A meloxicam nanocrystal composition with high bioavailability and application thereof

Abstract

The present application relates to a kind of meloxicam nanocrystal compositions, with 1-10% meloxicam, 0.1-10% stabilizer, 1-10% suspending agent in composition in mass volume percentage ratio, wherein, the particle size of meloxicam nanocrystal≤80nm.The present application significantly improves the stability and bioavailability of meloxicam nanocrystal etc., and significantly shortens analgesic onset time, prolongs analgesic duration, improves drug quality and improves patient medication compliance, ensures clinical medication safety and effectiveness.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, specifically relating to a meloxicam nanocrystal composition with high bioavailability, its preparation method, and its application. Background Technology

[0002] Rheumatoid arthritis and osteoarthritis are common types of arthritis. In my country, the incidence of rheumatoid arthritis is approximately 0.5%, affecting about 5 million people across all age groups. Osteoarthritis typically develops in people over 40 years of age, with an incidence rate of 10%-17% in the 40-60 age group, surging to 50% in those over 60, and reaching as high as 70% in those over 70. Current treatments mainly include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and antirheumatoid agents, but their specificity and efficacy need further improvement.

[0003] Meloxicam is an enol nonsteroidal anti-inflammatory drug (NSAID) with anti-inflammatory, analgesic, and antipyretic effects. Clinically, it is used to treat short-term symptoms of osteoarthritis exacerbations, long-term symptoms of rheumatoid arthritis and ankylosing spondylitis, and moderate to severe pain in rheumatoid arthritis and osteoarthritis. However, meloxicam suffers from drawbacks such as poor solubility, low bioavailability, complex manufacturing processes, and high cost. Existing technologies disclose meloxicam drug compositions, but these suffer from problems such as large nanocrystal size, instability at room temperature, large particle size variations, and low bioavailability. Therefore, it is necessary to improve drug stability and bioavailability to meet clinical needs.

[0004] Summary of the Invention

[0005] The present invention aims to provide a meloxicam nanocrystal composition, which, by mass-volume percentage, contains 1-10% meloxicam, 0.1-10% stabilizer, and 1-10% suspending agent, wherein the meloxicam nanocrystals have a particle size ≤80nm, and the stabilizer is selected from any one or a combination of hydroxypropyl methylcellulose, polyvinylpyrrolidone PVPK12 PF, PVPK15, PVPK17 PF, lecithin, polyethylene glycol, poloxamer P luronics F68, P luronics F108, Tween-80, sodium cholate, sodium deoxycholate, sodium docusate, sodium lauryl sulfate, and sodium lauryl sulfonate, and the suspending agent is selected from any one or a combination of sucrose, glycerin, povidone, hydroxypropyl cellulose, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, carboxymethylcellulose, polyvinyl alcohol, gum arabic, and dextrin.

[0006] In a preferred embodiment of the present invention, the composition contains 1.5-8% meloxicam, 0.2-5% stabilizer, 2-8% suspending agent, and the balance being water, by mass-volume percentage. The particle size of the meloxicam nanocrystals is ≤75nm.

[0007] In a preferred embodiment of the present invention, the composition contains 2-5% meloxicam, 0.3-2% stabilizer, 4-6% suspending agent, and the balance being water, by mass-volume percentage. The particle size of the meloxicam nanocrystals is ≤75nm.

[0008] In a preferred embodiment of the present invention, the composition contains, by mass-volume percentage, 1-10% meloxicam, 0.1-1% PVPK17 PF, 0.1-1% sodium deoxycholate, and 1-10% sucrose, with the balance being water, and the particle size of the meloxicam nanocrystals is ≤75nm.

[0009] In a preferred embodiment of the present invention, the composition contains, by mass-volume percentage, 2-5% meloxicam, 0.6-1% PVPK17 PF, 0.3-0.5% sodium deoxycholate, and 2-8% sucrose, with the balance being water, and the particle size of the meloxicam nanocrystals is ≤75nm.

