3D printing micro-fluidic chip and preparation method of leuprorelin acetate sustained-release microspheres

Abstract

The invention relates to a 3D printing micro-fluidic chip and a preparation method of leuprorelin acetate sustained-release microspheres, and the preparation method comprises the following steps: preparing a micro-fluidic chip, forming a dispersed phase, a continuous phase and a microsphere runner in the micro-fluidic chip, intersecting the dispersed phase and the continuous phase runner to form a microsphere forming part, and forming a dispersed phase inlet, a continuous phase inlet and a microsphere outlet in the surface of the microsphere forming part; a dispersed phase and a continuous phase are prepared, the dispersed phase comprises an organic solvent, leuprorelin or a salt thereof and a degradable polymer, and the continuous phase is a PVA aqueous solution; respectively injecting the dispersed phase and the continuous phase into a dispersed phase runner and a continuous phase runner according to a set proportion to form leuprorelin acetate droplet microspheres, and solidifying the droplet microspheres after the droplet microspheres flow out from a microsphere outlet to obtain the leuprorelin acetate sustained-release microspheres. According to the preparation method, the particle size uniformity of the leuprorelin acetate sustained-release microspheres can be improved, the drug loading capacity and the encapsulation efficiency of the leuprorelin acetate sustained-release microspheres are improved, the drug release period is prolonged, and the drug utilization efficiency is improved.

Description

Technical Field

[0001] The present application relates to the field of drug delivery, and in particular to a method for preparing a 3D printed microfluidic chip and leuprorelin acetate sustained-release microspheres. Background Art

[0002] Leuprorelin is a synthetic gonadotropin drug that mainly acts on the anterior pituitary gland and can promote an early, transient increase in gonadotropin release. It can be used clinically to treat a variety of sex hormone-dependent diseases such as endometriosis, uterine fibroids, precocious puberty and prostate cancer.

[0003] However, because leuprolide is a synthetic polypeptide drug that is easily hydrolyzed, it is unstable in the human body fluid environment. Ordinary leuprolide preparations are easily excreted by the human body after administration and require repeated administration, which can cause certain harm to patients.

[0004] At present, the mainstream long-acting preparation of leuprolide on the market is leuprolide microsphere injection, which is prepared by using a biodegradable polymer as a carrier and fusing leuprolide with the polymer through a certain technology to form small spheres with a particle size of tens of microns. When administering the drug, the microspheres are dispersed in a specific dispersion medium and injected into the subcutaneous tissue or muscle tissue of the human body through a syringe. The leuprolide-polymer microspheres injected into the human body release leuprolide as the polymer skeleton is gradually degraded and absorbed by the human body, thereby achieving the purpose of long-term drug administration.

[0005] Existing leuprorelin microsphere preparation technologies are all based on the double emulsion-solvent evaporation method. Although the double emulsion-solvent evaporation method has high technical maturity, due to the various preparation process parameters of the double emulsion-solvent evaporation method, and leuprorelin is easily soluble in water, this leads to poor drug encapsulation efficiency and unstable product quality of the produced leuprorelin microspheres during large-scale production. In addition, the microsphere preparations produced by the double emulsion-solvent evaporation method have a wide particle size distribution range and poor stability between different batches, which can cause the drug to be released suddenly in a short time, causing early toxic and side effects, shortening the effective action time of the drug, and poor therapeutic effect. Based on the deficiencies in the prior art, it is urgent to develop a new preparation technology for leuprorelin sustained-release microspheres, so as to prepare leuprorelin sustained-release microspheres with highly uniform particle size and high drug loading.

[0006] To this end, the present invention is proposed. Summary of the invention

[0007] In view of the problems existing in the background technology, the present application provides a 3D printed microfluidic chip and a single emulsification preparation method of leuprorelin acetate sustained-release microspheres, which can improve the particle size uniformity of leuprorelin acetate sustained-release microspheres, increase the drug loading and encapsulation rate of leuprorelin acetate sustained-release microspheres, extend the drug release cycle, and increase the utilization efficiency of the drug.

