System for preparing lipidosome polymer microspheres by using through-hole tubular filter membrane and control method

Abstract

The invention relates to the technical field of microsphere preparation, and discloses a system for preparing liposome polymer microspheres by using a through-hole tubular filter membrane and a control method. The system for preparing the liposome polymer microspheres by using the through-hole tubular filter membrane comprises a membrane emulsification device, the membrane emulsification device comprises a plurality of tubular filter membranes; the plurality of tubular filter membranes are arranged in parallel; an outer flow channel is formed between every two adjacent tubular filter membranes; an inner flow channel is formed in the tubular filter membrane in the axial direction of the tubular filter membrane, a plurality of micropores are formed in a tube arm of the tubular filter membrane, and the outer flow channel is communicated with the inner flow channel through the micropores. By arranging a plurality of tubular filter membranes in parallel, a large amount of raw materials can be synchronously treated, the microsphere yield in unit time is remarkably improved, the bottleneck of low efficiency of a traditional single filter membrane is overcome, the device is suitable for industrial enlarged production, and the problems that in the prior art, the yield of a membrane emulsification device is limited, and the production efficiency is low in a large-scale emulsification scene are solved. A plurality of film emulsifying devices need to be arranged to participate in the emulsifying process at the same time, so that the cost of the emulsifying process is relatively high.

Description

Technical Field

[0001] This invention relates to the field of microsphere preparation technology, and in particular to a system and control method for preparing liposome polymer microspheres using a porous tubular filter membrane. Background Technology

[0002] Membrane emulsification devices utilize the principles of membrane separation and capillary action, taking full advantage of the characteristics of microporous membranes. The membrane serves as the emulsification medium, with a dispersed phase and a continuous phase on either side. Nitrogen gas is applied to pressurize the membrane, causing the dispersed phase to permeate through the micropores and form droplets on the membrane surface. Under the flushing action of the flowing continuous phase, once the droplets reach a certain size, they detach from the membrane surface and disperse into the continuous phase. Different pore sizes of micropores can form droplets of different sizes; therefore, by controlling the pore size, the droplet size and distribution can be effectively controlled.

[0003] Existing membrane emulsification devices are typically equipped with one or two membranes, which limits the emulsification efficiency of the device. If a large-scale emulsification scenario with a limited time is required, multiple membrane emulsification devices are needed, thereby increasing the cost of the entire emulsification process.

[0004] Existing membrane emulsification equipment mainly uses SPG membranes, ceramic membranes, quartz glass membranes, and flat nickel membranes. Among them, SPG membranes developed and produced in Japan are the most widely used, and most laboratory emulsifiers currently use Japanese-made SPG membranes. However, existing SPG membranes are usually made of sintered ceramic with randomly distributed channels, resulting in limited emulsification uniformity. Furthermore, because random channels are very prone to dead pores, thorough cleaning and backflushing are difficult, posing challenges for use in GMP workshops. Summary of the Invention

[0005] This invention provides a system and control method for preparing liposome polymer microspheres using a perforated tubular filter membrane, thereby solving at least one of the problems existing in the membrane emulsification devices of the prior art.

[0006] This invention provides a system for preparing liposome polymer microspheres using a porous tubular filter membrane, comprising a membrane emulsification device; the membrane emulsification device includes: Multiple tubular filter membranes are arranged in parallel; an external flow channel is formed between two adjacent tubular filter membranes; an internal flow channel is formed inside each tubular filter membrane along its own axial direction; multiple micropores are formed on the wall of each tubular filter membrane; the external flow channel communicates with the internal flow channel through the micropores.

[0007] The system for preparing liposome polymer microspheres using a perforated tubular filter membrane according to the present invention further includes: A dispersed phase supply device, connected to the outer flow channel, is used to inject a dispersed phase into the outer flow channel; A continuous phase supply device is connected to the inner flow channel to form a continuous phase circulation loop.

[0008] The system for preparing liposome polymer microspheres using a porous tubular filter membrane according to the present invention includes a dispersed phase supply device comprising: Both the first dispersed phase storage unit and the second dispersed phase storage unit are used to store the dispersed phase; The first valve body unit has a first conducting state and a second conducting state; In the first conducting state, the first dispersed phase storage unit injects the dispersed phase into the outer channel; in the second conducting state, the second dispersed phase storage unit injects the dispersed phase into the outer channel.

[0009] The system for preparing liposome polymer microspheres using a perforated tubular filter membrane according to the present invention includes, wherein the first valve body unit comprises: The first three-way valve connects the external flow channel to the first dispersed phase storage unit and the second dispersed phase storage unit respectively.

[0010] The system for preparing liposome polymer microspheres using a porous tubular filter membrane according to the present invention includes a continuous phase supply device comprising: A continuous phase storage module is used to store the continuous phase; the inlet of the continuous phase storage module is connected to the outlet of the inner flow channel, and the outlet of the continuous phase supply device is connected to the inlet of the inner flow channel to form the continuous phase circulation loop. A circulating power source is provided in the continuous phase circulating loop.

