Analgesic composition for injection and preparation method thereof

Abstract

The invention discloses an injection analgesic composition and a preparation method thereof, and belongs to the technical field of medicines. The pain relieving composition for injection is prepared from lornoxicam, tromethamine, edetate disodium, an alcohol excipient and amino acid. In the preparation process of the composition, the tert-butyl alcohol is added, so that the problem of long dissolving time of the lornoxicam is solved, after the tert-butyl alcohol is added, the dissolving time of the lornoxicam is shortened from about 100 minutes to 45 minutes or below, and the problem of solution turbidity does not occur after the lornoxicam is placed for 2 hours. In addition, the glycine is added, so that the problem of poor clarity of a solution after the composition is redissolved is solved, and the clarity of the solution after the composition is redissolved is equivalent to that of water.

Description

Technical Field

[0001] The present application relates to an analgesic composition for injection and a preparation method thereof, and belongs to the field of medical technology. Background Art

[0002] Lornoxicam for injection, generic name Lornoxicam for Injection, is a non-steroidal anti-inflammatory analgesic with strong analgesic and anti-inflammatory effects. It is used for short-term symptomatic treatment of acute mild to moderate pain in adults after surgery.

[0003] Lornoxicam is a water-insoluble substance with a solubility of 20 μg / ml in water, and is unstable in water. During operation, the time for dissolving lornoxicam is long, and the solution becomes turbid. In addition, after the lornoxicam lyophilized powder containing tromethamine and disodium edetate is redissolved, the clarity of the solution cannot meet the requirements. Chinese patent CN101278906A provides a stable lornoxicam lyophilized preparation, including lornoxicam, meglumine, phosphate and mannitol, but the side effect of using meglumine is larger. Summary of the invention

[0004] According to one aspect of the present application, an analgesic composition for injection is provided. The addition of tert-butyl alcohol during the preparation process solves the problem of long dissolution time of lornoxicam. After the addition of tert-butyl alcohol, the dissolution time of lornoxicam is reduced from about 100 minutes to less than 45 minutes, and the solution does not become turbid after being placed for 2 hours. In addition, the addition of glycine solves the problem of poor clarity of the solution after re-dissolution of the composition, and the clarity of the solution after re-dissolution is equivalent to that of water.

[0005] An analgesic composition for injection comprises: lornoxicam, tromethamine, disodium edetate, an alcohol excipient and amino acid.

[0006] Optionally, the alcohol excipient is selected from any one or more of mannitol, sugar alcohol, glycerol, and sorbitol.

[0007] Optionally, the alcohol excipient comprises mannitol.

[0008] Optionally, the amino acid is selected from any one or more of glycine, histidine, arginine, lysine and proline.

[0009] Preferably, the amino acid is glycine.

[0010] Optionally, the weight ratio of the alcohol excipient to lornoxicam is (10-11.5):1; preferably, the weight ratio of the alcohol excipient to lornoxicam is (10.6-10.9):1.

[0011] Optionally, the weight ratio of the alcohol excipient to lornoxicam is independently selected from any value of 10:1, 10.5:1, 10.6:1, 10.7:1, 10.9:1, 11:1, 11.5:1 or a range between any two of the above.

[0012] Optionally, the weight ratio of the amino acid to lornoxicam is 1:(1-2); preferably, the weight ratio of the amino acid to lornoxicam is 1:(1.3-1.5).

[0013] Optionally, the weight ratio of the amino acid to lornoxicam is independently selected from any value of 1:1, 1:1.3, 1:1.4, 1:1.5, 1:2 or a range between any two of the above.

[0014] Optionally, the weight ratio of tromethamine to lornoxicam is 1:(1.8-2.5); preferably, the weight ratio of amino acid to lornoxicam is 1:(2.0-2.2).

[0015] Optionally, the weight ratio of tromethamine to lornoxicam is independently selected from any value of 1:1.8, 1:2.0, 1:2.2, 1:2.5 or a range between any two of the above.

[0016] Optionally, the weight ratio of edetate disodium to lornoxicam is 1:(31-36); preferably, the weight ratio of edetate disodium to lornoxicam is 1:34.

[0017] On the other hand, the present application provides a method for preparing an injectable analgesic composition, comprising: mixing a mixture including lornoxicam, tromethamine, disodium edetate, an alcohol excipient, and amino acids with water for injection, stirring and dissolving to obtain an intermediate drug solution, sterilizing and filtering, and then freeze-drying to obtain the product.

