pressing and capping to obtain succinate adenosylmethionine for injection; wherein freeze-drying comprises pretreatment, prefreezing, sublimation drying and analytical drying in sequence; the pretreatment comprises: setting the temperature to -5 to 0°C, setting the holding time to 60 to 120 minutes, and then setting the vacuum degree to 80 Pa to 150 Pa and maintaining for 0.5 to 2 minutes; and the sublimation drying is a single sublimation.

[0008] In a preferred embodiment of the present invention, the temperature during the pretreatment is -5 to -3°C and the vacuum degree is 80 to 100 Pa.

[0009] In a preferred embodiment of the present invention, the pre-freezing comprises: setting the temperature to -50 to -40°C, the cooling time to 40 to 60 minutes, and the holding time to 120 to 180 minutes.

[0010] In a preferred embodiment of the present invention, the sublimation drying comprises: setting the temperature to -25°C to -15°C, the heating time to 60 to 80 minutes, the holding time to 2000 to 3000 minutes, and the vacuum degree to 0.1 to 0.3 mbar.

[0011] In a preferred embodiment of the present invention, the analytical drying comprises: setting the temperature to 35-50° C., the heating time to 60-120 min, the holding time to 300-420 min, and the vacuum degree to 0.1-0.3 mbar.

[0012] In a preferred embodiment of the present invention, the concentration of adenosylmethionine butanedisulfonate in the drug solution is 50 mg / ml to 150 mg / ml.

[0013] Adenosylmethionine butanedisulfonate for injection is prepared by any of the above-mentioned preparation methods.

[0014] In a preferred embodiment of the present invention, the water content of adenosylmethionine butanedisulfonate for injection does not exceed 0.8%.

[0015] In a preferred embodiment of the present invention, the water content of adenosylmethionine butanedisulfonate for injection does not exceed 0.6%.

[0016] The beneficial effects of the present invention are:

[0017] The present invention provides a method for preparing adenosylmethionine butanedisulfonate for injection, which can effectively improve the nucleation and ice growth mode by adding a pretreatment process before freeze-drying. The freeze-drying technology in the prior art often adopts an annealing process, a supercooling process or a slow / fast freezing process to solve the problem of improving the uniformity of ice crystals. However, in these processes, when the sample is frozen from a solution state to a solid state, it is inevitable that the samples in the batch will nucleate and grow ice at different temperatures and times. The nucleation temperature difference is as large as nearly 10°C, resulting in different forms of ice growth in the samples, and then resulting in differences in quality attributes such as appearance moisture within the batch. In the pretreatment process of the present invention, the sample can be rapidly nucleated at a relatively high supercooling temperature, and large ice crystals can be uniformly formed, which not only ensures the uniformity within the batch, but also shortens the time of sublimation drying once, and makes the moisture content of the obtained freeze-dried preparation lower. At the same time, it can effectively ensure that the product meets the quality standards during the shelf life and improve clinical safety and effectiveness. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 This is the appearance of adenosylmethionine butanedisulfonate injection products prepared by different methods. DETAILED DESCRIPTION

[0019] The above contents of the present invention are further described in detail below through specific implementation methods in the form of embodiments. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention.

[0020] Comparative Example 1

[0021] A. Preparation of drug solution: Weigh the prescribed amount of adenosylmethionine butanedisulfonate, add water for injection, stir until completely dissolved, and obtain a drug solution with a concentration of 100 mg / ml. The drug solution is filtered through 0.22 μm PES and dispensed into 7 mL vials, each with a dispensing volume of 5 mL. After half-stoppering, the sample is obtained.

[0022] B. Place the sample in a freeze-drying chamber and then perform annealing treatment: set the shelf temperature to -40°C, cool for 60 minutes, hold for 30 minutes, then heat to -10°C, hold for 30 minutes, set the shelf temperature to -50°C, and hold for 120 minutes.

