Dexamethasone palmitate injection and preparation method thereof

Abstract

The application provides a preparation method of dexamethasone palmitate injection and the preparation method, aiming at the problems of strong fat solubility, extremely low water solubility of dexamethasone palmitate injection, and the injection prepared by high shear dispersion, such as instability, large particle size, and large batch difference, etc., high-efficiency micro-mixing is carried out by using microfluidic technology, and the flow rate ratio of oil phase solution and water phase solution is controlled, without high shear dispersion and defoaming steps, the preparation method is simple, the prepared injection is stable in nature, the average particle size of the drug is less than or equal to 120 nm, the preparation method is strong in controllability, good in repeatability, the batch RSD is less than 3%, and the in-vitro stability is good, the problems of large drug particle size, large batch difference and poor stability in the existing preparation method are solved. In addition, the microfluidic device can be connected with the existing production line, the chip can be repeatedly used, the production cost is low, and the industrialized continuous production is suitable.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a method for preparing dexamethasone palmitate injection, and an injection prepared by the method. Background Technology

[0002] Dexamethasone palmitate is a palmitate derivative of dexamethasone and belongs to the category of synthetic glucocorticoids. Compared with dexamethasone, it has significantly enhanced lipid solubility, making it easier to penetrate biological membranes and target and accumulate at the site of inflammation. It has advantages such as strong anti-inflammatory effect, long duration of action, and few systemic adverse reactions. Clinically, it is widely used in the treatment of rheumatoid arthritis, ankylosing spondylitis, allergic diseases, and autoimmune diseases. It is a commonly used lipid-soluble steroid hormone injection in clinical practice.

[0003] Dexamethasone palmitate has extremely low solubility in water (<0.01 mg / mL), making it impossible to directly prepare an aqueous injection solution. The current mainstream preparation process is an oil-phase-aqueous emulsification dispersion method, which uses vegetable oil as the oil phase matrix, adds a solubilizer to dissolve the drug, and then mixes it with the aqueous phase under high-speed shearing to achieve drug dispersion. However, the traditional process has significant technical drawbacks: First, the mixing efficiency of the high-speed shearing machine is limited, making it difficult to achieve molecular-level dispersion between the oil and aqueous phases, which easily leads to local drug aggregation, resulting in demulsification of the injection solution and large drug particle size, affecting in vivo absorption and targeting. Second, the process has poor controllability; parameters such as the rotation speed and time of the high-speed shearing are easily affected by the equipment condition, resulting in large batch-to-batch variations and insufficient product quality stability. Third, bubbles are easily generated during the shearing process, introducing microparticle impurities, increasing the sterility risk of the injection solution, and the subsequent degassing step is cumbersome, reducing production efficiency.

[0004] Microfluidics is a novel technology that enables precise control, mixing, and dispersion of fluids at the microscale. Its core advantage lies in the ability of the special structure of microchannels (such as Tesla and SHM structures) to create microscale shearing, collision, and swirling of fluids, achieving efficient and uniform mixing of two phases. The particle size can be precisely controlled, and the process parameters are digitally controllable with good repeatability.

[0005] Given the shortcomings of existing methods for preparing dexamethasone palmitate injection, as well as problems such as uneven drug dispersion, large particle size, and poor stability in the injection, it is particularly important to provide a different method for preparing dexamethasone palmitate injection. Summary of the Invention

[0006] The purpose of this invention is to address the problems of high lipid solubility and extremely low water solubility in current dexamethasone palmitate injections, as well as the instability, large particle size, and large batch-to-batch variability of injections prepared using high-shear dispersion. This invention utilizes microfluidic technology for efficient micro-mixing and controls the flow rate ratio of the oil and aqueous phases, eliminating the need for high-shear dispersion and degassing steps. The preparation method is simple, the resulting injection exhibits stable properties, an average drug particle size ≤120nm, and strong controllability and repeatability, with a batch-to-batch RSD <3%. It also demonstrates good in vitro stability, solving the problems of large drug particle size, large batch-to-batch variability, and poor stability associated with existing preparation methods. Furthermore, the microfluidic device can be integrated with existing production lines, the chip is reusable, production costs are low, and it is suitable for continuous industrial production.

[0007] Another object of the present invention is to provide a dexamethasone palmitate injection prepared by the above preparation method.

