A method for preparing microspheres based on an emulsion tank with a countercurrent zone

Abstract

The present invention relates to the field of microsphere production, and specifically to a method for preparing microspheres based on an emulsion tank with a countercurrent zone, comprising the following steps: S1 injecting an external aqueous phase into an emulsion tank through an external aqueous phase inlet, so that the external aqueous phase is substantially filled in the internal volume of the emulsion tank, wherein the emulsion tank comprises a tank body and a homogenizer inserted into the tank body; the dispersing blade comprises a stator and a rotor, and a countercurrent zone exists below the rotor; S2 continuously injecting colostrum and an external aqueous phase into the internal volume; S3 collecting the homogenized emulsion flowing out of the outlet. The preparation method provided by the present invention can not only continuously and in large quantities prepare emulsions, but also the prepared emulsions have stable quality and good consistency, thereby realizing the industrial production of microspheres.

Description

Technical Field

[0001] The invention relates to the field of microsphere production, and in particular to a method for preparing microspheres based on an emulsion tank with a countercurrent zone. Background Art

[0002] Conventional preparation methods for microspheres include double emulsion method, phase separation method, spray drying method and hot melt extrusion method, among which the most classic preparation method is double emulsion method. Many microsphere production processes in the prior art are based on double emulsion-solvent evaporation method (w / o / w method). However, due to the strong water solubility of polypeptide drugs, the many process parameters of double emulsion-solvent evaporation method, and the high performance requirements of equipment, most of the current industrial microsphere production processes use non-continuous processes (which can also be understood as micro-batch production processes). Non-continuous processes, and the prepared microspheres are not only small in batch size, but also have too wide a particle size distribution (for example, a distribution of 1-400μm), easy to agglomerate, and the particle size distribution of microspheres will change with changes in production scale, making it impossible to achieve large-scale production of microspheres.

[0003] In order to expand the scale of production, the conventional idea of ​​the prior art is to expand the volume of the emulsion production container (e.g., 50-500L) to expand the emulsion production, but the practice of expanding the emulsion production container is easy to cause a part of the emulsion to be repeatedly homogenized while the other part of the emulsion cannot be homogenized in actual production. As the production time and batch size increase, this will cause the oil-water ratio of the material in the emulsion production container to be unbalanced, thereby causing quality problems of the emulsion (and microspheres). In other words, in the field of microsphere production, there is a problem of difficulty in expanding the production scale, and it is difficult to expand the current laboratory scale to the industrial production scale.

[0004] In order to overcome the above technical problems, the prior art has developed a method for producing emulsions based on high-pressure homogenization, cyclic shearing, etc. to try to expand the production of emulsions (or microspheres). For example, Chinese patent application CN110787134A discloses a method for preparing microspheres in a continuous process, and its main technical route is to subject the instantly formed emulsion to high pressure treatment to instantly generate microspheres; Chinese patent application CN102389756B discloses a method for producing emulsions of a two-tank circulation method of an emulsion tank and a volatilizer, and its main technical route is to prepare the first part of the emulsion-two-tank overall circulation-prepare the second part of the emulsion-two-tank overall circulation; Chinese patent application CN106668831B discloses a method for preparing leuprorelin microspheres, and its main route is to use a fully enclosed online emulsification (multiple cyclic shearing) method to produce emulsions by accurately controlling temperature and pressure. However, the above-mentioned emulsion production processes all have problems such as complex production systems and the need to control multiple parameters, and are difficult to apply to industrial production. US patent application US5945126 discloses a method for continuously producing microspheres based on an integrally formed in-line mixer, the main technical route of which is to use one end of the working head of the in-line mixer (e.g., including a precisely machined rotor / blade) to instantly absorb and homogenize the external aqueous phase and colostrum to instantly generate a double emulsion, and the generated double emulsion is instantly discharged directly from the in-line mixer along the pipeline system located at the other end of the working head. Although such a production process can speed up the production speed of microspheres and promote the continuous production of microspheres to a certain extent, the production process has low stability, especially in the process of mass-producing and rapid microsphere production, it is easy to have quality problems such as low drug embedding rate of the obtained microspheres. Therefore, it is still difficult to truly achieve stable and continuous production of high-quality microspheres, and it has not been promoted in practical applications.

[0005] In summary, achieving continuous production of microspheres with stable quality is the bottleneck for process scale-up in the field of microsphere production. Summary of the invention

[0006] The present invention provides a method for continuously preparing a double emulsion, characterized in that it comprises the following steps:

[0007] S1: injecting the external aqueous phase into the emulsion tank through the external aqueous phase inlet, so that the external aqueous phase substantially fills the internal volume of the emulsion tank, wherein the emulsion tank comprises a tank body and a homogenizer inserted into the tank body, the tank body comprises a tank inner wall, the tank inner wall comprises a side wall, a bottom wall and a top wall, the two sides of the side wall are respectively connected to the bottom wall and the top wall, and together form the internal volume of the emulsion tank; the homogenizer comprises a homogenizing rod and a dispersing blade head connected to the lower end of the homogenizing rod, the dispersing blade head extends to the internal volume; the tank body further comprises one or more colostrum inlets, and one or more external aqueous phase inlets, the colostrum inlet is used to guide the colostrum to be injected into the internal volume; the external aqueous phase The inlet is used to guide the external aqueous phase to be injected into the internal volume; the tank body also includes one or more outlets for guiding the emulsion formed in the tank body to flow out of the internal volume; the first end of the colostrum inlet is arranged to be opposite to the dispersion cutter head; the dispersion cutter head includes a stator and a rotor, the stator includes a stator wall, the stator wall is arranged to be cylindrical and accommodates the rotor therein; the lower end opening of the stator wall is used to allow liquid to enter the dispersion cutter head, and there is a countercurrent zone under the rotor, the countercurrent zone is used to provide space for liquid to flow in the reverse direction in the internal volume, the volume of the countercurrent zone accounts for 20%-80% of the internal volume, and the volume of the internal volume is 0.1-5.0L;

[0008] S2: continuously injecting colostrum and external aqueous phase into the internal volume through the colostrum inlet and the external aqueous phase inlet respectively, and starting the homogenizer to emulsify and homogenize the mixed solution of the colostrum and the external aqueous phase to generate a homogenized double emulsion;

[0009] S3 collects the homogenized emulsion flowing out from the outlet;

[0010] The colostrum comprises a mixed solution of a homogenized oil phase and an inner aqueous phase, the oil phase comprises an organic solvent and a high molecular polymer dissolved in the organic solvent, the inner aqueous phase comprises an aqueous solution and a polypeptide drug dissolved in the aqueous solution, and the outer aqueous phase comprises a polyvinyl alcohol aqueous solution; the injection rate of the colostrum is at most 0.30 L / min, and the injection rate of the outer aqueous phase is at least 30 times the injection rate of the colostrum.