[0011] The system for preparing liposome polymer microspheres using a porous tubular filter membrane according to the present invention includes a continuous phase storage module comprising: Both the first continuous phase storage unit and the second continuous phase storage unit are used to store the continuous phase; The second valve body unit has a third conduction state and a fourth conduction state; In the third conducting state, the first continuous phase storage unit injects the continuous phase into the inner flow channel; in the fourth conducting state, the second continuous phase storage unit injects the continuous phase into the inner flow channel.

[0012] The system for preparing liposome polymer microspheres using a perforated tubular filter membrane according to the present invention includes, wherein the second valve body unit comprises: The inlet of the inner flow channel is connected to the outlet of the first continuous phase storage unit and the outlet of the second continuous phase storage unit through the second three-way valve. The fourth three-way valve connects the outlet of the inner flow channel to the inlet of the first continuous phase storage unit and the inlet of the second continuous phase storage unit, respectively.

[0013] The system for preparing liposome polymer microspheres using a perforated tubular filter membrane according to the present invention further includes: An emulsion storage device, connected to the inner flow channel, is used to store the emulsion discharged from the inner flow channel.

[0014] The system for preparing liposome polymer microspheres using a perforated tubular filter membrane according to the present invention further includes: A pressure supply device, connected to the outer flow channel, is used to introduce protective gas into the outer flow channel to push the dispersed phase through the micropores to form droplets in the inner flow channel.

[0015] A second aspect of the present invention provides a controlled method for preparing liposome polymer microspheres using a porous tubular filter membrane, employing the system for preparing liposome polymer microspheres using a porous tubular filter membrane as described in any one of the preceding claims, the method comprising: The dispersed phase is injected into the outer channel, and the continuous phase is injected into the inner channel; A protective gas is introduced into the outer flow channel to push the dispersed phase through the micropores, forming droplets in the inner flow channel, and mixing with the continuous phase to form an emulsion. After emulsification is complete, the emulsion in the inner channel is discharged into the emulsion storage device for storage; The emulsion was stirred, the solvent was evaporated, and the mixture was freeze-dried to obtain microspheres.

[0016] This invention provides a system for preparing liposome polymer microspheres using porous tubular filter membranes. By arranging multiple tubular filter membranes in parallel, it can simultaneously process large quantities of raw materials, significantly increasing the microsphere yield per unit time. This overcomes the bottleneck of low efficiency in traditional single filter membranes and is suitable for industrial-scale production. It also solves the problem of limited output of existing membrane emulsification devices, which require multiple devices to participate simultaneously in the emulsification process in large-scale emulsification scenarios, leading to high costs. Furthermore, the tubular filter membranes of this invention are free of dead pores, solving the problem of dead pores in existing ceramic-sintered SPG membranes, which makes thorough cleaning and backflushing difficult. Attached Figure Description

[0017] To more clearly illustrate the technical solutions in this invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of this invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0018] Figure 1 This is a schematic diagram of the system for preparing liposome polymer microspheres using a porous tubular filter membrane provided by the present invention.

[0019] Figure 2 This is a top-view structural schematic diagram of the membrane emulsification device of the system for preparing liposome polymer microspheres using a perforated tubular filter membrane provided by the present invention.

[0020] Figure 3 This is a schematic diagram of the tubular filter membrane structure of the membrane emulsification device provided by the present invention.

[0021] Figure 4 yes Figure 3 A magnified structural diagram of point A in the middle.

[0022] Figure 5 This is a flowchart of a control method for preparing liposome polymer microspheres using a perforated tubular filter membrane, provided by the present invention.

[0023] Figure 6 This is an electron micrograph of the liposome polymer microspheres prepared in Example 1.

[0024] Figure 7 This is a schematic diagram of a filter membrane processing system based on a traditional Bessel beam.

[0025] Figure 8 This is a schematic diagram of the filter membrane processing system provided by the present invention.

[0026] Figure 9 This is a schematic diagram illustrating the principle of the reflective axial pyramid provided by the present invention reflecting incident light rays to form a Bessel beam; wherein, The reflectivity of the reflective axial pyramid. The base angle of the reflective axial pyramid. The diffraction angle of the Bessel region; The focal depth of the non-diffraction region of the Bessel beam; Represents the incident laser. The wavelength representing the incident laser light. Represents the radius of the incident laser beam.

[0027] Figure 10 It is an image of the spot of the incident laser after passing through the reflective axial pyramid and at the processing station.

[0028] Figure 11 These are simulation diagrams of the transverse and longitudinal light intensity distribution of Bessel and Gaussian beams: (a) and (b) are simulation diagrams of the light field of the Bessel beam; (c) and (d) are simulation diagrams of the light field of the Gaussian beam.

