Preparation method of triamcinolone acetonide sustained-release microspheres

Abstract

The invention provides a triamcinolone acetonide microsphere and a preparation method thereof, and particularly provides a method for preparing the triamcinolone acetonide microsphere by utilizing an emulsification-solvent evaporation method. The triamcinolone acetonide microspheres prepared by the invention have no obvious burst release, and can realize slow-release and long-acting treatment effects.

Description

Technical Field

[0001] The present invention relates to a triamcinolone acetonide microsphere and a preparation method thereof, and particularly relates to a sustained-release triamcinolone acetonide microsphere and a preparation method thereof. Background Art

[0002] Triamcinolone acetonide is a kind of synthetic medium- and long-acting glucocorticoid, which has anti-inflammatory and immunomodulatory effects. Its anti-inflammatory and anti-allergic effects are strong, and it takes effect quickly, which can significantly improve the condition of patients. The anti-inflammatory and anti-allergic effects of triamcinolone acetonide are similar to those of hydrocortisone, and its anti-inflammatory effect is 5-20 times that of hydrocortisone. The marketed product dosage forms include (compound) creams, nasal sprays, injections, etc., and the indications are mostly anti-inflammatory. Among the marketed products, there are two dosage forms whose indications include the treatment of knee pain in osteoarthritis: microcrystalline injection and microsphere injection suspension.

[0003] The original research product of triamcinolone acetonide microcrystalline injection is Kenalog-10 / 40 / 80, which is prone to an initial burst release effect during drug administration, will have an obvious inhibitory effect on the hypothalamic-pituitary-adrenal axis, and cause systemic side effects. The original research product of the microsphere injection suspension is Zilretta, developed by Flexion Therapeutics and approved for marketing by the FDA in October 2017 for single intra-articular administration. Compared with the microcrystalline injection, the drug in the microsphere injection suspension is slowly and continuously released in the joint cavity, which increases the local concentration of the drug in the joint cavity, reduces the systemic exposure of glucocorticoids, reduces the inhibitory effect on the hypothalamic-pituitary-adrenal axis of the human endocrine gland, reduces side effects while improving the therapeutic effect, and the analgesic effect can reach 3-4 months.

[0004] Zilretta adopts a spray drying preparation process, disperses triamcinolone acetonide and PLGA in dichloromethane (solubility in water at 20 °C is 13 g / L), and atomizes the dispersion into microdroplets by rotating a turntable. The organic solvent in the atomized droplets can diffuse into the carrier gas in an extremely short time to generate solid particles. During the preparation process, since no aqueous phase medium is introduced, water molecules can only gradually penetrate into the interior of the microspheres through the pores generated by drug release, so the obtained microspheres have a longer drug release period.

[0005] To ensure the sterility of the microsphere samples, the original research adopted an irradiation sterilization method, which will affect the degradation of the microsphere materials. At present, the vast majority of microspheres adopt a sterile preparation production process. To achieve a sterile production process, in the present invention, an emulsification-solvent evaporation method will be used to prepare triamcinolone acetonide microspheres.

[0006] The main difference between the emulsification-solvent evaporation method and the spray drying method is that the formulation contains an aqueous phase, and the solvent in the emulsion droplets solidifies the microspheres by diffusing in water. There is an order-of-magnitude difference in the solidification rate, which will lead to different release behaviors. It has been found that the triamcinolone acetonide microspheres prepared by the conventional emulsification-solvent evaporation method release rapidly, with an obvious burst release phenomenon and poor sustained release effect. At the same time, it will also increase the risk of side effects. Summary of the Invention

[0007] To solve the above technical problems, the present invention is achieved by the following technical solutions:

[0008] The first aspect of the present invention is to provide a method for preparing triamcinolone acetonide microspheres, comprising the following steps:

[0009] (1) Preparation of the aqueous phase: Dissolve the emulsifier in water to obtain an aqueous phase solution;