[0011] In some embodiments, the linear speed of the dispersing blade head comprises 4.7-26.0 m / s.

[0012] In some embodiments, the high molecular polymer includes one or more of PLGA, polylactic acid, polyglycolic acid, polycitric acid, polymalic acid, polycaprolactone, poly-β-hydroxybutyric acid, lactic acid-hydroxyglycolic acid copolymer, polylactic acid-polyethylene glycol copolymer and 2-hydroxybutyric acid-glycolic acid copolymer.

[0013] In some embodiments, the organic solvent includes one or more of dichloromethane, chloroform, and ethyl acetate.

[0014] In some embodiments, the polypeptide drug includes one or more of leuprolide, goserelin, triptorelin, octreotide, exenatide, semaglutide, GLP-1 receptor agonist and GIP receptor agonist.

[0015] In some embodiments, a distance L between the rotor and the bottom wall is ≤ 20 cm.

[0016] In some embodiments, the diameter D of the lower opening of the stator wall is 1 Including 0.5-7.0cm.

[0017] In some embodiments, the diameter D of the lower opening of the stator wall is 1 Includes 1.5–5.0cm.

[0018] In some embodiments, the width of the gap between the stator wall and the rotor is set to a second distance X 2 In some embodiments, the second distance X 2 Including 0.1–5.0mm.

[0019] In some embodiments, a third distance X is set between the first end of the colostrum inlet and the dispersion blade head. 3 , the third distance X 3 At most 5cm.

[0020] In some embodiments, the third distance X 3 Can be set to nearly 0.

[0021] In some embodiments, the volume of the internal volume comprises 0.5-2.0L.

[0022] In some embodiments, the concentration of the high molecular weight polymer in the oil phase comprises 10-40 wt %.

[0023] In some embodiments, the concentration of the polypeptide drug in the internal aqueous phase comprises 30-70 wt %.

[0024] In some embodiments, the temperature of the internal volume comprises 0-30°C.

[0025] The continuous emulsion preparation method based on the emulsion tank with a countercurrent zone provided by the present invention has at least the following advantages:

[0026] (1) The emulsion tank provided by the present invention and the homogenizer inserted therein constitute a three-layer structure ("side wall-stator wall-rotor") from outside to inside and a two-layer area (a pre-curing flow channel S formed by the gap between the side wall and the stator wall and a homogenizing zone H formed by the gap between the stator wall and the rotor). The above three-layer structure can change the flow mode of the liquid (for example, colostrum, external water phase, and emulsion formed by the mixture of colostrum and external water phase, etc.) in the emulsion tank and the environment in which it flows to a certain extent, thereby being more conducive to the continuous generation of emulsion. In addition to the above homogenizing zone H and the above pre-curing flow channel S, the present invention also sets a countercurrent zone Z below the rotor 109. The continuous emulsion preparation method provided by the present invention is to continuously add the external water phase and colostrum into an emulsion tank having the three-layer structure ("side wall-stator wall-rotor"), two-layer area and countercurrent zone Z as described above. Under the appropriate shearing action of the dispersion blade, the generated second emulsion can be pre-cured to a certain extent in the internal volume of the emulsion tank and then continuously flow out from the outlet, thereby continuously preparing an emulsion with good quality and high yield.

[0027] (2) In the continuous emulsion preparation process of the present invention, the oil-water ratio of the material in the internal volume can be further controlled to always be maintained at a suitable ratio by matching the injection speed of the external water phase and the colostrum. In other words, in one emulsion preparation, the generation and pre-curing environment of the second emulsion produced at an earlier time and the second emulsion produced at a later time can be kept highly similar, which to a certain extent ensures the quality stability of the emulsion continuously prepared by the present invention (e.g., smaller batch differences, see t1 Dv50 and t2 Dv50 in Table 1 of the present invention). In addition, the continuous emulsion preparation method provided by the present invention also to a certain extent ensures that the second emulsion can stay in the internal volume for a more suitable time, avoiding the quality problems of the microspheres caused by rapid outflow or long-term retention.

[0028] (3) The second emulsion prepared by the method provided by the present invention can achieve a certain degree of pre-solidification in the internal volume, reduce the organic solvent residue of the microspheres in the homogenized emulsion and ensure a high embedding rate of the microspheres. Specifically, after the second emulsion overflows from the homogenization zone H and contacts the external aqueous phase in the countercurrent zone Z provided by the present invention, it will begin to "pre-solidify". On the one hand, as the second emulsion continues to flow in the countercurrent zone Z, the flow path and residence time of the second emulsion in the internal volume will be further extended, which enables the external aqueous phase in the countercurrent zone Z to extract the organic solvent therein to a certain extent. Therefore, the emulsion prepared by the continuous emulsion preparation method provided by the present invention can be pre-solidified more fully before undergoing the solidification step, and the organic solvent residue of the microspheres in the second emulsion is reduced. On the other hand, due to the "pre-solidification" of the second emulsion, the polypeptide drug in the microspheres is not easy to diffuse in the external aqueous phase. Therefore, even if the residence time of the second emulsion in the internal volume is extended, the problem of the polypeptide drug diffusing to the external aqueous phase often faced by the prior art will not occur. In summary, the continuous emulsion preparation method provided by the present invention can produce high-quality emulsions in large quantities, and the microspheres in the emulsions can also maintain a high embedding rate level (for example, above 90%).

[0029] (4) Based on the substantial filling of the external aqueous phase and the sealing setting of the emulsion tank, the continuous emulsion preparation method provided by the present invention can avoid the introduction of external gas into the internal volume and its contact with the liquid in the tank to a certain extent, thereby avoiding the influence of foam on the quality of the emulsion (or microspheres) during the emulsion preparation process.

[0030] (5) Without the need for complex parameter control (such as special temperature, pressure and steps (such as cyclic shear), the continuous emulsion preparation method provided by the present invention can not only continuously, in large quantities and stably prepare emulsions, but also the prepared emulsions have stable quality and good consistency, thus realizing the industrial production of microspheres. Specifically, the batch-to-batch difference is small, and the quality of microspheres in different stages of the same batch and in the same stage of different batches can be kept stable. According to the continuous emulsion preparation method provided by the present invention, the D50 average particle size of the microspheres in the prepared emulsion can be controlled at 11-13 μm, which is particularly suitable for preparing injections.