[0010] In a preferred embodiment of the present invention, the composition contains, by mass-volume percentage, 3% meloxicam, 0.9% PVPK17 PF, 0.3% sodium deoxycholate, and 6% sucrose, with the balance being water, and the particle size of the meloxicam nanocrystals is ≤75nm.

[0011] In the preferred embodiment of the present invention, the PDI of meloxicam nanocrystals is ≤0.5, preferably ≤0.4, and more preferably ≤0.35.

[0012] In a preferred embodiment of the present invention, the meloxicam nanocrystals have D10≤50nm, D50≤100nm, and D90≤200nm.

[0013] In a preferred embodiment of the present invention, the meloxicam nanocrystal composition has a particle size ≤100nm, preferably ≤95nm, and more preferably ≤80nm after being placed at room temperature (20-25°C) for 30 days.

[0014] In a preferred embodiment of the present invention, the meloxicam nanocrystal composition has a particle size ≤120nm, preferably ≤100nm, and more preferably ≤95nm after being placed at 40°C for 40 days.

[0015] Another object of the present invention is to provide a method for preparing a meloxicam nanocrystal composition, wherein the composition contains 1-10% meloxicam, 0.1-10% stabilizer, and 1-10% suspending agent by weight-volume percentage, wherein the meloxicam nanocrystals have a particle size ≤100nm, the stabilizer is selected from any one of hydroxypropyl methylcellulose, polyvinylpyrrolidone PVPK12 PF, PVPK15, PVPK17 PF, lecithin, polyethylene glycol, any one of Poloxamer Plutonics F68 or Plutonics F108, Tween-80, sodium cholate, sodium deoxycholate, sodium docusate, sodium lauryl sulfate, sodium lauryl sulfonate, or a combination thereof, and the suspending agent is selected from any one of sucrose, glycerin, povidone, hydroxypropyl cellulose, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, carboxymethyl cellulose, polyvinyl alcohol, gum arabic, dextrin, or a combination thereof, and the preparation method includes the following steps:

[0016] (1) Weigh the required amount of stabilizer, dissolve it in water, add the required amount of meloxicam, stir it at 25-35℃ and 500-1500rpm for 30-60 min, and then shear it at 1000-3500rpm for 1-10 min to obtain a shear mixture.

[0017] (2) Using grinding beads with a particle size of 0.1-0.3 mm as the grinding medium, the prepared shear suspension is ground at 25-35℃ and 1500-3500 rpm for 30-60 min. After adding the stabilizer, it is ground at 25-35℃ and 1500-3500 rpm for 30-60 min. Then, the suspending agent solution is added and mixed to obtain the solution. The grinding speed is gradually increased from 1500 rpm to 3500 rpm and then decreased to 1500-3000 rpm. The rate of increase or decrease of the grinding speed is 500 rpm every 5 min.

[0018] In a preferred embodiment of the present invention, the stabilizer in step (1) is selected from any one or a combination of hydroxypropyl methylcellulose, polyvinylpyrrolidone PVPK12 PF, PVPK15, PVPK17 PF, lecithin, polyethylene glycol, poloxamer P luronics F68, P luronics F108, and Tween-80.

[0019] In a preferred embodiment of the present invention, the stabilizer in step (2) is selected from any one or a combination of sodium cholate, sodium deoxycholate, sodium docusate, sodium dodecyl sulfate, and sodium dodecyl sulfonate.

[0020] In the preferred embodiment of the present invention, the stirring speed in step (1) is 600-1200 rpm, preferably 800-1000 rpm, the high-speed shearing speed is 2000-3000 rpm, and the high-speed shearing is 3-10 min.

[0021] In the preferred embodiment of the present invention, the grinding speed in step (2) is increased from 1500 rpm to 3500 rpm and then decreased to 1500 rpm, and the grinding speed is increased or decreased by 500 rpm every 5 min.

