Preparation process of lornoxicam freeze-dried powder injection for injection

Abstract

The invention discloses a preparation process of lornoxicam freeze-dried powder injection for injection, and belongs to the technical field of freeze-dried powder injection. The preparation process of the lornoxicam freeze-dried powder injection for injection comprises the following steps: stirring, filtering and freeze-drying a mixture containing lornoxicam to obtain the lornoxicam freeze-dried powder injection for injection, the freeze drying comprises the steps of pre-freezing, sublimation drying, desorption drying and cooling. The preparation process is simple, the components are controllable, under the condition that other auxiliary materials such as cosolvents and excipients are not additionally added, the freeze-drying process is adopted, the redissolving time can be within a controllable range, the clarity of related substances and solutions is controllable, meanwhile, the technological process is simple and easy to operate, and the preparation method is suitable for industrial production. The prepared lornoxicam freeze-dried powder injection has good stability, and the technical problems that in the prior art, related substances are uncontrollable, the solution clarity exceeds the limit, and the redissolution time is long are solved.

Description

Technical Field

[0001] The present application relates to a preparation process of lornoxicam freeze-dried powder injection for injection, belonging to the technical field of freeze-dried powder injection. Background Art

[0002] Lornoxicam, whose chemical name is 6-chloro-4-hydroxy-2-methyl-3-(2-pyridineaminocarboxamide)-2H-thieno[2,3-e]-1,2-thiazine-1,1-dichloride, is a non-steroidal anti-inflammatory analgesic drug with strong analgesic and anti-inflammatory effects.

[0003] The original developer of lornoxicam for injection is Takeda. The injection was first launched by Takeda Pharma A / S in Denmark in February 1997 with a specification of 8 mg. It was subsequently launched in EU countries such as Austria, Sweden and Italy. my country has approved the import of injections under the trade name of Xafon. The license holder is Takeda Austria GmbH and the manufacturer is Wasserburger Arzneimittelwerk GmbH.

[0004] For injection products, if the reconstitution time is long, it will affect the quality of the drug and thus affect clinical safety. In addition, the current freeze-drying process increases the content of related substances in the freeze-dried powder injection, and may also cause clarity problems in the solution, affecting the stability and quality of the drug. Chinese Patent 201611097663.5 provides a freeze-drying process for lornoxicam injection, which requires strict control of the freeze-drying process during the preparation process, especially the sublimation drying conditions. The process is cumbersome and not conducive to industrial production. Chinese Patent 200810126749.5 provides a method for preparing lornoxicam freeze-dried powder injection, which requires the addition temperature of lornoxicam to be controlled at 2-6°C, which is low and difficult to control. Chinese Patent 202311367395.4 provides a method for preparing a lornoxicam pharmaceutical composition for injection, with a pH of 9.5-11 and requiring 2-3 annealing processes. The reconstitution time of the obtained pharmaceutical composition is about 25s. The process recorded is not only cumbersome, but also the reconstitution time needs to be improved. Summary of the invention

[0005] According to one aspect of the present application, a preparation process of lornoxicam lyophilized powder injection for injection is provided. The preparation process is simple and the components are controllable. Without adding other auxiliary materials such as cosolvents and excipients, the lyophilization process of the present application is adopted, not only the reconstitution time can be within a controllable range, the clarity of related substances and solutions can be controlled, and the process is simple and easy to operate. The prepared lornoxicam lyophilized powder injection has good stability, which solves the technical problems in the prior art that related substances are uncontrollable, the clarity of the solution exceeds the limit, and the reconstitution time is long.

[0006] The preparation process of the lornoxicam lyophilized powder injection for injection of the present application comprises: stirring, filtering and freeze-drying a mixture including lornoxicam to obtain the lornoxicam lyophilized powder injection for injection;

[0007] The freeze drying comprises the steps of pre-freezing, sublimation drying, analytical drying and cooling;

[0008] The pre-freezing includes the steps of pre-freezing I, pre-freezing II and pre-freezing III;

[0009] The temperature of the pre-freezing I is -38 to -42°C;

[0010] The temperature of the pre-freezing II is -8 to -12°C;

[0011] The temperature of the pre-freezing III is -38 to -42°C.