[0031] (6) The method for preparing the multiple emulsion provided by the present invention has high repeatability. After testing, microspheres with stable quality can be continuously produced under various production conditions, without being restricted by specific raw materials (e.g., oil phase, external aqueous phase, internal aqueous phase), and is suitable for large-scale and stable production of microspheres of various drugs. In addition, the multiple emulsion prepared by the method for preparing the multiple emulsion provided by the present invention can directly proceed to the subsequent steps of solidification, freeze drying, etc., without the need for re-emulsification (or homogenization), and has high production efficiency. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] In order to more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings required for use in the embodiments or the prior art descriptions are briefly introduced below. In all the drawings, similar elements or parts are generally identified by similar reference numerals. In the drawings, each element or part is not necessarily drawn according to the actual scale. Obviously, the drawings described below are some embodiments of the present invention. For those of ordinary skill in the art, other drawings can also be obtained based on these drawings without paying creative labor.

[0033] Figure 1 This is a first structural schematic diagram of an emulsion tank according to Embodiment 1 of the present invention;

[0034] Figure 2 This is a second structural schematic diagram of the emulsion tank according to the first embodiment of the present invention;

[0035] Figure 3 The third structural schematic diagram of the emulsion tank according to the first embodiment of the present invention;

[0036] Figure 4 This is a fourth structural schematic diagram of an emulsion tank according to the first embodiment of the present invention;

[0037] Figure 5 is a schematic diagram of the flow path of the second emulsion in the internal volume;

[0038] Figure 6 It is a schematic diagram of preparing multiple emulsions using an online mixer in the prior art.

[0039] Summary of reference numerals:

[0040] 100 is an emulsion tank, 101 is a homogenizer, 102 is a tank body, 103 is a homogenizing rod, 104 is an internal volume, 105 is a dispersing blade, 106 is an inner wall of the tank, 107 is a stator, 108A is a colostrum inlet, 108B is an external water phase inlet, 109 is a rotor, 110 is an outlet, 111 is a stator wall, 113A is an upper end of the stator wall, 113B is an opening at the lower end of the stator wall, and 114A is an emulsion tank 1 00 is the side wall of the emulsion tank 100, 114B is the bottom wall of the emulsion tank 100, 114C is the top wall of the emulsion tank 100, 115A is the upper end of the homogenizing rod, 115B is the lower end of the homogenizing rod, 117 is the inside of the homogenizing rod, 118 is the gap between the stator wall 111 and the side wall 114A, 119 is the gap between the stator wall 111 and the rotor 109, 130 is the jacket, 131 is the cooling water inlet, and 132 is the cooling water outlet. DETAILED DESCRIPTION

[0041] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution in the embodiments of the present invention will be clearly and completely described below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0042] Herein, suffixes such as "module", "component" or "unit" used to represent elements are only used to facilitate the description of the present invention, and have no specific meanings by themselves. Therefore, "module", "component" or "unit" can be used mixedly.

[0043] In this document, the directions or positional relationships indicated by the terms "upper", "lower", "inner", "outer", "front", "rear", "one end", "the other end", etc. are based on the directions or positional relationships shown in the drawings, and are only for the convenience of describing the present invention and simplifying the description, and do not indicate or imply that the devices or elements referred to must have a specific direction, be constructed and operate in a specific direction, and therefore cannot be understood as limiting the present invention. In addition, the terms "first" and "second" are used for descriptive purposes only and cannot be understood as indicating or implying relative importance.

[0044] In this document, unless otherwise clearly specified and limited, the terms "installed", "provided with", "connected", etc. should be understood in a broad sense. For example, "connected" can be a fixed connection, a detachable connection, or an integral connection; it can be a mechanical connection, a direct connection, or an indirect connection through an intermediate medium, or it can be the internal communication of two components. For ordinary technicians in this field, the specific meanings of the above terms in the present invention can be understood according to specific circumstances.

[0045] Herein "and / or" includes any and all combinations of one or more of the associated listed items.

[0046] Herein, "plurality" means two or more than two, ie, it includes two, three, four, five, etc.

[0047] It should be noted that, in this article, the terms "include", "comprises" or any other variations thereof are intended to cover non-exclusive inclusion, so that a process, method, article or device including a series of elements includes not only those elements, but also other elements not explicitly listed, or also includes elements inherent to such process, method, article or device. In the absence of further restrictions, an element defined by the sentence "comprises a ..." does not exclude the existence of other identical elements in the process, method, article or device including the element.

[0048] As used in this specification, the term "about" typically means + / - 5% of the stated value, more typically + / - 4% of the stated value, more typically + / - 3% of the stated value, more typically + / - 2% of the stated value, even more typically + / - 1% of the stated value, and even more typically + / - 0.5% of the stated value.

[0049] In this specification, certain embodiments may be disclosed in a format of being in a certain range. It should be understood that such description of "being in a certain range" is merely for convenience and brevity, and should not be interpreted as a rigid limitation on the disclosed range. Therefore, the description of the range should be considered to have specifically disclosed all possible sub-ranges and independent numerical values ​​within this range. For example, the description of the range 1 to 6 should be considered to have specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc., as well as individual numbers within this range, such as 1, 2, 3, 4, 5 and 6. Regardless of the breadth of the range, the above rules apply.

[0050] In the present invention, Example 1 provides a non-limiting embodiment of an emulsion tank 100 for preparing an emulsion, and Example 2 provides a non-limiting embodiment of a method for preparing an emulsion based on the emulsion tank 100 .

[0051] Example 1 Emulsion tank

[0052] like Figure 1 , Figure 2 and Figure 3 As shown, this example provides a non-limiting embodiment of an emulsion tank 100 for preparing an emulsion.

[0053] The emulsion tank 100 includes a tank body 102 and a homogenizer 101 inserted into the tank body 102. The tank body 102 includes a tank inner wall 106. The tank inner wall 106 includes a side wall 114A, a bottom wall 114B and a top wall 114C, and the two sides of the side wall 114A are respectively connected to the bottom wall 114B and the top wall 114C, and together enclose the internal volume 104 of the emulsion tank 100. The homogenizer 101 includes a homogenizing rod 103 and a dispersing blade head 105 connected to the lower end 115B of the homogenizing rod 103. The dispersing blade head 105 extends into the internal volume 104 to a certain position (for example, a depth in the tank body 102).

[0054] In some embodiments, the shape of the emulsion tank 100 can be a cylinder, a sphere, a nearly spherical body, or a cuboid.