[0010] (2) Preparation of the oil phase: Dissolve the poly (lactic-co-glycolic acid) (PLGA) in an organic solvent to form an oil phase solution;

[0011] (3) Preparation of the primary emulsion: Disperse triamcinolone acetonide in the poly (lactic-co-glycolic acid) oil phase solution and homogenize to form a primary emulsion;

[0012] (4) Preparation of the double emulsion: Mix the sample obtained in step (3) with the aqueous phase solution in step (1) in a certain ratio and emulsify to form a double emulsion;

[0013] (5) Stir the double emulsion to volatilize and remove the organic solvent, collect, wash, and then freeze-dry;

[0014] (6) Resuspend the freeze-dried sample obtained in step (5) in the aqueous phase solution, heat and stir, wash, collect, and then freeze-dry to obtain triamcinolone acetonide microspheres.

[0015] According to an embodiment of the present invention, in step (1) of the preparation method, the emulsifier is selected from one or more of polyvinyl alcohol (PVA), poloxamer, carboxymethyl cellulose, and polyvinylpyrrolidone, and preferably polyvinyl alcohol (PVA).

[0016] According to an embodiment of the present invention, in step (1) of the preparation method, the mass concentration of the emulsifier in the aqueous phase solution is 0.5%-2.5%, preferably 1% to 2.5%, such as 1%, 1.5%, 2% or 2.5%.

[0017] According to an embodiment of the present invention, in step (2) of the preparation method, the organic solvent is selected from one or more of ester solvents, and preferably acetate solvents, such as ethyl acetate and / or butyl acetate;

[0018] According to an embodiment of the present invention, in step (2) of the preparation method, the organic solvent is selected from ethyl acetate.

[0019] According to an embodiment of the present invention, in step (2) of the preparation method, the concentration of PLGA in the oil phase solution is 0.1 - 0.3 g / ml, preferably 0.15 - 0.2 g / ml, such as 0.15 g / ml, 0.16 g / ml, 0.17 g / ml, 0.18 g / ml, 0.19 g / ml or 0.2 g / ml.

[0020] According to an embodiment of the present invention, in step (3) of the preparation method, the concentration of triamcinolone acetonide in the oil phase solution is 0.05 - 0.07 g / ml, preferably 0.05 - 0.067 g / ml, such as 0.05 g / ml, 0.06 g / ml or 0.067 g / ml.

[0021] According to an embodiment of the present invention, in step (3) of the preparation method, the homogenization is carried out using a high - speed shearer, and the conditions are homogenization at 4000 - 6000 rpm for 0.5 - 2.5 min and then continued homogenization at 14000 - 16000 rpm for 0.5 - 2 min;

[0022] Preferably, homogenization is carried out at 4000 - 6000 rpm for 1 - 2 min and then continued homogenization at 14000 - 16000 rpm for 1 - 1.5 min;

[0023] More preferably, homogenization is carried out at 5000 rpm for 1 - 2 min and then continued homogenization at 15000 rpm for 1 - 1.5 min, such as homogenization at 5000 rpm for 1 min and then continued homogenization at 15000 rpm for 1 min.

[0024] According to an embodiment of the present invention, in step (4) of the preparation method, the ratio of the aqueous phase solution to the primary emulsion is (10 - 100):1, preferably (70 - 100):1, such as 80:1, 90:1 or 100:1.

[0025] According to an embodiment of the present invention, in step (4) of the preparation method, the emulsification is carried out by passing through an in - line shearer for shear emulsification, and the shear speed is 1400 - 2100 rpm, preferably 1500 - 2000 rpm, such as 1500 rpm, 1600 rpm or 2000 rpm.

[0026] According to an embodiment of the present invention, in step (5) of the preparation method, the stirring condition is stirring at room temperature for 3 - 5 h, such as stirring at room temperature for 3 h, 4 h or 5 h.

[0027] According to an embodiment of the present invention, in step (6) of the preparation method, the concentration of the freeze-dried sample in the aqueous solution is 0.5 to 0.53% (w / v), preferably 0.51 to 0.52% (w / v), such as 0.513% (w / v), 0.517% (w / v), 0.518% (w / v), 0.519% (w / v) or 0.52% (w / v).