[0012] Preferably, the temperature of the pre-freezing I is -40°C.

[0013] Preferably, the temperature of the pre-freezing II is -10°C.

[0014] Preferably, the temperature of the pre-freezing III is -40°C.

[0015] Optionally, the insulation time of the pre-freezing I is 170 to 190 minutes; preferably, the insulation time of the pre-freezing I is 180 minutes.

[0016] Optionally, the insulation time of the pre-freezing I is independently selected from any value among 170min, 175min, 180min, 185min, 190min or a range between any two of the above.

[0017] Optionally, the insulation time of the pre-freezing II is 55 to 65 minutes; preferably, the insulation time of the pre-freezing II is 60 minutes.

[0018] Optionally, the insulation time of the pre-freeze II is independently selected from any value among 55min, 58min, 60min, 62min, 65min or a range between any two of the above.

[0019] Optionally, the insulation time of the pre-freezing III is 170 to 190 minutes; preferably, the insulation time of the pre-freezing III is 180 minutes.

[0020] Optionally, the insulation time of the pre-freeze III is independently selected from any value among 170min, 175min, 180min, 185min, 190min or a range between any two of the above.

[0021] Optionally, in the pre-freezing step I, the temperature is lowered to -38 to -42°C at a rate of 0.6 to 0.7°C / min; preferably, in the pre-freezing step I, the temperature is lowered to -38 to -42°C at a rate of 0.67°C / min.

[0022] Optionally, in the pre-freezing step II, the temperature is raised to -8 to -12°C at a rate of 0.55 to 0.65°C / min; preferably, in the pre-freezing step II, the temperature is raised to -8 to -12°C at a rate of 0.58°C / min.

[0023] Optionally, in the pre-freezing step III, the temperature is lowered to -38 to -42°C at a rate of 0.55 to 0.65°C / min; preferably, in the pre-freezing step III, the temperature is lowered to -38 to -42°C at a rate of 0.58°C / min.

[0024] Optionally, the conditions for sublimation drying are: temperature: -10 to 10°C, and insulation time: 1000 to 1250 minutes.

[0025] Optionally, the conditions for sublimation drying are:

[0026] Sublimation drying Ⅰ: temperature: -10~5℃, insulation time: 900~1100min;

[0027] Sublimation drying II: temperature: 0°C, holding time: 55-65min;

[0028] Sublimation drying III: temperature: 8-12°C, insulation time: 55-65min.

[0029] Optionally, in the sublimation drying step I, the temperature is raised to -10 to 5°C at a heating rate of 0.2 to 0.4°C / min.

[0030] Optionally, in the sublimation drying step II, the temperature is raised or lowered to 0°C at a rate of 0.05-0.2°C / min.

[0031] Optionally, in the sublimation drying step III, the temperature is raised to 8-12° C. at a heating rate of 0.2-0.4° C. / min.

[0032] Optionally, the vacuum gauge pressure of sublimation drying is 15-25Pa.

[0033] Specifically, the vacuum gauge pressure of sublimation drying is 20Pa.

[0034] Optionally, the mixing temperature is 50-65°C; preferably, the mixing temperature is 60°C.

[0035] Optionally, the mixing temperature is independently selected from any one of 50°C, 60°C, 65°C, or a range between any two of the above.

[0036] Optionally, the stirring rate is 40-60 Hz; preferably, the stirring rate is 50 Hz.

[0037] Optionally, the temperature of the analytical drying is 35-45°C; preferably, the temperature of the analytical drying is 40°C.

[0038] Optionally, the analytical drying time is 250 to 350 minutes; preferably, the analytical drying time is 300 minutes.

[0039] Optionally, the vacuum gauge pressure of the analytical drying is 3-8Pa; preferably, the vacuum gauge pressure of the analytical drying is 5Pa.

[0040] Optionally, the mixture comprises lornoxicam, tromethamine, edetate disodium, mannitol and water for injection.

