WO2021027703A1 - 胚胎微球制备方法及制备机构、微球制备方法及制备装置 - Google Patents

胚胎微球制备方法及制备机构、微球制备方法及制备装置 Download PDF

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WO2021027703A1
WO2021027703A1 PCT/CN2020/107670 CN2020107670W WO2021027703A1 WO 2021027703 A1 WO2021027703 A1 WO 2021027703A1 CN 2020107670 W CN2020107670 W CN 2020107670W WO 2021027703 A1 WO2021027703 A1 WO 2021027703A1
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liquid
microsphere
microspheres
embryonic
porous membrane
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PCT/CN2020/107670
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English (en)
French (fr)
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金拓
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百剂博递医药科技(上海)有限公司
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Priority to US17/633,471 priority Critical patent/US20220287982A1/en
Publication of WO2021027703A1 publication Critical patent/WO2021027703A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5089—Processes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
    • B01J13/02—Making microcapsules or microballoons
    • B01J13/04—Making microcapsules or microballoons by physical processes, e.g. drying, spraying

Definitions

  • the invention relates to the field of microsphere preparation, in particular to an embryonic microsphere preparation method and preparation mechanism, a microsphere preparation method and preparation device.
  • Microspheres are tiny spherical entities with particle sizes ranging from 1-250 ⁇ m. Polymer microspheres have great potential in the field of medical science because of their good fluidity, ease of injection, and slow-release of the contained ingredients. They have been extensively studied since the 1970s. . This concept was first proposed from the article "Polymers for sustained release of proteins and other macromolecules" published in the journal Nature (263:793-800) by R. Langer and J. Folkman. In view of the outstanding curative effect of biological drugs, they are difficult to be absorbed through the tissue membrane and have to be injected frequently. The author proposes the use of biodegradable polymer microspheres to achieve long-term sustained release injection.
  • the drug effect is generally only maintained for one week, and the maximum is not more than two weeks; and the specific activity of the drug is reduced due to the shielding effect of the modified group, and it must Increase the dose.
  • the latter can theoretically maintain the efficacy of a single injection for several weeks or even months, but it is only successful in microsphere injection, and there are only 8 drugs using long-acting sustained-release microsphere preparations (excluding two contrast agents).
  • microspheres are only used in extremely limited drugs? The only key reason is the cumbersome production process of microsphere preparations and the quality is difficult to reproduce.
  • the current production process of microsphere preparation in the pharmaceutical industry includes two types: double emulsification method and silicone oil phase separation method.
  • the steps of the double-emulsification method include: first emulsify and disperse the polypeptide aqueous solution in the organic solution of the biodegradable polymer, and then further emulsify and disperse the formed "water-in-oil” emulsion in the continuous phase of the polyvinyl alcohol aqueous solution to form a "complex” Emulsion”; finally, the organic solvent is extracted under reduced pressure to solidify the polymer dispersed phase into balls.
  • This method has two outstanding shortcomings: 1) The particle size of the microspheres is different. It must be pre-lyophilized and sieved under aseptic conditions to remove the too large and too small microspheres.
  • the silicone oil phase separation method uses silicone oil in which the drug does not dissolve as the continuous phase of the emulsification operation, which can ensure that more than 95% of the drug is encapsulated inside the microspheres.
  • the silicone oil extracts the organic solvent that dissolves the polymer at the same time, so that the polymer is dispersed and solidified into a ball at the same time.
  • the difference in particle size and the low yield caused by it still exist. What is even more difficult is that a large amount of silicone oil used as a continuous phase must be cleaned and removed with a hydrocarbon solvent, and the hydrocarbons used are precisely the components of gasoline, causing problems in environmental protection and production safety.
  • microfluidic method and the membrane emulsification method
  • the core of the microfluidic method is to spray the mixture of drug and polymer solution one by one from the nozzle into the flowing continuous phase, and extract the organic solvent in the flow to solidify into balls, thereby achieving uniform particle size and complete drug encapsulation .
  • the fatal disadvantage of this method is that the efficiency is too low.
  • the method of spraying liquid beads one by one is only suitable for producing millimeter balls. When producing microspheres with a diameter of hundreds of times smaller, the production efficiency will be reduced by a million times (the volume is 3 times the diameter) square).
  • the key of the membrane emulsification method is to extrude the drug-loaded polymer solution that forms the microspheres with a pressurized inert gas to prepare a membrane tube made of porous materials; the diameter of the microspheres can be controlled through the pre-customized membrane tube aperture.
  • the membrane emulsification method improves the uniform distribution of the particle size of the microspheres and increases the encapsulation rate of water-soluble drugs.
  • the droplets of the drug-loaded polymer solution (the so-called "embryonic microspheres”) are like snowflakes from thousands of membrane holes. In the middle extrusion, the production efficiency is guaranteed.
  • the membrane emulsification method also has a series of shortcomings, which restrict its industrial application: 1) The embryo microspheres that exit the membrane will fuse into large particles when they settle at the bottom of the container, and stirring to prevent their adhesion will cause a certain degree of shear failure. Fusion with collision; 2) The gas pressure as the driving force for extrusion and the outflow of the polymer solution are not always linear. The extrusion rate is affected by factors such as the concentration of the polymer solution, viscosity, drug loading, and indoor temperature; 3) Hydrophobicity The gas has considerable solubility in the organic solvent that dissolves the polymer, so that part of the polymer droplets float to the water surface after being extruded to form a flake.
  • membrane emulsification sedimentation method which combines membrane emulsification and microfluidics to settle the embryonic microspheres. Or the polymer solvent is extracted and solidified in the flow, and then collected and cleaned.
  • the membrane emulsification sedimentation method solves one of the three problems of the membrane emulsification method and leaves the other two problems.
  • the present invention proposes a precise injection membrane emulsification solution for the other two problems.
  • the invention provides an embryonic microsphere preparation method and a preparation mechanism, a microsphere preparation method and a preparation device, which accurately control the particle size of the embryonic microsphere, avoids the floating of the embryonic microsphere, and improves the yield rate.
  • a method for preparing embryo microspheres includes the following steps:
  • the microsphere-forming liquid is delivered to the porous membrane in the receiving liquid through the liquid delivery member, and the embryonic microspheres are extruded from the membrane holes; wherein the flow rate of the liquid output by the liquid delivery member is controllable.