[0028] According to an embodiment of the present invention, in step (6) of the preparation method, the heating and stirring is carried out at 40 to 70 °C for 10 to 130 min, preferably at 40 to 60 °C for 15 to 120 min, such as heating and stirring at 40 °C for 120 min; more preferably at 40 to 60 °C for 15 to 60 min, such as heating and stirring at 50 °C for 15 min, heating and stirring at 50 °C for 60 min or heating and stirring at 60 °C for 60 min.

[0029] The second aspect of the present invention is to provide a triamcinolone acetonide microsphere prepared by the above method.

[0030] According to an embodiment of the present invention, the triamcinolone acetonide microsphere is a sustained-release microsphere, and the release rate of the sustained-release microsphere in the first 48 h is less than 84%;

[0031] Preferably, the release rate of the sustained-release microsphere in the first 48 h is less than 75%;

[0032] Preferably, the release rate of the sustained-release microsphere in the first 48 h is 60% to 75%, such as 60.4% to 73.5%.

[0033] According to an embodiment of the present invention, the triamcinolone acetonide microsphere has no burst release phenomenon in the initial stage, and the release rate in the first 8 h is less than 40%;

[0034] Preferably, the release rate of the sustained-release microsphere in the first 8 h is 26% to 40%, such as 28.4% to 36.6%.

[0035] According to an embodiment of the present invention, the release rate of the triamcinolone acetonide microsphere in the first 4 h is less than 26%;

[0036] Preferably, the release rate of the sustained-release microsphere in the first 4 h is 19% to 26%, such as 19.6% to 25.6%.

[0037] According to an embodiment of the present invention, the release rate of the triamcinolone acetonide microsphere in the first 2 h is less than 19%;

[0038] Preferably, the release rate of the sustained-release microsphere in the first 2 h is 14% to 19%, such as 13.3% to 18.2%.

[0039] According to an embodiment of the present invention, the release rate of the triamcinolone acetonide microspheres in the first 1 h is less than 14%;

[0040] Preferably, the release rate of the sustained-release microspheres in the first 1 h is 8% - 14%, such as 8.6% - 13.3%.

[0041] According to an embodiment of the present invention, the particle size D50 range of the triamcinolone acetonide microspheres is 40 - 60 μm, preferably 40.4 - 57.9 μm, such as 40.4 μm, 46.6 μm, 47.4 μm, 54.6 μm or 57.9 μm.

[0042] According to an embodiment of the present invention, the drug loading of the triamcinolone acetonide microspheres is 23% - 25%, preferably 23.4% - 24.3%, such as 23.40%, 23.60%, 23.70%, 23.70%, 24.00% or 24.30%.

[0043] It should be understood that the magnitudes of the sequence numbers of the above processes do not mean the order of execution. Some or all of the steps can be executed in parallel or sequentially. The execution order of each process should be determined by its function and internal logic, and should not constitute any limitation to the implementation process of the embodiments of the present application.

[0044] In the present application, the term "and / or" describes the association relationship of associated objects, indicating that there can be three relationships. For example, A and / or B can represent: A exists alone, A and B exist simultaneously, and B exists alone. Where A and B can be singular or plural.

[0045] Beneficial effects

[0046] The method for preparing triamcinolone acetonide microspheres provided by the present invention uses the emulsification-solvent evaporation method. By adjusting the oil phase and performing heat treatment on the microspheres, the release behavior of the microspheres can be adjusted, the burst release is reduced, and at the same time, the release period is extended, achieving the effect of stable and long-term drug release. Detailed implementation manners