[0008] The technical solution of the present invention is as follows: A method for preparing dexamethasone palmitate injection includes the following steps: (1) Add dexamethasone palmitate to soybean oil, stir to dissolve, then add egg yolk lecithin, and shear and disperse until completely dissolved to obtain a clear and homogeneous oil phase solution; (2) Add glycerol to water for injection and stir until homogeneous to obtain an aqueous solution; (3) Inject the oil phase solution and the aqueous phase solution into the dual-channel injection pump of the microfluidic device, start the injection pump, so that the oil phase solution and the aqueous phase solution are fully mixed and dispersed in the microfluidic chip, collect the effluent, and obtain the initial solution of dexamethasone palmitate; (4) Adjust the pH of the initial solution to 7.5-8.5, stir evenly at 25-30℃, add water for injection to make up the volume, filter, fill and seal to obtain the injection solution.

[0009] The dexamethasone palmitate injection prepared by the method of the present invention has a concentration of 1.0-10.0 g / ml in the injection solution, which may be, but is not limited to, 1.0 g / ml, 2.0 g / ml, 2.5 g / ml, 3.0 g / ml, 4.0 g / ml, 5.0 g / ml, 6.0 g / ml, 7.0 g / ml, 8.0 g / ml, 9.0 g / ml or 10 g / ml. Preferably, the concentration of dexamethasone palmitate in the injection solution is 2.5-5.0 g / ml.

[0010] For the purposes of this invention, in step (1), the weight ratio of dexamethasone palmitate, soybean oil and egg yolk lecithin is 1:10-50:1-6, which may be, but is not limited to, 1:20:2, 1:20:3, 1:20:4, 1:20:5, 1:30:2, 1:30:3, 1:30:4, 1:30:5, 1:40:2, 1:40:3, 1:40:4 or 1:40:5. Preferably, the weight ratio of dexamethasone palmitate, soybean oil and egg yolk lecithin is 1:20-40:2-5.

[0011] For the purposes of this invention, in step (1), the stirring and dissolving temperature is 60-70°C, which may be, but is not limited to, 60°C, 61°C, 62°C, 63°C, 64°C, 65°C, 66°C, 67°C, 68°C, 69°C or 70°C. Preferably, the stirring and dissolving temperature is 65°C.

[0012] For the purposes of this invention, in step (1), during shear dispersion, the rotation speed is controlled at 6-20 krpm, which may be, but is not limited to, 6 krpm, 7 krpm, 8 krpm, 9 krpm, 10 krpm, 11 krpm, 12 krpm, 13 krpm, 14 krpm, 15 krpm, 16 krpm, 17 krpm, 18 krpm, 19 krpm or 20 krpm. Preferably, during shear dispersion, the rotation speed is controlled at 10-15 krpm; more preferably, the rotation speed is controlled at 12 krpm.

[0013] For the purposes of this invention, in step (2), the concentration of glycerol in the aqueous solution is 15-60 g / ml, which may be, but is not limited to, 15 g / ml, 20 g / ml, 25 g / ml, 30 g / ml, 35 g / ml, 40 g / ml, 45 g / ml, 50 g / ml, 55 g / ml or 60 g / ml. Preferably, the concentration of glycerol in the aqueous solution is 25-50 g / ml.

[0014] In this invention, in step (3), the flow rate ratio of the oil phase solution to the aqueous phase solution is controlled to be 1:5-10, which can be, but is not limited to, 1:5, 1:6, 1:7, 1:8, 1:9 or 1:10. Preferably, the flow rate ratio of the oil phase solution to the aqueous phase solution is controlled to be 1:7.

[0015] In this invention, in step (3), the microfluidic chip is a Tesla structure.

[0016] In this invention, in step (4), the pH of the initial solution is adjusted to 7.5-8.5 using hydrochloric acid solution and / or sodium hydroxide solution.

[0017] The advantages of using the technical solution of this invention are as follows: (1) This invention utilizes microfluidic technology to perform efficient micro-mixing, thereby achieving molecular-level dispersion of dexamethasone palmitate oil phase-water phase. The resulting injection drug has an average particle size of ≤120nm, which solves the technical problem of instability and large particle size in injections prepared by high shear dispersion.