[0022] In the preferred embodiment of the present invention, the grinding speed in step (2) is first increased from 1500 rpm to 3500 rpm and then decreased to 2000 rpm, and the grinding speed is increased or decreased by 500 rpm every 5 minutes.

[0023] In the preferred embodiment of the present invention, the grinding speed in step (2) is first increased from 1500 rpm to 3500 rpm and then decreased to 2500 rpm, and the grinding speed is increased or decreased by 500 rpm every 5 min.

[0024] In the preferred embodiment of the present invention, the grinding speed in step (2) is first increased from 1500 rpm to 3500 rpm and then decreased to 3000 rpm, and the grinding speed is increased or decreased by 500 rpm every 5 minutes.

[0025] In a preferred embodiment of the present invention, the composition contains 1.5-8% meloxicam, 0.2-5% stabilizer, 2-8% suspending agent, and the balance being water, by mass-volume percentage. The particle size of the meloxicam nanocrystals is ≤75nm.

[0026] In a preferred embodiment of the present invention, the composition contains 2-5% meloxicam, 0.3-2% stabilizer, 4-6% suspending agent, and the balance being water, by mass-volume percentage. The particle size of the meloxicam nanocrystals is ≤75nm.

[0027] In a preferred embodiment of the present invention, the composition contains, by mass-volume percentage, 1-10% meloxicam, 0.1-1% PVPK17 PF, 0.1-1% sodium deoxycholate, and 1-10% sucrose, with the balance being water, and the particle size of the meloxicam nanocrystals is ≤75nm.

[0028] In a preferred embodiment of the present invention, the composition contains, by mass-volume percentage, 2-5% meloxicam, 0.6-1% PVPK17 PF, 0.3-0.5% sodium deoxycholate, and 2-8% sucrose, with the balance being water, and the particle size of the meloxicam nanocrystals is ≤75nm.

[0029] In a preferred embodiment of the present invention, the composition contains, by mass-volume percentage, 3% meloxicam, 0.9% PVPK17 PF, 0.3% sodium deoxycholate, and 6% sucrose, with the balance being water, and the particle size of the meloxicam nanocrystals is ≤75nm.

[0030] In a preferred embodiment of the present invention, the PDI of the meloxicam nanocrystals is ≤0.5, preferably ≤0.4, and more preferably ≤0.35.

[0031] In a preferred embodiment of the present invention, the meloxicam nanocrystals have D10≤50nm, D10≤100nm, and D90≤200nm.

[0032] In a preferred embodiment of the present invention, the meloxicam nanocrystal composition has a particle size ≤100nm, preferably ≤95nm, and more preferably ≤80nm after being placed at room temperature (20-25°C) for 30 days.

[0033] In a preferred embodiment of the present invention, the meloxicam nanocrystal composition has a particle size ≤120nm, preferably ≤100nm, and more preferably ≤95nm after being placed at 40°C for 40 days.

[0034] Another object of the present invention is to provide the use of the meloxicam nanocrystal composition of the present invention in the preparation of a medicament for treating any of the following conditions or complications: rheumatoid arthritis or osteoarthritis, postoperative analgesia, and fever reduction.

[0035] In a preferred embodiment of the present invention, the disease is selected from any one of arthritis, inflammatory disease, pain, fever, inflammation-related cardiovascular disease, joint stiffness, bronchitis, allergic neuritis, and back pain.

[0036] In a preferred embodiment of the present invention, the analgesia is selected from any one of the following: analgesia after abdominoplasty, colorectal surgery, bunion resection, total knee replacement, and arthroscopic surgery.

[0037] Unless otherwise stated, when this invention relates to percentages between liquids, the percentage is volume / volume percentage; when this invention relates to percentages between liquids and solids, the percentage is volume / weight percentage; when this invention relates to percentages between solids and liquids, the percentage is weight / volume percentage; the remainder is weight / weight percentage.