[0041] Optionally, the weight ratio of mannitol, tromethamine, edetate disodium and lornoxicam is (13-15):(1.5-2.5):(0.01-0.03):1; preferably, the weight ratio of mannitol, tromethamine, edetate disodium and lornoxicam is 14.5:2:0.02:1.

[0042] Optionally, the weight ratio of the water for injection to lornoxicam is (235-245):1; preferably, the weight ratio of the water for injection to lornoxicam is 238.6:1.

[0043] The beneficial effects of this application include:

[0044] 1. In the preparation process of freeze-dried powder injection, the freeze-drying process is a key step. During the freeze-drying process, the content of related substances is likely to increase. The present application controls the pre-freezing and drying conditions, reduces the growth trend of product impurities, and improves the stability of the product. According to the test results, the clarity of the solution and the related substances after 10 days of high temperature, 10 days of light, and 1 month of acceleration still meet the requirements, which solves the problem of the increase of the content of related substances and the clarity of the solution caused by the excessively long freeze-drying process in the prior art, and ensures the quality of the drug;

[0045] 2. Without adding other co-solvents, excipients, etc., the sublimation drying process needs to be strictly controlled, requiring more than 5 stages of control, including sublimation drying temperature and vacuum degree. The operation process is cumbersome, and once an operation error occurs at a certain stage, it will lead to changes in the appearance of the freeze-dried product. The pre-freezing process of the present application solves the problem of damaging the product appearance during the sublimation drying process on the basis of simplifying the sublimation drying steps, simplifies the sublimation drying process, improves the efficiency of sublimation drying, and the sublimation drying steps are easy to manage and control.

[0046] 3. The pre-freezing of the present application includes the steps of pre-freezing I, pre-freezing II and pre-freezing III. The pre-freezing operation is relatively simple. Combined with the subsequent sublimation drying, analytical drying and cooling steps, the entire freeze-drying step is easy to operate, which not only avoids the problem of cumbersome pre-freezing process in the prior art, but also shortens the re-dissolution time. Compared with the complex pre-freezing process used in the prior art, the re-dissolution time is more than 20 seconds, which has significant advantages.

[0047] 4. In the preparation process of the lyophilized powder injection of the present application, the pre-freezing conditions are combined with the drying and sublimation conditions of the present application, so that the reconstitution time of the finally obtained lyophilized powder injection is further reduced to as low as 9s. The shortened reconstitution time ensures clinical safety and further improves the use value;

[0048] 5. The formula of the lornoxicam lyophilized powder injection for injection of the present application is simple. Without adding other auxiliary materials such as cosolvents and excipients, the freeze-drying process of the present application is adopted, which not only can keep the reconstitution time within a controllable range, but also can control the clarity of related substances and solutions. At the same time, the process is simple and easy to operate, and the prepared lornoxicam lyophilized powder injection has good stability, which solves the technical problems of uncontrollable related substances, excessive solution clarity and long reconstitution time in the prior art. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] Figure 1 This is the XRD powder diffraction pattern of the lornoxicam lyophilized powder for injection prepared in Example 3. DETAILED DESCRIPTION

[0050] The present application is described in detail below with reference to embodiments, but the present application is not limited to these embodiments.

[0051] Unless otherwise specified, the raw materials in the examples of this application were purchased through commercial channels.

[0052] Related substances: Import registration standard JX20090339; other tests refer to CHP2020.

[0053] High temperature conditions: 50°C;

[0054] Lighting conditions: 5000lx;

[0055] Acceleration conditions: 40℃±2℃, RH75%±5%.

[0056] Example 1

[0057] The preparation process of lornoxicam lyophilized powder for injection is as follows:

[0058] At 60°C, mix 107.5 kg of water for injection, 0.90 kg of tromethamine, 9.02 g of disodium edetate, 6.53 kg of mannitol, and 451 g of lornoxicam, stir at 50 Hz, filter, and freeze-dry to obtain lornoxicam lyophilized powder injection.

