A kind of lornoxicam injection preparation and preparation method thereof

Abstract

The invention relates to a lornoxicam injection preparation and a preparation method thereof, comprising the following steps: adding edetate disodium and tromethamine to water for injection, adding lornoxicam raw material medicine after dissolving, adding mannitol after dissolving, cooling while dissolving, and adding water for injection to the prescribed amount; wherein, before cooling, the temperature of the water for injection is maintained at 45-70° C. The lornoxicam injection preparation prepared by the invention has a fast dissolution speed, reduces the generation of by-products, ensures the stability and solubility of the finished product, and the sample preparation process is simple and convenient, and is suitable for large-scale production.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, in particular to a lornoxicam injection preparation and a preparation method thereof. Background Art

[0002] Lornoxicam belongs to the class of nonsteroidal anti-inflammatory analgesics (NSAIDs) of the oxicams. Its sites of action include the central nervous system and peripheral pain areas. It works through multiple mechanisms and has analgesic, anti-inflammatory and antipyretic effects. In recent years, with the progress of research on inflammatory pathology, selective action on cyclooxygenase 2 (COX2) produced only during the inflammatory process has become one of the important development directions of the new generation of nonsteroidal anti-inflammatory drugs (NSAIDs), and has also stimulated the enthusiasm of many domestic manufacturers for the research and development of oxicams nonsteroidal anti-inflammatory drugs. Lornoxicam has a very important position in nonsteroidal analgesics and anti-inflammatory drugs and has a good market prospect.

[0003] But lornoxicam has poor solubility and unstable physicochemical properties in solution, for example, lornoxicam is almost insoluble in water, slightly soluble in 0.1mol / L sodium hydroxide solution, has oxidation reaction and hydrolysis cleavage reaction in its solution, and produces a large amount of by-products, so the water-soluble preparations of the drug have certain difficulty. At present, mainly tablets and injections are clinically provided. Wherein injection lornoxicam is deeply welcomed clinically due to the advantages such as fast onset, high bioavailability, good stability, being convenient to clinical postoperative application.

[0004] The stability of injection is the premise of its application. At present, most of them are prepared into freeze-dried preparations to solve this problem. For example, CN102846558A uses lornoxicam, poloxamer 188, mannitol, EDTA-CaNa and NaOH as raw materials to prepare freeze-dried agents. However, although the stability of lornoxicam solution can be improved by freeze-drying technology, the raw materials need to be dissolved before freeze-drying. Therefore, how to improve the dissolution rate of lornoxicam and reduce the generation of by-products is a technical problem that needs to be solved at present.

[0005] In view of the above problems, since lornoxicam dissolves better in an alkaline environment, the dissolution effect is usually achieved by adding a pH adjuster (such as NaOH, etc.) to increase the pH of the drug solution, thereby improving the solubility of lornoxicam in the drug solution. However, it has no obvious improvement on improving the dissolution rate, and there are certain safety issues when using too much alkaline reagent. Summary of the invention

[0006] In order to solve the above technical problems, the present invention provides a method for preparing a lornoxicam injection preparation, which increases the dissolution rate of lornoxicam, reduces the dissolution time, reduces the generation of by-products, ensures the stability of the drug solution, and has a simple and convenient sample preparation process, saves energy, improves production efficiency, and is suitable for large-scale production.

[0007] The first object of the present invention is to provide a method for preparing a lornoxicam injection preparation, comprising the following steps:

[0008] Adding disodium edetate and tromethamine to water for injection, adding lornoxicam API after dissolving, adding mannitol after dissolving, cooling while dissolving, adding water for injection to the prescribed amount, and obtaining the lornoxicam injection preparation;

[0009] Wherein, before cooling, the temperature of the water for injection is maintained at 45-70°C.

[0010] Furthermore, the mass ratio of the lornoxicam bulk drug, mannitol, edetate disodium and tromethamine is 1:(10-15):(0.01-0.05):(1-2).

[0011] Furthermore, the particle size of the lornoxicam raw material is ≤70 μm.

[0012] Furthermore, the lornoxicam raw material is micronized.

[0013] Further, cool to 25-35°C.

