Meloxicam injection and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and specifically discloses a meloxicam injection and a preparation method thereof, wherein: the raw and auxiliary material components of the meloxicam injection include meloxicam, sodium deoxycholate and polyvidone, the pH value of the sodium deoxycholate solution with a mass concentration of 0.3% is 6.8-8.0 or the sodium content in the sodium deoxycholate is 5.0-5.5wt%. The meloxicam injection of the invention uses sodium deoxycholate and polyvidone as surfactants, and by controlling the pH value of the sodium deoxycholate solution or the sodium content in the sodium deoxycholate, the stability of the meloxicam nanocrystal suspension can be maintained without the addition of sugar or buffer, and almost no flake aggregates are precipitated. At the same time, the preparation method of the meloxicam injection of the invention has stable process and simple operation, almost no flake aggregates are precipitated in the prepared suspension, the system is more stable, and is conducive to industrial production, transportation and storage.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a meloxicam injection and a preparation method thereof. Background Art

[0002] Meloxicam injection (trade name: Anjeso injection, specification: 1mL: 30mg) is a non-steroidal analgesic injection developed by Baudax Bio in the United States. It was approved for marketing by the US FDA in 2020. It is mainly used clinically to treat moderate to severe pain in adults alone or in combination with non-NSAID analgesics. Its chemical structure is:

[0003]

[0004] Meloxicam is a nonsteroidal anti-inflammatory drug that exerts its analgesic effect mainly by inhibiting the activity of cyclooxygenase (COX) and reducing the production of prostaglandins (PGS). Meloxicam can selectively inhibit cyclooxygenase (COX-2), while its inhibitory effect on cyclooxygenase (COX-1) is milder, so compared with other similar drugs, it has less adverse reactions to the gastrointestinal tract or kidneys.

[0005] Meloxicam API has the appearance of light yellow powder, molecular weight of 351.4, and poor solubility in water (0.154 mg / mL). Baudax Bio's Anjeso injection is a nanocrystalline suspension injection.

[0006] The biggest problem of nanocrystalline suspension is its poor physical stability, and crystal growth and particle aggregation often occur during storage. In order to stabilize meloxicam injection, the existing technology usually adopts the method of adding surface stabilizers (such as sodium deoxycholate and povidone) and flaky aggregation inhibitors (such as buffers and sugars) to the prescription at the same time, adding sugars and buffers to meloxicam injection, and adjusting the pH of meloxicam injection to alkaline conditions to achieve the reduction of flaky aggregates. The researchers found that the above technical scheme has many types of excipients, high production costs, and it is still easy to produce flaky precipitates in production. The mechanism of the production of flaky precipitates in meloxicam injection is still unclear, which brings great risks to the production and preservation of the product. The presence of flaky precipitates also brings safety risks to clinical patients. Therefore, it is of great significance to completely solve the flaky precipitates of meloxicam injection. Summary of the invention

[0007] The present invention aims to solve at least one of the technical problems existing in the above-mentioned prior art. To this end, the present invention provides a meloxicam injection and a preparation method thereof.

[0008] During the research and development process, the applicant unexpectedly discovered that by controlling the pH value of the sodium deoxycholate solution within a specific range, the stability of the meloxicam nanocrystal suspension can still be maintained without adding sugar or buffer, with almost no precipitation of flaky aggregates.

[0009] To solve the above technical problems, the first aspect of the present invention provides a meloxicam injection, wherein the raw and auxiliary material components of the meloxicam injection include meloxicam, sodium deoxycholate and povidone, the pH value of the sodium deoxycholate solution with a mass concentration of 0.3% is 6.8-8.0 or the sodium content in the sodium deoxycholate is 5.0-5.5wt%.

[0010] The present invention can effectively reduce the precipitation of flake aggregates by controlling the pH value of the sodium deoxycholate solution to 6.8-8.0 or the sodium content in the sodium deoxycholate to 5.0-5.5wt% without adding sugar or buffer solution.

[0011] It should be pointed out that the raw material in the raw and auxiliary materials of the present invention refers to meloxicam, and the auxiliary materials include sodium deoxycholate and povidone. The sodium content in the sodium deoxycholate of the present invention refers to the mass ratio of the sodium element in the sodium deoxycholate (calculated as a dry product). The selection of the sodium deoxycholate of the present invention is to first measure the pH value of the sodium deoxycholate solution with a mass concentration of 0.3% or the sodium content in the sodium deoxycholate. When the pH value or the sodium content is within the protection scope of the present invention, it can be used as a spare auxiliary material of the sodium deoxycholate of the present invention.