[0018] (2) This invention utilizes microfluidic technology for efficient micro-mixing, and the process parameters are digitally controllable. The oil-water phase flow rate ratio, total flow rate and other parameters can be precisely adjusted. The batch-to-batch RSD is less than 3%, and the product quality stability is significantly improved. This invention overcomes the problem of large batch-to-batch differences in injections made by high shear dispersion.

[0019] (3) The present invention utilizes microfluidic technology for efficient micro-mixing, which is a continuous operation that does not require high shear dispersion and subsequent degassing steps. The preparation method is simple to operate, and no bubbles are generated during the mixing process, which reduces the risk of introducing microparticle impurities.

[0020] (4) The present invention utilizes microfluidic technology for efficient micro-mixing, and the resulting injection solution has good stability. When stored at 25°C for 6 months, the drug content change rate is <5%, and the dispersed particle size does not change significantly.

[0021] (5) The preparation method of the present invention can be miniaturized and modularized, enabling continuous industrial production. The microfluidic chip can be repeatedly sterilized and reused, reducing production costs and making it suitable for large-scale promotion. Detailed Implementation

[0022] The present invention can be better understood from the following embodiments. However, those skilled in the art will readily understand that the descriptions in the embodiments are for illustrative purposes only and should not, and will not, limit the invention as detailed in the claims.

[0023] Example 1

[0024] A method for preparing dexamethasone palmitate injection includes the following steps: (1) Add 5.0g of dexamethasone palmitate to 100g of soybean oil and stir to dissolve at 65℃. Then add 10g of egg yolk lecithin and control the rotation speed at 12krpm. Shear and disperse until completely dissolved to obtain a clear and homogeneous oil phase solution. The mass ratio of dexamethasone palmitate, soybean oil and egg yolk lecithin is 1:20:2. (2) Add 20g of glycerol to 700ml of water for injection and stir well to obtain an aqueous solution; wherein the concentration of glycerol in the aqueous solution is 35g / ml; (3) Inject the oil phase solution and the aqueous phase solution into the dual-channel injection pump of the microfluidic device, set the flow rate ratio of the oil phase solution and the aqueous phase solution to 1:7, and the total flow rate to 5 mL / min. Start the injection pump to allow the oil phase solution and the aqueous phase solution to be fully mixed and dispersed in the microfluidic chip. Collect the effluent to obtain the initial solution of dexamethasone palmitate; wherein, the microfluidic chip is a Tesla structure. (4) Transfer the obtained initial solution to a constant temperature stirring tank, adjust its pH to 7.5-8.5 with hydrochloric acid solution and / or sodium hydroxide solution, stir at a constant temperature of 25-30℃ for 10-20 min, add water for injection to make up to 1000 ml, filter through a microporous membrane terminal, fill and seal to obtain dexamethasone palmitate injection solution, wherein the concentration of dexamethasone palmitate in the injection solution is 5.0 mg / mL.

[0025] Example 2

[0026] A method for preparing dexamethasone palmitate injection includes the following steps: (1) Add 2.5g of dexamethasone palmitate to 50g of soybean oil and stir to dissolve at 65℃. Then add 5g of egg yolk lecithin and control the rotation speed at 12krpm. Shear and disperse until completely dissolved to obtain a clear and homogeneous oil phase solution. The mass ratio of dexamethasone palmitate, soybean oil and egg yolk lecithin is 1:20:2. (2) Add 20g of glycerol to 700ml of water for injection and stir well to obtain an aqueous solution; wherein the concentration of glycerol in the aqueous solution is 35g / ml; (3) Inject the oil phase solution and the aqueous phase solution into the dual-channel injection pump of the microfluidic device, set the flow rate ratio of the oil phase solution and the aqueous phase solution to 1:7, and the total flow rate to 5 mL / min. Start the injection pump to allow the oil phase solution and the aqueous phase solution to be fully mixed and dispersed in the microfluidic chip. Collect the effluent to obtain the initial solution of dexamethasone palmitate; wherein, the microfluidic chip is a Tesla structure. (4) Transfer the obtained initial solution to a constant temperature stirring tank, adjust its pH to 7.5-8.5 with hydrochloric acid solution and / or sodium hydroxide solution, stir at a constant temperature of 25-30℃ for 10-20 min, add water for injection to make up to 1000 ml, filter through a microporous membrane terminal, fill and seal to obtain dexamethasone palmitate injection solution, wherein the concentration of dexamethasone palmitate in the injection solution is 2.5 mg / mL.