[0014] Furthermore, the temperature of the water for injection added after cooling is 25-35°C.

[0015] Furthermore, the preparation method also includes the steps of sterilization, filling and freeze-drying after the liquid preparation is completed.

[0016] Furthermore, the sterilization is performed by filtering with a 0.22-0.45 μm filter element.

[0017] Furthermore, the freeze-drying includes the steps of pre-freezing, sublimation drying and analytical drying.

[0018] The second object of the present invention is to provide a lornoxicam injection preparation obtained by the above preparation method.

[0019] By means of the above scheme, the present invention has at least the following advantages:

[0020] The invention finds the balance point between the dissolution temperature and the dissolution time of lornoxicam. By controlling the temperature of the water for injection during the preparation of the solution, it is not necessary to wait for the water temperature to drop to room temperature before dissolving the drug components during the preparation of the solution, thereby saving time and improving production efficiency. At the same time, the dissolution speed of lornoxicam is increased, the dissolution time is shortened, the generation of by-products is reduced, and the stability of the lornoxicam injection is significantly improved. The storage time of the lornoxicam injection is significantly prolonged, thereby greatly increasing the feasibility of its clinical application. In addition, the dissolution process of mannitol can reduce the temperature of the liquid medicine, thereby further reducing the cooling time of the liquid medicine, reducing the generation of by-products, and improving the stability of the liquid medicine and production efficiency.

[0021] The above description is only an overview of the technical solution of the present invention. In order to more clearly understand the technical means of the present invention and implement it according to the contents of the specification, the following is a description of the preferred embodiments of the present invention. DETAILED DESCRIPTION

[0022] The present invention is further described below in conjunction with specific embodiments so that those skilled in the art can better understand the present invention and implement it, but the embodiments are not intended to limit the present invention.

[0023] In the present invention, unless otherwise specified, the ratio ranges and replacement schemes of the components in lornoxicam for injection can be combined with each other to form new formulation schemes.

[0024] In the present invention, unless otherwise specified, the preparation process of lornoxicam for injection is carried out sequentially.

[0025] In the present invention, unless otherwise specified, the original preparation is lornoxicam for injection marketed by Takeda Austria GmbH.

[0026] Example 1

[0027] 1) Liquid preparation: Measure about 180 ml of water for injection, cool to 45°C, keep warm in a 45°C water bath, add 1.2 g of tromethamine and 0.02 g of disodium edetate, and stir until dissolved; then add lornoxicam with a particle size of 30 μm, stir until dissolved and record the dissolution time; add 10.00 g of mannitol, and cool to room temperature while dissolving; dilute to the mark with the remaining 20 ml of water for injection cooled to room temperature;

[0028] 2) Sterilization filtration and canning: The solution prepared in step 1) is filtered through a 0.45 μm filter membrane, and then filtered through a 0.22 μm filter membrane, and canned into 2.15 ml / bottle;

[0029] 3) Freeze drying: put the canned product into the freeze drying box and start the freeze dryer;

[0030] 4) Pressed plug and rolled aluminum cover.

[0031] Example 2

[0032] 1) Liquid preparation: Measure about 180 ml of water for injection, cool to 55°C, keep warm in a 55°C water bath, add 1.2 g of tromethamine and 0.02 g of disodium edetate, and stir until dissolved; then add lornoxicam with a particle size of 30 μm, stir until dissolved and record the dissolution time; add 10.00 g of mannitol, and cool to room temperature while dissolving; dilute to the mark with the remaining 20 ml of water for injection cooled to room temperature;

[0033] 2) Sterilization filtration and canning: The solution prepared in step 1) is filtered through a 0.45 μm filter membrane, and then filtered through a 0.22 μm filter membrane, and canned into 2.15 ml / bottle;

[0034] 3) Freeze drying: put the canned product into the freeze drying box and start the freeze dryer;

[0035] 4) Pressed plug and rolled aluminum cover.

