Lornoxicam freeze-dried preparation for injection and preparation method thereof

Abstract

The invention relates to a lornoxicam freeze-dried preparation for injection and a preparation method of the lornoxicam freeze-dried preparation, and belongs to the technical field of pharmaceutical preparations. The preparation method of the freeze-dried preparation comprises the following steps: step 1, sequentially adding edetate disodium, mannitol and tromethamine into water at 53-65 DEG C, and mixing and dissolving to obtain a mixed solution A; 2, adding lornoxicam into the mixed solution A at 53-65 DEG C, and dissolving to obtain a mixed solution B; and step 3, filtering the mixed solution B to obtain the lornoxicam freeze-dried preparation. According to the preparation method of the lornoxicam freeze-dried preparation for injection, auxiliary materials do not need to be changed, and the lornoxicam freeze-dried preparation which is good in solubility, low in impurity content, good in redissolution clarity and stable can be obtained only through the specific liquid preparation temperature.

Description

Technical Field

[0001] This application relates to the technical field of pharmaceutical preparations, and particularly relates to a freeze-dried preparation of lornoxicam for injection and a preparation method thereof. Background Art

[0002] Lornoxicam for injection, with the generic name Lornoxicam for Injection, belongs to non-steroidal anti-inflammatory analgesics and has a strong analgesic and anti-inflammatory effect. It is an antipyretic analgesic and non-steroidal anti-inflammatory drug. It is used for pain after acute moderate surgery and pain related to acute lumbar and sciatic nerves. The original research company of lornoxicam for injection is Takeda. The injection was first launched in Denmark by Takeda Pharma A / S in February 1997, with a specification of 8 mg. Subsequently, it was successively launched in EU countries such as Austria, Sweden, and Italy. The historically approved imported injection of this product has the trade name Xafon, the license holder is Takeda Austria GmbH, and the manufacturer is Wasserburger Arzneimittelwerk GmbH. The marketed specification is 8 mg. The prescription composition and dosage are as follows:

[0003] Material Name Dosage Lornoxicam 8mg Mannitol 100mg Trometamol 12mg Disodium Edetate 0.2mg

[0004] Like most non-steroidal anti-inflammatory drugs, lornoxicam is very difficult to dissolve in water. Due to its very low solubility in water and poor stability in liquid preparations, it poses challenges to the preparation of injection preparations. The prescription of foreign lornoxicam for injection contains trometamol as a cosolvent, but there are problems such as a slow dissolution process of trometamol for lornoxicam and the resulting liquid medicine being turbid.

[0005] Patent 201210350403.X discloses a freeze-dried preparation of lornoxicam and a preparation method thereof. This patent uses poloxamer 188 as a cosolvent and sodium hydroxide as a pH regulator to improve the dissolution rate of lornoxicam and ensure stability, etc., but does not solve the technical problems of the slow dissolution process of trometamol for lornoxicam and the resulting liquid medicine being turbid.

[0006] Patent 200810126749.5 discloses a freeze-dried powder injection of lornoxicam and a preparation method thereof. This powder injection includes lornoxicam, mannitol, and trometamol, and also includes EDTA and a pH regulator. The pH is adjusted with sodium hydroxide during the preparation process to dissolve the raw material drug. After complete dissolution, the pH is adjusted to 8.5 - 9.5 with hydrochloric acid. This patent solves problems such as the stability and clarity of the freeze-dried powder injection by adding two pH regulators.

[0007] In the prior art, the problems of the stability, solubility, and clarity of lyophilized powder injections are solved by replacing the excipients of the marketed Lornoxicam lyophilized preparation or adding new excipients. However, the change of excipients has uncertainties in affecting the drug quality, especially key factors such as dissolution curves and bioequivalence, and the cost of newly developed preparations is high. Therefore, how to improve the solubility, stability, and clarity of Lornoxicam lyophilized preparations using Trometamol as a cosolvent without changing the excipients is an urgent problem to be solved. Summary of the Invention

[0008] To solve the above technical problems, the present application provides a Lornoxicam lyophilized preparation for injection and a preparation method thereof. The preparation method of the Lornoxicam lyophilized preparation for injection provided by the present application controls the temperature of the mixed solution at 53-65°C during the liquid preparation process, achieving the problems of improving the solubility (such as dissolution rate), stability, and reconstitution clarity of the Lornoxicam lyophilized preparation using Trometamol as a cosolvent without changing the excipients.