[0008] According to one aspect of the present invention, a 3D printed microfluidic chip and a single emulsification preparation method of leuprorelin acetate sustained-release microspheres are provided, comprising the following steps: preparing a microfluidic chip, wherein a dispersed phase flow channel, a continuous phase flow channel and a microsphere flow channel are formed in the microfluidic chip, wherein the dispersed phase flow channel and the continuous phase flow channel intersect to form a microsphere formation location and are connected to the microsphere flow channel, and a dispersed phase inlet connected to the dispersed phase flow channel, a continuous phase inlet connected to the continuous phase flow channel and a microsphere flow channel are formed on the surface of the microfluidic chip. The microsphere flow channel is connected to a microsphere outlet; a dispersed phase and a continuous phase are configured, wherein the components of the dispersed phase include an organic solvent, leuprorelin or its salt and a degradable polymer, and the continuous phase is a PVA aqueous solution; the dispersed phase and the continuous phase are respectively injected into the dispersed phase flow channel and the continuous phase flow channel according to a set ratio, and leuprorelin acetate droplet microspheres are formed at the microsphere formation location, and the leuprorelin acetate droplet microspheres flow through the microsphere flow channel and flow out from the microsphere outlet and then solidify to obtain leuprorelin acetate sustained-release microspheres.

[0009] In some embodiments of the present invention, the microfluidic chip is prepared based on 3D printing technology, and the preparation of the microfluidic chip includes the following steps: designing a microfluidic chip structure; preparing the designed microfluidic chip using 3D printing technology; cleaning the prepared microfluidic chip and performing a hydrophilic treatment; and connecting the inlet and outlet of the hydrophilic treated microfluidic chip.

[0010] In some embodiments of the present invention, more than one group of the dispersed phase flow channel, continuous phase flow channel and microsphere flow channel is provided in the microfluidic chip, and each group of the dispersed phase flow channel, continuous phase flow channel and microsphere flow channel is respectively connected to the dispersed phase inlet, continuous phase inlet and microsphere outlet on the surface of the microfluidic chip.

[0011] In some embodiments of the present invention, the cleaning and hydrophilic treatment of the microfluidic chip includes: after cleaning the internal flow channel of the microfluidic chip with fluoride solution, the internal flow channel of the microfluidic chip is treated with piranha solution and potassium hydroxide / sodium hydroxide solution in sequence.

[0012] In some embodiments of the present invention, the solidification process of the leuprorelin acetate droplet microspheres includes: dispersing the leuprorelin acetate droplet microspheres into a receiving liquid; then solidifying the leuprorelin acetate droplet microspheres under magnetic stirring in the receiving liquid; centrifuging, washing and drying the solidified leuprorelin acetate sustained-release microspheres in sequence to obtain leuprorelin acetate sustained-release microspheres.

[0013] In some embodiments of the present invention, after the dispersed phase is prepared, the dispersed phase is filtered using an organic filter membrane; and / or after the continuous phase is prepared, the continuous phase is filtered using an aqueous filter membrane.

[0014] In some embodiments of the present invention, the flow ratio of the dispersed phase to the continuous phase is 1:10 to 1:1000.

[0015] In some embodiments of the present invention, the degradable polymer is selected from one of PLGA, PLA, PGA, and PCL.

[0016] In some embodiments of the present invention, the organic solvent is selected from one or more of ethyl acetate, dichloromethane, methyl acetate, chloroform, ethanol, methanol, acetonitrile, acetone and chloroform.

[0017] Compared with the prior art, the present invention achieves the following technical effects:

[0018] 1. The present invention prepares leuprorelin acetate sustained-release microspheres based on droplet microfluidics technology. Compared with traditional emulsification-volatilization method, phase separation method, spray drying method, etc., the particle size of leuprorelin acetate sustained-release microspheres prepared by this technology is uniform and controllable.