[0036] Example 3

[0037] 1) Liquid preparation: Measure about 180 ml of water for injection, cool to 65°C, keep warm in a 65°C water bath, add 1.2 g of tromethamine and 0.02 g of disodium edetate, and stir until dissolved; then add lornoxicam with a particle size of 30 μm, stir until dissolved and record the dissolution time; add 10.00 g of mannitol, and cool to room temperature while dissolving; dilute to the mark with the remaining 20 ml of water for injection cooled to room temperature;

[0038] 2) Sterilization filtration and canning: The solution prepared in step 1) is filtered through a 0.45 μm filter membrane, and then filtered through a 0.22 μm filter membrane, and canned into 2.15 ml / bottle;

[0039] 3) Freeze drying: put the canned product into the freeze drying box and start the freeze dryer;

[0040] 4) Pressed plug and rolled aluminum cover.

[0041] Example 4

[0042] 1) Preparation of liquid: Measure about 180 ml of water for injection, cool to 70°C, keep warm in a 70°C water bath, add 1.2 g of tromethamine and 0.02 g of disodium edetate, and stir until dissolved; then add lornoxicam with a particle size of 30 μm, stir until dissolved and record the dissolution time; add 10.00 g of mannitol, and cool to room temperature while dissolving; dilute to the mark with the remaining 20 ml of water for injection cooled to room temperature;

[0043] 2) Sterilization filtration and canning: The solution prepared in step 1) is filtered through a 0.45 μm filter membrane, and then filtered through a 0.22 μm filter membrane, and canned into 2.15 ml / bottle;

[0044] 3) Freeze drying: put the canned product into the freeze drying box and start the freeze dryer;

[0045] 4) Pressed plug and rolled aluminum cover.

[0046] Example 5

[0047] 1) Preparation of liquid: Measure about 180 ml of water for injection, cool to 65°C, keep warm in a 65°C water bath, add 1.2 g of tromethamine and 0.02 g of disodium edetate, and stir until dissolved; then add 15 μm of lornoxicam, stir until dissolved and record the dissolution time; add 10.00 g of mannitol, and cool to room temperature while dissolving; dilute to the mark with the remaining 20 ml of water for injection cooled to room temperature;

[0048] 2) Sterilization filtration and canning: The solution prepared in step 1) is filtered through a 0.45 μm filter membrane, and then filtered through a 0.22 μm filter membrane, and canned into 2.15 ml / bottle;

[0049] 3) Freeze drying: put the canned product into the freeze drying box and start the freeze dryer;

[0050] 4) Pressed plug and rolled aluminum cover.

[0051] Example 6

[0052] 1) Preparation of liquid: Measure about 180 ml of water for injection, cool to 65°C, keep warm in a 65°C water bath, add 1.2 g of tromethamine and 0.02 g of disodium edetate, and stir until dissolved; then add 50 μm of lornoxicam, stir until dissolved and record the dissolution time; add 10.00 g of mannitol, and cool to room temperature while dissolving; dilute to the mark with the remaining 20 ml of water for injection cooled to room temperature;

[0053] 2) Sterilization filtration and canning: The solution prepared in step 1) is filtered through a 0.45 μm filter membrane, and then filtered through a 0.22 μm filter membrane, and canned into 2.15 ml / bottle;

[0054] 3) Freeze drying: put the canned product into the freeze drying box and start the freeze dryer;

[0055] 4) Pressed plug and rolled aluminum cover.

[0056] Example 7

[0057] 1) Preparation of liquid: Measure about 180 ml of water for injection, cool to 65°C, keep warm in a 65°C water bath, add 1.2 g of tromethamine and 0.02 g of disodium edetate, and stir until dissolved; then add 70 μm of lornoxicam, stir until dissolved and record the dissolution time; add 10.00 g of mannitol, and cool to room temperature while dissolving; dilute to the mark with the remaining 20 ml of water for injection cooled to room temperature;

[0058] 2) Sterilization filtration and canning: The solution prepared in step 1) is filtered through a 0.45 μm filter membrane, and then filtered through a 0.22 μm filter membrane, and canned into 2.15 ml / bottle;

[0059] 3) Freeze drying: put the canned product into the freeze drying box and start the freeze dryer;

[0060] 4) Pressed plug and rolled aluminum cover.