[0055] The tank body 102 further includes one or more colostrum inlets 108A and one or more external aqueous phase inlets 108B. The colostrum inlet 108A is used to guide the colostrum to be injected into the internal volume 104; the external aqueous phase inlet 108B is used to guide the external aqueous phase to be injected into the internal volume 104. The tank body 102 further includes one or more outlets 110, which are used to guide the double emulsion formed in the tank body 102 to flow out of the internal volume 104.

[0056] In some embodiments, the homogenizer 101 is inserted into the tank body 102 from the top wall 114C, the upper end 115A of the homogenizing rod 103 is in a static sealing state with the top wall 114C, and the interior 117 of the homogenizing rod 103 is in a dynamic sealing state.

[0057] The sealing arrangement can keep the emulsion tank 100 sealed during the entire working process (i.e., the emulsion preparation process, the same below), and to a certain extent avoid or reduce the introduction of external gas into the internal volume 104. The sealing arrangement can to a certain extent control the generation of bubbles or foams in the internal volume 104 that may be caused by the introduction of new gas from the outside, thereby to a certain extent ensuring that the quality of the large amount of emulsion (and the microspheres generated subsequently) formed in the emulsion tank 100 is always stable and not disturbed by gas (or foam).

[0058] In some embodiments, when the homogenizer 101 is inserted into the tank body 102 from the top wall 114C, the colostrum inlet 108A can be set on the bottom wall 114B; the external water phase inlet 108B can be set on the side wall 114A or the bottom wall 114B; the outlet 110 can be set on the side wall 114A or the top wall 114C.

[0059] like Figure 2 As shown, the dispersing cutter head 105 includes a stator 107 and a rotor 109, the stator 107 includes a stator wall 111, the stator wall 111 is configured to be cylindrical and accommodates the rotor 109 therein; the upper end 113A of the stator wall 111 is connected to the lower end 115B of the homogenizing rod 103, and the lower end opening 113B of the stator wall 111 is used to allow liquid (or material) to enter the dispersing cutter head 105.

[0060] In some embodiments, the cylindrical shape means that even if there are slightly shaped parts, the general shape as a whole is still a cylinder (hollow cylinder). In some embodiments, the stator wall 111 can be configured as a cylinder with multiple pores or gaps in the form of a fence, so that liquid can flow therethrough.

[0061] In some embodiments, the external aqueous phase inlet 108B and the colostrum inlet 108A are in the form of pipes.

[0062] In some embodiments, the external water phase inlet 108B and the colostrum inlet 108A are both disposed on the bottom wall 114B. In some embodiments, the external water phase inlet 108B and the colostrum inlet 108A adopt a "large tube sleeve small tube" structure, that is, the external water phase inlet 108B adopts a larger tube diameter, and the colostrum inlet 108A adopts a smaller tube diameter and is disposed inside the tube of the external water phase inlet 108B. The first end of the external water phase inlet 108B may be arranged to be almost flush with the bottom wall 114B, and the colostrum inlet 108A may be arranged to extend from the internal volume 104 to a third distance X from the rotor 109. 3 It should be understood that the present invention has no restrictive requirements on the position setting of the external water phase inlet 108B and the colostrum inlet 108A, as long as the external water phase inlet 108B and the colostrum inlet 108A can inject the external water phase and colostrum into the working range of the dispersion blade 105.

[0063] The present invention has no restrictive requirements for the specific position of the colostrum inlet 108A, as long as the colostrum injected from the colostrum inlet 108A can enter the dispersion blade head 105. In some embodiments, the first end of the colostrum inlet 108A is arranged to be opposite to the dispersion blade head 105, as long as the first end of the colostrum inlet 108A can inject colostrum into the working range of the dispersion blade head 105. In some preferred embodiments, the first end of the colostrum inlet 108A is opposite to the central position of the rotor 109 or the center line of the emulsion tank 100.

[0064] In some embodiments, the diameter D of the lower opening 113B of the stator wall 111 is 1 Including 0.5–7.0cm.

[0065] In some embodiments, the diameter D of the lower opening 113B of the stator wall 111 is 1 Includes 1.5–5.0cm.

[0066] In some embodiments, the distance between the side wall 114A and the center line of the emulsion tank 100 is set to a first distance X 1 In some embodiments, the first distance X 1 At least 1.0cm.

[0067] In some embodiments, the first distance X 1 Includes 1.0–15.0cm.

[0068] In some embodiments, the width of the gap 119 between the stator wall 111 and the rotor 109 is set to a second distance X 2 In some embodiments, the second distance X 2 Including 0.1–5.0mm.

[0069] It is particularly noted that the emulsion tank 100 provided by the present invention and the homogenizer 101 inserted therein actually constitute a three-layer structure from the outside to the inside ("side wall 114A-stator wall 111-rotor 109") and a two-layer area (a pre-curing flow channel S formed by the gap 118 between the side wall 114A and the stator wall 111 and a homogenizing zone H formed by the gap 119 between the stator wall 111 and the rotor 109).

[0070] The three-layer structure can change the flow mode of liquid (e.g., colostrum, external aqueous phase, and emulsion formed by the mixture of colostrum and external aqueous phase, etc.) in the emulsion tank 100 and the environment in which it flows to a certain extent, thereby being more conducive to the formation of emulsion, achieving higher production efficiency, and better stability and quality of microspheres. Specifically, in the gap 119 between the stator wall 111 and the rotor 109, when the dispersing blade 105 is in the working state (in the process of continuously producing emulsion), on the one hand, due to the push of the continuously injected liquid (for example, colostrum, external aqueous phase), and on the other hand, due to the rotation of the dispersing blade 105 driven by the rotor 109, the liquid or material (for example, a mixture of colostrum and external aqueous phase, or a first emulsion initially formed by colostrum and external aqueous phase) is introduced or directed into the homogenizing zone H from the lower end opening 113B of the stator wall 111, and is subjected to the shearing effect and the like generated by the high-speed rotating dispersing blade in the homogenizing zone H, so as to achieve the homogenization of the initially formed first emulsion (i.e., to form a second emulsion). The structure and size of the homogenizing zone H are mainly determined by the diameter D of the lower end opening 113B of the stator wall 111. 1 and a second distance X between the gap 119 between the stator wall 111 and the rotor 109 2 Decide.

[0071] In some embodiments, when there is a preset distance L (eg, at least 1.0 cm) between the rotor 109 and the bottom wall 114B, outside the homogenization zone H and the pre-curing flow channel S, there is a countercurrent zone Z below the rotor 109 .