  • the method of delivering the microsphere-generated liquid is changed from the traditional air pressure to a liquid delivery member with a controllable output flow rate. Different from the gas pressure when the air pressure is pushed, it is only one of the influencing factors of the output rate of the microsphere formation liquid.
  • the liquid delivery member can directly control the amount of the microsphere formation liquid output per unit time, which can better control the particles that form the microspheres. path.
  • the technical solution eliminates the pressure to promote the process, it also avoids the problem that the surface tension distribution of the embryonic microspheres changes due to the mixing of bubbles in the embryonic microspheres, which ultimately leads to the inability to form spheroids, which improves the microspheres Product yield.
  • the liquid delivery member can be a syringe pump, a syringe, or other pumps whose flow can be precisely regulated to push the microsphere-forming liquid to the porous membrane.
  • a shearing force or vibration is applied to detach the embryonic microspheres from the porous membrane, wherein:
  • the intensity and/or frequency of the applied shear force or vibration is controllable.
  • the applied frequency and intensity of the shearing force or vibration will affect the rate at which the microsphere formation liquid detaches from the porous membrane surface, change the adhesion of the embryonic microspheres on the porous membrane surface, and thereby regulate the particle size of the embryonic microspheres. .
  • stirring, shaking, or other disturbing actions are applied to the microsphere generating liquid in the liquid conveying member.
  • the microsphere forming liquid contains solid particles
  • the microsphere forming liquid in the liquid conveying member is disturbed, so that the particles do not settle and are uniformly distributed during conveyance.
  • a method for preparing microspheres includes the following steps:
  • S10 Transporting the microsphere-forming liquid to the porous membrane in the receiving liquid through the liquid conveying member to form embryonic microspheres; wherein the flow rate of the liquid output by the liquid conveying member is controllable;
  • the embryonic microspheres shed from the porous membrane flow along the channel filled with the receiving fluid, so that the organic solvent in the microsphere forming solution is extracted, and the embryonic microspheres become hard to form microspheres.
  • step S10 Preferably, in the step S10:
  • the liquid delivery member can be a syringe pump, a syringe or other pumps with adjustable flow; and/or; applying a shear force or vibration to make the embryo microspheres detach from the porous membrane, and the intensity and frequency of the applied shear force or vibration can be And/or: applying a stirring action to the microsphere generating liquid in the liquid conveying member; and/or; venting the device for preparing embryo microspheres before the microsphere generating liquid is delivered.
  • An embryonic microsphere preparation mechanism comprising: a liquid conveying member for conveying the microsphere-forming liquid at a controllable flow rate; a porous membrane that receives the microsphere-forming liquid from the liquid conveying member and passes it through the micropores to form embryonic microspheres;
  • the porous membrane stent is used to install the porous membrane and connect the liquid transport member and the porous membrane through its tubular structure.
  • a liquid conveying part is used to replace the previous gas input device and the container for generating liquid.
  • the gas pressure is only one of the influencing factors of the output rate of the microsphere generation liquid, and the flow rate of the output microsphere generation liquid cannot be controlled.
  • the liquid conveying member can directly control the amount of the microsphere generated liquid output per unit time, and thus can better control the particle size of the generated microspheres.
  • the mechanism of the gas input device is eliminated in this technical solution, the problem that the surface tension distribution of the embryonic microspheres changes due to the mixing of bubbles in the embryonic microspheres and ultimately causes the formation of spheroids is improved, and the product of the microspheres is improved. Yield rate.
  • the liquid delivery member can be a syringe pump, a syringe or other pumps with adjustable flow;
  • the liquid delivery member includes: a storage cavity for storing the microsphere generating liquid; a pushing member slidably arranged along the inner wall of the storage cavity for pushing the microsphere generating liquid; and a power source, driving The pushing member performs a pushing action.
  • the bottom of the liquid conveying member further includes a stirring structure for disturbing the microspheres to generate liquid.
  • a concave groove is provided at the bottom of the storage cavity to accommodate the stirring mechanism.
  • the lower end side wall of the storage cavity is provided with a raw material inlet and outlet.
  • it further comprises a feed pipe which communicates the liquid transport member and the porous membrane support, and the porous membrane support includes a tapered hole for installing the feed pipe, the The radial dimension of the tapered hole gradually increases from the outside to the inside.
  • the tapered hole is designed for better sealing effect when the internal pressure is higher.
  • an exhaust structure is provided on the porous membrane support.
  • the gas when gas exists in the porous membrane support, the gas can be discharged through the exhaust structure at this time.
  • the feed pipe extends to the porous membrane.
  • the feed tube extends to the porous membrane, and the microsphere production liquid can be directly delivered to the porous membrane to avoid introducing gas into the porous membrane, thereby affecting the yield of embryonic microspheres.
  • a microsphere preparation device comprising: an embryo microsphere preparation mechanism; a curing tube connected to the embryo microsphere preparation mechanism, the embryo microspheres are settled in the curing tube and solidified by solvent extraction to form microspheres; and , A collector, connected with the curing tube to collect the microspheres.
  • it further includes a post-processing mechanism for removing organic solvents and other impurities from the microspheres.
  • the present invention can achieve the following beneficial effects:
  • the liquid delivery member can directly control the amount of the microsphere generated liquid output per unit time.
  • the size of the embryonic microspheres is related to the timing of their shedding from the porous membrane tube, and the timing of shedding is determined by the growth rate of the embryonic microspheres, surface tension, and the shear force (or vibration force) exerted on the membrane tube surface. Among the above three factors, the growth rate of embryonic microspheres directly depends on the flow rate of the microsphere production liquid out of the membrane.
  • the gas pressure used to prepare embryo microspheres by membrane emulsification is related to the flow rate of the liquid, it does not necessarily maintain a constant linear relationship with the flow rate.
  • concentration, viscosity, and amount of gas dissolved in the microspheres produced liquid all affect The relationship between air pressure and flow rate.
  • Directly using the flow rate of the microsphere generating solution to control the particle size of the embryonic microspheres also eliminates other interferences, and the display accuracy of the liquid flow rate is much higher than the gas pressure, which greatly optimizes the precise control of the embryonic microsphere particle size.
  • the liquid conveying part is used to control the flow rate of the liquid produced by the microspheres, with the shear force and vibration of controllable intensity or frequency, and the pore size of the porous membrane can be precisely designed, so that the particle size of the microspheres can be effectively controlled.