[0029] Figure 12This invention describes the use of a filter membrane processing system to create 1-micron pores in stainless steel.

[0030] Figure label: 110. Beam shaping assembly; 120. Transmission assembly; 121. Lens; 122. Field lens; 130. Galvanometer assembly; 140. Beam expander; 150. Polarization assembly; 151. Half-wave plate; 152. Polarizer; 160. Laser source; 170. Mirror; 210. Membrane emulsification device; 211. Tubular filter membrane; 212. External flow channel; 213. Internal flow channel; 214. Micropores; 215. Outer shell; 220. Dispersed phase supply device; 221. First dispersed phase storage unit; 222. Second dispersed phase storage unit; 223. First valve body unit; 230. Continuous phase supply device; 231. Continuous phase storage module; 2311. First continuous phase storage unit; 2312. Second continuous phase storage unit; 2313. Second three-way valve; 2314. Fourth three-way valve; 232. Circulation power source; 2321. Circulation pump; 2322. Flow detection unit; 240. Emulsion storage device; 250. Pressure supply device; 251. Air pump; 252. Pressure gauge; 253. Third three-way valve; 254. Sixth three-way valve; 260. Third valve body unit. Detailed Implementation

[0031] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions of this invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some, not all, of the embodiments of this invention. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention.

[0032] The following is combined Figures 1 to 4 The results and working principle of the system for preparing liposome polymer microspheres using a porous tubular filter membrane provided by the present invention are described in detail.

[0033] like Figures 1 to 4As shown, a specific embodiment of the first aspect of the present invention provides a system for preparing liposome polymer microspheres using a perforated tubular filter membrane. The system includes a membrane emulsification device 210; the membrane emulsification device 210 includes a plurality of tubular filter membranes 211; the plurality of tubular filter membranes 211 are arranged in parallel; an outer flow channel 212 is formed between two adjacent tubular filter membranes 211; an inner flow channel 213 is formed within the tubular filter membrane 211 along its own axial direction; a plurality of micropores 214 are formed on the wall of the tubular filter membrane 211; the outer flow channel 212 communicates with the inner flow channel 213 through the micropores 214.

[0034] In this embodiment, by arranging multiple tubular filter membranes 211 in parallel, a large amount of raw materials can be processed simultaneously, significantly increasing the microsphere yield per unit time. This overcomes the bottleneck of low efficiency in traditional single filter membranes, making it suitable for industrial-scale production. It also solves the problem of limited output of existing membrane emulsification devices 210, which require multiple devices 210 to participate simultaneously in the emulsification process in large-scale emulsification scenarios, leading to high costs. Furthermore, the filter membrane in this embodiment is free of dead pores, solving the problem of dead pores in existing ceramic-sintered SPG membranes, which makes thorough cleaning and backwashing difficult.

[0035] Furthermore, the outer flow channels 212 between adjacent tubular filter membranes 211 form directional fluid channels, which, together with the micropores 214, enable a more uniform transmembrane pressure distribution and avoid localized eddies or dead zones. The inner flow channels 213 and outer flow channels 212, through the micropores 214, form a controllable cross-flow shear force, which is beneficial for generating microspheres with better dispersion. The parallel modular design allows for flexible increases or decreases in the number of tubular filter membranes 211, satisfying both small-scale process optimization and scaling up to large-scale production. The tubular filter membranes 211 can be maintained or replaced individually, reducing overall downtime losses due to localized blockage or damage. The collaborative work of multiple tubular filter membranes 211 maintains a more stable transmembrane pressure, and combined with the uniformity of the micropore size 214, ensures uniform microsphere particle size.

[0036] Optionally, adjacent tubular filter membranes 211 are arranged at intervals. The interval arrangement of the tubular filter membranes 211 can reduce vibration interference and avoid the risk of mechanical damage to the tubular filter membranes 211 caused by dense arrangement.

[0037] Furthermore, the micropores 214 on the tubular filter membrane 211 can be formed by laser processing. The micropores 214 formed by laser processing have a uniform pore distribution, which improves the uniformity of emulsification and solves the problem of random pore distribution and limited emulsification uniformity in existing SPG membranes formed by ceramic sintering.

[0038] Preferably, the micropores 214 on the tubular filter membrane 211 are formed using a reflective Bezier beam processing method. In the prior art, micropores are typically formed by ceramic sintering, resulting in randomly distributed channels. This limits the emulsification uniformity of the membrane emulsification device. Furthermore, because random channels are prone to dead pores, thorough cleaning and backflushing are difficult, posing challenges for use in GMP (cleanroom) facilities. In this embodiment, the micropores 214 on the tubular filter membrane 211 are preferably formed using a reflective Bezier beam processing method, which avoids dead pores and provides better pore size uniformity for the micropores 214.