[0047] Example 1

[0048] Weigh 12 g of PLGA and dissolve it in 60 ml of ethyl acetate to form an oil phase. Add 4 g of triamcinolone acetonide to the above oil phase and homogenize it with a high-speed shear mixer (homogenize at 5000 rpm for 1 min and then at 15000 rpm for 1 min) to obtain the S / O primary emulsion. Fix the ratio of the aqueous phase to the primary emulsion at 100 / 1. Pass the primary emulsion and a 1% aqueous solution of polyvinyl alcohol through an in-line shear mixer for shear emulsification at a shear speed of 1600 rpm, stir at room temperature for 4 h to volatilize and remove the organic solvent, wash, collect, and freeze-dry. Take 3.9 g of the freeze-dried sample, add it to 760 ml of an aqueous solution, heat and stir at 50 °C for 15 minutes, wash, collect, and freeze-dry again to obtain triamcinolone acetonide microspheres. The drug loading of the microspheres is 23.7%, and the particle size D 50 is 54.6 μm.

[0049] Example 2

[0050] Weigh 12 g of PLGA and dissolve it in 60 ml of ethyl acetate to form an oil phase. Add 4 g of triamcinolone acetonide to the above oil phase and homogenize it with a high-speed shear mixer (homogenize at 5000 rpm for 1 min and then at 15000 rpm for 1 min) to obtain the S / O primary emulsion. Fix the ratio of the aqueous phase to the primary emulsion at 100 / 1. Pass the primary emulsion and a 1% aqueous solution of polyvinyl alcohol through an in-line shear mixer for shear emulsification at a shear speed of 1600 rpm, stir at room temperature for 4 h to volatilize and remove the organic solvent, wash, collect, and freeze-dry. Take 3.9 g of the freeze-dried sample, add it to 760 ml of an aqueous solution, heat and stir at 50 °C for 60 minutes, wash, collect, and freeze-dry again to obtain triamcinolone acetonide microspheres. The drug loading of the microspheres is 23.4%, and the particle size D 50 is 57.9 μm.

[0051] Example 3

[0052] Weigh 12 g of PLGA and dissolve it in 60 ml of ethyl acetate to form an oil phase. Add 4 g of triamcinolone acetonide to the above oil phase and homogenize it with a high-speed shear mixer (homogenize at 5000 rpm for 1 min and then at 15000 rpm for 1 min) to obtain the S / O primary emulsion. Fix the ratio of the aqueous phase to the primary emulsion at 100 / 1. Pass the primary emulsion and a 1% aqueous solution of polyvinyl alcohol through an in-line shear mixer for shear emulsification at a shear speed of 2000 rpm, stir at room temperature for 4 h to volatilize and remove the organic solvent, wash, collect, and freeze-dry. Take 2.6 g of the freeze-dried sample, add it to 500 ml of an aqueous solution, heat and stir at 50 °C for 30 minutes, wash, collect, and freeze-dry again to obtain triamcinolone acetonide microspheres. The drug loading of the microspheres is 24.0%, and the particle size D 50 is 46.6 μm.

[0053] Example 4

[0054] Weigh 12 g of PLGA and dissolve it in 60 ml of ethyl acetate to form an oil phase. Add 4 g of triamcinolone acetonide to the above oil phase and homogenize it with a high-speed shearing machine (homogenize at 5000 rpm for 1 min and then at 15000 rpm for 1 min) to obtain the S / O primary emulsion. Fix the ratio of the water phase to the primary emulsion at 100 / 1. Pass the primary emulsion and 1% polyvinyl alcohol aqueous solution through an in-line shearing machine for shear emulsification at a shearing speed of 2000 rpm, stir at room temperature for 4 h to volatilize and remove the organic solvent, wash, collect, and freeze-dry. Take 3.9 g of the freeze-dried sample, add it to 760 ml of the aqueous solution, heat and stir at 50 °C for 30 minutes, wash, collect, and freeze-dry again to obtain triamcinolone acetonide microspheres. The drug loading of the microspheres is 23.7%, and the particle size D 50 is 47.4 μm.