  • the concave groove is designed in the liquid conveying part to ensure that the liquid can be better conveyed in the actual conveying process. At the same time, it is equipped with a stirring structure to stir the liquid at the bottom of the storage cavity to ensure that the conveyed microspheres generate liquid Uniformity, so that the quality of the embryonic microspheres produced can be uniform.
  • Figure 1 is a process flow diagram of the microspheres of the present invention
  • Figure 2 is a schematic diagram of the structure of an embryonic microsphere mechanism of the present invention.
  • Fig. 3 is a schematic structural diagram of another embodiment of an embryonic microsphere mechanism structure
  • FIG. 4 is a schematic structural diagram of another embodiment of an embryonic microsphere mechanism structure
  • Figure 5 is a schematic diagram of the structure of the microsphere preparation device.
  • liquid conveying member 1 storage cavity 101, pushing member 102, push rod 103, drain hole 104, connecting member 105, stirring mechanism 106, driving device 107, generating device 2, porous membrane holder 201, inlet Material pipe 202, exhaust structure 203, gas retention chamber 204, porous membrane 205, curing pipe 3, collector 4, and conveying pipe 5.
  • the present invention provides an embodiment of a method for preparing embryonic microspheres, which includes the following steps:
  • the microsphere-forming liquid is delivered to the porous membrane in the receiving liquid through the liquid delivery member, and the embryonic microspheres are extruded from the membrane holes; wherein the flow rate of the liquid output by the liquid delivery member is controllable.
  • the microsphere-forming liquid is transported to the porous membrane through the liquid transport member 1, so that the raw liquid can be extruded and formed through the porous membrane.
  • the flow rate of the liquid conveying member is controllable, that is, it can choose one or more of the following control methods:
  • the output flow rate of the microsphere generating solution can be adjusted to different parameters to adapt to different working conditions and requirements;
  • the output flow rate of the microsphere generating liquid is not a constant value, but can be changed in a fluctuating or stepwise manner according to actual needs to adapt to different working conditions and requirements.
  • the liquid conveying member enables the microsphere generating liquid to reach the porous membrane at a controllable flow rate, thereby achieving the purpose of controlling the particle size of the formed embryonic microspheres.
  • the liquid delivery member can be a syringe pump, a syringe, or other pumps whose flow can be precisely adjusted to push the microsphere-generated liquid to the porous membrane.
  • the delivery flow rate can be adjusted to a constant flow rate, or The delivery flow rate is adjusted to a variable speed, and gradually increases or gradually decreases during the delivery process; when the syringe is used to inject liquid, the syringe can be adjusted manually or can be pushed by connecting the push mechanism, which can make the flow rate of the syringe increase continuously , Continuously reduce or maintain a constant flow rate.
  • the adjusted flow rate is not limited, and the specific structure of the liquid transport member 1 used is not limited. It should be noted that, except for the two listed in this embodiment In addition to the liquid conveying member, other conveying devices capable of conveying liquid and having a controllable flow rate can be used in this technical solution.
  • a shearing force or vibration can also be applied to make the embryo microspheres detach from the porous membrane.
  • the vibration is transmitted to the microsphere forming material, so that the polymer microsphere droplets formed after being extruded from the porous membrane are more easily separated from the porous membrane surface, reducing the adhesion of the microsphere droplets on the porous membrane surface.
  • the vibrator can be pneumatically pushed Rod, electric push rod, manual push rod or any other form of reciprocating mechanism.
  • the vibration intensity and frequency can be adjusted at the same time, and the vibration intensity can be increased separately or the vibration frequency can be separately changed to ensure that the particle size of the formed microspheres is more uniform and the production efficiency is higher.
  • a stirring action is applied to the microsphere-generated liquid in the liquid conveying member 1 when the liquid is output.
  • exhaust the equipment for preparing embryo microspheres so that the micro-sphere-forming liquid can be left smoothly and can pass through the porous membrane more easily.
  • Figure 1 is a schematic diagram of an embodiment of a method for preparing microspheres.
  • the method for preparing microspheres includes the following steps:
  • the microsphere generating liquid is delivered to the porous membrane in the receiving liquid through the liquid conveying member to form embryonic microspheres; wherein the flow rate of the liquid output by the liquid conveying member is controllable;
  • the embryonic microspheres shed from the porous membrane flow along the channel filled with the receiving fluid, so that the organic solvent in the microsphere forming solution is extracted, and the embryonic microspheres become hard to form microspheres.
  • the microsphere generating liquid is output by the liquid conveying member, and reaches the porous membrane through the feed tube.
  • the output of the microsphere generating liquid is controllable, so Regulation affects the particle size of embryonic microspheres.
  • the embryonic microspheres shed from the porous membrane flow along the channel filled with the receiving fluid to make the embryonic microsphere production fluid harden and shape, and then collected by the subsequent collector.
  • FIG. 2 is a schematic diagram of an embodiment of the embryonic microsphere preparation mechanism.
  • the embryonic microsphere preparation mechanism includes: a liquid transport member 1, a porous membrane 205, and a porous membrane support.
  • the liquid transport member 1 is used to transport the microsphere production liquid at a controllable flow rate;
  • the porous membrane 205 receives the microsphere production liquid from the liquid transport member 1 and passes it through the micropores to form embryonic microspheres;
  • the porous membrane support 201 is used to install the porous membrane
  • the membrane 205 is connected to the liquid transport member 1 and the porous membrane 205 through its tubular structure.
  • the liquid delivery member 1 can be a syringe pump, a syringe, or other pumps with adjustable flow, such as a metering pump, a molecular pump, a turbo pump, and the like.
  • a syringe it is preferable to use a syringe to control the delivery flow rate of the microsphere-forming liquid through the syringe, and control the delivery flow rate to control the particle size of the generated embryonic microspheres.
  • the liquid conveying member includes a storage cavity 101, a pushing member 102 and a power source.
  • the pushing member 102 is slidably arranged along the inner wall of the storage cavity 101 to push the microsphere-forming liquid; and the power source drives the pushing member 102 to perform a pushing action.
  • the pushing member 102 is connected with the pushing rod 103, and then the power source drives the pushing rod 103 to drive the pushing member 102 to slide, and the pushing member 102 is driven to move by the power source to ensure that the pushing member 102 can be kept constant.