[0072] Specifically, when the second emulsion is pushed by the injected liquid and the centrifugal force generated by the high-speed rotation of the dispersing blade 105, it overflows from the homogenizing zone H. Due to the setting of the countercurrent zone Z, at least part of the overflowed second emulsion can directly flow into the countercurrent zone Z in the reverse direction (in the present invention, the forward direction is the direction of flow toward the outlet 110 (or the top wall 114C), and the reverse direction is the direction of flow in the opposite direction of the outlet 110 (which can also be understood as the direction of flow toward the bottom wall 114B)), and after flowing therein for a period of time, it flows forwardly through the pre-curing flow channel S to the outlet 110, and then flows out of the internal volume 104 through the outlet 110, as shown in FIG. Figure 5 The structure and size of the pre-curing flow channel S are mainly determined by the first width Y of the gap 118 between the side wall 114A and the stator wall 111. 1 Due to the setting of the countercurrent zone Z, the first width Y 1 There is no restrictive requirement that the first width Y 1 The width may be set to a suitable value to enable the second emulsion to flow through the pre-curing flow channel S to the outlet 110 .

[0073] After the second emulsion contacts the external water phase in the countercurrent zone Z, the external water phase begins to extract the organic solvent in the second emulsion, so that the microspheres in the second emulsion begin to solidify. As the second emulsion continues to flow in the countercurrent zone Z, the flow path and residence time of the second emulsion in the countercurrent zone Z are further extended, so that the external water phase in the countercurrent zone Z can extract the organic solvent therein to a certain extent, thereby enabling the second emulsion to achieve a certain degree of pre-solidification before undergoing the solidification step.

[0074] In some embodiments, the volume of the countercurrent zone Z accounts for 20%-80% of the internal volume. As the volume of the countercurrent zone Z increases, the amount of liquid (especially the external aqueous phase) that the countercurrent zone Z can accommodate will also increase accordingly, providing a wider flow space for the countercurrent flow of the second emulsion, so that the second emulsion stays in the internal volume 104 for a longer time and has a higher degree of pre-solidification. In some embodiments, the volume of the countercurrent zone Z can be increased by adjusting the shape of the countercurrent zone Z (for example, setting the countercurrent zone Z to be a sphere or an ellipsoid), such as Figure 4 shown.

[0075] In some embodiments, the structure and size of the countercurrent zone Z are mainly determined by the distance L between the rotor 109 and the bottom wall 114B. In some embodiments, L includes 1.3–20.0 cm. It has been verified by the present invention that when the distance L between the rotor 109 and the bottom wall 114B is set to ≤20 cm, in combination with a specific colostrum injection speed and an external water phase injection speed (see Example 2), the second emulsion can be generated, flowed and flowed out of the tank at a suitable time and speed. If the distance L is too long (for example, set to more than 20 cm), the second emulsion will be retained on the bottom wall of the tank and cannot flow to the outlet, affecting the overall preparation process of the emulsion and the quality of the microspheres in the emulsion.

[0076] Furthermore, as the diameter D of the lower opening 113B of the stator wall 111 increases 1 The homogenization zone H will be expanded accordingly, that is, the homogenization range of the dispersing blade head 105 (for example, the volume or flux of the material that can be homogenized) will be wider, and the speed and volume of the second emulsion will also increase accordingly. In order to make the operation of the entire emulsion tank 100 more stable, the volume of the countercurrent zone Z can be increased to 38%-80% of the internal volume, so as to further ensure that the second emulsion can be generated at the expected speed and volume, and also ensure that the second emulsion can undergo a relatively sufficient pre-solidification in the homogenization zone H, thereby ensuring that a higher quality emulsion can be continuously produced in the emulsion tank 100.

[0077] In summary, the present invention, by setting the countercurrent zone Z, balances the problem in the prior art that the homogenized emulsion is either directly discharged or retained in the tank for a long time. Figure 6As shown, in the prior art based on the in-line mixer, the material will first be sucked in and instantly homogenized by one end of the high-speed rotating working head (e.g., including a precision-machined rotor / blade), and then the homogenized material (e.g., emulsion) will be directly and instantly discharged along the pipeline system located at the other end of the working head, and the entire in-line mixer is equivalent to the homogenization zone H of the present invention. In this case, the homogenized emulsion is directly discharged in a very short time (e.g., within 5, 10, 20 seconds), and the microspheres in the discharged emulsion may not only have a large amount of organic solvent residues, but also the quality of the microspheres generated subsequently is not stable (e.g., affecting the particle size distribution, embedding rate, etc. of the microspheres). The existing technology for expanding the production of microspheres based on containers with larger volumes (e.g., 50-500L) is to directly homogenize the materials in the container in order to prepare a large batch of double emulsions. During the preparation of the double emulsions, a portion of the double emulsion is often repeatedly homogenized for a long time. Moreover, as oily materials (e.g., colostrum) are continuously added, the materials in the container will gradually have an oil-water ratio imbalance caused by excessive oily materials, which seriously affects the production efficiency, quality and stability of the double emulsion (or microspheres), making it easy for the generated microspheres to have defects such as large differences in quality before and after (e.g., large batch differences).

[0078] In some embodiments, the volume of the internal volume 104 includes 0.1-5.0 L. It has been verified that when the volume of the internal volume 104 is controlled at 0.1-5.0 L, the emulsion (or microsphere) can be produced continuously and with stable quality in the internal volume 104, and during the preparation of the emulsion, the oil-water ratio of the material is always maintained at a ratio suitable for production. Preferably, when the volume of the internal volume 104 is controlled at 0.5-2.0 L, the generation speed and outflow speed of the second emulsion can be further balanced, so that the preparation efficiency and yield of the emulsion are higher and the quality is better.

[0079] In some embodiments, a third distance X is set between the first end of the colostrum inlet 108A and the rotor 109. 3 .

[0080] In some embodiments, the third distance X 3 Can be set to nearly 0.

[0081] In some embodiments, the third distance X 3 It can be set to ≤1 cm. In some embodiments, the third distance X 3 It can be 1.0cm, 0.9cm, 0.8cm, 0.7cm, 0.6cm, 0.5cm, 0.4cm, 0.3cm, 0.2cm, or 0.1cm.

[0082] In some embodiments, the third distance X 3It can also be set to ≤5 cm. In some embodiments, the third distance X 3 It can be 5cm, 4.5cm, 4cm, 3.5cm, 3cm, 2.5cm, 2cm, 1.5cm, 1cm, 0.5cm.

[0083] The third distance X in the present invention 3 The setting ensures, to a certain extent, that the material can be introduced into the homogenizing zone H with a higher introduction efficiency and generate a homogenized emulsion with a higher efficiency.