[0027] Example 3

[0028] A method for preparing dexamethasone palmitate injection includes the following steps: (1) Add 5.0g of dexamethasone palmitate to 100g of soybean oil and stir to dissolve at 65℃. Then add 10g of egg yolk lecithin and control the rotation speed at 12krpm. Shear and disperse until completely dissolved to obtain a clear and homogeneous oil phase solution. The mass ratio of dexamethasone palmitate, soybean oil and egg yolk lecithin is 1:20:2. (2) Add 20g of glycerol to 500ml of water for injection and stir well to obtain an aqueous solution; wherein the concentration of glycerol in the aqueous solution is 25g / ml; (3) Inject the oil phase solution and the aqueous phase solution into the dual-channel injection pump of the microfluidic device, set the flow rate ratio of the oil phase solution and the aqueous phase solution to 1:5, and the total flow rate to 5 mL / min. Start the injection pump to allow the oil phase solution and the aqueous phase solution to be fully mixed and dispersed in the microfluidic chip. Collect the effluent to obtain the initial solution of dexamethasone palmitate; wherein, the microfluidic chip is a Tesla structure. (4) Transfer the obtained initial solution to a constant temperature stirring tank, adjust its pH to 7.5-8.5 with hydrochloric acid solution and / or sodium hydroxide solution, stir at a constant temperature of 25-30℃ for 10-20 min, add water for injection to make up to 1000 ml, filter through a microporous membrane terminal, fill and seal to obtain dexamethasone palmitate injection solution, wherein the concentration of dexamethasone palmitate in the injection solution is 5.0 mg / mL.

[0029] Example 4

[0030] A method for preparing dexamethasone palmitate injection includes the following steps: (1) Add 2.5g of dexamethasone palmitate to 50g of soybean oil and stir to dissolve at 65℃. Then add 5g of egg yolk lecithin and control the rotation speed at 12krpm. Shear and disperse until completely dissolved to obtain a clear and homogeneous oil phase solution. The mass ratio of dexamethasone palmitate, soybean oil and egg yolk lecithin is 1:20:2. (2) Add 10g of glycerol to 500ml of water for injection and stir well to obtain an aqueous solution; wherein the concentration of glycerol in the aqueous solution is 50g / ml; (3) Inject the oil phase solution and the aqueous phase solution into the dual-channel injection pump of the microfluidic device, set the flow rate ratio of the oil phase solution and the aqueous phase solution to 1:10, and the total flow rate to 5 mL / min. Start the injection pump to allow the oil phase solution and the aqueous phase solution to be fully mixed and dispersed in the microfluidic chip. Collect the effluent to obtain the initial solution of dexamethasone palmitate; wherein, the microfluidic chip is a Tesla structure. (4) Transfer the obtained initial solution to a constant temperature stirring tank, adjust its pH to 7.5-8.5 with hydrochloric acid solution and / or sodium hydroxide solution, stir at a constant temperature of 25-30℃ for 10-20 min, add water for injection to make up to 1000 ml, filter through a microporous membrane terminal, fill and seal to obtain dexamethasone palmitate injection solution, wherein the concentration of dexamethasone palmitate in the injection solution is 2.5 mg / mL.

[0031] Example 5

[0032] A method for preparing dexamethasone palmitate injection includes the following steps: (1) Add 2.5g of dexamethasone palmitate to 100g of soybean oil and stir to dissolve at 65℃. Then add 10g of egg yolk lecithin and control the rotation speed at 12krpm. Shear and disperse until completely dissolved to obtain a clear and homogeneous oil phase solution. The mass ratio of dexamethasone palmitate, soybean oil and egg yolk lecithin is 1:40:4. (2) Add 20g of glycerol to 700ml of water for injection and stir well to obtain an aqueous solution; wherein the concentration of glycerol in the aqueous solution is 35g / ml; (3) Inject the oil phase solution and the aqueous phase solution into the dual-channel injection pump of the microfluidic device, set the flow rate ratio of the oil phase solution and the aqueous phase solution to 1:7, and the total flow rate to 5 mL / min. Start the injection pump to allow the oil phase solution and the aqueous phase solution to be fully mixed and dispersed in the microfluidic chip. Collect the effluent to obtain the initial solution of dexamethasone palmitate; wherein, the microfluidic chip is a Tesla structure. (4) Transfer the obtained initial solution to a constant temperature stirring tank, adjust its pH to 7.5-8.5 with hydrochloric acid solution and / or sodium hydroxide solution, stir at a constant temperature of 25-30℃ for 10-20 min, add water for injection to make up to 1000 ml, filter through a microporous membrane terminal, fill and seal to obtain dexamethasone palmitate injection solution, wherein the concentration of dexamethasone palmitate in the injection solution is 2.5 mg / mL.