[0019] 2. The present invention prepares leuprorelin acetate microspheres by a single emulsification method, thereby avoiding the problems of cumbersome process, low yield, low drug loading, and rapid drug burst release in the traditional double (compound) emulsification method for preparing leuprorelin microspheres.

[0020] 3. The microfluidic chip used in the present invention is prepared by 3D printing integrated processing; the use of 3D printing technology to prepare microfluidic chips has the advantages of flexible design, low processing cost and simple process. When the microchannel structure needs to be adjusted, it only needs to be re-modeled and printed, eliminating the step of remaking the mold or mask in the traditional process; the printed microfluidic chip can be used to prepare leuprorelin acetate sustained-release microspheres after a simple hydrophilic treatment. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Various other advantages and benefits will become apparent to those of ordinary skill in the art by reading the detailed description of the preferred embodiments below. The accompanying drawings are only for the purpose of illustrating the preferred embodiments and are not to be considered as limiting the present application. Also, the same reference symbols are used throughout the accompanying drawings to represent the same components. In the accompanying drawings:

[0022] Figure 1 A flow chart of preparing leuprorelin acetate sustained-release microspheres by a single emulsification method based on microfluidic technology provided by the present invention;

[0023] Figure 2 A top view of a co-flow 3D printed microfluidic chip provided by the present invention;

[0024] Figure 3 A front view of a co-flow 3D printed microfluidic chip provided by the present invention;

[0025] Figure 4 A diagram showing the formation process of leuprorelin acetate sustained-release microspheres based on a co-flow 3D printed microfluidic chip provided by the present invention;

[0026] Figure 5 A top view of a shear-type 3D printed microfluidic chip provided by the present invention;

[0027] Figure 6 A front view of a shear-type 3D printed microfluidic chip provided by the present invention;

[0028] Figure 7 A diagram showing the formation process of leuprorelin acetate sustained-release microspheres based on a shear-type 3D-printed microfluidic chip provided by the present invention;

[0029] Figure 8 An optical microscope image of leuprorelin acetate sustained-release microspheres prepared by the preparation method provided by the present invention;

[0030] Fig. 9 The particle size distribution diagram of leuprorelin acetate sustained-release microspheres prepared by the preparation method provided by the present invention.

[0031] The reference numerals in the accompanying drawings represent the following: 1, dispersed phase inlet; 2, continuous phase inlet; 3, microsphere outlet; 4, dispersed phase flow channel; 5, continuous phase flow channel; 6, microsphere formation site; 7, microsphere flow channel; 8, dispersed phase solution; 9, continuous phase solution; 10, leuprorelin acetate droplet microspheres. DETAILED DESCRIPTION

[0032] It should be clear that the described embodiments are only part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in the field without creative work are within the scope of protection of the present application.

[0033] When the following description refers to the drawings, unless otherwise indicated, the same numbers in different drawings represent the same or similar elements. The embodiments described in the following exemplary embodiments do not represent all embodiments consistent with the present application. Instead, they are only examples of devices and methods consistent with some aspects of the present application as detailed in the attached claims.

[0034] In the description of the present application, it should be understood that the terms "first", "second", etc. are used for descriptive purposes only and should not be understood as indicating or implying relative importance. For those of ordinary skill in the art, the specific meanings of the above terms in the present application can be understood according to the specific circumstances. In addition, in the description of the present application, unless otherwise specified, "multiple" refers to two or more. "And / or" describes the association relationship of associated objects, indicating that three relationships may exist. For example, A and / or B can represent: A exists alone, A and B exist at the same time, and B exists alone. The character " / " generally indicates that the previously associated objects are in an "or" relationship.

[0035] The present application discloses a 3D printed microfluidic chip and a single emulsion preparation method for leuprorelin acetate sustained-release microspheres. Figure 1 As shown, the preparation method of leuprorelin acetate sustained-release microspheres comprises the following steps:

[0036] Step S1, designing a microfluidic chip structure.