[0039] It should be noted that reflective Bessel beams can be generated by a filter membrane processing system.

[0040] Optionally, the micropores 214 on the tubular filter membrane 211 can be made of... Figure 8 The filter membrane processing system shown is used for processing. The structure and working principle of the filter membrane processing system of the present invention will be described in detail below.

[0041] In the late 1980s, Durnin of the University of Rochester formally proposed the concept of a diffraction-free beam. He essentially discovered a set of rigorous solutions to the zeroth-order Bessel function form of Maxwell's wave equation and experimentally proved, using simple optical components, that the corresponding wave of this particular solution is a Bessel beam, exhibiting diffraction-free characteristics. Due to the excellent optical propagation properties of diffraction-free Bessel beams, their research quickly attracted widespread attention from research groups both domestically and internationally.

[0042] The wave equation for an ideal Bessel beam is given by formula (1): Formula (1).

[0043] In formula (1), t represents electric field intensity; r represents spatial position coordinates; t represents time; c is the speed of light in vacuum. For the second-order partial derivative with respect to time; It is the Laplace operator.

[0044] A particular solution along the Z-axis can be expressed as formula (2): In formula (2), ε represents the electric field strength; r represents the spatial coordinates; t represents time; exp is the natural exponential function; i is the imaginary unit; For the longitudinal component of the propagation constant; ω is the angular frequency; z is the spatial coordinate along the main propagation direction of the beam (i.e., the Z-axis); For the transverse component of the propagation constant; The azimuth angle is x; x and y are rectangular coordinates in a plane perpendicular to the beam propagation direction (i.e., the Z-axis). Radial coordinates; This is a Bessel function.

[0045] For an ideal Bessel beam, its cross-sectional intensity distribution A Bessel beam is characterized by a central spot (main lobe) and numerous concentric rings (side lobes). The energy density of the main lobe is much higher than that of the side lobes, and the light intensity decreases sequentially from the inside out. However, the energy carried by the main lobe is equal to that of the side lobes, and the intensity distribution does not change with increasing propagation distance. The intensity of a Bessel beam does not change with propagation distance; this is commonly referred to as its "diffraction-free characteristic." Since the laser beam emitted from a laser in a real optical system is limited by an aperture, its beam width and energy are finite. In experiments, only an approximate Bessel beam can be obtained; that is, its "diffraction-free characteristic" manifests in practice as a limited distance along the propagation direction. Within this range, the lateral light intensity distribution remains essentially constant. Once this maximum distance is exceeded, the beam diverges and loses its "non-diffraction characteristic".

[0046] like Figure 11 These are simulation diagrams of the transverse and longitudinal light intensity distribution of Bessel and Gaussian beams: (a) and (b) are simulation diagrams of the light field of the Bessel beam; (c) and (d) are simulation diagrams of the light field of the Gaussian beam.

[0047] Figure 7 This is a schematic diagram of a filter film processing system based on a traditional Bessel beam. The laser source emits a laser beam, which, after passing through a beam expander, is incident on a transmission axial pyramid. The transmission axial pyramid transmits the incident Gaussian beam and converts it into a Bessel beam. This Bessel beam is then focused onto the processing station by a lens to drill holes in the workpiece. However, this transmission axial pyramid is not suitable for high-power laser drilling requirements.

[0048] like Figure 8 As shown in the figure, a specific embodiment of the present invention provides a filter membrane processing system. The filter membrane processing system includes a beam shaping component 110 and a transmission component 120; the beam shaping component 110 is used to reflect the incident laser and convert it into a Bessel beam; the transmission component 120 is disposed in the optical path of the Bessel beam and is used to transmit the non-diffraction region of the Bessel beam to the processing station.

[0049] In this embodiment, the incident laser beam is reflected and converted into a Bessel beam by the beam shaping component 110, instead of being transmitted to form a Bessel beam. Then, the non-diffraction region of the Bessel beam is transmitted to the processing station by the transmission component 120, allowing drilling of the workpiece placed at the processing station. The reflective design avoids energy absorption by the transmission element, making it suitable for long-term high-power processing. The reflective design does not require consideration of the material's transmittance, supporting incident lasers from the ultraviolet to the infrared band. The reflective design eliminates the thermal lensing effect, resulting in high focal depth stability in the non-diffraction region of the Bessel beam, and also avoids the aperture inconsistency problem caused by heat accumulation in the transmission method.

[0050] Furthermore, the incident laser is a pulsed laser.

[0051] Furthermore, the beam shaping assembly 110 includes a reflective axial pyramid; the reflective axial pyramid is positioned in the optical path of the incident laser to reflect the incident laser and convert it into a Bessel beam. The reflective design avoids the dispersion problems of the transmitting material and is suitable for multi-wavelength / ultrafast lasers. The metal reflective film of the reflective axial pyramid (such as a gold film with an infrared reflectivity >98%) can withstand kilowatt-level lasers without thermal lensing effects. The reflection angle allows for a foldable optical path, saving space and making it suitable for integrated equipment.