[0055] Example 5

[0056] Weigh 12 g of PLGA and dissolve it in 60 ml of ethyl acetate to form an oil phase. Add 4 g of triamcinolone acetonide to the above oil phase and homogenize it with a high-speed shearing machine (homogenize at 5000 rpm for 1 min and then at 15000 rpm for 1 min) to obtain the S / O primary emulsion. Fix the ratio of the water phase to the primary emulsion at 100 / 1. Pass the primary emulsion and 1% polyvinyl alcohol aqueous solution through an in-line shearing machine for shear emulsification at a shearing speed of 1500 rpm, stir at room temperature for 4 h to volatilize and remove the organic solvent, wash, collect, and freeze-dry. Take 2.8 g of the freeze-dried sample, add it to 540 ml of the aqueous solution, heat and stir at 40 °C for 120 minutes, wash, collect, and freeze-dry again to obtain triamcinolone acetonide microspheres. The drug loading of the microspheres is 24.3%.

[0057] Example 6

[0058] Weigh 18 g of PLGA and dissolve it in 120 ml of ethyl acetate to form an oil phase. Add 6 g of triamcinolone acetonide to the above oil phase and homogenize it with a high-speed shearing machine (homogenize at 5000 rpm for 2 min and then at 15000 rpm for 1.5 min) to obtain the S / O primary emulsion. Fix the ratio of the water phase to the primary emulsion at 100 / 1. Pass the primary emulsion and 1% polyvinyl alcohol aqueous solution through an in-line shearing machine for shear emulsification at a shearing speed of 2000 rpm, stir at room temperature for 4 h to volatilize and remove the organic solvent, wash, collect, and freeze-dry. Take 3.0 g of the freeze-dried sample, add it to 580 ml of the aqueous solution, heat and stir at 60 °C for 60 minutes, wash, collect, and freeze-dry again to obtain triamcinolone acetonide microspheres. The drug loading of the microspheres is 23.6%, and the particle size D 50 is 40.4 μm.

[0059] Comparative Example 1

[0060] Weigh 12 g of PLGA and dissolve it in 60 ml of dichloromethane to form an oil phase. Add 4 g of triamcinolone acetonide to the above oil phase and homogenize it under a high-speed shear mixer (homogenize at 5000 rpm for 1 min and then at 15000 rpm for 1 min) to obtain the S / O primary emulsion. Fix the ratio of the water phase to the primary emulsion at 100 / 1. Pass the primary emulsion and a 1% polyvinyl alcohol aqueous solution through an in-line shear mixer for shear emulsification at a shear speed of 2100 rpm, stir at room temperature for 5 h to volatilize the organic solvent, wash, collect, and then lyophilize to obtain triamcinolone acetonide microspheres.

[0061] Comparative Example 2

[0062] Weigh 12 g of PLGA and dissolve it in 60 ml of ethyl acetate to form an oil phase. Add 4 g of triamcinolone acetonide to the above oil phase and homogenize it under a high-speed shear mixer (homogenize at 5000 rpm for 1 min and then at 15000 rpm for 1 min) to obtain the S / O primary emulsion. Fix the ratio of the water phase to the primary emulsion at 100 / 1. Pass the primary emulsion and a 1% polyvinyl alcohol aqueous solution through an in-line shear mixer for shear emulsification at a shear speed of 1800 rpm, stir at room temperature for 4 h to volatilize the organic solvent, wash, collect, and then lyophilize to obtain triamcinolone acetonide microspheres.

[0063] Example 7

[0064] Refer to the second method (paddle method) of the General Rules for the Determination of Dissolution and Release Rates in Part IV of the Chinese Pharmacopoeia 2020 Edition. Using 1000 mL of 0.3% SDS + 10 mM PBS, pH 7.2 + 0.02% sodium azide as the medium, measure the in vitro release curves of Examples 1 - 6 and Comparative Examples 1 - 2 at a temperature of 35 ± 0.5 °C and a rotation speed of 75 rpm.

