Cyclic mandelate-tenoxicam spherical composite particle and preparation method thereof

Abstract

The invention belongs to the technical field of crystallization in chemical engineering industry, and provides a cyclomandelate-tenoxicam spherical composite particle and a preparation method thereof, and the preparation method comprises the following steps: mixing cyclomandelate and water, heating, and stirring until liquid-liquid phase separation occurs to obtain a cyclomandelate-water solution; adding tenoxicam into the cyclomandelate-water solution, mixing and stirring to obtain a mixed solution; cooling the mixed solution and continuously stirring; and adding a surfactant into the cooled solution, mixing and stirring until crystals appear, and sequentially filtering, washing and drying to obtain the cyclomandelate-tenoxicam spherical composite particles. The prepared cyclomandelate-tenoxicam spherical composite particle crystal is smooth in surface and high in roundness, the average particle size of the cyclomandelate-tenoxicam spherical composite particle ranges from 1322 micrometers to 1720 micrometers, the angle of repose ranges from 26 degrees to 29 degrees, and the tap density ranges from 0.47 g / cm < 3 > to 0.51 g / cm < 3 >.

Description

Technical Field

[0001] The present invention relates to the technical field of crystallization technology in the chemical engineering industry, and particularly relates to a cyclandelate-tenoxicam spherical composite particle and a preparation method thereof. Background Art

[0002] Tenoxicam (CAS: 59804-37-4), with the chemical name of 4-hydroxy-2-methyl-N-2-pyridin-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide 1,1-dioxide, has the molecular formula of C 13 H 11 N3O4S2, and the structural formula is Tenoxicam is a new type of antipyretic and analgesic drug, which is a yellow crystalline powder. Tenoxicam is almost insoluble in water, slightly soluble in dichloromethane, very slightly soluble in absolute ethanol, and soluble in acid and alkali solutions. Tenoxicam belongs to non-steroidal anti-inflammatory drugs and is a long-acting antipyretic, analgesic, and anti-inflammatory drug. It is used to treat rheumatoid arthritis, rheumatic fever, rheumatic arthritis and other diseases, and has remarkable effects such as rapid oral absorption and quick onset. The pain can be relieved half an hour after administration. However, long-term use will cause abdominal pain, nausea, indigestion, vomiting, and even damage liver function.

[0003] Cyclandelate (CAS: 456-59-7), with the chemical name of 3,3,5-trimethylcyclohexyl mandelate, has the molecular formula of C 17 H 24 O3, and the structural formula is It is a fat-soluble vasodilator, and its effect is similar to that of papaverine. It is usually a white crystalline powder. Cyclandelate is extremely soluble in ethanol or acetone and almost insoluble in water. Pharmacological studies have shown that cyclandelate can directly relax vascular smooth muscle, dilate blood vessels, and its vasodilatory effect has a certain specificity. It significantly dilates the blood vessels of the brain, kidneys, extremities and coronary arteries, increases blood flow, and promotes blood circulation. Its effect is slightly weaker than that of papaverine but more persistent.

[0004] As two important pharmaceutically active ingredients, cyclandelate and tenoxicam have extensive applications in the fields of anti - inflammation, analgesia, etc. However, in the prior art, the development of their compound preparations faces multiple challenges and there are few reports. The patent with the publication number CN105949212A discloses a pharmaceutical composition preparation of cyclandelate and a compound with a specific structure, which can improve the therapeutic effect on cervical cancer; the patent with the publication number CN108451956A discloses a pharmaceutical composition, specifically including a class of tenoxicam and other oxicam - type pharmaceutically active ingredients and (1r,4r)-6'-fluoro - N,N - dimethyl - 4 - phenyl - 4',9'-dihydro - 3'H - spiro[cyclohexane - 1,1'-pyrano[3,4,b]indole]-4 - amine and its salts as pharmaceutically active ingredients. This pharmaceutical composition can exert the synergistic effect of these two pharmaceutically active compounds and effectively prevent or treat pain, but there are few reports on the compound preparation of cyclandelate and tenoxicam. In addition, the cyclandelate - tenoxicam compound drugs in the prior art are all physical mixtures of finished products. The particle size distribution range of the formed drug compound particles is wide and difficult to accurately control. The uncontrollability of the particle size may cause unstable drug release rate and reduce bioavailability.