[0052] As Figure 10 The images shown, including the incident laser after passing through the reflective axial pyramid and the spot image at the machining station, demonstrate that the reflective axial pyramid can convert the incident laser into a Bessel beam, and the transmission component can transmit the Bessel beam to the machining station.

[0053] like Figure 9 As shown, the base angle α of the reflective axial pyramid is further ranging from 0.5° to 15°. This design allows for flexible adaptation to different precision machining requirements while avoiding the limitations of traditional transmission-type axial pyramids. For example, Preferably, the base angle α of the reflective axial pyramid is 2° to 5°, which is suitable for long focal depths and wide-range processing.

[0054] like Figure 9 As shown, furthermore, the angle γ between the incident laser and the normal of the reflecting axial pyramid is half the base angle α. This further ensures the quality of the Bessel beam formed after passing through the reflecting axial pyramid.

[0055] Furthermore, the focal depth of the non-diffraction region is greater than the thickness of the filter membrane tube wall, ensuring that the non-diffraction region can cover the tube wall of the filter membrane, and micropores that penetrate the filter membrane tube wall can be punched on the filter membrane.

[0056] like Figure 9 As shown, after passing through the reflective axial pyramid, the focal depth of the Bessel beam is... The focal spot diameter of the Bessel beam is... ,in Let be the focal radius of the Bessel beam.

[0057] in, The diffraction angle in the Bessel region can also be described as follows: The angle between the Bessel region and the optical axis of the reflected beam is π; π is 3.1415926. Represents the radius of the incident laser beam; The focal depth is the non-diffraction region of the Bessel beam.

[0058] For example, if the actual diameter of the emitted Bessel spot is 100 micrometers, but the required spot diameter for processing is 20 micrometers, then the focal length ratio of the field lens to the lens is 1:5.

[0059] In some embodiments, the filter membrane processing system further includes a galvanometer assembly 130; the galvanometer assembly 130 is disposed in the optical path of the Bessel beam and is used to adjust the deflection direction of the Bessel beam. By setting the galvanometer assembly 130, the deflection of the Bessel beam can be controlled, enabling rapid movement of the light spot on the workpiece. The operating speed of the galvanometer can generally reach 10 m / s, for example, the ExtraScan10 galvanometer.

[0060] Furthermore, the transfer assembly 120 includes a lens 121 and a field lens 122; the lens 121 is disposed at the incident end of the galvanometer assembly 130 and is used to focus the Bessel beam onto the galvanometer assembly 130; the field lens 122 is disposed at the exit end of the galvanometer assembly 130 and forms a 4F system with the lens 121, so that the field lens 122 transfers the non-diffraction region of the Bessel beam to the processing station.

[0061] In this embodiment, lens 121 and field lens 122 follow a 4F system to ensure that the diffraction-free characteristics of the Bessel beam are not compromised during scanning; wavefront distortion caused by traditional field lenses is avoided; and the depth of focus retention in the diffraction-free region is higher in this embodiment compared to non-4F systems. The galvanometer is placed on the central image plane of the 4F system, and its deflection only changes the beam angle rather than the focusing position, achieving zero field distortion and dynamic processing consistency.

[0062] Optionally, lens 121 is positioned at a distance from the optical center of the Bessel beam reflected and converged by beam shaping assembly 110, equal to the focal length of lens 121. In other words, the optical center of lens 121 must coincide with the optical axis of the Bessel beam, and the distance between lens 121 and the reflective axial pyramid must be equal to the focal length of lens 121. This allows the non-diffraction region of the Bessel beam to be effectively transferred to the processing station.

[0063] Furthermore, the filter membrane processing system also includes a beam expander 140; the beam expander 140 is disposed in the optical path of the incident laser and is used to adjust the beam size and / or divergence angle of the incident laser. Specifically, the beam expander 140 is disposed at the incident end of the reflective axial pyramid, and the incident laser passes through the beam expander 140 and is incident on the reflective axial pyramid; the reflective axial pyramid is used to reflect the incident laser and convert it into a Bessel beam.

[0064] Optionally, the beam expander 140 can be a 1x to 8x beam expander 140.

[0065] Furthermore, the filter membrane processing system also includes a laser source 160; the laser source 160 is used to emit incident laser light; the wavelength of the incident laser light... satisfy: In other words, the incident laser wavelength of the filter membrane processing system in this embodiment covers a broad band from deep ultraviolet (DUV) to terahertz (THz).

[0066] Optionally, the laser source 160 includes, but is not limited to, a picosecond laser.

[0067] Furthermore, the filter membrane processing system also includes a reflector 170; the reflector 170 is disposed at the exit end of the beam expander 140 and is used to reflect the beam emitted from the beam expander 140 to the reflective axial pyramid. By setting the reflector 170, the direction of the incident laser can be changed, making the layout of the entire system more flexible.