[0037] In some embodiments of the present invention, according to the production requirements of the leuprorelin acetate droplet microspheres 10, the microfluidic chip may include one or more microfluidic unit structures, preferably a microfluidic chip integrating multiple microfluidic unit structures to increase the production of the leuprorelin acetate sustained-release microspheres.

[0038] It should be understood that the microfluidic chip may include 1, 4, 5, 12, 48 or 96 microfluidic unit structures.

[0039] In this embodiment, each microfluidic unit structure includes a dispersed phase flow channel 4, a continuous phase flow channel 5 and a microsphere flow channel 7, and the dispersed phase flow channel 4, the continuous phase flow channel 5 and the microsphere flow channel 7 are arranged in the microfluidic chip, wherein the dispersed phase flow channel 4 and the continuous phase flow channel 5 intersect to form a microsphere forming area 6 for microsphere generation and connected with the microsphere flow channel 7.

[0040] A dispersed phase inlet 1, a continuous phase inlet 2 and a microsphere outlet 3 are formed on the surface of the microfluidic chip. The dispersed phase flow channel 4 of each microfluidic unit structure is respectively connected to the dispersed phase inlet 1, the continuous phase flow channel 5 is respectively connected to the continuous phase inlet 2, and the microsphere flow channel 7 is respectively connected to the microsphere outlet 3.

[0041] In some embodiments of the present invention, a main flow channel is also provided in the microfluidic chip, and the main flow channel includes a dispersed phase main flow channel connected to the dispersed phase inlet 1, a continuous phase main flow channel connected to the continuous phase inlet 2, and a microsphere main flow channel connected to the microsphere outlet 3. The dispersed phase flow channel 4, continuous phase flow channel 5 and microsphere flow channel 7 of each microfluidic unit structure are respectively connected to the corresponding main flow channel as branch channels.

[0042] In some embodiments of the present invention, according to the formation method of the leuprolide acetate droplet microspheres 10, a microfluidic chip such as a co-flow microfluidic chip or a shear microfluidic chip can be designed.

[0043] like Figure 2 and Figure 3 Shown are a top view and a front view of a co-flow microfluidic chip, respectively. The co-flow microfluidic chip includes five microfluidic unit structures.

[0044] like Figure 5 and Figure 6 Shown are a top view and a front view of a shear-type microfluidic chip, respectively. The shear-type microfluidic chip includes four microfluidic unit structures.

[0045] In some embodiments of the present invention, the width of the continuous phase flow channel 5 and the dispersed phase flow channel 4 as branch channels is 30-100 μm, and the width of the intersection of the continuous phase flow channel 5 and the dispersed phase flow channel 4 for microsphere generation is 20-60 μm.

[0046] Step S2, printing the microfluidic chip using 3D printing technology.

[0047] In some embodiments of the present invention, 3D printing technology includes but is not limited to photo-stereolithography 3D printing technology and digital light processing 3D printing technology.

[0048] The specific steps of printing microfluidic chips using 3D printing technology can be as follows: first, slice the designed microfluidic chip model before printing; then use acrylic photosensitive resin as the printing material, adjust the parameters of the 3D printer with a printing accuracy of 2μm in advance according to different printing requirements, and then start printing the microfluidic chip.

[0049] The use of 3D printing technology to prepare microfluidic chips has high flexibility. When the chip structure needs to be adjusted, it only needs to be remodeled, which greatly simplifies the preparation process of microfluidic chips, and the prepared microfluidic chips can be reused.

[0050] Step S3, cleaning the microfluidic chip and performing hydrophilic treatment.

[0051] First, the internal flow channel of the printed microfluidic chip is filled with uncured resin material. The cleaning liquid can be sucked out of the syringe to repeatedly rinse the flow channel until it is clean and dry, and then the microfluidic chip is cured again for 10 to 20 minutes using a UV curing device.