[0005] Therefore, there is an urgent technical need to develop a preparation method of cyclandelate - tenoxicam composite particles that is green and environmentally friendly, has a simple process, controllable particle size, and excellent particle morphology. Summary of the Invention

[0006] The object of the present invention is to provide a cyclandelate - tenoxicam spherical composite particle and its preparation method. The spherical crystals prepared by the above method have round crystal particles and high fluidity, and are suitable for large - scale continuous production.

[0007] In order to achieve the above - mentioned invention object, the present invention provides the following technical solutions:

[0008] The present invention provides a preparation method of cyclandelate - tenoxicam spherical composite particles, which comprises the following steps:

[0009] (1) Mix cyclandelate and water, heat and stir until liquid - liquid phase separation occurs to obtain a cyclandelate - aqueous solution;

[0010] (2) Add tenoxicam to the cyclandelate - aqueous solution, mix and stir to obtain a mixed solution;

[0011] (3) Cool the mixed solution and continue to stir;

[0012] (4) Add a surfactant to the cooled solution, mix and stir until crystallization occurs, and then filter, wash and dry in sequence to obtain the cyclandelate - tenoxicam spherical composite particles.

[0013] Preferably, the temperature of mixing in step (1) is 50 to 80 °C;

[0014] In step (1), the concentration of cyclandelate-aqueous solution is 0.01 to 0.05 g / mL.

[0015] Preferably, in step (2), the concentration of tenoxicam in the mixed solution is 0.001 to 0.005 g / mL.

[0016] Preferably, in step (3), the cooling rate is 40 to 45 °C / 10 min, and the temperature is cooled to 5 to 25 °C.

[0017] Preferably, in step (4), the surfactant is one of sodium stearate, sodium hexametaphosphate, sodium dodecylbenzenesulfonate, and sodium dodecyl sulfate.

[0018] Preferably, in step (4), the addition amount of the surfactant is 0.05 to 0.1% of the mass fraction of the mixed solution.

[0019] Preferably, in step (4), the stirring time is 0.5 to 3 h.

[0020] Preferably, in step (4), the washing solvent is water;

[0021] In step (4), the drying temperature is 30 to 40 °C, and the drying time is 12 to 24 h.

[0022] The present invention also provides cyclandelate-tenoxicam spherical composite particles obtained by the described preparation method.

[0023] The present invention has the following beneficial effects:

[0024] 1. In the whole process of the present invention, water is used as the only solvent, abandoning the use of traditional organic solvents, avoiding the emission and residue of toxic and harmful substances, conforming to the concept of green chemistry, and at the same time reducing the production cost and the burden of environmental governance.

[0025] 2. Through the synergistic effect of liquid-liquid phase separation and rapid cooling crystallization, the present invention can efficiently complete drug compounding and the formation of spherical crystals, without multiple solvent replacements or complex equipment, significantly shortening the production cycle and reducing energy consumption.

[0026] 3. The cyclandelate-tenoxicam spherical composite particle crystals prepared by the present invention have a smooth surface, high roundness, excellent fluidity, and the particle size of the product can be effectively adjusted by the stirring rate.

[0027] 4. The spherical structure and uniform particle size distribution of the product obtained by the present invention are beneficial to realizing the synchronous release of the drug, avoiding the phenomena of sudden release or lag, thereby improving the bioavailability and clinical efficacy.

[0028] 5. The process of the present invention is simple, suitable for large-scale continuous production, and has significant economic benefits and application prospects. Description of the Drawings

[0029] Figure 1 SEM image of the cyclandelate spherical crystals of Example 1. Detailed Description of the Invention

[0030] The present invention provides a method for preparing cyclandelate-tenoxicam spherical composite particles, comprising the following steps:

[0031] (1) Mix cyclandelate and water, heat and stir until liquid-liquid phase separation occurs to obtain a cyclandelate-aqueous solution;

[0032] (2) Add tenoxicam to the cyclandelate-aqueous solution, mix and stir to obtain a mixed solution;

[0033] (3) Cool the mixed solution and continue stirring;

[0034] (4) Add a surfactant to the cooled solution, mix and stir until crystallization occurs, and then filter, wash and dry in sequence to obtain the cyclandelate-tenoxicam spherical composite particles.

[0035] In the present invention, the mixing temperature in step (1) is preferably 50-80°C, more preferably 55-75°C, and even more preferably 60-70°C.