[0068] Furthermore, the filter membrane processing system also includes a polarization component 150; the polarization component 150 is positioned between the beam expander 140 and the laser source 160; the incident laser passes through the polarization component 150 and is directed towards the beam expander 140. This design can further optimize the polarization state of the incident laser to improve system efficiency and energy distribution; it also allows control of the shape of the filter membrane perforations by preset polarization direction. The polarization component 150 can block back-reflected light (such as laser light reflected from the processing station) from returning to the laser source 160, preventing instability or damage to the light source.

[0069] Optionally, the polarization assembly 150 includes a polarizer 152 and a half-wave plate 151; the half-wave plate 151 is disposed between the laser source 160 and the polarizer 152.

[0070] It should be noted that the material of the filter membrane is not limited in the specific embodiments of the present invention. Optionally, the filter membrane can be made of metal. Metals include, but are not limited to, stainless steel, copper, and aluminum. Figure 12 The filter membrane processing system of this embodiment is used to drill 1-micron pores in stainless steel.

[0071] A specific embodiment of the present invention provides a filter membrane processing method. This filter membrane processing method employs the filter membrane processing system described in any of the above embodiments. The filter membrane processing method includes: S100. Place the workpiece to be processed in the processing station of the filter membrane processing system.

[0072] S200, the incident laser is emitted into the beam shaping assembly 110, and the beam shaping assembly 110 reflects the incident laser and converts it into a Bessel beam.

[0073] Specifically, the laser source 160 is activated to emit an incident laser. The incident laser passes through a half-wave plate 151, a polarizer 152, a beam expander 140, and a reflector 170 before being incident on a reflective axial pyramid. The reflective axial pyramid reflects the incident laser and converts it into a Bessel beam.

[0074] S300 and the transfer component 120 transfer the non-diffraction region of the Bessel beam to the processing station to process micropores on the workpiece to obtain a tubular filter membrane.

[0075] Specifically, the Bessel beam is focused by lens 121 onto galvanometer assembly 130; the Bessel beam emitted from galvanometer assembly 130 is focused by field lens 122 to transmit the non-diffraction region of the Bessel beam to the processing station, thereby realizing the drilling of the workpiece to be processed; the deflection of the Bessel beam is adjusted by galvanometer assembly 130 to achieve dynamic drilling, and finally a tubular filter membrane is obtained.

[0076] Furthermore, the pore size of the micropore 214 is from 0.1 micrometers to 40 micrometers. In other words, the pore size of the micropore 214 can be 0.1 micrometers, 40 micrometers, or any value between 0.1 micrometers and 40 micrometers. The specific value of the pore size of the micropore 214 is not limited in the specific embodiments of the invention.

[0077] like Figure 2 As shown, the membrane emulsification device 210 further includes a housing 215; the housing 215 has a receiving cavity inside; multiple tubular filter membranes 211 are arranged in parallel in the receiving cavity; and an outer flow channel 212 is located in the receiving cavity. The housing 215 has a dispersed phase inlet, a continuous phase inlet, and a continuous phase outlet; the dispersed phase inlet is connected to the outer flow channel 212, the continuous phase inlet is connected to one end of the inner flow channel 213, and the continuous phase outlet is connected to the other end of the inner flow channel 213.

[0078] In this embodiment, the receiving cavity provides installation space for the tubular filter membrane 211, and the outer shell 215 isolates the tubular filter membrane 211 from the outside world to prevent environmental particles or microorganisms from contaminating the microsphere product. This is especially suitable for pharmaceutical-grade liposomes with sterility requirements (such as vaccine carriers and nucleic acid delivery systems).

[0079] Optionally, multiple tubular filter membranes 211 are arranged in a periodic array within the receiving cavity.

[0080] Optionally, the outer casing 215 is also provided with a vent for venting air; the vent is connected to the outer flow channel 212. When the dispersed phase is injected into the outer flow channel 212, the vent can be opened to vent the air in the outer flow channel 212 and the inner flow channel 213.

[0081] In some embodiments, the system for preparing liposome polymer microspheres using a perforated tubular filter membrane further includes an emulsion storage device 240; the emulsion storage device 240 is connected to an inner flow channel 213 for storing the emulsion discharged from the inner flow channel 213. Specifically, a continuous phase outlet is connected to the emulsion storage device 240 for discharging the emulsion from the inner flow channel 213 into the emulsion storage device 240 for storage.

[0082] In this embodiment, the continuous phase outlet is directly connected to the emulsion storage device 240 (such as a buffer tank with stirring) to achieve immediate collection and stable storage of the emulsion and avoid droplet aggregation.