[0038] Unless otherwise stated, the present invention uses a ball mill (WAB AK71M-2WKF, Switzerland) for grinding and a nanoparticle size analyzer (Nano-ZS90, Malvern, UK) for particle size measurement.

[0039] Compared with the prior art, the present invention has the following beneficial technical effects:

[0040] 1. This invention scientifically screens the components, proportions, and process parameters of meloxicam nanocrystal compositions. The prepared meloxicam nanocrystal compositions (particle size ≤ 80 nm) have advantages such as no need for carrier materials, easy industrialization, diversified dosage forms, and significantly improved solubility and bioavailability of poorly soluble drugs. It also significantly improves the stability and bioavailability of meloxicam nanocrystals, significantly shortens the analgesic onset time, prolongs the analgesic duration, improves drug quality and patient compliance, and ensures safe and effective clinical use.

[0041] 2. The wet media milling (WMM) method of the present invention uses the high-energy shear force generated by the collision between the drug, the grinding media and the grinding chamber to break the drug particles, resulting in smaller drug particles with a narrower particle size distribution. It has the advantages of simple operation, significantly shortened production cycle, significant cost-effectiveness and suitability for large-scale industrial production. Attached Figure Description

[0042] Figure 1 Stability study of the meloxicam nanocrystalline composition of the present invention;

[0043] Figure 2 Bioavailability study of the meloxicam nanocrystal composition of the present invention. Detailed Implementation

[0044] The present invention will be described below with reference to the embodiments, but the present invention is not limited to the embodiments.

[0045] Example 1 Preparation of meloxicam nanocrystal compositions

[0046] Formulation of meloxicam nanocrystal composition:

[0047]

[0048] The preparation of the meloxicam nanocrystal composition includes the following steps:

[0049] (1) Weigh the required amount of PVPK17 PF, dissolve it in 95ml of water, add the required amount of meloxicam, and place it under high-speed shearing at 25-35℃ and 3000rpm for 3min to obtain a shearing mixture.

[0050] (2) Using grinding beads with a particle size of 0.1 mm as the grinding medium, the prepared shear suspension was ground at 25-35℃ and 1500-3500 rpm for 40 min. The grinding speed was gradually increased from 1500 rpm to 3500 rpm and then gradually decreased to 1500 rpm. The grinding speed was increased or decreased by 500 rpm every 5 min. The required amount of sodium deoxycholate solution was added, and the mixture was ground at 1500 rpm for 60 min. The required amount of sucrose solution was added, and water was added to make up to 400 ml.

[0051] Example 2 Preparation of meloxicam nanocrystal compositions

[0052] Formulation of meloxicam nanocrystal composition:

[0053]

[0054]

[0055] The preparation of the meloxicam nanocrystal composition includes the following steps:

[0056] (1) Weigh the required amount of PVPK17 PF, dissolve it in 95 mL of water, add the required amount of meloxicam, and place it under high-speed shearing at 25-35℃ and 3000 rpm for 3 min to obtain a shearing mixture.

[0057] (2) Using grinding beads with a particle size of 0.1 mm as the grinding medium, the prepared shear suspension was ground at 25-35℃ and 1500-3500 rpm for 35 min. The grinding speed was gradually increased from 1500 rpm to 3500 rpm and then decreased to 2000 rpm. The grinding speed was increased or decreased by 500 rpm every 5 min. Then, sodium deoxycholate solution was added, and the grinding was continued at 2000 rpm for 60 min. The required amount of sucrose solution was added, and water was added to make up to 400 ml.

[0058] Example 3 Preparation of meloxicam nanocrystal compositions

[0059] Formulation of meloxicam nanocrystal composition:

[0060]

[0061] The preparation of the meloxicam nanocrystal composition includes the following steps:

[0062] (1) Weigh the required amount of PVPK17 PF, dissolve it in 95 mL of water, add the required amount of meloxicam, and place it under high-speed shearing at 25-35℃ and 3000 rpm for 3 min to obtain a shearing mixture.