[0065]

[0066] From the release data of Comparative Example 1, it can be seen that the triamcinolone acetonide microspheres prepared by the emulsification-solvent evaporation method (using dichloromethane as the organic solvent in the oil phase) showed an obvious burst release phenomenon in the initial stage, with rapid release, and about 85% was released in 48 h, unable to achieve the sustained release effect.

[0067] From the release data of Comparative Example 2, it can be seen that after replacing the organic solvent in the oil phase with ethyl acetate, the release in the first 8 h decreased significantly. In Comparative Example 2, the drug was released rapidly in the later stage, and the release reached more than 85% in 48 h, still requiring further optimization to achieve a good sustained release effect.

[0068] In Examples 1 - 6, after heat treatment of the triamcinolone acetonide microspheres, compared with Comparative Example 2, while further reducing the burst release of the drug in the initial stage of release, the drug was able to maintain slow release in the later stage of release, and the in vitro drug release period was extended to more than 5 days.

[0069] According to the above results, the triamcinolone acetonide sustained-release microspheres prepared in the present invention have no obvious initial burst release and can achieve the treatment effects of sustained release and long duration.

[0070] The above has given an exemplary description of the implementation manner of the technical solution of the present invention. It should be understood that the protection scope of the present invention is not limited to the above implementation manner. Any modifications, equivalent replacements, improvements, etc. made by those skilled in the art within the spirit and principle of the present invention shall be included within the protection scope of the claims of this application.

Claims

1. A method for preparing triamcinolone acetonide microspheres, comprising the following steps: (1) Preparation of the aqueous phase: Dissolve an emulsifier in water to obtain an aqueous phase solution; (2) Preparation of the oil phase: Dissolve poly (lactic-co-glycolic acid) (PLGA) in an organic solvent to form an oil phase solution; (3) Preparation of the primary emulsion: Disperse triamcinolone acetonide in the poly (lactic-co-glycolic acid) oil phase solution and homogenize to form a primary emulsion; (4) Preparation of the multiple emulsion: Mix the sample obtained in step (3) with the aqueous phase solution in step (1) in a certain ratio and emulsify to form a multiple emulsion; (5) Stir and volatilize the multiple emulsion to remove the organic solvent, collect, wash and then freeze-dry; (6) Resuspend the freeze-dried sample obtained in step (5) in the aqueous phase solution, heat and stir, wash, collect and then freeze-dry to obtain triamcinolone acetonide microspheres.

2. The preparation method according to claim 1, wherein, In step (1), the emulsifier is selected from one or more of polyvinyl alcohol (PVA), poloxamer, carboxymethyl cellulose, and polyvinylpyrrolidone, and is preferably polyvinyl alcohol (PVA).

3. The preparation method according to claim 1, wherein, In step (1), the mass concentration of the emulsifier in the aqueous phase solution is 0.5%-2.5%, preferably 1% to 2.5%, such as 1%, 1.5%, 2% or 2.5%.

4. The preparation method according to claim 1, wherein In step (2), the organic solvent is selected from one or more of ester solvents, and is preferably an acetate solvent.

5. The preparation method according to claim 4, wherein In step (2), the organic solvent is ethyl acetate.

6. The preparation method according to claim 1, wherein In step (2), the concentration of PLGA in the oil phase solution is 0.1-0.3 g / ml, preferably 0.15-0.2 g / ml, such as 0.15 g / ml, 0.16 g / ml, 0.17 g / ml, 0.18 g / ml, 0.19 g / ml or 0.2 g / ml.

7. The preparation method according to claim 1, wherein In step (3), the concentration of triamcinolone acetonide in the oil phase solution is 0.05-0.07 g / ml, preferably 0.05-0.067 g / ml, such as 0.05 g / ml, 0.06 g / ml or 0.067 g / ml.