[0061] Comparative Example 1

[0062] 1) Preparation of liquid: Measure about 180 ml of water for injection, cool to 40°C, and keep warm in a water bath at this temperature, add 1.2 g of tromethamine and 0.02 g of disodium edetate, and stir until dissolved; then add lornoxicam with a particle size of 30 μm, stir until dissolved and record the dissolution time; add 10.00 g of mannitol, and cool to room temperature while dissolving; dilute to the scale with the remaining 20 ml of water for injection cooled to room temperature;

[0063] 2) Sterilization filtration and canning: The solution prepared in step 1) is filtered through a 0.45 μm filter membrane, and then filtered through a 0.22 μm filter membrane, and canned into 2.15 ml / bottle;

[0064] 3) Freeze drying: put the canned product into the freeze drying box and start the freeze dryer;

[0065] 4) Pressed plug and rolled aluminum cover.

[0066] Comparative Example 2

[0067] 1) Preparation of liquid: Measure about 180 ml of water for injection, cool to 75°C, and keep warm in a water bath at this temperature, add 1.2 g of tromethamine and 0.02 g of disodium edetate, and stir until dissolved; then add lornoxicam with a particle size of 30 μm, stir until dissolved and record the dissolution time; add 10.00 g of mannitol, and cool to room temperature while dissolving; dilute to the scale with the remaining 20 ml of water for injection cooled to room temperature;

[0068] 2) Sterilization filtration and canning: The solution prepared in step 1) is filtered through a 0.45 μm filter membrane, and then filtered through a 0.22 μm filter membrane, and canned into 2.15 ml / bottle;

[0069] 3) Freeze drying: put the canned product into the freeze drying box and start the freeze dryer;

[0070] 4) Pressed plug and rolled aluminum cover.

[0071] Comparative Example 3

[0072] 1) Preparation of liquid: Measure about 180 ml of water for injection, cool to 65°C, and keep warm in a water bath at 65°C, add 1.2 g of tromethamine and 0.02 g of disodium edetate, and stir until dissolved; then add lornoxicam with a particle size of 100 μm, stir until dissolved and record the dissolution time; add 10.00 g of mannitol, and cool to room temperature while dissolving; dilute to the mark with the remaining 20 ml of water for injection cooled to room temperature;

[0073] 2) Sterilization filtration and canning: The solution prepared in step 1) is filtered through a 0.45 μm filter membrane, and then filtered through a 0.22 μm filter membrane, and canned into 2.15 ml / bottle;

[0074] 3) Freeze drying: put the canned product into the freeze drying box and start the freeze dryer;

[0075] 4) Pressed plug and rolled aluminum cover.

[0076] Comparative Example 4

[0077] 1) Preparation of liquid: Measure about 180 ml of water for injection, cool to 65°C, and keep warm in a water bath at 65°C, add 1.2 g of tromethamine, 0.02 g of disodium edetate and 10.00 g of mannitol, and stir until dissolved; then add lornoxicam with a particle size of 30 μm, stir until dissolved and record the dissolution time; cool to room temperature; dilute to the mark with the remaining 20 ml of water for injection cooled to room temperature;

[0078] 2) Sterilization filtration and canning: The solution prepared in step 1) is filtered through a 0.45 μm filter membrane, and then filtered through a 0.22 μm filter membrane, and canned into 2.15 ml / bottle;

[0079] 3) Freeze drying: put the canned product into the freeze drying box and start the freeze dryer;

[0080] 4) Pressed plug and rolled aluminum cover.

[0081] Test Case

[0082] (1) Dissolution time results are shown in Table 1.

[0083] Table 1 Dissolution time

[0084]

[0085]

[0086] As can be seen from Table 1, the dissolution time of lornoxicam injection prepared at 45-70°C is short, within 15-62min, indicating that lornoxicam has a high dissolution rate. More preferably, the dissolution transition from 40°C to 45°C is more important, and starting from 45°C, the dissolution rate continues to increase with the increase in temperature, reaching a peak at 70°C, and after 70°C, the dissolution rate remains unchanged with the increase in temperature. Secondly, the effect of lornoxicam particle size on the dissolution rate cannot be ignored. When the particle size is 70μm or less, the dissolution rate is good, especially the smaller the particle size, the higher the dissolution rate, and when the particle size is as high as 100μm, the dissolution time is extended.