[0059] The freeze-drying conditions were as follows:

[0060] Pre-freezing: enter the box at 0℃, cool to -40℃ at 0.67℃ / min, keep warm for 180min;

[0061] Raise the temperature to -10°C at 0.58°C / min and keep warm for 60 min;

[0062] Cool down to -40℃ at 0.58 / min and keep warm for 180min;

[0063] Sublimation drying: heating to -10°C at 0.25°C / min, keeping warm for 1080min, vacuum gauge pressure 20Pa;

[0064] Raise the temperature to 0℃ at 0.17℃ / min, keep warm for 60min, vacuum gauge pressure 20Pa;

[0065] Heat up to 10℃ at 0.33℃ / min, keep warm for 60min, the air gauge pressure is 20Pa;

[0066] Desorption drying: heating to 40°C at 0.5°C / min, keeping warm for 300 min, vacuum gauge pressure 5 Pa;

[0067] Cooling: cool to 25℃ at 0.5℃ / min, keep warm for 120min, vacuum gauge pressure 5Pa.

[0068] Example 2

[0069] The preparation process of lornoxicam lyophilized powder for injection is as follows:

[0070] At 60°C, mix 107.5 kg of water for injection, 0.90 kg of tromethamine, 9.02 g of disodium edetate, 6.53 kg of mannitol, and 451 g of lornoxicam, stir at 50 Hz, filter, and freeze-dry to obtain lornoxicam lyophilized powder injection.

[0071] The freeze-drying conditions were as follows:

[0072] Pre-freezing: enter the box at 0℃, cool to -40℃ at 0.67℃ / min, keep warm for 170min;

[0073] Raise the temperature to -10°C at 0.58°C / min and keep warm for 55 min;

[0074] Cool down to -40℃ at 0.58 / min and keep warm for 170min;

[0075] Sublimation drying conditions were as follows: heating to -5°C at 0.29°C / min, keeping warm for 1080 min, vacuum gauge pressure 20 Pa;

[0076] Raise the temperature to 0℃ at 0.08℃ / min, keep warm for 60min, vacuum gauge pressure 20Pa;

[0077] The temperature was raised to 10°C at a rate of 0.33°C / min and kept at that temperature for 60 min. The air surface pressure was 20 Pa.

[0078] Desorption drying: heating to 40°C at 0.5°C / min, keeping warm for 300 min, vacuum gauge pressure 5 Pa;

[0079] Cooling: cool to 25℃ at 0.5℃ / min, keep warm for 120min, vacuum gauge pressure 5Pa.

[0080] Example 3

[0081] The preparation process of lornoxicam lyophilized powder for injection is as follows:

[0082] At 60°C, mix 107.5 kg of water for injection, 0.90 kg of tromethamine, 9.02 g of disodium edetate, 6.53 kg of mannitol, and 451 g of lornoxicam, stir at 50 Hz, filter, and freeze-dry to obtain lornoxicam lyophilized powder injection.

[0083] The freeze-drying conditions were as follows:

[0084] Pre-freezing: enter the box at 0℃, cool to -40℃ at 0.67℃ / min, keep warm for 190min;

[0085] Raise the temperature to -10°C at 0.58°C / min and keep warm for 65 min;

[0086] Cool down to -40℃ at 0.58 / min and keep warm for 190min;

[0087] Sublimation drying conditions were as follows: heating to 5°C at 0.375°C / min, keeping warm for 900 min, vacuum gauge pressure 20 Pa;

[0088] Cool down to 0℃ at 0.08℃ / min, keep warm for 60min, vacuum gauge pressure 20Pa;

[0089] The temperature was raised to 10°C at a rate of 0.33°C / min and kept at that temperature for 60 min. The air surface pressure was 20 Pa.

[0090] Desorption drying: heating to 40°C at 0.5°C / min, keeping warm for 300 min, vacuum gauge pressure 5 Pa;

[0091] Cooling: cool to 25℃ at 0.5℃ / min, keep warm for 120min, vacuum gauge pressure 5Pa.

[0092] The XRD powder diffraction pattern of the lyophilized powder injection prepared in Example 3 is shown in Figure 1 .