[0063] (2) Using grinding beads with a particle size of 0.1 mm as the grinding medium, the prepared shear suspension was ground at 25-35℃ and 1500-3500 rpm for 30 min, wherein the grinding speed was gradually increased from 1500 rpm to 3500 rpm and then decreased to 2500 rpm, wherein the grinding speed was increased or decreased by 500 rpm every 5 min. Sodium deoxycholate solution was added, and the grinding was continued at 2500 rpm for 60 min. The required amount of sucrose solution was added, and water was added to make up to 400 ml.

[0064] Example 4 Preparation of meloxicam nanocrystal compositions

[0065] Formulation of meloxicam nanocrystal composition:

[0066]

[0067] The preparation of the meloxicam nanocrystal composition includes the following steps:

[0068] (1) Weigh the required amount of PVPK17 PF, dissolve it in 95 mL of water, add the required amount of meloxicam, and place it under high-speed shearing at 25-35℃ and 3000 rpm for 3 min to obtain a shearing mixture.

[0069] (2) Using grinding beads with a particle size of 0.1 mm as the grinding medium, the prepared shear suspension was ground at 25-35℃ and 1500-3500 rpm for 25 min. The grinding speed was gradually increased from 1500 rpm to 3500 rpm and then decreased to 3000 rpm. The grinding speed was increased or decreased by 500 rpm every 5 min. Then, sodium deoxycholate solution was added, and the grinding was continued at 3000 rpm for 60 min. The required amount of sucrose solution was added, and water was added to make up to 400 ml.

[0070] Comparative Example 1 Preparation of meloxicam nanocrystal compositions

[0071] Formulation of meloxicam nanocrystal composition:

[0072]

[0073] The preparation of the meloxicam nanocrystal composition includes the following steps:

[0074] (1) Weigh the required amount of PVPK17 PF, dissolve it in 95 mL of water, add the required amount of meloxicam and sodium deoxycholate, and then place it under high-speed shearing at 25-35℃ and 3000 rpm for 3 min to obtain a shearing mixture.

[0075] (2) Using grinding beads with a particle size of 0.1 mm as the grinding medium, the prepared shear suspension is ground at 25-35℃ and 1500 rpm for 60 min, the required amount of sucrose solution is added, and water is added to make up to 400 ml.

[0076] Comparative Example 2 Preparation of meloxicam nanocrystal compositions

[0077] Composition of the meloxicam nanocrystal composition:

[0078]

[0079]

[0080] The preparation of the meloxicam nanocrystal composition includes the following steps:

[0081] (1) Weigh the required amount of PVPK17 PF, dissolve it in 95 mL of water, add the required amount of meloxicam, and place it under high-speed shearing at 25-35℃ and 3000 rpm for 3 min to obtain a shearing mixture.

[0082] (2) Using grinding beads with a particle size of 0.1-0.3 mm as the grinding medium, the prepared shear suspension is ground at 25-35℃ and 1500 rpm for 60 min. The required amount of mixed solution (1.2 g sodium deoxycholate and 24 g sucrose dissolved in 280 mL of water) is added and the volume is adjusted to 400 mL with water.

[0083] Experimental Example 1 Stability study of meloxicam nanocrystalline compositions

[0084] Take 10 ml of the meloxicam nanocrystal composition prepared in Examples 1-2 and Comparative Examples 1-2, put it into a test tube, and use a Nano-ZS90 particle size analyzer to observe the particle size, PDI and changes after being placed at room temperature (20-25℃) for 0 days (see Table 1), 3 days, 7 days, 15 days and 30 days (see Table 1). Figure 1 The meloxicam nanocrystal compositions prepared in Examples 1-2 showed no stratification or crystallization, and the particle size and PDI remained stable.