[0018] Optionally, the mixture further comprises an alcohol solvent.

[0019] Optionally, the alcohol solvent is selected from any one or more of ethanol, propylene glycol, tert-butyl alcohol, and isopropanol.

[0020] Optionally, the alcohol solvent is tert-butanol.

[0021] Optionally, the weight ratio of the alcohol solvent to lornoxicam is 1:(1.2-1.5); preferably, the weight ratio of the alcohol solvent to lornoxicam is 1:1.4.

[0022] Optionally, the weight ratio of the alcohol solvent to lornoxicam is independently selected from any value of 1:1.2, 1:1.3, 1:1.4, 1:1.5 or a range between any two of the above.

[0023] Optionally, the weight ratio of the alcohol excipient to lornoxicam is (10-11.5):1; preferably, the weight ratio of the alcohol excipient to lornoxicam is (10.6-10.9):1.

[0024] Optionally, the weight ratio of the amino acid to lornoxicam is 1:(1-2); preferably, the weight ratio of the amino acid to lornoxicam is 1:(1.3-1.5).

[0025] Optionally, the weight ratio of tromethamine to lornoxicam is 1:(1.8-2.5); preferably, the weight ratio of amino acid to lornoxicam is 1:(2.0-2.2).

[0026] Optionally, the weight ratio of edetate disodium to lornoxicam is 1:(31-36); preferably, the weight ratio of edetate disodium to lornoxicam is 1:34.

[0027] Optionally, the weight ratio of water for injection to the mixture is (15-20):1; preferably, the weight ratio of water for injection to the mixture is 17.6:1.

[0028] Optionally, the freeze-drying process includes: pre-freezing at -35 to -45°C for 390-410 minutes, then drying at -3 to -8°C and 20 to 30Pa for 930-990 minutes, then heating to 30 to 40°C, continuing to dry at a vacuum condition of 1 to 10Pa for 100 to 140 minutes, and then drying at 15 to 25°C and 1 to 10Pa for 100 to 140 minutes.

[0029] Specifically, the freeze-drying process includes: pre-freezing at -40°C for 400 minutes, then drying at -5°C, 25Pa for 960 minutes, then heating to 35°C, continuing drying at a vacuum condition of 5Pa for 120 minutes, and then drying at 20°C, 5Pa for 120 minutes.

[0030] The beneficial effects of this application include:

[0031] 1. Lornoxicam has poor solubility in water, and its solubility in water is only 20 μg / mL. In the prior art, tromethamine is usually added to improve the dissolution effect of lornoxicam. However, the method takes a long time to dissolve lornoxicam, which seriously affects the production efficiency. Moreover, after being placed for a period of time, the solution becomes turbid. The inventors have found that when tert-butyl alcohol is added during the preparation process, and the weight ratio of the added tert-butyl alcohol to lornoxicam is 1: (32-36), the dissolution time of lornoxicam is significantly reduced, and the solution becomes clear after being placed for 2 hours, which solves the problem of long dissolution time and low production efficiency of lornoxicam in the prior art.

[0032] 2. Tromethamine and disodium edetate are added to the injectable analgesic composition of the present application, and the resulting composition has the problem of poor clarity of the solution after reconstitution, and its clarity is greater than that of turbidity liquid No. 1. After a series of research, thinking and improvement, the inventors found that the additional addition of amino acids, and the weight ratio of amino acids to lornoxicam is 1: (1-2), improves the clarity of the solution after reconstitution, solves the problem of poor clarity of the solution after reconstitution, and the clarity of the solution after reconstitution is significantly improved, and the clarity is equivalent to that of water.

[0033] 3. The analgesic composition for injection provided in the present application solves the problems in the prior art of long dissolution time of raw materials, turbidity of intermediate drug solution, and poor clarity of solution, thereby improving production efficiency and product quality.

[0034] 4. The analgesic composition for injection provided in this application has good compatibility of raw and auxiliary materials, good formability, short reconstitution time of less than 20 seconds, and visible foreign matter, insoluble particles, related substances, etc. are all within the quality standards.

[0035] 5. The preparation method of the analgesic composition for injection provided in the present application is simple, easy to operate, and easy to mass produce. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 This is a diagram showing the clarity of the solution after reconstitution of the analgesic composition for injection in Example 3. DETAILED DESCRIPTION

[0037] The present application is described in detail below with reference to embodiments, but the present application is not limited to these embodiments.

[0038] Unless otherwise specified, the raw materials in the examples of this application were purchased through commercial channels.