[0009] According to one aspect of the present application, there is provided a preparation method of a Lornoxicam lyophilized preparation for injection, which includes the following steps:

[0010] Step 1: Add disodium edetate, mannitol, and Trometamol to water at 53-65°C in sequence and dissolve them to obtain a mixed solution A;

[0011] Step 2: Add Lornoxicam to the mixed solution A at 53-65°C and dissolve it to obtain a mixed solution B;

[0012] Step 3: Filter and lyophilize the mixed solution B to obtain the Lornoxicam lyophilized preparation.

[0013] Optionally, the temperatures of Step 1 and Step 2 are the same at 53-65°C, and the temperature can be, for example, 53°C, 55°C, 57°C, 59°C, 60°C, 65°C.

[0014] Optionally, the temperatures of Step 1 and Step 2 are the same at 55°C. At this temperature, the comprehensive effects of the dissolution rate, clarity, and total impurities of the prepared Lornoxicam lyophilized preparation are the best.

[0015] Optionally, in Step 2, Lornoxicam is dissolved by stirring with the mixed solution A, and the stirring time is 90-110 min.

[0016] Optionally, in Step 3, a 0.22 μm polyethersulfone filter membrane is used for filtration. The Lornoxicam lyophilized preparation prepared using this filter membrane has good stability.

[0017] Optionally, the water in Step 1 is injection water.

[0018] Optionally, the weight ratio of trometamol, mannitol and disodium edetate is (10 - 14):(80 - 120):(0.1 - 0.3).

[0019] Optionally, the weight ratio of trometamol, mannitol and disodium edetate is 12:100:0.2.

[0020] Optionally, the weight ratio of lornoxicam, trometamol, mannitol and disodium edetate is (6 - 10):(10 - 14):(80 - 120):(0.1 - 0.3). Preferably, the weight ratio of lornoxicam, trometamol, mannitol and disodium edetate is 8:12:100:1.2.

[0021] Optionally, the content of trometamol is 6 - 12 mg / mL; the content of mannitol is 50 - 100 mg / mL, and the content of disodium edetate is 0.1 - 0.2 mg / mL.

[0022] Optionally, the content of lornoxicam is 4 mg / mL.

[0023] Optionally, the preparation method of the freeze-dried lornoxicam injection preparation includes the following specific steps:

[0024] Step (1): Add disodium edetate, mannitol and trometamol in turn to the water for injection at 53 - 65 °C, stir and dissolve to obtain a mixed solution A;

[0025] Step (2): Keep the temperature at 53 - 65 °C, add lornoxicam to the mixed solution A in step (1), stir and dissolve fully, and make up to the total weight to obtain a mixed solution B;

[0026] Step (3): Cool the mixture in step ② to room temperature and then filter;

[0027] Step (4): Seal the filtrate obtained in step (3) into a glass ampoule for injection and perform freeze-drying to obtain the freeze-dried lornoxicam preparation.

[0028] According to another aspect of the present application, there is provided a freeze-dried lornoxicam injection preparation prepared by any of the above preparation methods.

[0029] The beneficial effects of the present application are as follows:

[0030] In the preparation method of the freeze-dried lornoxicam injection preparation of the present application, by controlling the liquid preparation temperature within the range of 53 - 65 °C during the liquid preparation process of the freeze-dried lornoxicam injection preparation, trometamol is used as a co-solvent, without changing the types of the original research excipients, the solubility of the lornoxicam raw material drug in the freeze-dried lornoxicam preparation is improved, the impurity content is low, and the stability and clarity after reconstitution of the freeze-dried lornoxicam preparation are significantly improved; the process cost is low and it is easy to implement.