[0023] C. Single sublimation: Set the partition temperature to -25°C, heat up for 60 minutes, maintain for 3000 minutes, and the vacuum degree is 0.1 mbar.

[0024] D. Analytical drying: Set the shelf temperature to 35°C, heat for 120 min, maintain for 400 min, and the vacuum degree to 0.1 mbar.

[0025] E. After freeze-drying, fill with nitrogen and press the stopper. After re-pressing, take it out of the box and crimp the cap to obtain adenosylmethionine butanedisulfonate for injection.

[0026] Comparative Example 2

[0027] A. Preparation of drug solution: same as Comparative Example 1.

[0028] B. Place the sample in a freeze-drying chamber and then perform supercooling treatment: set the shelf temperature to -10°C, cool for 30 minutes, and maintain for 60 minutes.

[0029] C. Pre-freezing: Set the shelf temperature to -45°C, cool for 30 minutes, and maintain for 120 minutes.

[0030] D. Primary sublimation: Set the partition temperature to -20°C, heat for 60 min, maintain for 2700 min, and the vacuum degree is 0.1 mbar.

[0031] E. Analytical drying: Set the partition temperature to 45°C, heat for 120 min, maintain for 400 min, and the vacuum degree is 0.1 mbar.

[0032] F. After freeze-drying, fill with nitrogen and press the stopper. After re-pressing, take it out of the box and crimp the cap to obtain adenosylmethionine butanedisulfonate for injection.

[0033] Comparative Example 3

[0034] A. Preparation of drug solution: same as Comparative Example 1.

[0035] B. Place the sample in a freeze-drying chamber and then perform a slow freezing process: set the shelf temperature to -45°C, cool for 180 minutes, and hold for 120 minutes.

[0036] C. Single sublimation: Set the partition temperature to -20°C, heat for 60 minutes, maintain for 2800 minutes, and the vacuum degree is 0.1 mbar.

[0037] D. Analytical drying: Set the partition temperature to 45°C, heat for 120 min, maintain for 400 min, and the vacuum degree is 0.1 mbar.

[0038] E. After freeze-drying, fill with nitrogen and press the stopper. After re-pressing, take it out of the box and crimp the cap to obtain adenosylmethionine butanedisulfonate for injection.

[0039] Example 1

[0040] A. Preparation of drug solution: Weigh the prescribed amount of adenosylmethionine butanedisulfonate, add water for injection, stir until completely dissolved, and obtain a drug solution with a concentration of 100 mg / ml. The drug solution is filtered through 0.22 μm PES and dispensed into 7 mL vials, each with a dispensing volume of 5 mL. After half-stoppering, the sample is obtained.

[0041] B. Place the sample in a freeze-drying chamber and perform pretreatment: set the shelf temperature to -5°C for 60 min, then set the vacuum degree to 80 Pa for 1 min.

[0042] C. Pre-freezing: Set the shelf temperature to -45°C, cool for 60 minutes, and maintain for 120 minutes.

[0043] D. Primary sublimation: Set the shelf temperature to -25°C, heat for 60 minutes, maintain for 2200 minutes, and the vacuum degree is 0.1 mbar

[0044] E. Analytical drying: Set the shelf temperature to 35°C, heat for 60 min, maintain for 360 min, and the vacuum degree is 0.1 mbar.

[0045] F. After freeze-drying, fill with nitrogen and press the stopper. After re-pressing, take it out of the box and crimp the cap to obtain adenosylmethionine butanedisulfonate for injection.

[0046] Example 2

[0047] A. Preparation of drug solution: Same as Example 1.

[0048] B. Place the sample in a freeze-drying chamber and perform pretreatment: set the shelf temperature to 0°C for 60 min, then set the vacuum degree to 80 Pa for 1 min.

[0049] C. Pre-freezing: Set the shelf temperature to -45°C, cool for 40 minutes, and maintain for 180 minutes.