[0012] Preferably, the pH value of the sodium deoxycholate solution is 7.0-7.5.

[0013] Preferably, the sodium content in the sodium deoxycholate is 5.1-5.4 wt %.

[0014] Preferably, the povidone is povidone K12.

[0015] As a further improvement of the above scheme, the raw and auxiliary material components of the meloxicam injection include, by weight: 5-200 parts of meloxicam, 1-50 parts of sodium deoxycholate solution and 3-100 parts of povidone.

[0016] As a further improvement of the above scheme, the raw material components of the meloxicam injection also include sucrose, and the added amount of the sucrose is 5-150 parts by weight. Studies have found that the present invention only controls the pH value of the sodium deoxycholate solution to 6.8-8.0 or the sodium content in the sodium deoxycholate to 5.0-5.5wt%, and whether to add sucrose has little effect on the stability of the meloxicam injection.

[0017] Preferably, the raw and auxiliary material components of the meloxicam injection include, by weight: 15-40 parts of meloxicam, 1-10 parts of sodium deoxycholate solution, 6-15 parts of povidone and 40-80 parts of sucrose.

[0018] As a further improvement of the above scheme, the particle size range of the meloxicam injection is 40-1000 nm.

[0019] Preferably, the particle size range of the meloxicam injection is 50-100 nm.

[0020] The second aspect of the present invention provides a method for preparing meloxicam injection, which is used to prepare the meloxicam injection described in the first aspect of the present invention, comprising the following steps:

[0021] Firstly, sodium deoxycholate and povidone are dissolved; then meloxicam is added, stirred and dispersed; and then ground to obtain the meloxicam injection.

[0022] Preferably, the sodium deoxycholate and povidone are dissolved by stirring with water for injection.

[0023] As a further improvement of the above scheme, sucrose is added before, during or after the grinding. The timing of adding sucrose has little effect on the stability of meloxicam injection.

[0024] As a further improvement of the above scheme, the grinding process conditions are: the grinding medium is selected from at least one of yttrium stabilized zirconia beads, polystyrene grinding beads, and glass beads; the grinding medium occupies 50-85% of the grinding chamber volume; and the grinding linear speed is 3-18m / s.

[0025] Preferably, the grinding medium is yttrium-stabilized zirconia beads, and the particle size of the yttrium-stabilized zirconia beads is 0.1-0.2 mm.

[0026] Preferably, the grinding linear speed is 8-16 m / s.

[0027] Preferably, the grinding time is 3-5 hours.

[0028] Compared with the prior art, the above technical solution of the present invention has at least the following technical effects or advantages:

[0029] The meloxicam injection of the present invention uses sodium deoxycholate and povidone as surfactants, and by controlling the pH value of a sodium deoxycholate solution with a mass concentration of 0.3% to be 6.8-8.0 or the sodium content in the sodium deoxycholate to be 5.0-5.5wt%, the stability of the meloxicam nanocrystal suspension can be maintained without adding sugar or buffer, and almost no flaky aggregates are precipitated.

[0030] The preparation method of meloxicam injection of the present invention has stable process and simple operation, almost no flakes are precipitated in the prepared suspension, the system is more stable, and it is conducive to industrial production, transportation and storage. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 This is a microscope image of the meloxicam injection prepared in Example 2 placed at 60° C. for 5 days;

[0032] Figure 2 This is a microscope image of the meloxicam injection prepared in Comparative Example 3 after being placed at 60°C for 5 days. DETAILED DESCRIPTION

[0033] The present invention is described in detail below in conjunction with the examples, so that the technical personnel of the relevant technical field can understand the present invention. It is necessary to point out here that the examples are only used to further illustrate the present invention and cannot be understood as limiting the scope of protection of the present invention. Non-essential improvements and adjustments made to the present invention by the skilled person in the relevant field according to the above invention content should still fall within the scope of protection of the present invention. At the same time, the raw and auxiliary materials mentioned below that are not described in detail are all commercially available products; the process steps or preparation methods that are not mentioned in detail are all process steps or preparation methods known to those skilled in the art.