[0084] In some embodiments, the emulsion tank 100 further includes a jacket 130 disposed outside the tank body 102, and the jacket 130 is used to control the temperature of the tank body 102. In some embodiments, the jacket 130 includes a cooling water inlet 131 for guiding cooling water to flow into the jacket 130 and a cooling water outlet 133 for guiding cooling water to flow out of the jacket 130.

[0085] Example 2: Preparation method of double emulsion

[0086] This embodiment provides a method for continuously producing an emulsion based on the emulsion tank 100 .

[0087] First, cooling water (eg, 20±5° C.) is filled into the jacket 130 to control the overall temperature of the emulsion tank 100 within a range suitable for a specific emulsion preparation process, and a self-circulation check of the emulsion tank is started to ensure that the emulsion tank 100 can operate normally.

[0088] Then, the external aqueous phase is injected into the internal volume 104 through the external aqueous phase inlet 108B (i.e., the external aqueous phase is injected into the emulsion tank 100), and the internal volume 104 is completely filled or substantially filled (substantially filled in the present invention means that there is no gas in the internal volume, or although there is a trace amount of gas in the internal volume (for example, in the dead corner of the emulsion tank), it will not interfere with the normal emulsion preparation in the internal volume), and then the gas is relatively completely discharged from the internal volume 104 and the introduction of new gas from the outside is avoided, so that the emulsion tank 100 reaches a state where the emulsion preparation is not interfered by bubbles or gas. If the liquid in the internal volume 104 contacts with bubbles or gas, foam will appear in the internal volume 104. As the emulsion preparation process proceeds, the disappearance of the foam may cause the liquid level in the internal volume 104 to drop, thereby increasing the batch-to-batch difference of the emulsion. In other words, in the method for preparing an emulsion adopted in the present invention, the liquid in the internal volume 104 is mainly in direct contact with the inner wall 106 of the tank, which to a certain extent avoids or reduces the interference caused by bubbles, foam, etc. generated by the contact between the liquid in the internal volume 104 and the gas (for example, gas from the outside or gas remaining in the tank) during the emulsion preparation process.

[0089] Subsequently, the homogenizer 101 is started to rotate its dispersing blade 105 , thereby stirring the external water phase and further exhausting the bubbles or gas that may exist in the external water phase in the emulsion tank 100 .

[0090] After all bubbles or gases in the aqueous phases inside and outside the emulsion tank 100 are exhausted, the colostrum and the external aqueous phase are respectively injected through the colostrum inlet 108A and the external aqueous phase inlet 108B at respective preset rates. Since the internal volume 104 is already filled with the external aqueous phase at this time, the colostrum immediately contacts and mixes with the external aqueous phase after flowing out from the colostrum inlet 108A to generate the first emulsion (i.e., a mixed solution of the colostrum and the external aqueous phase that has not been homogenized).

[0091] Because the first end of the colostrum inlet 108A is directly opposite to the dispersing blade 105, the first double emulsion moves toward the rapidly rotating dispersing blade 105 under the impetus of the colostrum newly injected continuously from the colostrum inlet 108A, and is then emulsified and homogenized in the homogenization area H formed in the dispersing blade 105 (i.e., the gap 119 between the stator wall 111 of the dispersing blade 105 and the rotor 109), to form a second double emulsion (i.e., a mixed solution of homogenized colostrum and external aqueous phase).

[0092] The second emulsion formed in the homogenizing zone H is pushed by the newly formed first emulsion that continuously flows toward the dispersing blade head 105 and the centrifugal force generated by the high-speed rotation of the dispersing blade head 105, and will continuously overflow from the homogenizing zone H (for example, pass through the pores or gaps on the stator wall 111, or flow out from the lower end opening 113B of the dispersing blade head 105), thereby directly flowing into the countercurrent zone Z in the reverse direction, and after flowing therein for a period of time, it will flow to the outlet 110 through the pre-curing flow channel S formed by the gap 118 between the side wall 114A and the stator wall 111, and then flow out of the internal volume 104 through the outlet 110.

[0093] In some embodiments, the linear velocity of the dispersing blade 105 is 4.7-26.0 m / s. The above linear velocity range can ensure that the first emulsion can be homogenized efficiently, that is, it can ensure that the first emulsion can be fully homogenized to generate microspheres of a suitable particle size range (and the microspheres will not be further broken), and avoid the high energy consumption caused by excessive work of the dispersing blade and the problem of increased liquid temperature in the emulsion tank.

[0094] Based on the above linear velocity range, the diameter D of the lower end opening of the stator wall can be combined with the specific 1 To determine the rotation speed of the dispersing blade head. In some embodiments, the rotation speed of the dispersing blade head 105 includes 5000-12000 rpm.

[0095] In some embodiments, the overall temperature of the emulsion tank 100 is controlled at 0-30°C.

[0096] In other words, the injection of colostrum and external water phase at suitable temperatures, the setting of the jacket and the appropriate linear speed of the dispersion blade synergistically ensure that the overall temperature of the emulsion tank 100 can be controlled within a suitable range, thereby ensuring that the overall oil-water ratio in the internal volume 104 can be relatively stably maintained within a ratio range suitable for emulsion preparation throughout the emulsion preparation process without being affected by temperature changes.

[0097] In some embodiments, the colostrum comprises a mixed solution of a homogenized oil phase and an internal aqueous phase, the oil phase comprises an organic solvent and a high molecular polymer soluble in the organic solvent, the internal aqueous phase comprises an aqueous solution and a polypeptide drug soluble in the aqueous solution, and the external aqueous phase comprises polyvinyl alcohol or a dextran aqueous solution.

[0098] In some embodiments, the concentration of polyvinyl alcohol or dextran in the external aqueous phase comprises 0.1-0.5 wt %.

[0099] In some embodiments, the method for preparing colostrum comprises: adding all the oil phase to the internal water phase and mixing (preferably in a water bath with a temperature control of 25±0.5°C), starting a homogenizer (e.g., IKaT25-25F) and homogenizing at 15000-20000 rpm for 2-5 minutes to prepare colostrum, and setting aside for use. The temperature of the colostrum is maintained at 20-30°C.

[0100] In some embodiments, the oil phase and the internal water phase are mixed in a weight ratio of 10-50: 1. The colostrum prepared by mixing in the above ratio has better quality and is more suitable for the preparation of multiple emulsion.