[0033] Example 6

[0034] A method for preparing dexamethasone palmitate injection includes the following steps: (1) Add 2.5g of dexamethasone palmitate to 100g of soybean oil and stir to dissolve at 65℃. Then add 12.5g of egg yolk lecithin and control the rotation speed at 12krpm. Shear and disperse until completely dissolved to obtain a clear and homogeneous oil phase solution. The mass ratio of dexamethasone palmitate, soybean oil and egg yolk lecithin is 1:40:5. (2) Add 14g of glycerol to 700ml of water for injection and stir well to obtain an aqueous solution; wherein the concentration of glycerol in the aqueous solution is 50g / ml; (3) Inject the oil phase solution and the aqueous phase solution into the dual-channel injection pump of the microfluidic device, set the flow rate ratio of the oil phase solution and the aqueous phase solution to 1:7, and the total flow rate to 5 mL / min. Start the injection pump to allow the oil phase solution and the aqueous phase solution to be fully mixed and dispersed in the microfluidic chip. Collect the effluent to obtain the initial solution of dexamethasone palmitate; wherein, the microfluidic chip is a Tesla structure. (4) Transfer the obtained initial solution to a constant temperature stirring tank, adjust its pH to 7.5-8.5 with hydrochloric acid solution and / or sodium hydroxide solution, stir at a constant temperature of 25-30℃ for 10-20 min, add water for injection to make up to 1000 ml, filter through a microporous membrane terminal, fill and seal to obtain dexamethasone palmitate injection solution, wherein the concentration of dexamethasone palmitate in the injection solution is 2.5 mg / mL.

[0035] Comparative Example 1

[0036] A method for preparing dexamethasone palmitate injection includes the following steps: (1) Add 5.0g of dexamethasone palmitate to 100g of soybean oil and stir to dissolve at 65℃. Then add 10g of egg yolk lecithin and control the rotation speed at 12krpm. Shear and disperse until completely dissolved to obtain a clear and homogeneous oil phase solution. The mass ratio of dexamethasone palmitate, soybean oil and egg yolk lecithin is 1:20:2. (2) Add 20g of glycerol to 700ml of water for injection and stir well to obtain an aqueous solution; wherein the concentration of glycerol in the aqueous solution is 35g / ml; (3) The oil phase solution is slowly added to the aqueous phase solution and sheared and dispersed in a high-speed shear machine at a speed of 15krpm for 30min to obtain the initial solution. The pH is adjusted to 7.5-8.5 with hydrochloric acid solution and / or sodium hydroxide solution, and then water for injection is added to make up to 1000mL. The solution is filtered through a microporous membrane terminal, filled, and sealed to obtain dexamethasone palmitate injection solution, wherein the concentration of dexamethasone palmitate in the injection solution is 5.0mg / mL.

[0037] Comparative Example 2

[0038] A method for preparing dexamethasone palmitate injection includes the following steps: (1) Add 2.5g of dexamethasone palmitate to 50g of soybean oil and stir to dissolve at 65℃. Then add 5g of egg yolk lecithin and control the rotation speed at 12krpm. Shear and disperse until completely dissolved to obtain a clear and homogeneous oil phase solution. The mass ratio of dexamethasone palmitate, soybean oil and egg yolk lecithin is 1:20:2. (2) Add 20g of glycerol to 700ml of water for injection and stir well to obtain an aqueous solution; wherein the concentration of glycerol in the aqueous solution is 35g / ml; (3) The oil phase solution is slowly added to the aqueous phase solution and sheared and dispersed in a high-speed shear machine at a speed of 15krpm for 30min to obtain the initial solution. The pH is adjusted to 7.5-8.5 with hydrochloric acid solution and / or sodium hydroxide solution, and then water for injection is added to make up to 1000mL. The solution is filtered through a microporous membrane terminal, filled, and sealed to obtain dexamethasone palmitate injection solution, wherein the concentration of dexamethasone palmitate in the injection solution is 5.0mg / mL.