[0083] Furthermore, the emulsion storage device 240 includes a third storage tank and a third agitator; the third storage tank is connected to the inner flow channel 213 and is used to store the emulsion. The third agitator is installed in the third storage tank to reduce the risk of emulsion droplet aggregation in the emulsion.

[0084] In some embodiments, the system for preparing liposome polymer microspheres using a perforated tubular filter membrane further includes a pressure supply device 250; the pressure supply device 250 is connected to an outer channel 212 and is used to introduce a protective gas into the outer channel 212 to push the dispersed phase through the micropores 214 to form droplets in the inner channel 213.

[0085] In this embodiment, by setting up a pressure supply device 250, the speed at which the dispersed phase (such as the oil phase) permeates through the micropores 214 can be controlled by adjusting the gas pressure (such as nitrogen or air), thereby achieving dynamic control of droplet formation. Compared to mechanical pumping, gas pressure drive is more stable and avoids uneven droplet size caused by pulsed flow. The gas forms an "air cushion" barrier in the outer flow channel 212, reducing direct contact between the two phases and preventing component mixing (such as surfactant migration). Gas-assisted propulsion can reduce the retention of high-viscosity dispersed phase in the micropores 214, reducing the probability of clogging.

[0086] Furthermore, the pressure supply device 250 includes a gas tank (not shown in the figure), an air pump 251, and a pressure regulator 252. The gas tank stores protective gas. The inlet of the air pump 251 is connected to the outlet of the gas tank, and the outlet of the air pump 251 is connected to the outer flow channel 212 for supplying protective gas to the outer flow channel 212. The pressure regulator 252 is located at the outlet of the air pump 251 and is used to adjust the gas pressure entering the outer flow channel 212. The gas pressure entering the outer flow channel 212 can be adjusted by adjusting the pressure regulator 252 according to the viscosity of the dispersed phase and the target particle size of the microspheres to prepare microspheres that meet the target particle size.

[0087] Optional, the protective gas includes, but is not limited to, nitrogen.

[0088] Furthermore, the pressure supply device 250 also includes a sixth three-way valve 254 and a third three-way valve 253; the inlet of the sixth three-way valve 254 is connected to the outlet of the air pump 251, and the first outlet of the sixth three-way valve 254 is connected to the outer flow channel 212; the second outlet of the sixth three-way valve 254 is connected to the inlet of the third three-way valve 253, the first outlet of the third three-way valve 253 is connected to the inlet of the first dispersed phase storage unit 221, and the second outlet of the third three-way valve 253 is connected to the inlet of the second dispersed phase storage unit 222. When it is necessary to inject the dispersed phase of the first dispersed phase storage unit 221 into the outer flow channel 212, the gas discharged by the air pump 251 can enter the inlet of the third three-way valve 253 through the second outlet of the sixth three-way valve 254, and enter the first dispersed phase storage unit 221 from the first outlet of the third three-way valve 253, so as to force the dispersed phase into the outer flow channel 212. When it is necessary to inject the dispersed phase from the second dispersed phase storage unit 222 into the outer flow channel 212, the gas discharged by the air pump 251 can enter the inlet of the third three-way valve 253 through the second outlet of the sixth three-way valve 254, and then enter the second dispersed phase storage unit 222 from the second outlet of the third three-way valve 253, so as to force the dispersed phase into the outer flow channel 212. When it is necessary to pressurize the outer flow channel 212, the protective gas discharged by the air pump 251 is discharged into the outer flow channel 212 through the first outlet of the sixth three-way valve 254.

[0089] In some embodiments, the system for preparing liposome polymer microspheres using a perforated tubular filter membrane further includes a dispersed phase supply device 220 and a continuous phase supply device 230; the dispersed phase supply device 220 is connected to an outer channel 212 for injecting the dispersed phase into the outer channel 212; the continuous phase supply device 230 is connected to an inner channel 213 to form a continuous phase circulation loop.

[0090] In this embodiment, the flow pattern of the dispersed phase in the outer channel 212 and the continuous phase in the inner channel 213 enhances the turbulence effect, reduces the risk of micropore 214 clogging, and increases flux. Furthermore, the two phases mix rapidly near the inner surface of the tubular filter membrane 211, avoiding pre-emulsification and reducing batch variations caused by phase separation.

[0091] Furthermore, the dispersed phase supply device 220 includes a dispersed phase storage module; the dispersed phase storage module includes a first dispersed phase storage unit 221, a second dispersed phase storage unit 222, and a first valve body unit 223; both the first dispersed phase storage unit 221 and the second dispersed phase storage unit 222 are used to store dispersed phase; the first valve body unit 223 has a first conducting state and a second conducting state; in the first conducting state, the first dispersed phase storage unit 221 injects dispersed phase into the outer flow channel 212; in the second conducting state, the second dispersed phase storage unit 222 injects dispersed phase into the outer flow channel 212. This design ensures continuous production of the system. For example, after the dispersed phase stored in the first dispersed phase storage unit 221 is used up, the first valve body unit 223 can be switched from the first conducting state to the second conducting state, so that the dispersed phase in the second dispersed phase storage unit 222 is injected into the outer flow channel 212, thereby ensuring the continuity of production.