[0036] In the present invention, the concentration of the cyclandelate-aqueous solution in step (1) is preferably 0.01-0.05 g / mL, more preferably 0.015-0.045 g / mL, and even more preferably 0.02-0.04 g / mL.

[0037] In the present invention, the concentration of tenoxicam in the mixed solution in step (2) is preferably 0.001-0.005 g / mL, more preferably 0.0015-0.0045 g / mL, and even more preferably 0.002-0.004 g / mL.

[0038] In the present invention, the cooling rate in step (3) is preferably 40-45°C / 10 min, more preferably 40.5-44.5°C / min, and even more preferably 41-44°C / min.

[0039] In the present invention, the cooling is preferably to 5-25°C, more preferably to 7-23°C, and even more preferably to 10-20°C.

[0040] In the present invention, the surfactant in the step (4) is preferably one of sodium stearate, sodium hexametaphosphate, sodium dodecylbenzenesulfonate and sodium dodecyl sulfate.

[0041] In the present invention, the addition amount of the surfactant in the step (4) is preferably 0.05-0.1% of the mass fraction of the mixed solution, more preferably 0.06-0.09%, and even more preferably 0.07-0.08%.

[0042] In the present invention, the stirring time in the step (4) is preferably 0.5-3 h, more preferably 1-2.5 h, and even more preferably 1.5-2 h.

[0043] In the present invention, after adding the surfactant, the stirred crystals aggregate into a compact sphere, and then are sequentially filtered, washed and dried to obtain the cyclandelate-tenoxicam spherical composite particles.

[0044] In the present invention, the washing solvent is preferably water.

[0045] In the present invention, the drying temperature in the step (4) is preferably 30-40 °C, more preferably 32-38 °C, and even more preferably 34-36 °C.

[0046] In the present invention, the drying time is preferably 12-24 h, more preferably 14-22 h, and even more preferably 16-20 h.

[0047] The present invention also provides cyclandelate-tenoxicam spherical composite particles obtained by the preparation method described above.

[0048] The technical solutions provided by the present invention will be described in detail below with reference to the examples, but they should not be construed as limiting the protection scope of the present invention.

[0049] Example 1

[0050] Cyclomandelate and 200 mL of water are mixed and heated at 60° C. and stirred at a rate of 600 rpm until liquid-liquid phase separation occurs and cyclomandelate droplets are dispersed in water to obtain a cyclomandelate-water solution with a concentration of 0.02 g / mL. The temperature and stirring rate are kept constant, tenoxicam is added to the cyclomandelate-water solution, and stirring is continued for 0.5 h to allow the tenoxicam particles and cyclomandelate oil droplets to fully contact to obtain a mixed solution, wherein the concentration of tenoxicam is 0.0025 g / mL, the mixed solution is cooled to 10° C. at a rate of 40° C. / 10 min, and continued to be stirred uniformly at a rate of 600 rpm; at this temperature, 0.08% sodium dodecyl sulfate (based on the mass of the mixed solution) is added, mixed and stirred for 1.5 h until crystals appear, so that the crystals agglomerate into compact particles, and vacuum filtration, washing with water, and drying at 30° C. for 12 h are successively performed to obtain the cyclomandelate-tenoxicam spherical composite particles.

[0051] The product obtained in this example was tested by X-ray diffractometer. The product prepared in this example was a stable crystal with round crystal particles and high fluidity. The average particle size of the spherical particles was 1524 μm, the angle of repose was 29°, and the tap density was 0.48 g / cm 3 .

[0052] The spherical crystals of cyclomandelate obtained in this example were scanned by a scanning electron microscope. Figure 1 shown.

[0053] from Figure 1 It can be seen that the crystal morphology of the product obtained in this example has been greatly improved.

[0054] Example 2

[0055] Cyclomandelate and 200 mL of water are mixed and heated at 60° C. and stirred at a rate of 600 rpm until liquid-liquid phase separation occurs and cyclomandelate droplets are dispersed in water to obtain a cyclomandelate-water solution with a concentration of 0.02 g / mL. The temperature and stirring rate are kept unchanged, tenoxicam is added to the cyclomandelate-water solution, and stirring is continued for 0.5 h to allow the tenoxicam particles and cyclomandelate oil droplets to fully contact to obtain a mixed solution, wherein the concentration of tenoxicam is 0.0025 g / mL, the mixed solution is cooled to 10° C. at a rate of 40° C. / 10 min, and continued to be stirred uniformly at a rate of 600 rpm; at this temperature, 0.08% sodium hexametaphosphate (based on the mass of the mixed solution) is added, mixed and stirred for 1.5 h until crystals appear, so that the crystals agglomerate into compact particles, and vacuum filtration, washing with water, and drying at 30° C. for 12 h are successively performed to obtain the cyclomandelate-tenoxicam spherical composite particles.