[0050] D. Primary sublimation: Set the partition temperature to -15°C, heat for 60 min, maintain for 2700 min, and the vacuum degree is 0.2 mbar.

[0051] E. Analytical drying: Set the partition temperature to 40°C, heat for 120 min, maintain for 400 min, and the vacuum degree is 0.2 mbar.

[0052] F. After freeze-drying, fill with nitrogen and press the stopper. After re-pressing, take it out of the box and crimp the cap to obtain adenosylmethionine butanedisulfonate for injection.

[0053] Example 3

[0054] A. Preparation of drug solution: Same as Example 1.

[0055] B. Place the sample in a freeze-drying chamber and then perform pretreatment: set the shelf temperature to -3°C for 60 min, then set the vacuum degree to 80 Pa for 1 min.

[0056] C. Pre-freezing: Set the shelf temperature to -50°C, cool for 60 minutes, and maintain for 120 minutes.

[0057] D. Primary sublimation: Set the partition temperature to -20°C, heat for 60 min, maintain for 2500 min, and the vacuum degree is 0.3 mbar.

[0058] E. Analytical drying: Set the partition temperature to 50°C, heat for 120 min, maintain for 300 min, and the vacuum degree is 0.3 mbar.

[0059] F. After freeze-drying, fill with nitrogen and press the stopper. After re-pressing, take it out of the box and crimp the cap to obtain adenosylmethionine butanedisulfonate for injection.

[0060] Comparative Example 4

[0061] A. Preparation of drug solution: Same as Example 1.

[0062] B. Place the sample in a freeze-drying chamber and perform pretreatment: set the shelf temperature to -10°C for 60 min, then set the vacuum degree to 180 Pa for 1 min.

[0063] C. Pre-freezing: Set the shelf temperature to -45°C, cool for 60 minutes, and maintain for 120 minutes.

[0064] D. Primary sublimation: Set the partition temperature to -25°C, heat for 60 min, maintain for 2200 min, and the vacuum degree is 0.1 mbar.

[0065] E. Analytical drying: Set the shelf temperature to 35°C, heat for 60 min, maintain for 360 min, and the vacuum degree is 0.1 mbar.

[0066] F. After freeze-drying, fill with nitrogen and press the stopper. After re-pressing, take it out of the box and crimp the cap to obtain adenosylmethionine butanedisulfonate for injection.

[0067] Experimental example

[0068] The injection of adenosylmethionine butanedisulfonate prepared by different preparation methods in Comparative Examples 1-4 and Examples 1-3 was selected, wherein 20 bottles prepared by each method were selected and the physical and chemical properties were tested respectively, and the data are shown in Table 1. Since the data in Examples 2 and 3 are not different from those in Example 1 as a whole, the data of Examples 2 and 3 are omitted in Table 1.

[0069] Table 1 Comparison of properties of adenosylmethionine butanedisulfonate for injection prepared by different methods

[0070]

[0071] From the results shown in Table 1, it can be seen that the appearance and moisture content of the injection of adenosyl methionine butane disulfonate prepared by Examples 1-3 are the best, and the appearance is a complete white cake-like powder with a moisture content between 0.4 and 0.5%. At the same time, the clarity is also excellent. In Comparative Example 3, a slow freezing process was adopted, and the appearance of the injection of adenosyl methionine butane disulfonate prepared has collapsed, showing an incomplete powder, which does not meet the requirements of freeze-dried products at all, and no subsequent stability test is required. In Comparative Example 1, an annealing process was adopted to prepare injection of adenosyl methionine butane disulfonate, and in Comparative Example 2, a supercooling process was adopted to prepare injection of adenosyl methionine butane disulfonate. There was no obvious difference in the overall physical and chemical tests of the two, and the moisture content was between 0.8 and 1.5%, and some products shrank at the bottom. The pretreatment method used in Comparative Example 4 is similar to that in Example 1, except that a lower temperature and a higher pressure are used. The results are similar to those in Comparative Example 3. The appearance of some of the prepared injection succinate adenosylmethionine has collapsed, showing an incomplete powder cake, so the stability test is no longer carried out. The appearance of the injection succinate adenosylmethionine products prepared by different methods is as follows: Figure 1 As shown. Since the appearance of the succinate ademethionine for injection obtained in Examples 2 and 3 is almost the same as that of the succinate ademethionine for injection in Example 1, the product pictures in Examples 2 and 3 are omitted. Figure 1 In the figure, AD are schematic diagrams of the appearance of the products in Comparative Examples 1-3 and Example 1, respectively; wherein, Figure 1 -The left half of the picture in A is a view of the bottom of the product, which intuitively shows the shrinkage state of the bottom of the product in Comparative Example 1.