[0039] Related substances: Import registration standard JX20090339;

[0040] Solution clarity: CHP2020;

[0041] Content: CHP2020;

[0042] Reconstitution time: CHP2020;

[0043] Visible foreign matter: CHP2020;

[0044] Insoluble particles: CHP2020;

[0045] Osmolality ratio: CHP2020;

[0046] Extraction loss rate: CHP2020.

[0047] Example 1

[0048] 1000 bottles

[0049] Lornoxicam 8.6g

[0050] Tromethamine 4.3g

[0051] Tert-Butanol 7.2g

[0052] Mannitol 91.16g

[0053] Glycine 6.6g

[0054] Edetate disodium 0.27g

[0055] Water for injection 1771.95g

[0056] The preparation method comprises the following steps: mixing water for injection, lornoxicam, tromethamine, tert-butyl alcohol, mannitol, glycine and disodium edetate to obtain an intermediate drug solution, sterilizing and filtering the solution, and then freeze-drying the solution to obtain the drug solution.

[0057] The freeze-drying process was as follows: pre-freezing at -40°C for 400 min, then drying at -5°C, 25 Pa for 960 min, then heating to 35°C, continuing drying at 5 Pa vacuum for 120 min, and then drying at 20°C, 5 Pa for 120 min.

[0058] Example 2

[0059] 1000 bottles

[0060] Lornoxicam 8.6g

[0061] Tromethamine 3.9g

[0062] Tert-Butanol 5.7g

[0063] Mannitol 93.74g

[0064] Glycine 5.7g

[0065] Edetate disodium 0.24g

[0066] Water for injection 2357.6g

[0067] The preparation method and its specific implementation method are the same as those in Example 1.

[0068] Example 3

[0069] 1000 bottles

[0070] Lornoxicam 8.6g

[0071] Tromethamine 4g

[0072] Tert-Butanol 6g

[0073] Mannitol 92.5g

[0074] Glycine 6g

[0075] Edetate disodium 0.25g

[0076] Water for injection 2062.65g

[0077] The preparation method and its specific implementation method are the same as those in Example 1.

[0078] Example 4

[0079] The prescription is the same as Example 3, except that glycine is not added and the added amount of mannitol is 98.5 g.

[0080] The preparation method has the same specific implementation as Example 1, except that glycine is not added.

[0081] Example 5

[0082] The prescription is the same as Example 3, except that the amount of glycine added is 17.2 g and the amount of water for injection added is 2262.48 g.

[0083] The preparation method and its specific implementation method are the same as those in Example 1.

[0084] Example 6

[0085] The prescription is the same as that of Example 3, except that the amount of glycine added is 2.15 g and the amount of water for injection added is 1997.6 g.

[0086] The preparation method and its specific implementation method are the same as those in Example 1.

[0087] Example 7

[0088] The prescription is the same as Example 3, except that glycine is replaced by arginine.

[0089] The preparation method has the same specific implementation as Example 1, except that glycine is replaced by arginine.

[0090] Example 8

[0091] The prescription is the same as that of Example 3, except that mannitol is replaced by sucrose.

[0092] The preparation method has the same specific implementation as Example 1, except that mannitol is replaced by sucrose.

[0093] Example 9

[0094] The prescription is the same as that of Example 3, except that tert-butyl alcohol is replaced by propylene glycol.

[0095] The preparation method has the same specific implementation as Example 1, except that tert-butyl alcohol is replaced by propylene glycol.

[0096] Example 10

[0097] The prescription is the same as that of Example 3, except that no tert-butyl alcohol is added and the amount of tromethamine added is 10 g.

[0098] The preparation method and its specific implementation method are the same as those in Example 1.

[0099] Embodiment 11

[0100] The prescription is the same as Example 3, except that the added amount of tert-butyl alcohol is 2.9 g and the amount of water for injection is 2010.8 g.

[0101] The preparation method and its specific implementation method are the same as those in Example 1.

[0102] Example 12

[0103] The prescription is the same as that of Example 3, except that the added amount of tert-butyl alcohol is 17.2 g and the amount of water for injection is 2262.48 g.

[0104] The preparation method and its specific implementation method are the same as those in Example 1.

[0105] 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.

[0106] Compatibility of raw materials and auxiliary materials:

[0107] The analgesic composition for injection prepared in Example 3 was placed under a light illumination of 5000 lx, and the total illumination of the light source should not be less than 1.2×10 6 lux·hr, near-ultraviolet lamp energy not less than 200W·hr / m 2 Under the condition of 50℃ and high temperature, the compatibility of API and excipients was investigated with relevant substances and contents as detection indexes. The test results are shown in Table 1.