[0085] Table 1 Nanocrystal particle size on day 0

[0086]

[0087]

[0088] Experimental Example 2 Stability study of meloxicam nanocrystalline compositions

[0089] 10 ml of the meloxicam nanocrystalline composition prepared in Example 1 was placed in a test tube, and the particle size and changes were observed using a Nano-ZS90 particle size analyzer after being left to stand naturally at 40°C for 0, 10, 20, and 40 days. The meloxicam nanocrystalline composition prepared in Example 1 showed no stratification or crystallization. The results are shown in Table 2.

[0090] Table 2. Variation of nanocrystal size

[0091] Time (d) Particle size / nm 0 72.83 10 84.03 20 92.87 40 93.60

[0092] Experimental Example 3 Bioavailability study of meloxicam nanocrystal compositions

[0093] Twenty male SD rats weighing 200g ± 5g were randomly divided into two groups of ten each. The experimental group received a tail vein injection of the meloxicam nanocrystal composition described in Example 1; the control group received a tail vein injection of commercially available meloxicam nanocrystals (300nm particle size). Following the tail vein injection, 0.5ml of blood was collected from the orbital sinus at 1 min, 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h, 48 h, and 72 h. The blood was centrifuged at 4000 rpm for 10 min, and the supernatant was collected and frozen. The plasma drug concentration was determined using LC-MS. The results are shown in Table 3 and [Table data missing]. Figure 2 The meloxicam nanocrystal composition of the present invention has significantly better bioavailability.

[0094] Table 3

[0095]

[0096] The above description of specific embodiments of the present invention does not limit the present invention. Those skilled in the art can make various changes or modifications based on the present invention, and as long as they do not depart from the spirit of the present invention, they should all fall within the scope of protection of the claims of the present invention.

Claims

1. A meloxicam nanocrystalline composition, comprising, by mass-volume percentage, 1-10% meloxicam, 0.1-1% PVPK17 PF, 0.1-1% sodium deoxycholate, and 1-10% sucrose, with the balance being water, wherein the meloxicam nanocrystalline particles have a particle size ≤80 nm, and the preparation method of the meloxicam nanocrystalline composition comprises the following steps: (1) Weigh the required amount of PVPK17, dissolve it in water, add the required amount of meloxicam, stir it at 25-35℃ and 500-1500rpm for 30-60min, and then shear it at 1000-3500rpm for 1-10min to obtain a shearing mixture. (2) Using grinding beads with a particle size of 0.1-0.3 mm as the grinding medium, the prepared shear suspension is ground at 25-35℃ and 1500-3500 rpm for 30-60 min. Then, sodium deoxycholate is added, and the mixture is ground again at 25-35℃ and 1500-3500 rpm for 30-60 min. Finally, sucrose is added and mixed to obtain the final product. The grinding speed was gradually increased from 1500 rpm to 3500 rpm and then decreased to 1500-3000 rpm. The grinding speed was increased or decreased by 500 rpm every 5 minutes.

2. The nanocrystalline composition according to claim 1, wherein, by mass-volume percentage, the composition contains 2-5% meloxicam, 0.6-1% PVPK17 PF, 0.3-0.5% sodium deoxycholate, and 2-8% sucrose, with the balance being water, and the particle size of the meloxicam nanocrystals is ≤75nm.

3. The nanocrystalline composition of claim 2, wherein, by mass-volume percentage, the composition contains 3% meloxicam, 0.9% PVPK17 PF, 0.3% sodium deoxycholate, and 6% sucrose, with the balance being water, and the particle size of the meloxicam nanocrystals is ≤75nm.

4. The nanocrystalline composition of claim 3, wherein the PDI of the meloxicam nanocrystals is ≤0.

5.

5. The nanocrystalline composition of claim 4, wherein the PDI of the meloxicam nanocrystals is ≤0.

4.

6. The nanocrystalline composition of claim 5, wherein the PDI of the meloxicam nanocrystals is ≤0.

35.