[0031] The lyophilized lornoxicam injection preparation of the present application has beneficial technical effects of high solubility, high stability, high clarity after reconstitution, and the preparation quality not being lower than that of the original research. Detailed implementation manners

[0032] The content of the present application will be further described below in conjunction with specific embodiments, but it should not be construed as a limitation to the present application. Unless otherwise specified, the technical means used in the embodiments are conventional means well-known to those skilled in the art; the raw materials in the following embodiments, unless otherwise specifically described, are all obtained by commercial purchase. The original research preparation of this product is selected for listing in the European Union, and its license holder is Takeda Austria GmbH, and the trade name is Xefo, and the specification is 8 mg.

[0033] Example 1

[0034] A lyophilized lornoxicam injection preparation comprises the following components:

[0035]

[0036]

[0037] Preparation method:

[0038] Step (1): Add about 85% of the prescribed amount of water for injection into a beaker, place it in a constant-temperature heating magnetic stirrer with the temperature set at 53 °C and stir. After the water temperature is constant, add disodium edetate, mannitol, and trometamol in sequence, and stir well to dissolve to obtain a mixed solution A;

[0039] Step (2): Keep the temperature at 53 °C, add lornoxicam to the mixed solution A in step (1), stir for 90 min until fully dissolved, and then add water for injection for sterilization to make up the total weight to obtain a mixed solution B;

[0040] Step (3): After cooling the mixed solution B in step (2) to room temperature, filter it through a 0.22 μm polyethersulfone membrane filter, then fill it into a 2 ml glass tube injection bottle, and perform freeze-drying, nitrogen filling, plugging, and capping to obtain the lyophilized lornoxicam injection preparation.

[0041] Example 2:

[0042] The prescription composition is the same as that in Example 1

[0043] Preparation method:

[0044] Step (1): Add about 85% of the prescribed amount of water for injection into a beaker, place it in a constant-temperature heating magnetic stirrer with the temperature set at 55 °C and stir. After the water temperature is constant, add disodium edetate, mannitol, and trometamol in sequence, and stir well to dissolve to obtain a mixed solution A;

[0045] Step (2): Maintain the temperature at 55°C, add lornoxicam to the mixture A in step (1), stir for 95 min until fully dissolved, and then add sterile injection water to make up to the total weight to obtain mixture B.

[0046] Step (3): After cooling the mixture B in step (2) to room temperature, filter it through a 0.22-μm polyethersulfone membrane filter, then fill and seal it in a 2-ml glass ampoule for injection, and perform lyophilization, nitrogen filling, plugging, and capping to obtain the lyophilized preparation of lornoxicam for injection.

[0047] Example 3:

[0048] The prescription composition is the same as that in Example 1.

[0049] Preparation method:

[0050] Step (1): Add about 85% of the prescription amount of injection water to a beaker, place it in a constant-temperature heating magnetic stirrer with the temperature set at 60°C and stir. After the water temperature is constant, add disodium edetate, mannitol, and tromethamine in sequence, and stir well until dissolved to obtain mixture A.

[0051] Step (2): Maintain the temperature at 60°C, add lornoxicam to the mixture A in step (1), stir for 100 min until fully dissolved, and then add sterile injection water to make up to the total weight to obtain mixture B.

[0052] Step (3): After cooling the mixture B in step (2) to room temperature, filter it through a 0.22-μm polyethersulfone membrane filter, then fill and seal it in a 2-ml glass ampoule for injection, and perform lyophilization, nitrogen filling, plugging, and capping to obtain the lyophilized preparation of lornoxicam for injection.

[0053] Example 4:

[0054] The prescription composition is the same as that in Example 1.

[0055] Preparation method:

[0056] Step (1): Add about 85% of the prescription amount of injection water to a beaker, place it in a constant-temperature heating magnetic stirrer with the temperature set at 65°C and stir. After the water temperature is constant, add disodium edetate, mannitol, and tromethamine in sequence, and stir well until dissolved to obtain mixture A.

[0057] Step (2): Maintain the temperature at 65°C, add lornoxicam to the mixture A in step (1), stir for 110 min until fully dissolved, and then add sterile injection water to make up to the total weight to obtain mixture B.

[0058] Step (3): After cooling the mixture B in step (2) to room temperature, it is filtered through a 0.22 μm polyethersulfone filter membrane, and then filled and sealed in a 2 ml glass vial for injection. After freeze-drying, nitrogen filling, plugging, and capping, the lyophilized preparation of lornoxicam for injection is obtained. Comparative Example 1:

[0059] The prescription composition is the same as that of Example 1.