[0034] The preparation method of the meloxicam injection in the following examples and comparative examples is as follows:

[0035] (1) Weigh 0.3 g of sodium deoxycholate and dissolve it in 100 mL of purified water to prepare a sodium deoxycholate solution with a mass concentration of 0.3%. Determine the pH value, and reserve the sodium deoxycholate that meets the required pH value;

[0036] (2) First, add an appropriate amount of water for injection into the container; then weigh sodium deoxycholate according to the prescribed dosage, stir and dissolve it, then add povidone K12 and stir until it is completely dissolved; then add the raw material meloxicam and stir until it is evenly dispersed; finally, grind and obtain the grinding solution, then perform post-treatment to fix the volume, and obtain the finished meloxicam injection solution. Wherein: sucrose is added before, during or after grinding; during grinding, yttrium-stabilized zirconium oxide balls with a particle size of 0.1-0.2 mm, which accounts for 80% of the volume of the grinding chamber, are added to the grinder, the grinding linear speed is 12.1-12.3 m / s, and the grinding time is 4 hours.

[0037] Examples 1-8

[0038] The raw material components of the meloxicam injection of Examples 1-8 and the pH values ​​of the obtained meloxicam injection products are shown in Table 1.

[0039] Table 1: Table of raw material components and finished product pH values ​​of meloxicam injection of Examples 1-8

[0040]

[0041] Examples 9-14

[0042] The raw material and auxiliary material components of the meloxicam injection of Examples 9-14 are shown in Table 2.

[0043] Table 2: Raw material and auxiliary material composition of meloxicam injection of Examples 9-14

[0044]

[0045] Comparative Examples 1-3

[0046] The raw and auxiliary material components of the meloxicam injections of Comparative Examples 1-3 are shown in Table 3.

[0047] Table 3: Raw material and auxiliary material composition of meloxicam injection of comparative examples 1-3

[0048]

[0049] Performance Testing

[0050] 1. Particle size and stability test

[0051] The finished meloxicam injections prepared in the embodiments and comparative examples were tested for particle size and particle size distribution using a Malvern nanoparticle size potentiometer, where: Z-average represents the average particle size of the cumulative distribution of particles, and PDI represents the particle size dispersion index; and the stability of the grinding solution was preliminarily investigated (stability was investigated by placing it at 60°C or 40°C); the particle size determination parameter settings are shown in Table 4.

[0052] Table 4: Particle size determination parameter setting table

[0053] project Parameter settings Sample pool PCS8501 (quartz material) or PCS1115 (quartz material) Material refractive index 1.72 Material Absorption Rate 0.01 Dispersant Refractive Index 1.33 temperature 25℃ Thermal equilibrium time 120s Analytical Model General Mode

[0054] The particle size and stability test results of the finished meloxicam injections of Examples 1-8 are shown in Table 5.

[0055] Table 5: Particle size and stability of the finished meloxicam injections of Examples 1-8

[0056]

[0057] As shown in Table 1 and Table 5, the meloxicam injection finished products obtained in Examples 1-8 have an average particle size of 73-76nm, a particle size dispersion index of 0.26-0.29, 6-13 insoluble particles of ≥10μm, and 2-8 insoluble particles of ≥25μm after being placed at 60°C for 5 days. The particle size, its dispersion index and the number of insoluble particles are similar to those after being placed at 0 days. That is, the meloxicam injection with a pH value of 6.8-8.0 of 0.3% sodium deoxycholate solution has a smaller particle size, a narrow particle size distribution range, a small number of insoluble particles, and good stability of the injection. At the same time, the particle size and stability results of the meloxicam injection finished products obtained in Examples 1 and 2 show that the particle size and stability performance of Example 2 with added sucrose are comparable to those of Example 1 without added sucrose, indicating that the addition of sucrose has little effect on the stability of the injection.

[0058] The particle size and stability test results of the finished meloxicam injections of Examples 9-14 are shown in Table 6.

[0059] Table 6: Particle size and stability of the finished meloxicam injections of Examples 9-14

[0060]

[0061]

[0062] As shown in Table 2 and Table 6, the meloxicam injection finished product obtained in Examples 10-12 has an average particle size of 73-74nm, a particle size dispersion index of 0.25-0.27, 6-28 insoluble particles of ≥10μm, and 2-13 insoluble particles of ≥25μm after being placed at 60°C for 5 days. The particle size, its dispersion index and the number of insoluble particles are similar to those after being placed at 0 days. That is, the meloxicam injection with a sodium content of 5.0-5.5wt% in sodium deoxycholate has a smaller particle size, a narrow particle size distribution range, a small number of insoluble particles, and good stability of the injection. However, since the sodium content in sodium deoxycholate is not within the range of 5.0-5.5wt%, the particle size of Examples 9 and 13-14 is larger than that of Examples 10-12, the number of insoluble particles is significantly increased, and the stability is also reduced.