7. The nanocrystalline composition of claim 1, wherein the meloxicam nanocrystals have D10≤50nm, D50≤100nm, and D90≤200nm.

8. The nanocrystalline composition according to any one of claims 1-7, wherein the meloxicam nanocrystalline composition has a particle size ≤100nm after being placed at room temperature (20-25°C) for 30 days.

9. The nanocrystalline composition of claim 8, wherein the meloxicam nanocrystalline composition has a particle size ≤95nm after being placed at room temperature (20-25°C) for 30 days.

10. The nanocrystalline composition of claim 9, wherein the meloxicam nanocrystalline composition has a particle size ≤80nm after being placed at room temperature (20-25°C) for 30 days.

11. The nanocrystalline composition according to any one of claims 1-7, wherein the meloxicam nanocrystalline composition has a particle size ≤120nm after being placed at 40°C for 40 days.

12. The nanocrystalline composition of claim 11, wherein the meloxicam nanocrystalline composition has a particle size of 100 nm after being placed at 40°C for 40 days.

13. The nanocrystalline composition of claim 12, wherein the meloxicam nanocrystalline composition has a particle size ≤95nm after being placed at 40°C for 40 days.

14. A method for preparing the meloxicam nanocrystalline composition according to any one of claims 1-13, wherein the preparation method comprises the following steps: (1) Weigh the required amount of PVPK17, dissolve it in water, add the required amount of meloxicam, stir it at 25-35℃ and 500-1500rpm for 30-60min, and then shear it at 1000-3500rpm for 1-10min to obtain a shearing mixture. (2) Using grinding beads with a particle size of 0.1-0.3 mm as the grinding medium, the prepared shear suspension is ground at 25-35℃ and 1500-3500 rpm for 30-60 min. Then, sodium deoxycholate is added, and the mixture is ground again at 25-35℃ and 1500-3500 rpm for 30-60 min. Finally, sucrose is added and mixed to obtain the final product. The grinding speed was gradually increased from 1500 rpm to 3500 rpm and then decreased to 1500-3000 rpm. The grinding speed was increased or decreased by 500 rpm every 5 minutes.

15. The method as described in claim 14, wherein the stirring speed in step (1) is 600-1200 rpm, the high-speed shearing speed is 2000-3000 rpm, and the high-speed shearing time is 3-10 min.

16. The method as described in claim 15, wherein the stirring speed in step (1) is 800-1000 rpm, the high-speed shearing speed is 2000-3000 rpm, and the high-speed shearing time is 3-10 min.

17. The method as described in claim 14, wherein the grinding speed in step (2) is increased from 1500 rpm to 3500 rpm and then decreased to 1500 rpm, and the grinding speed is increased or decreased by 500 rpm every 5 minutes.

18. The method as described in claim 14, wherein the grinding speed in step (2) is first increased from 1500 rpm to 3500 rpm and then decreased to 2000 rpm, and the grinding speed is increased or decreased by 500 rpm every 5 minutes.

19. The method as described in claim 14, wherein the grinding speed in step (2) is first increased from 1500 rpm to 3500 rpm and then decreased to 2500 rpm, and the grinding speed is increased or decreased by 500 rpm every 5 minutes.

20. The method as described in claim 14, wherein the grinding speed in step (2) is first increased from 1500 rpm to 3500 rpm and then decreased to 3000 rpm, and the grinding speed is increased or decreased by 500 rpm every 5 minutes.

21. The use of the meloxicam nanocrystal composition as described in claims 1-13 or the meloxicam nanocrystal composition prepared by the preparation method as described in any one of claims 14-20 in the preparation of a medicament for treating any one of the following conditions: rheumatoid arthritis or osteoarthritis, postoperative analgesia, or antipyresis.

22. The application as described in claim 21, wherein the analgesia is selected from any one of the following: analgesia after abdominoplasty, colorectal surgery, bunionectomy, total knee replacement, or arthroscopic surgery.

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