[0060] Preparation method:

[0061] Step (1): Add about 85% of the injection water in the prescription amount to a beaker, place it in a constant temperature heating magnetic stirrer with the temperature set at 50 °C and stir. After the water temperature is constant, add disodium edetate, mannitol, and tromethamine in sequence and stir well to dissolve, obtaining mixture A;

[0062] Step (2): Keep the temperature at 50 °C, add lornoxicam to the mixture A in step (1), stir for 90 min to fully dissolve, and then add sterile injection water to make up the total volume to obtain mixture B;

[0063] Step (3): After cooling the mixture B in step (2) to room temperature, it is filtered through a 0.22 μm polyethersulfone filter membrane, and then filled and sealed in a 2 ml glass vial for injection. After freeze-drying, nitrogen filling, plugging, and capping, the lyophilized preparation of lornoxicam for injection is obtained.

[0064] The experimental results show that the lornoxicam raw material drug in the lyophilized preparation of lornoxicam cannot be dissolved under the condition of 50 °C, and it is not feasible to prepare the solution at 50 °C.

[0065] Comparative Example 2:

[0066] The prescription composition is the same as that of Example 1.

[0067] Preparation method:

[0068] Step (1): Add about 85% of the injection water in the prescription amount to a beaker, place it in a constant temperature heating magnetic stirrer with the temperature set at 70 °C and stir. After the water temperature is constant, add disodium edetate, mannitol, and tromethamine in sequence and stir well to dissolve, obtaining mixture A;

[0069] Step (2): Keep the temperature at 70 °C, add lornoxicam to the mixture A in step (1), stir for 95 min to fully dissolve, and then add sterile injection water to make up the total volume to obtain mixture B;

[0070] Step (3): After cooling the mixture B in step (2) to room temperature, it is filtered through a 0.22 μm polyethersulfone filter membrane, and then filled and sealed in a 2 ml glass vial for injection. After freeze-drying, nitrogen filling, plugging, and capping, the lyophilized preparation of lornoxicam for injection is obtained.

[0071] The experimental results show that lornoxicam API in the lornoxicam freeze-dried preparation can be dissolved at 70 °C, but the total impurity detection amount is relatively large.

[0072] Comparative Example 3:

[0073] The prescription composition is the same as that of Example 1.

[0074] Preparation method:

[0075] Step (1): Add about 85% of the injection water in the prescription amount to a beaker, place it in a constant temperature heating magnetic stirrer with the temperature set at 75 °C and stir. After the water temperature is constant, add disodium edetate, mannitol, and trometamol in sequence, and stir well to dissolve to obtain a mixed solution A;

[0076] Step (2): Keep the temperature at 75 °C, add lornoxicam to the mixed solution A in step (1), stir for 110 min until fully dissolved, and then add sterilized injection water to make up the volume to the total weight to obtain a mixed solution B;

[0077] Step (3): Cool the mixed solution B in step (2) to room temperature, filter it through a 0.22 μm polyethersulfone filter membrane, then fill it into a 2 ml glass control injection bottle, and perform freeze-drying, nitrogen filling, plugging, and capping to obtain the lornoxicam freeze-dried preparation for injection.

[0078] The experimental results show that lornoxicam API in the lornoxicam freeze-dried preparation can be dissolved at 75 °C, but the total impurity detection amount is relatively large.

[0079] Test Example 1 Dissolution rate and total impurities of lornoxicam freeze-dried preparation

[0080] Under the same conditions, the dissolution time and total impurities of lornoxicam in the lornoxicam freeze-dried preparations prepared in Examples 1-4 and Comparative Examples 1-3 were tested respectively. The dissolution time required for lornoxicam API and the test results of related substances at the solution preparation temperatures of different examples and comparative examples are shown in Table 1.