  • the flow rate the liquid is transported at a gradually increasing flow rate or at a gradually decreasing flow rate, so that the flow rate of the microsphere formation liquid flowing to the porous membrane 205 is changed, and the pressure of the microsphere formation liquid when the microsphere formation liquid passes through the porous membrane 205 is also changed.
  • the particle size is more uniform, and it is not prone to stickiness.
  • the power source drives the pushing member 102 to push the liquid in the storage cavity 101, and the pushing member 102 slides along the inner wall of the storage cavity 101.
  • the power source can be manually pushed or External push mechanisms, such as hydraulic push and screw push. Which method is used specifically will not be described in detail in this embodiment.
  • FIG. 3 is a schematic diagram of another embodiment of the embryo microsphere preparation mechanism.
  • the bottom of the liquid conveying member 1 further includes a stirring mechanism 106, and the stirring mechanism 106 is used for Disturbing microspheres to generate liquid;
  • the stirring mechanism 106 can be a magnetic stirring paddle, the bottom of the storage cavity 101 is connected with a magnetic stirring paddle, and the lower end of the storage cavity 101 is connected with a driving device 107, which is driven by a motor 107a And a magnet 107b, the magnet is fixedly connected to the rotating end of the motor 107a, and the motor 107a drives the magnet 107b to rotate, thereby continuously changing the direction of the magnetic field to ensure the continuous rotation of the magnetic stirring blade.
  • the stirring mechanism 106 may also be a magnetic stirrer, and under the action of the driving device 107, the microsphere generating liquid can be at the bottom of the storage cavity 101 to achieve better stirring.
  • a concave groove is provided at the bottom of the storage cavity 101 to accommodate the magnetic stirring mechanism 106.
  • the concave groove is for the liquid to be better collected on the inner bottom wall of the storage cavity 101.
  • the lower end side wall of the storage cavity 101 is provided with a raw material inlet and outlet, so that during processing, the liquid can be delivered to the liquid delivery device 1 after the completion of a liquid delivery, without disassembling the device for refilling the liquid Or replace to ensure the simplicity of the operation process and improve work efficiency.
  • the embryo microsphere preparation mechanism further includes a feed tube 202, which connects the liquid conveying member 1 and the porous membrane support 201.
  • the liquid conveying member 1 The side wall is provided with a drain hole 104, and the inner wall of the drain hole 104 is connected with a connecting piece 105 for connecting the feed pipe 202, and the connecting piece 105 is barbed to make the connection firmer.
  • the porous membrane support 201 includes a tapered hole for installing the feed tube 202. The radial size of the tapered hole gradually increases from the outside to the inside; the design of the tapered hole ensures The greater the internal pressure, the better the sealing effect.
  • the feed tube 202 extends to the porous membrane 205, and the liquid is directly transported to the porous membrane 205 with the feed tube 202 to avoid locking air into the porous membrane 205. In actual operation At this time, air bubbles at the porous membrane 205 will affect the yield of microspheres generated.
  • the porous membrane support 201 is provided with an exhaust structure 203, and the exhaust hole where the exhaust structure 203 is installed is tapered, which can achieve a sealing effect.
  • the inner cavity of the porous membrane support 201 The upper end is the gas retention chamber 204, which can be discharged through the exhaust structure 203 when the gas increases.
  • the porous membrane support 201, the feed pipe 202, the exhaust structure 203, the gas retention chamber 204 and the porous membrane 205 constitute the generating device 2.
  • Fig. 5 is a schematic diagram of an embodiment of the microsphere preparation device.
  • the microsphere preparation device includes: the embryo microsphere preparation mechanism in any embodiment of the aforementioned embryo microsphere preparation mechanism; the curing tube 3 is connected with the embryo microsphere preparation mechanism, and the embryo The microspheres are settled in the curing tube and solidified by solvent extraction to form microspheres; and a collector 4 is connected to the curing tube 3 to collect the microspheres;
  • it also includes a post-processing mechanism, which is used to remove the organic solvent and other impurities from the microspheres.
  • the microsphere production liquid is prepared into embryo microspheres by the embryo microsphere preparation mechanism.
  • the embryonic microspheres generated pass through the curing tube 3, are extracted by the organic solvent in the curing tube 3 to form microspheres, and then pass through the collector 4 for collection, and meanwhile, the generating device 2 makes a circular motion in the curing tube 3 to apply a shearing force to facilitate the embryo microspheres to fall off the porous membrane 205, and then the pipeline 5 is transported to the post-processing equipment for post-processing.
  • the microspheres are washed first, and then the microspheres are freeze-dried.