8. The preparation method according to claim 1, wherein, In step (3), the homogenization is carried out using a high-speed shear machine, and the conditions are homogenizing at 4000-6000 rpm for 0.5-2.5 min and then continuing to homogenize at 14000-16000 rpm for 0.5-2 min; preferably homogenizing at 4000-6000 rpm for 1-2 min and then continuing to homogenize at 14000-16000 rpm for 1-1.5 min; more preferably homogenizing at 5000 rpm for 1-2 min and then continuing to homogenize at 15000 rpm for 1-1.5 min, such as homogenizing at 5000 rpm for 1 min and then continuing to homogenize at 15000 rpm for 1 min.

9. According to the preparation method described in claim 1, wherein In step (4), the ratio of the aqueous phase solution to the primary emulsion is (10-100):1, preferably (70-100):1, such as 80:1, 90:1 or 100:

1.

10. The preparation method according to claim 1, wherein In step (4), the emulsification is carried out by passing through an in-line shear machine for shear emulsification, and the shear speed is 1400-2100 rpm, preferably 1500-2000 rpm, such as 1500 rpm, 1600 rpm or 2000 rpm.

11. The preparation method according to claim 1, wherein, In step (5), the stirring condition is stirring at room temperature for 3 - 5 h, such as stirring at room temperature for 3 h, 4 h or 5 h.

12. According to the preparation method described in claim 1, wherein, In step (6), the concentration of the freeze-dried sample in the aqueous solution is 0.5 - 0.53% (w / v), preferably 0.51 - 0.52% (w / v), such as 0.513% (w / v), 0.517% (w / v), 0.518% (w / v), 0.519% (w / v) or 0.52% (w / v).

13. The preparation method according to claim 1, wherein In step (6), the heating and stirring is carried out at 40 - 70 °C for 10 - 130 min, preferably at 40 - 60 °C for 15 - 120 min, such as heating and stirring at 40 °C for 120 min; more preferably at 40 - 60 °C for 15 - 60 min, such as heating and stirring at 50 °C for 15 min, heating and stirring at 50 °C for 60 min or heating and stirring at 60 °C for 60 min.

14. A triamcinolone acetonide microsphere prepared by the preparation method according to any one of claims 1 - 13.

15. The triamcinolone acetonide microspheres according to claim 14, wherein, The release rate in the first 48 h is less than 84%; preferably, the release rate of the triamcinolone acetonide microsphere in the first 48 h is less than 75%; preferably, the release rate of the sustained-release microsphere in the first 48 h is 60% - 75%, such as 60.4% - 73.5%.

16. The triamcinolone acetonide microspheres according to claim 14, characterized in that, The release rate in the first 8 h is less than 40%; preferably, the release rate of the sustained-release microsphere in the first 8 h is 26% - 40%, such as 28.4% - 36.6%.

17. The triamcinolone acetonide microspheres according to claim 14, wherein Its release rate in the first 4 h is less than 26%; preferably, the release rate of the sustained-release microsphere in the first 4 h is 19% - 26%, such as 19.6% - 25.6%.

18. The triamcinolone acetonide microspheres according to claim 14, characterized in that, Its release rate in the first 2 h is less than 19%; preferably, the release rate of the sustained-release microsphere in the first 2 h is 14% - 19%, such as 13.3% - 18.2%.

19. The triamcinolone acetonide microspheres according to claim 14, wherein, Its release rate in the first 1 h is less than 14%; preferably, the release rate of the sustained-release microsphere in the first 1 h is 8% - 14%, such as 8.6% - 13.3%.

20. The triamcinolone acetonide microsphere according to claim 14, wherein Its particle size D50 ranges from 40 to 60 μm, preferably 40.4 to 57.9 μm, such as 40.4 μm, 46.6 μm, 47.4 μm, 54.6 μm or 57.9 μm.

21. The triamcinolone acetonide microspheres according to claim 14, characterized in that, Its drug loading is 23% - 25%, preferably 23.4% - 24.3%, such as 23.40%, 23.60%, 23.70%, 23.70%, 24.00% or 24.30%.

22. A pharmaceutical composition comprising the triptorelin acetate sustained-release microsphere according to any one of claims 14 - 21 and a pharmaceutically acceptable carrier.

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