[0101] In some embodiments, the oil phase includes an organic solvent and a high molecular polymer soluble in the organic solvent. In some embodiments, the organic solvent includes one or more of dichloromethane, chloroform and ethyl acetate. In some embodiments, the high molecular polymer includes hydroxy fatty acids and polyesters derived therefrom, such as one or more of PLGA, polylactic acid, polyglycolic acid, polycitric acid, polymalic acid, polycaprolactone, poly-β-hydroxybutyric acid, lactic acid hydroxyglycolic acid copolymer, polylactic acid-polyethylene glycol copolymer and 2-hydroxybutyric acid-glycolic acid copolymer. It should be understood that the method provided in this embodiment has no restrictive requirements on the molecular weight of the high molecular polymer, and those skilled in the art can select a high molecular polymer of suitable molecular weight according to actual production needs.

[0102] In fact, the method provided in this embodiment has strong applicability, and a high-molecular-weight polymer concentration in the oil phase in the range of 10-40wt% can continuously produce a high-quality emulsion. In some embodiments, a high-molecular-weight polymer concentration in the oil phase in the range of 20-35wt% can be selected to produce a high-quality and high-yield emulsion. In some embodiments, the concentration of the high-molecular-weight polymer in the oil phase is more preferably 25-30wt%.

[0103] In some embodiments, the inner aqueous phase includes an aqueous solution and a polypeptide drug dissolved in the aqueous solution. In some embodiments, the polypeptide drug includes one or more of leuprolide, goserelin, triptorelin, octreotide, exenatide, semaglutide, GLP-1 (glucagon-like peptide-1) receptor agonist and GIP (gastric inhibitory peptide) receptor agonist.

[0104] In some embodiments, the aqueous solution includes water, or a mixed solution of water and acetic acid or methanol.

[0105] In some embodiments, the weight ratio of the polypeptide drug to the aqueous solution is 3-12:1.

[0106] In some preferred embodiments, the concentration of the polypeptide drug in the inner aqueous phase is 30-70wt%. By simultaneously controlling the concentration of the polymer and the polypeptide drug, microspheres can be continuously produced with a high embedding rate, thereby improving production efficiency and avoiding the waste of raw materials.

[0107] In some embodiments, the weight ratio of the high molecular weight polymer to the polypeptide drug is 10-50:1.

[0108] In some embodiments, the internal aqueous phase and the oil phase are maintained at 25±5°C.

[0109] In some embodiments, the colostrum is injected at a rate of at most 0.30 L / min.

[0110] In some embodiments, the injection speed of the external aqueous phase is at least 30 times that of the colostrum. With the continuous injection of the external aqueous phase and colostrum and the continuous outflow of the second emulsion, the setting of the above ratio can make the overall oil-water ratio in the internal volume 104 relatively stable and maintained within the ratio range suitable for emulsion preparation during the entire emulsion preparation process, thereby effectively ensuring the quality stability of the outflowing emulsion, and to a certain extent avoiding the technical problems such as the imbalance of the oil-water ratio caused by the increase in batch size or the increase in time of emulsion preparation, resulting in low consistency and instability of the quality of the prepared emulsion. On the other hand, the setting of the above ratio can also make the second emulsion flow in the countercurrent zone Z in the reverse direction, while the second emulsion flowing in the countercurrent zone Z can flow forward under the impetus of the external aqueous phase that is constantly and dynamically updated. In addition, this can also ensure that the organic solvent in the newly formed second emulsion can always be efficiently extracted by the new external aqueous phase (i.e., the external aqueous phase in which the organic solvent is basically absent) in the countercurrent zone Z during the entire emulsion preparation process, so that the organic residue in the microspheres in the emulsion flowing out of the internal volume 104 is low and has been solidified to a certain extent, which is beneficial to the subsequent further solidification process.

[0111] Therefore, the emulsion flowing out of the emulsion tank of the present invention can be conveniently and directly subjected to subsequent processes (e.g., further solidification in a volatilizer) without further treatment (e.g., the common treatment methods of the prior art such as emulsification homogenization and cyclic shearing need to be adopted again).

[0112] Verification Example 1

[0113] In order to verify the actual effect of the emulsion tank 100 of the present invention and the emulsion preparation method based on the emulsion tank 100, a specific example is provided below to demonstrate the verification effect:

[0114] PLGA (polylactic acid-co-glycolic acid) was used as a high molecular polymer and dichloromethane was used as an organic solvent to form a 29% PLGA dichloromethane solution as the oil phase; a 50% leuprorelin aqueous solution was used as the inner aqueous phase; and a 0.1wt% polyvinyl alcohol aqueous solution was used as the outer aqueous phase. The oil phase was added to the inner aqueous phase and mixed and homogenized at a speed of 17000rpm to form colostrum. The colostrum was injected at a speed of 0.20L / min and the outer aqueous phase was injected at a speed of 6L / min into the internal volume at the same time, and the speed of the dispersion blade was adjusted to 7500rpm. The verification results are shown in Table 1.

[0115] Table 1

[0116]

[0117] Note: V 内部容积 V represents the volume of the internal volume 104 of the emulsion tank 100; 逆流区 represents the volume of the countercurrent zone Z of the emulsion tank 100; batch represents the total amount of microspheres in the emulsion generated in the first emulsion preparation process; Dv50 is the particle size corresponding to 50% of the volume distribution of microspheres in the emulsion generated in the first emulsion preparation process (measured using a laser particle size analyzer); t1Dv50 and t2 Dv50 represents the particle size corresponding to 50% of the volume distribution of microspheres in the emulsion flowing out of the emulsion tank at two time points t1 and t2 during the preparation process of a single emulsion (in Preparation Example 1, t1 is the 5th minute after the start of production, and t2 is the 15th minute after the start of production; in Preparation Example 2, t1 is the 5th minute after the start of production, and t2 is the 110th minute after the start of production; in Preparation Example 3, t1 is the 5th minute after the start of production, and t2 is the 110th minute after the start of production; in Preparation Example 4, t1 is the 5th minute after the start of production, and t2 is the 90th minute after the start of production; in Preparation Example 5, t1 is the 5th minute after the start of production, and t2 is the 25th minute after the start of production; in Preparation Example 6, t1 is the 5th minute after the start of production, and t2 is the 15th minute after the start of production); the yield represents the proportion of microspheres generated by the emulsion generated during the preparation process of a single emulsion; the batches of Preparation Examples 1-6 are different.

[0118] Unexpectedly, the experimental data in Table 1 show that the method for preparing an emulsion provided by the embodiment of the present invention can not only continuously and in large quantities generate an emulsion, but also generate an emulsion of stable quality and good consistency, which is specifically manifested in that the batch-to-batch difference is small, and the quality of the microspheres in different stages of the same batch and in the same stage of different batches can remain stable. The D50 average particle size of the microspheres in the emulsion prepared by the embodiment of the present invention can be controlled at 11-13 μm. The embedding rate of the microspheres finally generated can be maintained at more than 90%. In addition, Table 1 also shows that the method for preparing an emulsion provided by the embodiment of the present invention has high repeatability. After testing, other production conditions can continuously produce microspheres with stable quality, which is not limited by specific raw materials (for example, oil phase, external aqueous phase, internal aqueous phase), and is suitable for large-scale production of microspheres of various drugs.