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Abstract

一种胚胎微球制备方法及制备机构、微球制备方法及制备装置，微球制备方法包括以下步骤：通过液体输送件（1）将微球生成液输送至位于接收液中的多孔膜（2），形成胚胎微球；从多孔膜（205）上脱落的胚胎微球沿着充满接收液的通道流动，使胚胎微球变硬形成微球。收集所述微球。其中，所述液体输送件（1）输出液体的流速可控，可以直接控制单位时间内输出微球生成液的量，进而可以更好的调控生成微球的粒径以及均一性。

Description

胚胎微球制备方法及制备机构、微球制备方法及制备装置 技术领域
本发明涉及微球制备领域，尤其涉及胚胎微球制备方法及制备机构、微球制备方法及制备装置。
背景技术
微球是粒径范围在1-250μm的微小球状实体。聚合物微球因其较好地流动性、便于注射，以及缓释所包载的成分的性能使其在医药科学领域的应用中具备极大的潜力，自上个世纪70年代以来得到广泛研究。该概念最早提出来源于R.Langer和J.Folkman在《Nature》(263:793-800)杂志上发表的“Polymers for sustained release of proteins and other macromolecules”这篇文章。作者针对生物药疗效突出，却难以透过组织膜被口服吸收，不得不频繁注射给药的特点，提出了采用可降解聚合物微球包载，实现长效缓释注射的方案。
自上世纪80年代以来，重组蛋白药物的市场以14-16％的年增长率飙升，目前已超过了全部处方药的50％。现在，批准上市的蛋白和多肽药物超过230种，另有9000种在研发线上，其中的一些研发产品可能在未来几年陆续上市。与生物药的快速增长形成鲜明反差的是其给药方式停留在频繁注射的状态，给药技术亟待突破。
作为代替频繁注射的给药方式，长效注射剂和高效非注射剂是两个不难理解的制剂方案，吸引了本领域科技人员数十年的研发投入。时至今日，生物药非注射制剂没有突破；长效注射剂则上市了一系列产品。上市生物药长效注射剂采用了通过化学改构(PEG化)或生物改构(改变肽序列或蛋白融合)延长体内半衰期的方法以及在注射部位缓慢释药两类方案。前者受改构分子注射后的体内浓度呈指数函数下降的机制的限制，药效一般仅维持一周，最长不超过两周；并且药物的比活性因修饰基团的屏蔽作用而降低，而须增加剂量。后者理论上能够维持数周乃至数月的单针药效，却仅在微球注射剂上成功，而且采 用长效缓释微球制剂的药物只有8个(除去两个造影剂的话)。
为什么只能通过注射给药的多肽等生物药越来越多，而作为唯一能够实现数周长效的药物制剂，微球仅在极其有限的药物上采用？唯一关键的原因便是微球制剂繁琐而质量难以重现的生产工艺。制药工业上现行的微球制剂生产工艺包括两种：复乳化法和硅油相分离法。复乳化法的步骤包括：先将多肽水溶液乳化分散于可生物降解的聚合物的有机溶液中，再将所形成的“油包水”乳液进一步乳化分散于聚乙烯醇水溶液连续相中形成“复乳液”；最后将其中的有机溶剂减压抽提，使聚合物分散相固化成球。这一方法有两个突出的缺点：1)微球粒径大小不一，须预冻干在无菌条件下过筛分离，去除过大和过小的微球，不但工艺繁琐，合格微球的收率很低；2)作为复乳内水相的药物溶液在乳化搅拌时难免接触到外水相而造成药物泄漏，微球的载药量减小。无论粒径的不均以分布还是药物泄漏后的载药量均对乳化过程中的剪切搅拌的强度和时间极其敏感，生产批次间很难保持一致。为避免药物的不可控泄漏，硅油相分离法采用药物在其中不溶解的硅油作为乳化操作的连续相，可确保95％以上的药物包封于微球内部。硅油连续相同时萃取了溶解聚合物的有机溶剂，使聚合物分散相同时固化成球。但是，粒径大小不一及其引起的收率偏低的问题依然存在。更棘手的是作为连续相使用的大量的硅油须用烃类溶剂清洗除去，而所用烃类恰是汽油的成份，造成环保和生产安全的难题。
为解决上述方法的弊端，制药领域的研发人员尝试过各类改进方案；最有代表性两项是“微流控法”和“膜乳化法”。微流控法的核心是将药物和聚合物溶液的混合物由喷嘴一个个喷入流动着的连续相，在流动中萃取有机溶剂固化成球，从而实现了粒径的均一和药物的完全包封。这方法的致命缺点是效率太低，一个一个喷出液珠的方法只适合生产毫米球，当生产直径小了上百倍的微球时，生产效率将降低百万倍(体积是直径的3次方)。
膜乳化法的关键是将形成微球的载药聚合物溶液用加压惰性气体挤出多 孔材料制备的膜管；通过预先定制的膜管孔径实现对微球粒径的调控。膜乳化法改善了微球粒径的均一性分布，提高了水溶性药物的包封率，载药聚合物溶液的滴珠(即所谓“胚胎微球”)像雪花一样从上万个膜孔中挤出，生产效率得到了一定的保证。膜乳化法也存在着一系列缺点，制约着其产业化应用：1)出膜的胚胎微球沉降于容器底部会融合成大颗粒，而搅拌防止其粘连又会造成一定程度的剪切破淬和碰撞融合；2)作为挤出动力的气体压力与聚合物溶液的流出并非总是线性，挤出速率首聚合物溶液的浓度、粘度、载药多寡、室内温度等因素影响；3)疏水性气体在溶解聚合物的有机溶剂中有相当的溶解度，使得部分聚合物滴珠挤出后漂浮至水面，形成片状物。
有鉴于此，数十年来，微流控法和膜乳化法用于微球制备的尝试多有报道，却一直停留在研发阶段，至今未成为切实可行的微球生产技术。
针对微流控和膜乳化方法的缺陷，本发明的发明人此前公开了一种叫作“膜乳化沉降法”的微球制备工艺，将膜乳化与微流控结合，在胚胎微球的沉降或流动中萃取聚合物的溶剂而固化，然后收集清洗。膜乳化沉降法解决了膜乳化法的三个问题之一，遗留了另外两个问题。本发明针对另外两个问题提出了精准注射膜乳化的方案。
发明内容
本发明提供了胚胎微球制备方法及制备机构，微球制备方法及制备装置，精准化了胚胎微球粒径的控制，避免了胚胎微球的漂浮，提高了良品率。
本发明提供的技术方案如下：
一种胚胎微球的制备方法，包括如下步骤：
通过液体输送件将微球生成液输送至位于接收液中的多孔膜，由膜孔挤出形成胚胎微球；其中，所述液体输送件输出液体的流速可控。