[0063] The particle size and stability test results of the finished meloxicam injections of Comparative Examples 1-3 are shown in Table 7.

[0064] Table 7: Particle size and stability of meloxicam injection finished products of comparative examples 1-3

[0065]

[0066] As shown in Table 3 and Table 7, the meloxicam injection products prepared in Comparative Examples 1-3 have larger particle sizes, more insoluble particles, and poorer stability because the pH value of the 0.3% sodium deoxycholate solution is not within the range of 6.8-8.0.

[0067] At the same time, the particle size and stability of the meloxicam injection product prepared in Example 3 were tested at 40° C. for 6 months. The specific results are shown in Table 8.

[0068] Among them, the relevant substances were determined by high performance liquid chromatography, and the chromatographic conditions were: chromatographic column: octadecylsilane bonded silica gel chromatographic column; mobile phase: solution A is 0.1mol / L ammonium acetate solution-methanol (80:20), solution B is 0.1mol / L ammonium acetate solution-methanol (30:70); column temperature 35℃; detection wavelength 260nm and 350nm; flow rate 1.0mL / min; injection volume 20μL; injection plate temperature 2-8℃, gradient elution program. Impurity B in the relevant substance is 2-amino-5-methylthiazole, and its CAS number is 7305-71-7.

[0069] The content of meloxicam was determined by high performance liquid chromatography, and the chromatographic conditions were as follows: chromatographic column: octadecyl bonded silica gel chromatographic column; mobile phase: pH 2.5 phosphoric acid solution-acetonitrile (55:45); column temperature 30°C; detection wavelength 254nm; flow rate

[0070] 1.0mL / min; injection volume 25μL.

[0071] Table 8: Particle size and stability of the finished product of meloxicam injection of Example 3

[0072]

[0073] As shown in Table 8, after the meloxicam injection product prepared in Example 3 was placed at 40°C for 6 months, its average particle size, particle size distribution and the number of insoluble particles were similar to those after being placed for 0 days, and no impurities were detected, indicating that it has good stability.

[0074] 2. Microstructure test

[0075] The finished meloxicam injections obtained in Example 2 and Comparative Example 3 were observed under a microscope. Figure 1-2 As shown. Figure 1 It can be seen that in Example 2, 0.3% sodium deoxycholate solution with a pH value of 6.8 was added during the preparation, and no precipitate was observed under a microscope after the finished product was placed at 60°C for 5 days; while in Comparative Example 3, 0.3% sodium deoxycholate solution with a pH value of 8.5 was added during the preparation, and the precipitate was clearly visible under a microscope after the finished product was placed at 60°C for 5 days.

[0076] For ordinary technicians in the technical field to which the present invention belongs, several simple deductions or substitutions can be made without departing from the concept of the present invention, without having to go through creative labor. Therefore, simple improvements made to the present invention by those skilled in the art based on the disclosure of the present invention should be within the protection scope of the present invention. The above embodiments are preferred embodiments of the present invention, and all processes similar to the present invention and equivalent changes made should belong to the protection scope of the present invention.

Claims

1. A meloxicam injection, characterized in that: The raw and auxiliary material components of the meloxicam injection are calculated by weight as follows: 15-40 parts of meloxicam, 1-10 parts of sodium deoxycholate, 6-15 parts of povidone and 40-80 parts of sucrose; The pH value of the sodium deoxycholate solution with a mass concentration of 0.3% is 6.8-8.0 or the sodium content in the sodium deoxycholate is 5.0-5.5wt%.

2. The meloxicam injection according to claim 1, characterized in that: The pH value of the sodium deoxycholate solution is 7.0-7.

5.

3. The meloxicam injection according to claim 1, characterized in that: The sodium content of the sodium deoxycholate is 5.1-5.4 wt %.

4. The meloxicam injection according to claim 1, characterized in that: The particle size range of the meloxicam injection is 40-1000 nm.

5. A method for preparing meloxicam injection, characterized in that: The preparation method is used to prepare the meloxicam injection according to any one of claims 1 to 4, comprising the following steps: Firstly, sodium deoxycholate and povidone are dissolved; then meloxicam is added, stirred and dispersed; then grinding is performed, and sucrose is added before, during or after grinding to obtain the meloxicam injection.

6. The method for preparing meloxicam injection according to claim 5, characterized in that: The grinding process conditions are as follows: the grinding medium is selected from any one of yttrium stabilized zirconia beads, polystyrene grinding beads, and glass beads; the grinding medium occupies 50-85% of the volume of the grinding chamber; The grinding line speed is 3-18m / s.

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