[0052] In this embodiment, the cleaning liquid may be a fluorinated liquid.

[0053] Secondly, the internal flow channel of the microfluidic chip that has not been hydrophilically treated is not conducive to the generation of water-in-oil droplet microspheres, so piranha solution and sodium hydroxide / potassium hydroxide solution are used to hydrophilize the flow channel to form a hydrophilic layer.

[0054] The specific steps of hydrophilic treatment can be: use a syringe to inject the newly prepared piranha solution and sodium hydroxide solution into the microfluidic chip in sequence, filling the entire flow channel, and after standing for a period of time, repeatedly rinse the flow channel with ultrapure water, dry it and set it aside.

[0055] By performing hydrophilic treatment on the printed microfluidic chip, it can be used to prepare leuprorelin acetate sustained-release microspheres with highly uniform particle size.

[0056] Step S4, connection of microfluidic chip.

[0057] The microfluidic chip is connected to the microfluidic pressure control system through an external tube. The connection between the microfluidic chip and the external tube can be achieved by a glue-assisted PEEK joint connection or a clamp connection.

[0058] The connection method of the glue-assisted PEEK connector can be specifically: the PEEK connector is adhered to the continuous phase inlet 2, the dispersed phase inlet 1 and the microsphere outlet 3 on the surface of the microfluidic chip through glue, and after the glue is dried at room temperature, the microfluidic chip is connected to the microfluidic pressure control system through an external tube.

[0059] In addition, the glue and external pipe used for connection need to consider their resistance to water and organic solutions, and acrylic glue and Teflon external pipe are preferably selected.

[0060] Step S5, preparing leuprorelin acetate sustained-release microspheres.

[0061] Step S501, configuring a dispersed phase and a continuous phase.

[0062] In some embodiments of the present invention, the dispersed phase includes an organic solvent, leuprolide or a salt thereof and a degradable polymer, and the organic solvent, leuprolide or a salt thereof and the degradable polymer are uniformly mixed to obtain the dispersed phase.

[0063] In some embodiments of the present invention, the degradable polymer includes, but is not limited to, biodegradable materials such as poly(lactic-co-glycolic acid) (PLGA), polylactic acid (PLA), polyglycolic acid (PGA), polycaprolactone (PCL), etc. Preferably, the degradable polymer is PLGA.

[0064] In some embodiments of the present invention, the organic solvent is selected from one or more of ethyl acetate, dichloromethane, methyl acetate, chloroform, ethanol, methanol, acetonitrile, acetone, and chloroform. Preferably, the organic solvent is a combination of ethanol and ethyl acetate.

[0065] In some embodiments of the present invention, leuprolide or its salt is leuprolide acetate.

[0066] In some embodiments of the present invention, the components and contents of the dispersed phase are: 0.8-2 ml of ethanol; 3.2-8 mL of ethyl acetate; 30-250 mg of leuprorelin or its salt; and 0.125-2.35 g of a degradable polymer.

[0067] In some embodiments of the present invention, polyvinyl alcohol (PVA) is used as a solute, and a PVA aqueous solution is prepared as a continuous phase, and the concentration of the PVA aqueous solution is 0.25% w / v to 3% w / v. Preferably, a 1% w / v PVA aqueous solution is used.

[0068] In some embodiments of the present invention, after the dispersed phase is configured, the dispersed phase is filtered using an organic filter membrane, and after the continuous phase is configured, the continuous phase is filtered using an aqueous filter membrane to prevent the dispersed phase and the continuous phase from clogging the microfluidic chip.

[0069] Step S502, preparing leuprorelin acetate liquid droplet microspheres 10.

[0070] The dispersed phase and the continuous phase are respectively injected into the dispersed phase flow channel 4 and the continuous phase flow channel 5 according to a set ratio, and leuprorelin acetate droplet microspheres 10 are formed at the microsphere forming area 6.