本技术方案中，将输送微球生成液的方式从传统的气压推动变为输出流速可控的液体输送件。不同于气压推动时气体压力大小仅仅是微球生成液输出速 率的影响因素之一，液体输送件可以直接控制单位时间内输出微球生成液的量，进而可以更好的调控生成微球的粒径。除此以外，由于本技术方案中去除了气压推动这一工艺流程，也避免了由于胚胎微球中混入气泡而致使其表面张力分布出现变化最终导致无法形成球状体的问题，提升了微球的产品良率。
优选的，所述液体输送件可选用注射泵、注射器、或其他流量可精确调控的泵将微球生成液推向多孔膜。
优选的，施加剪切力或振动使胚胎微球脱离所述多孔膜，其中，
施加剪切力或振动的强度和/或频率可控。
本技术方案中，剪切力或者振动的施加频率以及强度会影响微球生成液从多孔膜表面脱离的速率，改变胚胎微球在多孔膜表面粘附性，进而调控生成胚胎微球的粒径。
优选的，对所述液体输送件内的微球生成液施加搅拌、摇动、或其他扰动动作。
本技术方案中，微球形成液中含有固体微粒时，对液体输送件内的微球生成液进行扰动，使微粒不发生不沉降，并且输送时分布均匀。
一种微球制备方法，包括如下步骤：
S10，通过液体输送件将微球生成液输送至位于接收液中的多孔膜，形成胚胎微球；其中，所述液体输送件输出液体的流速可控；
S20，从多孔膜上脱落的胚胎微球沿着充满接收液的通道流动，使微球形成液中的有机溶剂被萃取，胚胎微球变硬形成微球。
S30，收集所述微球。
优选的，在所述步骤S10中：
所述液体输送件可选用注射泵、注射器或其他流量可调控的泵；和/或；施加剪切力或振动使胚胎微球脱离所述多孔膜，施加剪切力或振动的强度及频率可控；和/或：对所述液体输送件内的微球生成液施加搅拌动作；和/或；在输 送微球生成液前，为制备胚胎微球的设备排气。
一种胚胎微球制备机构，包括：液体输送件，用于以可控流速输送微球生成液；多孔膜，接收来自液体输送件的微球生成液并使之通过微孔形成胚胎微球；多孔膜支架，用于装设多孔膜，并通过其管状结构连接液体输送件和多孔膜。
本技术方案中，使用液体输送件替换了之前了气体输入装置以及装设生成液体的容器。不同于使用气压推动时气体压力大小仅仅是微球生成液输出速率的影响因素之一，无法控制输出微球生成液的流速。液体输送件可以直接控制单位时间内输出微球生成液的量，进而可以更好的调控生成微球的粒径。除此以外，由于本技术方案中去除了气体输入装置这一机构，避免了由于胚胎微球中混入气泡而致使其表面张力分布出现变化最终导致无法形成球状体的问题，提升了微球的产品良率。
优选的，所述液体输送件可选用注射泵、注射器或其他流量可调控的泵；。
优选的，所述液体输送件包括：储存腔，用于储存微球生成液；推压件，沿所述储存腔内壁可滑移设置，用于推送微球生成液；以及，动力源，驱动所述推压件做推送动作。
优选的，所述液体输送件底部还包括搅拌结构，所述搅拌结构用于扰动微球生成液。
优选的，所述储存腔底部开设有凹形槽，以容纳搅拌机构。
优选的，所述储存腔的下端侧壁上设置有原料出入口。
优选的，进一步包括进料管，所述进料管连通所述液体输送件与所述多孔膜支架，所述多孔膜支架上包括有用于装设所述进料管的锥形孔，所述锥形孔的径向尺寸沿从外向内的方向逐渐增大。
本技术方案中，锥形孔的设计是为了内部压力越大时，密封效果更好。
优选的，所述多孔膜支架上设置有排气结构。
本技术方案中，当多孔膜支架内有气体存在时，此时可以通过排气结构将气体排出。
优选的，所述进料管延伸至多孔膜处。
本技术方案中，进料管延伸至多孔膜处，微球生成液可以直接输送到多孔膜处，避免将气体引入到多孔膜处，从而影响胚胎微球生成的良品率。
一种微球制备装置，包括：胚胎微球制备机构；固化管，与所述胚胎微球制备机构连接，胚胎微球在所述固化管中沉降并通过溶剂萃取固化成型，形成微球；以及，收集器，与所述固化管连接，以收集微球。
优选的，还包括后处理机构，所述后处理机构用于对微球进行有机溶剂和其他杂质的移出。
综上所述，本发明可以实现以下有益效果：
1、使用液体输送件替换了之前了气体输入装置以及装设生成液体的容器。不同于使用气压推动时气体压力大小仅仅是微球生成液输出速率的影响因素之一，无法精确控制输出微球生成液的量。液体输送件可以直接控制单位时间内输出微球生成液的量。胚胎微球的大小与其从多孔膜管上脱落的时机相关，而脱落的时机则由胚胎微球的增长速率、表面张力、以及对膜管表面施加的剪切力(或振动力)决定。上述三个因素中，胚胎微球的增长速率直接取决于微球生成液的出膜流速。目前膜乳化法制备胚胎微球所采用的气体压力虽然与液体的流速相关，却不一定与流速保持着恒定的线性关系，微球生成液的浓度、粘度、以及其中溶解的气体的多寡均影响着气压与流速之间的关系。直接用微球生成液的流速控制胚胎微球的粒径一并排除了其他干扰，且液体流速的显示精度远高于气体压力，大幅优化了胚胎微球粒径的精准调控.
2、通过液体输送件的输送，代替了传统的气体压力进行推送的方式，使得形成胚胎微球的过程不会过多的引入气体，避免了由于胚胎微球中混入气泡而致使其表面张力分布出现变化最终导致无法形成球状体的问题，提升了微球 的产品良率。
3、利用液体输送件控制输送微球生成液的流速，配合可控强度或者频率的剪切力和振动，再加之多孔膜的孔径亦可精确设计，微球的粒径可以得到有效的调控。
4、通过在液体输送件中设计凹形槽以保证在实际的输送过程中能够更好的输送液体，同时再配以搅拌结构对储存腔的底部液体进行搅拌，以保证输送的微球生成液均匀，这样就可以保证生成的胚胎微球质量均一。
附图说明
下面将以明确易懂的方式，结合附图说明优选实施方式，对胚胎微球制备方法及制备机构、微球制备方法及制备装置的上述特性、技术特征、优点及其实现方式予以进一步说明。
图1是本发明微球生成的工艺流程图；
图2是本发明一种胚胎微球机构结构示意图；
图3是一种胚胎微球机构结构另一实施例结构示意图；
图4是一种胚胎微球机构结构另一实施例结构示意图；
图5是微球制备装置结构示意图。
附图标号说明：液体输送件1、储存腔101、推压件102、推杆103、排液孔104、连接件105、搅拌机构106、驱动装置107、生成装置2、多孔膜支架201、进料管202、排气结构203、气体滞留腔204、多孔膜205、固化管3、收集器4、输送管道5。
具体实施方式