[0119] In addition, the preparation examples 1-6 in Table 1 show that V 逆流区 / V 内部容积 When the ratio of V is controlled within the range of 20%-80%, the second emulsion can be generated, flowed and discharged in the tank at a suitable time and speed. The experimental results of Preparation Examples 1 and 4 show that under the same internal volume, within the range of 20%-80%, V 逆流区 / V 内部容积 The larger the value, the higher the yield. In addition, the experimental results of Preparation Example 5 also show that 逆流区 / V 内部容积 When the ratio is controlled between 20% and 80%, the volume of the internal volume (i.e. V 内部容积 ) is not the case that the larger the volume, the higher the yield that can be achieved; when the quality requirements for the emulsion are high, an internal volume of 0.5-2.0L can be selected to produce an emulsion of better quality.

[0120] Verification Example 2

[0121] Next, see Table 2 (V 逆流区 / V 内部容积 The colostrum injection speed (V 初乳 ), and the external water phase injection rate and colostrum injection rate (i.e. V 外水相 / V 初乳 ) on the yield. The present invention finds that when the injection speed of colostrum is controlled within 0.3L / min, a better yield can be achieved; if the injection speed of colostrum is too high (for example, 0.4L / min), the proportion of colostrum (or "oil") in the internal volume will be too high, and as the emulsion preparation process is prolonged, an imbalance in the oil-water ratio may occur. When the ratio of the external water phase injection speed to the colostrum injection speed is maintained at more than 30 times, the oil-water ratio in the tank body can be dynamically balanced, further ensuring the quality of the prepared emulsion, so that a better yield can be achieved.

[0122] Table 2

[0123] <![CDATA[V 初乳 (L / min)]]> 0.3 0.2 0.3 0.4 <![CDATA[V 外水相 (L / min)]]> 6 6 8 12 <![CDATA[V 外水相 / V 初乳 ]]> 20 30 40 30 Yield (%) 74.0 84.3 84.5 75.6

[0124] The embodiments of the present invention are described above in conjunction with the accompanying drawings, but the present invention is not limited to the above-mentioned specific implementation modes, which are merely illustrative rather than restrictive. Under the guidance of the present invention, ordinary technicians in this field can also make many forms without departing from the scope of protection of the present invention and the claims, all of which are within the protection of the present invention.

Claims

1. A method for continuous preparation of a double emulsion, characterized in that: The following steps are involved: S1. Injecting the external aqueous phase into the emulsion tank through the external aqueous phase inlet, so that the external aqueous phase substantially fills the internal volume of the emulsion tank, wherein the emulsion tank comprises a tank body and a homogenizer inserted into the tank body, the tank body comprises a tank inner wall, the tank inner wall comprises a side wall, a bottom wall and a top wall, the two sides of the side wall are respectively connected to the bottom wall and the top wall, and together enclose the internal volume of the emulsion tank; the homogenizer comprises a homogenizing rod and a dispersing blade head connected to the lower end of the homogenizing rod, the dispersing blade head extends to the internal volume; the tank body further comprises one or more colostrum inlets, and one or more external aqueous phase inlets, the colostrum inlet is used to guide the colostrum to be injected into the tank body; The internal volume; the external aqueous phase inlet is used to guide the external aqueous phase to be injected into the internal volume; the tank body also includes one or more outlets for guiding the emulsion formed in the tank body to flow out of the internal volume; the first end of the colostrum inlet is arranged to be opposite to the dispersion cutter head; the dispersion cutter head includes a stator and a rotor, the stator includes a stator wall, the stator wall is arranged to be cylindrical and accommodates the rotor therein; the lower end opening of the stator wall is used to allow liquid to enter the dispersion cutter head, and there is a countercurrent zone under the rotor, the countercurrent zone is used to provide space for liquid to flow in the reverse direction in the internal volume, the volume of the countercurrent zone accounts for 20% - 80% of the internal volume, and the volume of the internal volume is 0.5 - 2.0 L; a third distance X3 is set between the first end of the colostrum inlet and the rotor, and the third distance X3 is at most 5 cm; S2: continuously injecting colostrum and external aqueous phase into the internal volume through the colostrum inlet and the external aqueous phase inlet respectively, and starting the homogenizer to emulsify and homogenize the mixed solution of the colostrum and the external aqueous phase to generate a homogenized double emulsion; S3 collecting the homogenized emulsion flowing out from the outlet; The colostrum comprises a mixed solution of a homogenized oil phase and an inner aqueous phase, the oil phase comprises an organic solvent and a high molecular polymer dissolved in the organic solvent, the inner aqueous phase comprises an aqueous solution and a polypeptide drug dissolved in the aqueous solution, and the outer aqueous phase comprises a polyvinyl alcohol aqueous solution; the injection rate of the colostrum is at most 0.30 L / min, and the injection rate of the outer aqueous phase is at least 30 times the injection rate of the colostrum.

2. The method according to claim 1, characterized in that The linear speed of the dispersing blade head is 4.7-26.0 m / s.

3. The method according to claim 1, characterized in that The high molecular polymer includes one or more of PLGA, polylactic acid, polyglycolic acid, polycitric acid, polymalic acid, polycaprolactone, poly-β-hydroxybutyric acid, lactic acid-hydroxyglycolic acid copolymer, polylactic acid-polyethylene glycol copolymer and 2-hydroxybutyric acid-glycolic acid copolymer; the organic solvent includes one or more of dichloromethane, chloroform and ethyl acetate; the polypeptide drug includes one or more of leuprorelin, goserelin, triptorelin, octreotide, exenatide, semaglutide, GLP-1 receptor agonist and GIP receptor agonist.

4. The method according to claim 1, wherein: The distance L between the rotor and the bottom wall is ≤ 20 cm.

5. The method according to claim 1, wherein The diameter D1 of the lower end opening of the stator wall is comprised between 0.5 and 7.0 cm.

6. The method according to claim 5, characterized in that The width of the gap between the stator wall and the rotor is set to a second distance X2 comprised between 0.1 and 5.0 mm.

7. The method according to claim 1, characterized in that The concentration of the high molecular weight polymer in the oil phase is comprised between 10 and 40 wt %.

8. The method according to claim 1, wherein The concentration of the polypeptide drug in the inner aqueous phase is 30-70 wt%.

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