[0081] Table 1 Results of dissolution time and total impurities in solution preparation investigation

[0082]

[0083]

[0084] As can be seen from Table 1, when the solution preparation temperature is set in the range of 53 °C - 65 °C, the lornoxicam freeze-dried preparation obtained has good stability. When the solution preparation temperature is too low, lornoxicam API in the lornoxicam freeze-dried preparation cannot be dissolved; when the solution preparation temperature is too high, although the dissolution rate is accelerated and the dissolution time is reduced, the total impurity detection amount is relatively large and more impurities are generated. In addition, the overall results at a solution preparation temperature of 55 °C are relatively good.

[0085] Test Example 2: Stability and Redissolution Clarity Test of Lornoxicam Freeze-Dried Preparation

[0086] The lornoxicam freeze-dried preparations prepared in Examples 1-4 and Comparative Examples 1-3, and the original research lornoxicam freeze-dried preparation were respectively subjected to stability tests at 50 °C for 5 days, 10 days, and 30 days. The test results showed that the stability of Example 2 was relatively excellent. Now, the stability test results of Example 2 are shown in Table 2 and compared with the original research preparation.

[0087] Table 2 Comparison of Stability Results between Example 2 and the Original Research Preparation

[0088]

[0089] It can be seen from Table 2 that the stability of the lornoxicam freeze-dried preparation for injection prepared by the method of the present application is not lower than that of the original research, and even better than that of the original research preparation.

[0090] From the above test results, it can be seen that when the solution preparation temperature is controlled in the range of 53-65 °C in the present application, better dissolution of the lornoxicam raw material in the lornoxicam freeze-dried preparation can be achieved, and the preparation quality of the lornoxicam freeze-dried preparation can be ensured not to be lower than that of the original research lornoxicam freeze-dried preparation.

[0091] Finally, it should be noted that the above are only the preferred embodiments of the present application and are not used to limit the present application. Although the present application has been described in detail with reference to the foregoing embodiments, for those skilled in the art, they can still modify the technical solutions recorded in the foregoing embodiments, or perform equivalent replacements on some of the technical features. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A preparation method of lornoxicam freeze-dried preparation for injection, characterized in that, It includes the following steps: Step 1: Add disodium edetate, mannitol and tromethamine to water at 53 - 65°C in sequence and dissolve them to obtain a mixed solution A; Step 2: At 53 - 65°C, add lornoxicam to the mixed solution A and dissolve it to obtain a mixed solution B; and Step 3: Filter and freeze-dry the mixed solution B to obtain the lornoxicam freeze-dried preparation.

2. The preparation method according to claim 1, characterized in that, The temperatures of Step 1 and Step 2 are the same, which is 53 - 60°C.

3. The preparation method according to claim 2, wherein The temperatures of Step 1 and Step 2 are the same, which is 55°C.

4. The preparation method according to claim 1, characterized in that, In Step 2, lornoxicam is dissolved by stirring with the mixed solution A, and the stirring time is 90 - 110 min.

5. The preparation method according to claim 1, characterized in that, In Step 3, a 0.22 μm polyethersulfone filter membrane is used for filtration.

6. The preparation method according to claim 1, wherein The weight ratio of tromethamine, mannitol and disodium edetate is (10 - 14):(80 - 120):(0.1 - 0.3).

7. The preparation method according to claim 6, characterized in that, The weight ratio of tromethamine, mannitol and disodium edetate is 12:100:0.

2.

8. The preparation method according to claim 6, characterized in that, The weight ratio of lornoxicam, tromethamine, mannitol and disodium edetate is (6 - 10):(10 - 14):(80 - 120):(0.1 - 0.3).

9. The preparation method according to any one of claims 1-8, characterized in that, It includes the following steps: Step 1: Add disodium edetate, mannitol and tromethamine to injection water at 53 - 60°C in sequence, stir and dissolve them to obtain a mixed solution A; Step 2: Keep the temperature at 53 - 60°C, add lornoxicam to the mixed solution A in Step 1, stir until fully dissolved and then make up the volume to the total weight to obtain a mixed solution B; and Step 3: Cool the mixed solution B in Step 2 to room temperature, then filter, seal and freeze-dry to obtain the lornoxicam freeze-dried preparation for injection.

10. The lornoxicam freeze-dried preparation for injection obtained by the preparation method according to any one of claims 1 - 9.

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