[0087] (2) Record the properties of the solution and finished product after the raw materials are dissolved. The test results are shown in Table 2. In the clarity test, "clear solution" means that it is not thicker than the No. 1 turbidity standard solution, otherwise it is "unclear solution" (see the test method in Part IV of the Chinese Pharmacopoeia 2020 Edition, 0902 Clarity Test Method 1); in the resolubility test, if the contents are completely dissolved within 60 seconds, it is considered to have passed. The results are shown in Table 2.

[0088] Table 2 Test results

[0089]

[0090]

[0091] As can be seen from Table 2, the lornoxicam for injection prepared by Examples 1-7 and Comparative Example 4 has good solution clarity after the raw materials are dissolved, the obtained product is well formed, the clarity and color of the solution meet the requirements, the solubility is consistent with the reference preparation, and the effective substance content and related substances are qualified after detection by high-phase liquid chromatograph, indicating that the preparation method of the injection of the present invention can effectively inhibit the oxidation reaction and hydrolysis reaction of the raw materials. And in the comparative examples: there is still a small amount of insoluble matter when comparative examples 1 and comparative examples 3 are stirred to the time recorded in the table, but it no longer dissolves, so this time is used as the dissolution time. It is speculated that the reason for not being completely dissolved is that the raw materials are not subjected to micro-powder treatment, the particle size is too large to cause a slow dissolution rate, or the solution preparation temperature cannot balance the dissolution temperature and the dissolution time to cause a slow dissolution rate. Although comparative example 2 can be dissolved normally, the total impurity ratio is too high (equivalent to the original preparation), and the reason may be that the raw materials are stored for too long at high temperature, and by-products are produced during the process, resulting in unqualified related substances.

[0092] (3) Stability test

[0093] The lornoxicam injection and the original preparation prepared in Example 1-7 were placed at 40°C for 30 days, and samples were taken at 10 and 30 days to determine the changes in impurities in the samples; they were placed at 60°C for 10 days, and samples were taken at 5 and 10 days to determine the changes in impurities in the samples; and the samples were placed at a light illumination of 4500 lx ± 500 lx for 10 days, with a total light illumination of not less than 1.2×10 6 lux·hr, near-ultraviolet energy not less than 200W·hr / m 2 , samples were taken after 5 days and 10 days to determine the changes in impurities in the samples. The stability test results are shown in the table below.

[0094] Table 3 Stability test results (total impurities / %)

[0095]

[0096] As can be seen from Table 3, after the samples prepared in Examples 1-7 were placed under different conditions for a period of time, the impurity growth rate was lower than that of the original preparation, while the sample of Comparative Example 4, the initial total impurities of the newly configured injection were slightly higher than those of all the examples, and performed poorly in the high temperature stability test, especially when stored at 60°C, the total impurity content was significantly higher than that of the examples, indicating that the stability of the lornoxicam injection prepared in Comparative Example 4 was worse than that of the examples.

[0097] Obviously, the above embodiments are merely examples for clear explanation and are not intended to limit the implementation methods. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived from these are still within the protection scope of the invention.

Claims

1. A method for preparing a lornoxicam injection preparation, characterized in that: The following steps are involved: Add disodium edetate and tromethamine to water for injection, add lornoxicam API after dissolving, add mannitol after dissolving, cool while dissolving, add water for injection to the prescribed amount, and obtain the lornoxicam injection preparation; wherein, Before cooling, the injection water temperature was maintained at 65°C. The mass ratio of the lornoxicam raw material, mannitol, edetate disodium and tromethamine is 1: (10-15): (0.01-0.05): (1-2), The particle size of the lornoxicam raw material is ≤70 μm, Cool to 25-35℃. The temperature of the water for injection added after cooling should be 25-35℃.

2. The preparation method according to claim 1, characterized in that: The preparation method also includes the steps of sterilization, filling and freeze-drying after the liquid preparation is completed.

3. The preparation method according to claim 2, characterized in that: The sterilization is performed by filtering with a 0.22-0.45 μm filter element.

4. The preparation method according to claim 2, characterized in that: The freeze drying comprises the steps of pre-freezing, sublimation drying and analytical drying.

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