[0039] Performance testing This invention conducts multiple performance tests on the dexamethasone palmitate injection prepared in the examples and comparative examples. The test methods all refer to the standards under the Injection section of the 2025 edition of the Chinese Pharmacopoeia and the commonly used test methods for pharmaceutical preparations. Each sample is measured in parallel 3 times, and the average value is taken.

[0040] 1. Basic physicochemical properties test: The test items include appearance, pH, osmolar concentration, and the results are shown in Table 1.

[0041]

[0042] As shown in Table 1, the injection solutions prepared in Examples 1-56 of this invention are within the pharmacopoeia-specified range in terms of appearance, pH, and osmolality. Furthermore, the injection solutions exhibit good stability after standing, without demulsification or stratification. The difference between Comparative Example 1 and Example 1 is that Example 1 uses microfluidic technology for efficient micromixing, while Comparative Example 1 uses high-shear dispersion. However, the injection solution prepared in Comparative Example 1 slightly stratifies after standing, indicating poorer stability. Similarly, the difference between Comparative Example 2 and Example 2 is that Example 2 uses microfluidic technology for efficient micromixing, while Comparative Example 2 uses high-shear dispersion. However, the injection solution prepared in Comparative Example 2 has oil droplets on its surface and stratifies after standing, showing significantly worse stability than Example 2. Therefore, this invention utilizes microfluidic technology for mixing, resulting in more stable injection solutions. Moreover, by controlling the flow rate ratio of the oil phase solution to the aqueous phase solution and the mixing ratio of the oil and water phases, stable injection solutions can still be prepared. High-shear dispersion, on the other hand, requires strict control of the mixing ratio of the oil and water phases.

[0043] 2. Drug dispersion particle size detection: The drug dispersion particle size in the injection solution was determined using a laser particle size analyzer, and the average particle size of the emulsion was detected. The results are shown in Table 2.

[0044]

[0045] As shown in Table 2, the injection solutions prepared in Examples 1-6 of this invention have an average particle size ≤120nm and a polydispersity index (PDI) ≤0.15. In contrast, Comparative Example 1, prepared using high-shear dispersion, has an average particle size >200nm and a PDI >0.2. Comparative Example 2, which uses high-shear dispersion and alters the oil-water two-phase ratio, has an average particle size close to 400nm and a PDI close to 0.6. Therefore, this invention utilizes microfluidic technology for efficient micro-mixing, achieving precise and uniform drug dispersion by controlling the material ratio, significantly superior to existing high-speed shear dispersion emulsification processes.

[0046] 3. Process repeatability test: Three batches of injection solution prepared continuously in Example 1 and Comparative Example 1 were used to test the drug content and average particle size, and the inter-batch RSD was calculated. The results are shown in Table 3.

[0047]

[0048] As shown in Table 3, the batch-to-batch RSD of the injection prepared by using microfluidic technology for efficient micro-mixing in Example 1 is much lower than that of the injection prepared by high-shear dispersion in Comparative Example 1. Therefore, it can be seen that the present invention uses microfluidic technology for efficient micro-mixing, which has strong controllability and good repeatability, and can effectively ensure the consistency of product quality.

[0049] 4. Stability test: The injection solutions prepared in Example 1 and Comparative Example 1 were stored at 25°C under light-protected conditions. Samples were taken at 0, 1, 3 and 6 months to test the properties, drug content and D90. The results are shown in Table 4.

[0050]

[0051] As shown in Table 4, the dexamethasone palmitate injection prepared in Example 1 of this invention, after being stored at 25°C for 6 months, showed a drug content change rate of <5%, no significant change in dispersed particle size, and its properties always met the requirements, demonstrating good in vitro stability. In contrast, the injections in Examples 2-6, after being stored at 25°C for 6 months, showed a drug content change rate of <5%, no significant change in dispersed particle size, and were similar to those in Example 1.

[0052] Comparative Example 1 showed slight stratification after being stored at 25°C for 3 months, and the drug content decreased significantly. After being stored at 25°C for 6 months, the drug content change rate was >5%. This indicates that the injectable emulsion prepared by high shear dispersion has poor stability and is prone to water-oil stratification after long storage time, with the drug content decreasing accordingly.