[0071] The specific process of forming the leuprorelin acetate droplet microspheres 10 is as follows: a continuous phase solution 9 and a dispersed phase solution 8 are respectively injected into the continuous phase inlet 2 and the dispersed phase inlet 1 of the microfluidic chip at a certain flow rate using a microfluidic pressure control system; the dispersed phase and the continuous phase solutions form leuprorelin acetate droplet microspheres 10 at the microsphere forming location 6 of the microfluidic chip; the leuprorelin acetate droplet microspheres 10 flow through the microsphere outlet 3 and then flow into a beaker containing a receiving solution through an external pipe.

[0072] like Figure 4 Shown is the microsphere formation process corresponding to the co-flow microfluidic chip.

[0073] like Figure 7 The figure shows the microsphere formation process corresponding to the shear-type microfluidic chip.

[0074] In some embodiments of the present invention, the flow ratio of the dispersed phase to the continuous phase is 1:10 to 1:1000.

[0075] Step S6, collecting leuprorelin acetate sustained-release microspheres.

[0076] The microspheres loaded with leuprolide acetate were dispersed in a beaker containing a receiving solution. In order to accelerate the solidification speed of the microspheres, they were collected under magnetic stirring. After the microspheres were collected, 0.45 μm organic filter paper was used to wash the microspheres by suction filtration using a circulating water pump and ultrapure water to remove the residual PVA, ethyl acetate and leuprolide acetate that were not encapsulated by PLGA on the surface of the microspheres.

[0077] The washed microspheres were placed in a freeze dryer and freeze-dried at -60°C for 24 to 48 hours to obtain leuprorelin acetate sustained-release microspheres.

[0078] In some embodiments of the present invention, the receiving solution may be a 1% to 3% w / v PVA aqueous solution.

[0079] In some embodiments of the present invention, the speed of magnetic stirring is 0 to 300 r / min, preferably 50 to 300 r / min.

[0080] The present invention utilizes a single emulsification method to prepare leuprolide acetate sustained-release microspheres, which can effectively avoid the cumbersome process of preparing leuprolide acetate microspheres by a double emulsion method. The method is used to prepare a microfluidic chip and leuprolide acetate sustained-release microspheres, which have the advantages of simple processing, concise preparation process, low production cost, easy high-throughput production, and the like. Not only can the prepared microfluidic chip be reused, but the particle size of the prepared leuprolide acetate sustained-release microspheres is uniform and controllable, thereby improving the drug loading amount and encapsulation rate of the leuprolide acetate sustained-release microspheres, prolonging the drug release cycle, and increasing the utilization efficiency of the drug. The microfluidic chip can be used to treat sex hormone-dependent diseases such as endometriosis, prostate cancer, uterine fibroids, and precocious puberty.

[0081] The preparation method of the above-mentioned leuprorelin acetate sustained-release microspheres in this application will be further described below in conjunction with specific examples.

[0082] Example 1

[0083] In this embodiment, leuprolide acetate is dissolved in ethanol as liquid A, PLGA is dissolved in ethyl acetate as liquid B, liquid A and liquid B are mixed evenly as dispersed phase, PVA aqueous solution is used as continuous phase, dispersed phase and continuous phase solutions are respectively injected into dispersed phase and continuous phase inlets of a microfluidic chip, and leuprolide acetate droplet microspheres are formed when the solution flows through the intersection of the dispersed phase and continuous phase flow channels, and then solidified after flowing out of the microsphere outlet. The solidified microspheres are washed and freeze-dried to obtain leuprolide acetate sustained-release microspheres.

[0084] The drug-loaded microspheres finally prepared in this example use biodegradable PLGA as the carrier skeleton, and leuprolide acetate is encapsulated in PLGA. Figure 8 and Fig. 9Shown are an optical microscope image and a particle size distribution diagram of leuprorelin acetate sustained-release microspheres, respectively. The average particle size of the prepared leuprorelin acetate sustained-release microspheres is 32 μm, and the CV value is 6.2%.