[0072] Comparative Examples 1, 2 and Examples 1-3 were selected for injection, wherein 20 bottles were selected for each method, and stability was investigated at 25°C and RH60%. The investigation data are shown in Table 2. Since the data in Examples 2 and 3 are not different from those in Example 1 as a whole, the data in Examples 2 and 3 are omitted in Table 1. The results show that the injection of adenosylmethionine butanedisulfonate prepared in Examples 1-3 has a complete white cake appearance throughout the shelf life, and the water content and solution clarity have almost no change, and the intra-batch difference is small. However, the products obtained by the annealing process in Comparative Example 1 and the supercooling process in Comparative Example 2 have shown obvious yellowing in the later stage, and the water content and clarity have shown an increasing trend. At the same time, the increase in the relevant substances is also significantly greater than that of the product in Example 1.

[0073] Table 2 Comparison of the stability of adenosylmethionine butanedisulfonate for injection prepared by the same method

[0074]

Claims

1. A method for preparing adenosylmethionine butanedisulfonate for injection, characterized in that: Dissolve adenosylmethionine butane disulfonate in water for injection to prepare a drug solution; filter the drug solution, divide and half-stopper the solution to obtain a sample, freeze-dry the sample, and then press the stopper with nitrogen, and then press and cap to obtain adenosylmethionine butane disulfonate for injection; wherein the freeze-drying includes pretreatment, prefreezing, sublimation drying and analytical drying in sequence; the pretreatment includes: setting the temperature to -5 to 0°C, setting the holding time to 60 min to 120 min, and then setting the vacuum degree to 80 Pa to 150 Pa, and keeping it for 0.5 to 2 min; the sublimation drying is a single sublimation.

2. The preparation method according to claim 1, characterized in that: The temperature during pretreatment is -5 to -3°C and the vacuum degree is 80 to 100 Pa.

3. The preparation method according to claim 1, characterized in that: The pre-freezing includes: setting the temperature to -50 to -40°C, the cooling time to 40 to 60 minutes, and the holding time to 120 to 180 minutes.

4. The preparation method according to claim 1, characterized in that: The sublimation drying comprises: setting the temperature to -25°C to -15°C, the heating time to 60 to 80 minutes, the holding time to 2000 to 3000 minutes, and the vacuum degree to 0.1 to 0.3 mbar.

5. The preparation method according to claim 1, characterized in that: The analytical drying comprises: setting the temperature to 35-50° C., the heating time to 60-120 min, the holding time to 300-420 min, and the vacuum degree to 0.1-0.3 mbar.

6. The preparation method according to any one of claims 1 to 5, characterized in that: The concentration of adenosylmethionine butanedisulfonate in the drug solution is 50-150 mg / ml.

7. A succinyl methionine butanedisulfonate for injection, characterized in that: The preparation method is described in any one of claims 1 to 6.

8. The adenosylmethionine butanedisulfonate for injection according to claim 7, characterized in that: The moisture content does not exceed 0.8%.

9. The adenosylmethionine butanedisulfonate for injection according to claim 7, characterized in that: The moisture content does not exceed 0.6%.

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