[0053] 5. Sterility and pyrogen testing The injection solutions prepared in Examples 1-6 of this invention were tested according to the methods in the 2025 edition of the Chinese Pharmacopoeia. The results showed that the sterility test was negative and the pyrogen test met the requirements. Therefore, it can be concluded that the injection solutions prepared by this invention using microfluidic technology for efficient micro-mixing have no additional sterility risk and meet the pharmaceutical safety requirements for injections.

[0054]

[0055] To address the problems of high lipid solubility and extremely low water solubility in current dexamethasone palmitate injections, as well as the instability, large particle size, and significant batch-to-batch variability associated with injections prepared using high-shear dispersion, this invention utilizes microfluidic technology for efficient micro-mixing and controls the flow rate ratio of the oil and aqueous phases. This eliminates the need for high-shear dispersion and degassing steps, resulting in a simple preparation method with stable properties. The prepared injection exhibits an average drug particle size ≤120 nm, strong controllability, good reproducibility, batch-to-batch RSD <3%, and excellent in vitro stability. This solves the problems of large particle size, significant batch-to-batch variability, and poor stability associated with existing preparation methods. Furthermore, the microfluidic device can be integrated with existing production lines, the chip is reusable, and the production cost is low, making it suitable for continuous industrial production. It also provides a reference for the preparation of other lipid-soluble steroid hormones and poorly soluble drug injections, possessing significant clinical application value and promising prospects for industrial application.

[0056] Specific embodiments of the present invention have been described above. It should be understood that the present invention is not limited to the specific embodiments described above. Those skilled in the art can make various changes or modifications within the scope of the claims, such as adjusting the type and ratio of the oil phase matrix and solubilizer, changing the structure of the microfluidic chip, and fine-tuning process parameters. All such changes or modifications should be covered within the protection scope of the present invention. Unless otherwise specified, the embodiments and features described in this application can be arbitrarily combined with each other.

Claims

1. A method for preparing dexamethasone palmitate injection, characterized in that, Includes the following steps: (1) Add dexamethasone palmitate to soybean oil, stir to dissolve, then add egg yolk lecithin, and shear and disperse until completely dissolved to obtain a clear and homogeneous oil phase solution; (2) Add glycerol to water for injection and stir until homogeneous to obtain an aqueous solution; (3) Inject the oil phase solution and the aqueous phase solution into the dual-channel injection pump of the microfluidic device, start the injection pump, so that the oil phase solution and the aqueous phase solution are fully mixed and dispersed in the microfluidic chip, collect the effluent, and obtain the initial solution of dexamethasone palmitate; (4) Adjust the pH of the initial solution to 7.5-8.5, stir evenly at 25-30℃, add water for injection to make up the volume, filter, fill and seal to obtain the injection solution.

2. The preparation method according to claim 1, characterized in that, The concentration of dexamethasone palmitate in the injection solution is 1.0-10.0 g / ml, preferably 2.5-5.0 g / ml.

3. The preparation method according to claim 2, characterized in that, In step (1), the weight ratio of dexamethasone palmitate, soybean oil and egg yolk lecithin is 1:10-50:1-6, preferably 1:20-40:2-5.

4. The preparation method according to claim 1, characterized in that, In step (1), the stirring and dissolving temperature is 60-70℃, preferably 65℃.

5. The preparation method according to claim 1, characterized in that, In step (1), during shear dispersion, the rotation speed is controlled at 6-20 krpm, preferably 10-15 krpm, and more preferably 12 krpm.

6. The preparation method according to claim 1, characterized in that, In step (2), the concentration of glycerol in the aqueous solution is 15-60 g / ml, preferably 25-50 g / ml.

7. The preparation method according to claim 1, characterized in that, In step (3), the flow rate ratio of the oil phase solution and the water phase solution is controlled to be 1:5-10, preferably 1:

7.

8. The preparation method according to claim 1, characterized in that, In step (3), the microfluidic chip is a Tesla structure.

9. The preparation method according to claim 1, characterized in that, In step (4), the pH is adjusted to 7.5-8.5 using hydrochloric acid solution and / or sodium hydroxide solution.

10. Dexamethasone palmitate injection prepared by any one of claims 1-9.

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