[0056] The same test method as in Example 1 was used for the cyclandelate-tenoxicam spherical composite particles obtained in this example. It was found that the average particle size of the obtained spherical composite particles was 1322 μm, the angle of repose was 28°, and the tapped density was 0.50 g / cm 3 .

[0057] Example 3

[0058] Cyclandelate and 200 mL of water were mixed and heated at 60 °C and stirred at a rate of 600 rpm until liquid-liquid phase separation occurred and the cyclandelate droplets were dispersed in water to obtain a cyclandelate-aqueous solution with a concentration of 0.02 g / mL. Keeping the temperature and stirring rate unchanged, tenoxicam was added to the cyclandelate-aqueous solution and stirring was continued for 0.5 h to allow the tenoxicam particles and cyclandelate oil droplets to come into full contact to obtain a mixed solution, in which the concentration of tenoxicam was 0.0025 g / mL. The mixed solution was cooled to 10 °C at a rate of 40 °C / 10 min and stirring was continued at a rate of 600 rpm until homogeneous; 0.08% (based on the mass of the mixed solution) of sodium dodecylbenzenesulfonate was added at this temperature, mixed and stirred for 1.5 h until crystallization occurred, and the crystals were aggregated into compact particles. Sequentially, vacuum filtration, washing with water, and drying at 30 °C for 12 h were carried out to obtain the cyclandelate-tenoxicam spherical composite particles.

[0059] The same test method as in Example 1 was used for the cyclandelate-tenoxicam spherical composite particles obtained in this example. It was found that the average particle size of the obtained spherical composite particles was 1550 μm, the angle of repose was 29°, and the tapped density was 0.49 g / cm 3 .

[0060] Example 4

[0061] Cyclandelate and 200 mL of water were mixed and heated at 60 °C and stirred at a rate of 600 rpm until liquid-liquid phase separation occurred and the cyclandelate droplets were dispersed in water to obtain a cyclandelate-aqueous solution with a concentration of 0.02 g / mL. Keeping the temperature and stirring rate unchanged, tenoxicam was added to the cyclandelate-aqueous solution and stirring was continued for 0.5 h to allow the tenoxicam particles and cyclandelate oil droplets to come into full contact to obtain a mixed solution, in which the concentration of tenoxicam was 0.0025 g / mL. The mixed solution was cooled to 5 °C at a rate of 40 °C / 10 min and stirring was continued at a rate of 600 rpm until homogeneous; 0.08% (based on the mass of the mixed solution) of sodium stearate was added at this temperature, mixed and stirred for 1.5 h until crystallization occurred, and the crystals were aggregated into compact particles. Sequentially, vacuum filtration, washing with water, and drying at 30 °C for 12 h were carried out to obtain the cyclandelate-tenoxicam spherical composite particles.

[0062] The same test method as in Example 1 was used for the cyclandelate-tenoxicam spherical composite particles obtained in this example. It was found that the average particle size of the obtained spherical composite particles was 1426 μm, the angle of repose was 27°, and the tapped density was 0.51 g / cm 3 .

[0063] Example 5

[0064] Cyclandelate and 200 mL of water were mixed and heated at 50 °C and stirred at a rate of 700 rpm until liquid-liquid phase separation occurred and the cyclandelate droplets were dispersed in water to obtain a cyclandelate-aqueous solution with a concentration of 0.01 g / mL. Keeping the temperature and stirring rate unchanged, tenoxicam was added to the cyclandelate-aqueous solution and stirring was continued for 1 h to allow the tenoxicam particles and cyclandelate oil droplets to come into full contact to obtain a mixed solution, in which the concentration of tenoxicam was 0.001 g / mL. The mixed solution was cooled to 5 °C at a rate of 40 °C / 10 min and stirring was continued at a rate of 700 rpm until homogeneous; 0.05% (based on the mass of the mixed solution) of sodium stearate was added at this temperature, mixed and stirred for 0.5 h until crystallization occurred, and the crystals were aggregated into compact particles. Sequentially, vacuum filtration was carried out, followed by washing with water and drying at 30 °C for 12 h to obtain the cyclandelate-tenoxicam spherical composite particles.