[0093] The test conditions of each embodiment of the present application are the same. The packaging material is a brown medium borosilicate glass injection bottle produced by Chongqing Zhengchuan Yongcheng Pharmaceutical Materials Co., Ltd., and the rubber stopper is a bromobutyl rubber stopper (ultrapure) for sterile powder for injection produced by Hebei Xiangyi Pharmaceutical Technology Co., Ltd.

[0094] The freeze-dried powder injection obtained in Example 1-3 was tested, and the test results are shown in the following table.

[0095]

[0096]

[0097] The stability of Example 1 was tested, and the test results are shown in the following table.

[0098]

[0099] Comparative Example 1

[0100] The preparation method of freeze-dried powder injection has the same specific implementation as Example 1, except that the freeze-drying conditions are different. The freeze-drying conditions are as follows:

[0101] Pre-freezing: enter the box at 0℃, cool to -40℃ at 0.67℃ / min, keep warm for 210min;

[0102] Sublimation drying: heating to 10°C at 0.375°C / min, keeping warm for 960min, vacuum gauge pressure 25Pa;

[0103] Desorption drying: heating to 40°C at 0.5°C / min, keeping warm for 300 min, vacuum gauge pressure 5 Pa;

[0104] Cooling: cool to 25℃ at 0.5℃ / min, keep warm for 120min, vacuum gauge pressure 5Pa.

[0105] The test results are shown in the following table.

[0106]

[0107] From the table above, we can see that changing the freeze-drying conditions and shortening the freeze-drying time within a certain range will result in poor stability. Specifically, compared with 0 days at high temperature for 10 days, impurities B and C increased slightly, impurities I, K and total impurities increased significantly, and the clarity exceeded the limit; compared with 0 days at high temperature for 30 days, impurities B, C, I, and K increased significantly, and the clarity exceeded the limit; compared with 0 days at accelerated temperature for 1 month, impurities B and I increased slightly, impurity K and total impurities increased significantly, and the clarity exceeded the limit.

[0108] Comparative Example 2

[0109] The preparation method of freeze-dried powder injection has the same specific implementation as Example 1, except that the freeze-drying conditions are different. The freeze-drying conditions are as follows:

[0110] Pre-freezing: enter the box at 0℃, cool to -40℃ at 0.67℃ / min, keep warm for 210min;

[0111] Sublimation drying: heating to 10°C at 0.375°C / min, keeping warm for 1020min, vacuum gauge pressure 25Pa;

[0112] Desorption drying: heating to 40°C at 0.5°C / min, keeping warm for 300 min, vacuum gauge pressure 5 Pa;

[0113] Cooling: cool to 25℃ at 0.5℃ / min, keep warm for 120min, vacuum gauge pressure 5Pa.

[0114] The test results are shown in the following table.

[0115]

[0116]

[0117] From the table above, we can see that changing the freeze-drying conditions leads to poor stability. Specifically, compared with day 0, the impurity K and total impurities increased significantly after 10 days of high temperature / light exposure, and the clarity was unqualified after 10 days of high temperature exposure.

[0118] Comparative Example 3

[0119] The preparation method of freeze-dried powder injection has the same specific implementation as Example 1, except that the freeze-drying conditions are different. The freeze-drying conditions are as follows:

[0120] Pre-freezing: enter the box at 0℃, cool to -40℃ at 0.67℃ / min, keep warm for 120min;

[0121] Raise the temperature to -10°C at 0.58°C / min and keep warm for 60 min;

[0122] Cool down to -40℃ at 0.58 / min, keep warm for 120min

[0123] Sublimation drying: heating to 5°C at 0.25°C / min, keeping warm for 1080min, vacuum gauge pressure 20Pa;

[0124] Desorption drying: heating to 45°C at 0.5°C / min, keeping warm for 300 min, vacuum gauge pressure 5Pa;

[0125] Cooling: cool to 25℃ at 0.5℃ / min, keep warm for 120min, vacuum gauge pressure 5Pa.

[0126] The test results are shown in the following table.