[0108] Table 1

[0109]

[0110] From the test results in the above table, it can be seen that the raw materials and auxiliary materials of the analgesic composition for injection prepared in Example 3 of the present application have good compatibility. After testing, the test results of Example 1 and Example 2 are close to those of Example 3.

[0111] The dissolution time of lornoxicam in the intermediate drug solution in the example was recorded respectively, and then the intermediate drug solution was placed for 2 hours, and the appearance of the solution at this time was recorded. The results are shown in Table 2.

[0112] Table 2

[0113]

[0114]

[0115] The clarity of the solution after reconstitution of the analgesic composition for injection of Examples 1-8 was tested respectively, and the test results are shown in Table 3. Among them, the clarity effect diagram of the solution after reconstitution of the analgesic composition for injection of Example 3 is shown in Figure 1 , the standard solution is on the left and the test sample is on the right.

[0116] Table 3

[0117] Solution clarity Example 1 Clear (equivalent to water) Example 2 Clear (equivalent to water) Example 3 Clear (equivalent to water) Example 4 >No.1 turbidity liquid Example 5 No. 0.5 turbidity liquid Example 6 >No.1 turbidity liquid Example 7 >No.1 turbidity liquid Example 8 Between 0.5 and 1 turbidity liquid

[0118] The intermediate drug solution of Example 3 and the reference preparation were tested for related substances, and the test results are shown in Table 4.

[0119] Table 4

[0120]

[0121]

[0122] The properties of the products prepared in Examples 1-3, the clarity of the solution, the re-dissolution time, the visible foreign matter, the insoluble particles, the osmotic pressure molar concentration ratio, and the extraction loss rate were tested respectively. The test results are shown in Table 5.

[0123] Table 5

[0124]

[0125]

[0126] 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. An analgesic composition for injection, characterized in that: include: Lornoxicam, tromethamine, edetate disodium, alcohol excipients and amino acids.

2. The analgesic composition for injection according to claim 1, characterized in that: The amino acid is selected from any one or more of glycine, histidine, arginine, lysine and proline.

3. The analgesic composition for injection according to claim 1, characterized in that: The weight ratio of the amino acid to lornoxicam is 1:(1-2); Preferably, the weight ratio of the amino acid to lornoxicam is 1:(1.3-1.5).

4. The analgesic composition for injection according to claim 1, characterized in that: The alcohol excipient is selected from any one or more of mannitol, sugar alcohol, glycerol and sorbitol.

5. The analgesic composition for injection according to claim 1, characterized in that: The weight ratio of the alcohol excipient to lornoxicam is (10-11.5):1; Preferably, the weight ratio of the alcohol excipient to lornoxicam is (10.6-10.9):

1.

6. The analgesic composition for injection according to claim 1, characterized in that: The weight ratio of the alcohol excipient to lornoxicam is (10.6-10.9):1; Preferably, the weight ratio of tromethamine to lornoxicam is 1:(1.8-2.5); Preferably, the weight ratio of edetate disodium to lornoxicam is 1:(31-36).

7. A method for preparing the analgesic composition for injection according to any one of claims 1 to 6, comprising: The mixture including lornoxicam, tromethamine, disodium edetate, alcohol excipients and amino acids is mixed with water for injection, stirred and dissolved to obtain an intermediate drug solution, sterilized and filtered, and then freeze-dried to obtain the product.

8. The method for preparing the analgesic composition for injection according to claim 7, characterized in that: The mixture also includes an alcohol solvent.

9. The method for preparing the analgesic composition for injection according to claim 8, characterized in that: The alcohol solvent is selected from any one or more of ethanol, propylene glycol, tert-butyl alcohol and isopropanol.

10. The method for preparing the analgesic composition for injection according to claim 8 or 9, characterized in that: The weight ratio of the alcohol solvent to lornoxicam is 1:(1.2-1.5); Preferably, the weight ratio of the water for injection to the mixture is (15-20):1; Preferably, the freeze-drying process includes: pre-freezing at -35 to -45°C for 390 to 410 minutes, then drying at -3 to -8°C and 20 to 30Pa for 930 to 990 minutes, then heating to 30 to 40°C, continuing to dry at a vacuum condition of 1 to 10Pa for 100 to 140 minutes, and then drying at 15 to 25°C and 1 to 10Pa for 100 to 140 minutes.

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