[0065] The same test method as in Example 1 was used for the cyclandelate-tenoxicam spherical composite particles obtained in this example. It was found that the average particle size of the obtained spherical composite particles was 1645 μm, the angle of repose was 26°, and the tapped density was 0.49 g / cm 3 .

[0066] Example 6

[0067] Cyclandelate and 200 mL of water were mixed and heated at 80 °C and stirred at a rate of 700 rpm until liquid-liquid phase separation occurred and the cyclandelate droplets were dispersed in water to obtain a cyclandelate-aqueous solution with a concentration of 0.05 g / mL. Keeping the temperature and stirring rate unchanged, tenoxicam was added to the cyclandelate-aqueous solution and stirring was continued for 0.8 h to allow the tenoxicam particles and cyclandelate oil droplets to come into full contact to obtain a mixed solution, in which the concentration of tenoxicam was 0.005 g / mL. The mixed solution was cooled to 25 °C at a rate of 45 °C / 10 min and stirring was continued at a rate of 700 rpm until homogeneous; 0.1% (based on the mass of the mixed solution) of sodium stearate was added at this temperature, mixed and stirred for 3 h until crystallization occurred, and the crystals were aggregated into compact particles. Sequentially, vacuum filtration was carried out, followed by washing with water and drying at 40 °C for 24 h to obtain the cyclandelate-tenoxicam spherical composite particles.

[0068] The same test method as in Example 1 was used for the cyclandelate-tenoxicam spherical composite particles obtained in this example. It was found that the average particle size of the obtained spherical composite particles was 1711 μm, the angle of repose was 29°, and the tapped density was 0.48 g / cm 3 .

[0069] Example 7

[0070] Cyclandelate and 200 mL of water were mixed and heated at 60 °C and stirred at a rate of 500 rpm until liquid-liquid phase separation occurred and the cyclandelate droplets were dispersed in water to obtain a cyclandelate-aqueous solution with a concentration of 0.02 g / mL. Keeping the temperature and stirring rate unchanged, tenoxicam was added to the cyclandelate-aqueous solution and stirring was continued for 0.5 h to allow the tenoxicam particles and cyclandelate oil droplets to come into full contact, obtaining a mixed solution in which the concentration of tenoxicam was 0.0025 g / mL. The mixed solution was cooled to 10 °C at a rate of 40 °C / 10 min and stirring was continued at a rate of 500 rpm until homogeneous; 0.08% (based on the mass of the mixed solution) of sodium dodecyl sulfate was added at this temperature, mixed and stirred for 1.5 h until crystallization occurred, and the crystals were aggregated into compact particles. Sequentially, vacuum filtration was carried out, followed by washing with water and drying at 30 °C for 12 h to obtain the cyclandelate-tenoxicam spherical composite particles.

[0071] The same test method as in Example 1 was used for the cyclandelate-tenoxicam spherical composite particles obtained in this example. It was found that the average particle size of the obtained spherical composite particles was 1720 μm, the angle of repose was 27°, and the tapped density was 0.47 g / cm 3 .

[0072] Example 8

[0073] Cyclandelate and 200 mL of water were mixed and heated at 70 °C and stirred at a rate of 600 rpm until liquid-liquid phase separation occurred and the cyclandelate droplets were dispersed in water to obtain a cyclandelate-aqueous solution with a concentration of 0.02 g / mL. Keeping the temperature and stirring rate unchanged, tenoxicam was added to the cyclandelate-aqueous solution and stirring was continued for 0.5 h to allow the tenoxicam particles and cyclandelate oil droplets to come into full contact, obtaining a mixed solution in which the concentration of tenoxicam was 0.0025 g / mL. The mixed solution was cooled to 5 °C at a rate of 40 °C / 10 min and stirring was continued at a rate of 600 rpm until homogeneous; 0.08% (based on the mass of the mixed solution) of sodium dodecyl sulfate was added at this temperature, mixed and stirred for 2 h until crystallization occurred, and the crystals were aggregated into compact particles. Sequentially, vacuum filtration was carried out, followed by washing with water and drying at 30 °C for 12 h to obtain the cyclandelate-tenoxicam spherical composite particles.