[0127]

[0128]

[0129] From the above table, we can see that the clarity exceeded the limit on day 0, and the impurity K and total impurities increased slightly after 10 days of high temperature and 10 days of light.

[0130] The above are only a few embodiments of the present application and do not constitute any form of limitation to the present application. Although the present application is disclosed as above with preferred embodiments, it is not intended to limit the present application. Any technician familiar with the profession, without departing from the scope of the technical solution of the present application, using the technical content disclosed above to make slight changes or modifications are equivalent to equivalent implementation cases and fall within the scope of the technical solution.

Claims

1. A preparation process of lornoxicam lyophilized powder injection for injection, It is characterized in that include: The mixture including lornoxicam is stirred, filtered, and freeze-dried to obtain lornoxicam freeze-dried powder injection for injection; The freeze drying comprises the steps of pre-freezing, sublimation drying, analytical drying and cooling; The pre-freezing includes the steps of pre-freezing I, pre-freezing II and pre-freezing III; The temperature of the pre-freezing I is -38 to -42°C; The temperature of the pre-freezing II is -8 to -12°C; The temperature of the pre-freezing III is -38 to -42°C.

2. The preparation process of the lornoxicam lyophilized powder injection for injection according to claim 1, It is characterized in that The pre-freezing I heat preservation time is 170 to 190 minutes; Preferably, the pre-freezing II insulation time is 55 to 65 minutes; Preferably, the insulation time of the pre-freezing III is 170 to 190 minutes.

3. The preparation process of the lornoxicam lyophilized powder injection for injection according to claim 1, It is characterized in that In the pre-freezing step I, the temperature is lowered to -38 to -42°C at a rate of 0.6 to 0.7°C / min; Preferably, in the pre-freezing step II, the temperature is raised to -8 to -12°C at a rate of 0.55 to 0.65°C / min; Preferably, in the pre-freezing step III, the temperature is lowered to -38 to -42°C at a rate of 0.55 to 0.65°C / min.

4. The preparation process of the lornoxicam lyophilized powder injection for injection according to claim 1, It is characterized in that The conditions of the sublimation drying are: temperature: -10 to 10°C, and insulation time: 1000 to 1250 minutes.

5. The preparation process of the lornoxicam lyophilized powder injection for injection according to claim 4, It is characterized in that The conditions for sublimation drying are: Sublimation drying Ⅰ: temperature: -10~5℃, insulation time: 900~1100min; Sublimation drying II: temperature: 0°C, holding time: 55-65min; Sublimation drying III: temperature: 8-12°C, insulation time: 55-65min.

6. The preparation process of the lornoxicam lyophilized powder injection for injection according to claim 5, It is characterized in that Sublimation drying step I, heating to -10-5°C at a heating rate of 0.2-0.4°C / min; Preferably, in the sublimation drying step II, the temperature is raised or lowered to 0°C at a rate of 0.05-0.2°C / min; Preferably, in the sublimation drying step III, the temperature is raised to 8-12° C. at a heating rate of 0.2-0.4° C. / min.

7. The preparation process of the lornoxicam lyophilized powder injection for injection according to any one of claims 4 to 6, It is characterized in that The vacuum gauge pressure of sublimation drying is 15~25Pa.

8. The preparation process of the lornoxicam lyophilized powder injection for injection according to claim 1, It is characterized in that The mixing temperature is 50-65°C.

9. The preparation process of the lornoxicam lyophilized powder injection for injection according to claim 1, It is characterized in that The drying temperature is 35-45°C. Preferably, the analytical drying time is 250 to 350 minutes; Preferably, the vacuum gauge pressure of the analytical drying is 3-8Pa.

10. The preparation process of the lornoxicam lyophilized powder injection for injection according to claim 1, It is characterized in that The mixture comprises lornoxicam, tromethamine, disodium edetate, mannitol and water for injection; Preferably, the weight ratio of mannitol, tromethamine, edetate disodium and lornoxicam is (13-15): (1.5-2.5): (0.01-0.03): 1; Preferably, the weight ratio of the water for injection to lornoxicam is (235-245):1.

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