为了更清楚地说明本发明实施例或现有技术中的技术方案，下面将对照附图说明本发明的具体实施方式。显而易见地，下面描述中的附图仅仅是本发明的一些实施例，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他的附图，并获得其他的实施方式。
为使图面简洁，各图中只示意性地表示出了与发明相关的部分，它们并不代表其作为产品的实际结构。另外，以使图面简洁便于理解，在有些图中具有相同结构或功能的部件，仅示意性地绘示了其中的一个，或仅标出了其中的一个。在本文中，“一个”不仅表示“仅此一个”，也可以表示“多于一个”的情形。
本发明提供一种胚胎微球的制备方法的实施例，其包括如下步骤：
通过液体输送件将微球生成液输送至位于接收液中的多孔膜，由膜孔挤出形成胚胎微球；其中，液体输送件输出液体的流速可控。微球生成液通过液体输送件1输送至多孔膜处，以使原液经过多孔膜能够挤压成型。
液体输送件的流速可控，即其可以选择下述一种或多种的调控方式：
a，以一恒定的输出流速在单位时间内输出定量的微球生成液；
b，微球生成液的输出流速可以调整至不同的参数，以适应不同的工况以及要求；
c，微球生成液的输出流速并不是一个恒定的值，而是可以根据实际需要以波动或阶跃的方式变化，以适应不同的工况以及要求。
液体输送件使得微球生成液以可控的流速到达多孔膜处，从而达到控制形成的胚胎微球粒径的目的。液体输送件可选用注射泵、注射器、或其他流量可精确调控的泵将微球生成液推向多孔膜，在使用注射泵进行输送液体时，可以将输送流速调节至恒定的流速，也可以将输送流速调节成变速，在输送的过程中逐渐增大或者逐渐减小；在使用注射器进行注射液体时，注射器可以手动进行调节，也可以通过连接推送机构进行推送，可以使注射器的流速不断增大、不断减小或者保持恒定流速，在本实施例中对调节的流速不做限制，对使用的液体输送件1的具体结构不做限制，需要说明的是，除了本实施例中列举的两种液体输送件外，其他能够达到输送液体且流速可控的输送装置均可以使用在本技术方案中。
可选的，在通过液体输送件将微球生成液输送至位于微球接收液中的多孔膜的同时，亦可以施加剪切力或振动使胚胎微球脱离多孔膜，在使用振动器可以将振动传递至微球形成材料，使其从多孔膜挤出后形成的聚合物微球液滴更易于脱离多孔膜表面，减少微球液滴在多孔膜表面的粘附，振动器可以是气动推杆、电动推杆、手动推杆或其他任何形式的往复机构。可以同时调节振动的强度和频率，也可以单独改变提高振动强度或者单独改变振动频率，以保证形成的微球粒径更均匀，生产效率更高。
可选的，在液体输出的时候对液体输送件1内的微球生成液施加搅拌动作。在输送微球生成液前，为制备胚胎微球的设备排气，微球生成液能够顺利留下，且较容易通过多孔膜。
图1是微球制备方法实施例的示意图，微球制备方法包括如下步骤：
S10，通过液体输送件将微球生成液输送至位于接收液中的多孔膜，形成胚胎微球；其中，液体输送件输出液体的流速可控；
S20，从多孔膜上脱落的胚胎微球沿着充满接收液的通道流动，使微球形成液中的有机溶剂被萃取，胚胎微球变硬形成微球。
S30，收集微球。
在本实施例中，微球生成液由液体输送件输出，通过进料管到达多孔膜处，微球生成液在液体输送件输送的情况下，微球生成液的输出量可控，进而可以调控影响生成胚胎微球的粒径。从多孔膜上脱落的胚胎微球沿着充满接受液的通道流动，使胚胎微球生成液变硬成型，再通过后续的收集器进行收集。
图2是胚胎微球制备机构的实施例示意图，胚胎微球制备机构包括：液体输送件1、多孔膜205以及多孔膜支架。液体输送件1用于以可控流速输送微球生成液；多孔膜205接收来自液体输送件1的微球生成液并使之通过微孔形成胚胎微球；多孔膜支架201用于装设多孔膜205，并通过其管状结构连接液体输送件1和多孔膜205。
可选的，液体输送件1可选用注射泵、注射器，或者其他流量可调控的泵，例如计量泵、分子泵、涡轮泵等。在本实施例中，优选用注射器，通过注射器控制微球生成液输送流速，通过控制输送流速以控制生成的胚胎微球的粒径。
具体的，再次参见图2，液体输送件包括储存腔101、推压件102以及动力源。推压件102沿储存腔101内壁可滑移设置，用于推送微球生成液；以及，动力源，驱动推压件102做推送动作。在实际操作时，推压件102连接有推杆103，然后动力源驱动推杆103来驱动推压件102进行滑动，通过动力源驱动推压件102运动，以保证推压件102能够以恒定流速、以逐渐增大的流速或者以逐渐减小的流速进行输送液体，从而使流到多孔膜205处的微球生成液的流速改变，随之微球生成液通过多孔膜205时的压力也不一样，这就使微球生成液通过多孔膜205时的流畅性不一样，粒径更均匀，且不会容易发生粘黏。
在本具体实施例中，动力源驱动推压件102进行推送储存腔101内的液体，推压件102沿着储存腔101的内壁滑动，在具体操作的过程中，动力源可以为手动推送或者外界的推送机构，如液压推送、丝杆推送。具体使用哪种方式，在本实施例中不做过多的赘述。
图3是胚胎微球制备机构的另一实施例的示意图，在参照图2的胚胎微球制备机构的任意实施例的基础上，液体输送件1底部还包括搅拌机构106，搅拌机构106用于扰动微球生成液；在具体实施的时候搅拌机构106可以为磁力搅拌浆，储存腔101的底部连接有磁力搅拌桨，在储存腔101的下端连接有驱动装置107，此驱动装置107由马达107a及磁铁107b构成，磁铁固定连接在马达107a的旋转端，通过马达107a带动磁铁107b旋转，从而不断的改变磁场方向，以保证磁力搅拌浆能够不断的转动。
可选的，如图4所示，搅拌机构106也可以为磁力搅拌子，在驱动装置107的作用下，微球生成液能够在储存腔101的底部，以达到更好的搅拌。
具体的，储存腔101底部开设有凹形槽，以容纳磁搅拌机构106，凹形槽是 为了液体能够更好的聚集在储存腔101的内底壁上，推压件102推动液体流动时，液体能够更好的聚集在凹形槽内，再匹配搅拌机构106，能够将微球生成液更好的搅拌，防止液体沉淀，将液体搅拌均匀；同时液体经过凹形槽底部再流出，这样不会出现储存腔101内的液体不能全部输送的现象
可选的，储存腔101的下端侧壁上设置有原料出入口，以便于在加工时，能够在完成一次液体输送结束的时候，向液体输送装置1中输送液体，不用拆卸装置再次进行灌装液体或者更换，以保证操作流程的简便，提高工作效率。