[0074] Using the same test method as in Example 1 for the cyclandelate-tenoxicam spherical composite particles obtained in this example, it can be known that the average particle size of the obtained spherical composite particles is 1693 μm, the angle of repose is 28°, and the tapped density is 0.49 g / cm 3 .

[0075] As can be seen from the above examples, the present invention provides a cyclandelate-tenoxicam spherical composite particle and a preparation method thereof, comprising the following steps: mixing cyclandelate and water, heating and stirring until liquid-liquid phase separation occurs to obtain a cyclandelate-aqueous solution; adding tenoxicam into the cyclandelate-aqueous solution, mixing and stirring to obtain a mixed solution; cooling the mixed solution and continuing to stir; adding a surfactant into the cooled solution, mixing and stirring until crystallization occurs, and then sequentially filtering, washing and drying to obtain the cyclandelate-tenoxicam spherical composite particle. The entire process of the present invention uses water as the only solvent, abandons the use of traditional organic solvents, avoids the emission and residue of toxic and harmful substances, conforms to the concept of green chemistry, and at the same time reduces the production cost and the burden of environmental governance. Through the synergistic effect of liquid-liquid phase separation and rapid cooling crystallization, the present invention can efficiently complete drug compounding and the formation of spherical crystals, without multiple solvent replacements or complex equipment, significantly shortening the production cycle and reducing energy consumption. The cyclandelate-tenoxicam spherical composite particle crystals prepared by the present invention have a smooth surface, high roundness, excellent fluidity, and the particle size of the product can be effectively adjusted by the stirring rate. The spherical structure and uniform particle size distribution of the product obtained by the present invention are beneficial to realizing the synchronous release of the drug, avoiding burst release or lag phenomenon, thereby improving the bioavailability and clinical efficacy. The process of the present invention is simple, suitable for large-scale continuous production, and has significant economic benefits and application prospects. The average particle size of the cyclandelate-tenoxicam spherical composite particles prepared by the present invention is between 1322 and 1720 μm, the angle of repose is between 26 and 29°, and the tapped density is 0.47 to 0.51 g / cm 3 .

[0076] The above are only the preferred embodiments of the present invention. It should be pointed out that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and refinements can be made, and these improvements and refinements should also be regarded as the protection scope of the present invention.

Claims

1. A preparation method of cyclandelate-tenoxicam spherical composite particles, characterized in that, It comprises the following steps: (1) Mix cyclandelate and water, heat and stir until liquid-liquid phase separation occurs to obtain a cyclandelate-aqueous solution; (2) Add tenoxicam to the cyclandelate-aqueous solution, mix and stir to obtain a mixed solution; (3) Cool down the mixed solution and continue stirring; (4) Add a surfactant to the cooled solution, mix and stir until crystallization occurs, then filter, wash and dry in sequence to obtain the cyclandelate-tenoxicam spherical composite particles.

2. The preparation method according to claim 1, characterized in that, In the step (1), the mixing temperature is 50-80°C; In the step (1), the concentration of the cyclandelate-aqueous solution is 0.01-0.05 g / mL.

3. The preparation method according to claim 1, characterized in that, In the step (2), the concentration of tenoxicam in the mixed solution is 0.001-0.005 g / mL.

4. The preparation method according to claim 1, characterized in that, In the step (3), the cooling rate is 40-45°C / 10 min, and the temperature is cooled down to 5-25°C.

5. The preparation method according to claim 1, wherein In the step (4), the surfactant is one of sodium stearate, sodium hexametaphosphate, sodium dodecylbenzenesulfonate and sodium dodecyl sulfate.

6. The preparation method according to claim 1, wherein In the step (4), the addition amount of the surfactant is 0.05-0.1% of the mass fraction of the mixed solution.

7. The preparation method according to claim 1, characterized in that, In the step (4), the stirring time is 0.5-3 h.

8. The preparation method according to claim 1, wherein, In the step (4), the washing solvent is water; In the step (4), the drying temperature is 30-40°C, and the drying time is 12-24 h.

9. A cyclandelate-tenoxicam spherical composite particle obtained by the preparation method according to any one of claims 1-8.

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