[0085] The above is only a preferred specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Any changes or substitutions that can be easily thought of by a person skilled in the art within the technical scope disclosed by the present invention should be included in the protection scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.

Claims

1. A single emulsification preparation method of a 3D printed microfluidic chip and leuprorelin acetate sustained-release microspheres, characterized in that: The following steps are involved: A microfluidic chip is prepared, wherein a dispersed phase flow channel, a continuous phase flow channel and a microball flow channel are formed in the microfluidic chip, the dispersed phase flow channel and the continuous phase flow channel intersect to form a microball formation location and are connected to the microball flow channel, and a dispersed phase inlet connected to the dispersed phase flow channel, a continuous phase inlet connected to the continuous phase flow channel and a microball outlet connected to the microball flow channel are formed on the surface of the microfluidic chip; A dispersed phase and a continuous phase are configured, wherein the dispersed phase comprises an organic solvent, leuprorelin or a salt thereof and a degradable polymer, and the continuous phase is a PVA aqueous solution; The dispersed phase and the continuous phase are respectively injected into the dispersed phase flow channel and the continuous phase flow channel according to a set ratio, and leuprorelin acetate droplet microspheres are formed at the microsphere formation site. The leuprorelin acetate droplet microspheres flow through the microsphere flow channel and flow out from the microsphere outlet and then solidify to obtain leuprorelin acetate sustained-release microspheres.

2. The preparation method according to claim 1, characterized in that: The microfluidic chip is prepared based on 3D printing technology, and the preparation of the microfluidic chip includes the following steps: Design microfluidic chip structure; The designed microfluidic chip was prepared using 3D printing technology; Cleaning the prepared microfluidic chip and subjecting it to hydrophilic treatment; Connect the inlet and outlet of the hydrophilic treated microfluidic chip.

3. The preparation method according to claim 2, characterized in that: The dispersed phase flow channel, continuous phase flow channel and microsphere flow channel are provided in more than one group in the microfluidic chip, and each group of dispersed phase flow channel, continuous phase flow channel and microsphere flow channel is respectively connected to the dispersed phase inlet, continuous phase inlet and microsphere outlet on the surface of the microfluidic chip.

4. The preparation method according to claim 2, characterized in that: The cleaning and hydrophilic treatment of the microfluidic chip includes: After the internal flow channel of the microfluidic chip was cleaned with fluoride solution, the internal flow channel of the microfluidic chip was treated with piranha solution and potassium hydroxide / sodium hydroxide solution in sequence.

5. The preparation method according to claim 1, characterized in that: The solidification process of the leuprorelin acetate droplet microspheres comprises: dispersing leuprolide acetate droplet microspheres into a receiving solution; Then, the leuprolide acetate droplet microspheres were solidified in the receiving solution under magnetic stirring; The solidified leuprorelin acetate sustained-release microspheres are centrifuged, washed and dried in sequence to obtain leuprorelin acetate sustained-release microspheres.

6. The preparation method according to claim 1, characterized in that: After the dispersed phase is prepared, the dispersed phase is filtered using an organic filter membrane; and / or After the continuous phase is prepared, the continuous phase is filtered using a water filter membrane.

7. The preparation method according to claim 1, characterized in that: The flow ratio of the dispersed phase to the continuous phase is 1:10 to 1:1000.

8. The preparation method according to claim 1, characterized in that: The degradable polymer is selected from one of polylactic acid-co-glycolic acid (PLGA), polylactic acid (PLA), polyglycolic acid (PGA), and polycaprolactone (PCL).

9. The preparation method according to claim 1, characterized in that: The organic solvent is selected from one or more of ethyl acetate, dichloromethane, methyl acetate, chloroform, ethanol, methanol, acetonitrile, acetone and chloroform.

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