可选的，如图3-4所示，胚胎微球制备机构还包括进料管202，进料管202连通液体输送件1与多孔膜支架201，在具体实施的时候，液体输送件1的侧壁上开设有排液孔104，排液孔104内壁上贯通连接有连接件105，用于连接进料管202，且连接件105呈倒刺状，使连接更加牢固，进料管202进行微球生成液的输送，多孔膜支架201上包括有用于装设进料管202的锥形孔，锥形孔的径向尺寸沿从外向内的方向逐渐增大；锥形孔的设计是保证能够内部压力越大，密封效果越好，进料管202延伸至多孔膜205处，液体随进料管202直接输送到多孔膜205处，避免将空气锁入多孔膜205内，在实际操作的时候，多孔膜205处的气泡会影响生成微球的良品率。
可选的，多孔膜支架201上设置有排气结构203，装设排气结构203的排气孔呈锥形，可以起到密封的效果，在具体实施的时候，多孔膜支架201的内腔上端为气体滞留腔204，当气体增多时可通过排气结构203排出，多孔膜支架201、进料管202、排气结构203、气体滞留腔204和多孔膜205构成生成装置2。
图5是微球制备装置的实施例示意图，微球制备装置包括：在前述胚胎微球制备机构的任意实施例中的胚胎微球制备机构；固化管3，与胚胎微球制备机构连接，胚胎微球在所述固化管中沉降并通过溶剂萃取固化成型，形成微球；以及，收集器4，与固化管3连接，以收集微球；
具体的还包括后处理机构，所述后处理机构用于对微球进行有机溶剂和其 他杂质的移出。
在本实施例中，通过胚胎微球制备机构将微球生成液制备成胚胎微球，生成的胚胎微球经过固化管3，被固化管3内的有机溶剂萃取形成微球，再通过收集器4进行收集，同时，生成装置2在固化管3中做圆周运动以施加剪切力，便于胚胎微球从多孔膜205脱落，然后又输送管道5输送至后处理设备中进行后处理，在后处理时，先对微球进行冲洗处理，然后再对微球进行冷冻干燥。
在上述实施例中，对各个实施例的描述都各有侧重，某个实施例中没有详细描述或记载的部分，可以参见其他实施例的相关描述。
应当说明的是，上述实施例均可根据需要自由组合。以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。

Claims (18)

  1. 一种胚胎微球的制备方法，其特征在于，包括如下步骤：
    通过液体输送件将微球生成液输送至位于微球接收液中的多孔膜，由膜孔挤出形成胚胎微球；其中，所述液体输送件输出液体的流速可控。
  2. 根据权利要求1所述的胚胎微球的制备方法，其特征在于，所述液体输送件可选用注射泵、注射器、或其他流量可调控的泵。
  3. 根据权利要求1所述的胚胎微球的制备方法，其特征在于，施加剪切力或振动使胚胎微球脱离所述多孔膜，其中，
    施加剪切力或振动的强度和/或频率可控。
  4. 根据权利要求1所述的胚胎微球的制备方法，其特征在于，对所述液体输送件内的微球生成液施加搅拌、摇动、或其他扰动动作。
  5. 根据权利要求1所述的胚胎微球的制备方法，其特征在于，在输送微球生成液前，为制备胚胎微球的设备排气。
  6. 一种微球制备方法，其特征在于，包括如下步骤：
    S10，通过液体输送件将微球生成液输送至位于接收液中的多孔膜，形成胚胎微球；其中，所述液体输送件输出液体的流速可控；
    S20，从多孔膜上脱落的胚胎微球沿着充满接收液的通道流动，使微球形成液中的有机溶剂被萃取，胚胎微球变硬形成微球。
    S30，收集所述微球。
  7. 根据权利要求6所述的微球制备方法，其特征在于，在所述步骤S10中：
    所述液体输送件可选用注射泵、注射器或其他流量可调控的泵；
    和/或；
    施加剪切力或振动使胚胎微球脱离所述多孔膜，施加剪切力或振动的强度及频率可控；
    和/或：
    对所述液体输送件内的微球生成液施加搅拌动作；
    和/或；
    在输送微球生成液前，为制备胚胎微球的设备排气。
  8. 一种胚胎微球制备机构，其特征在于，包括：
    液体输送件，用于以可控流速输送微球生成液；
    多孔膜，接收来自液体输送件的微球生成液并使之通过微孔形成胚胎微球；以及，
    多孔膜支架，用于装设多孔膜，并通过其管状结构连接液体输送件和多孔膜。
  9. 根据权利要求8所述的胚胎微球制备机构，其特征在于，所述液体输送件可选用注射泵、注射器、或其他流量可调控的泵。
  10. 根据权利要求8所述的胚胎微球制备机构，其特征在于，所述液体输送件包括：
    储存腔，用于储存微球生成液；
    推压件，沿所述储存腔内壁可滑移设置，用于推送微球生成液；以及，
    动力源，驱动所述推压件做推送动作。
  11. 根据权利要求10所述的胚胎微球制备机构，其特征在于，所述液体输送件底部还包括搅拌结构，所述搅拌结构用于扰动微球生成液。
  12. 根据权利要求8所述的胚胎微球制备机构，其特征在于，所述储存腔底部开设有凹形槽，以容纳搅拌机构。
  13. 根据权利要求8所述的胚胎微球制备机构，其特征在于，所述储存腔的下端侧壁上设置有原料出入口。
  14. 根据权利要求8所述的胚胎微球制备机构，其特征在于，进一步包括进料管，所述进料管连通所述液体输送件与所述多孔膜支架，所述多孔膜 支架上包括有用于装设所述进料管的锥形孔，所述锥形孔的径向尺寸沿从外向内的方向逐渐增大。
  15. 根据权利要求8所述的胚胎微球制备机构，其特征在于，所述多孔膜支架上设置有排气结构。
  16. 根据权利要求14所述的胚胎微球机构，其特征在于，所述进料管延伸至多孔膜处。
  17. 一种微球制备装置，其特征在于，包括：
    根据权利要求8-16任一所述的胚胎微球制备机构；
    固化管，与所述胚胎微球制备机构连接，胚胎微球在所述固化管中沉降并通过溶剂萃取固化成型，形成微球；以及，
    收集器，与所述固化管连接，以收集微球。
  18. 一种微球制备装置，其特征在于，还包括后处理机构，所述后处理机构用于对微球进行有机溶剂和其他杂质的移出。
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