[0092] Furthermore, the first dispersed phase storage unit 221 includes a first storage tank and a first stirrer; the first stirrer is installed inside the first storage tank, which contains the dispersed phase. By providing the first stirrer, the dispersiond phase can be prevented from accumulating inside the first storage tank.

[0093] Optionally, the first dispersed phase storage unit 221 and the second dispersed phase storage unit 222 may have the same structure.

[0094] It should be noted that, in this embodiment, there is no limitation on the number of the first dispersed phase storage unit 221 and the second dispersed phase storage unit 222.

[0095] Furthermore, the first valve body unit 223 includes a first three-way valve; the outer flow channel 212 is connected to the first dispersed phase storage unit 221 and the second dispersed phase storage unit 222 respectively through the first three-way valve. Specifically, the first inlet of the first three-way valve is connected to the outlet of the first dispersed phase storage unit 221, the second inlet of the first three-way valve is connected to the outlet of the second dispersed phase storage unit 222, and the outlet of the first three-way valve is connected to the outer flow channel 212 through the dispersion inlet.

[0096] Preferably, the first three-way valve is an electromagnetic three-way valve, which facilitates automated control.

[0097] Furthermore, the continuous phase supply device 230 includes a continuous phase storage module 231 and a circulation power source 232. The continuous phase storage module 231 is used to store the continuous phase. The inlet of the continuous phase storage module 231 is connected to the outlet of the inner flow channel 213, and the outlet of the continuous phase supply device 230 is connected to the inlet of the inner flow channel 213 to form a continuous phase circulation loop. The circulation power source 232 is disposed in the continuous phase circulation loop. When it is necessary to inject the continuous phase into the inner flow channel 213, the circulation power source 232 is activated, and the continuous phase in the continuous phase storage module 231 enters the inner flow channel 213. The continuous phase injected into the inner flow channel 213 washes the inner surface of the tubular filter membrane 211, causing the emulsion droplets to peel off from the micropores 214 and disperse into the continuous phase, and finally return to the continuous phase storage module 231. After the emulsification process is completed, the emulsion in the inner flow channel 213 can be discharged into the emulsion storage device 240 for storage.

[0098] Furthermore, the continuous phase storage module 231 includes a first continuous phase storage unit 2311, a second continuous phase storage unit 2312, and a second valve body unit. Both the first and second continuous phase storage units 2311 and 2312 are used to store the continuous phase. The second valve body unit has a third open state and a fourth open state. In the third open state, the first continuous phase storage unit 2311 injects the continuous phase into the inner flow channel 213; in the fourth open state, the second continuous phase storage unit 2312 injects the continuous phase into the inner flow channel 213. This design ensures continuous production of the system. For example, after the continuous phase stored in the first continuous phase storage unit 2311 is used up, the second valve body unit can be switched from the third open state to the fourth open state, allowing the continuous phase in the second continuous phase storage unit 2312 to be injected into the inner flow channel 213, thus ensuring the continuity of production.

[0099] Optionally, the second continuous phase storage unit 2312 includes a second storage tank and a second stirrer; the second stirrer is installed inside the second storage tank, which contains the continuous phase. The second stirrer helps prevent the accumulation of emulsion droplets within the second storage tank.

[0100] Optionally, the first continuous phase storage unit 2311 and the second continuous phase storage unit 2312 may have the same structure.

[0101] Optionally, the second valve body unit includes a second three-way valve 2313 and a fourth three-way valve 2314; the inlet of the inner flow channel 213 is connected to the outlet of the first continuous phase storage unit 2311 and the outlet of the second continuous phase storage unit 2312 through the second three-way valve 2313; the outlet of the inner flow channel 213 is connected to the inlet of the first continuous phase storage unit 2311 and the inlet of the second continuous phase storage unit 2312 through the fourth three-way valve 2314. Specifically, the first inlet and outlet of the second three-way valve 2313 are connected to the outlet of the first continuous phase storage unit 2311, the second inlet of the second three-way valve 2313 is connected to the outlet of the second continuous phase storage unit 2312, and the outlet of the second three-way valve 2313 is connected to the inlet of the inner flow channel 213 through the circulating power source 232. The first outlet of the fourth three-way valve 2314 is connected to the inlet of the first continuous phase storage unit 2311, the second outlet of the second three-way valve 2313 is connected to the inlet of the second continuous phase storage unit 2312, and the inlet of the second three-way valve 2313 is connected to the outlet of the inner flow channel 213.

[0102] Preferably, the second three-way valve 2313 is an electromagnetic three-way valve, which facilitates automated control.

[0103] Preferably, the fourth three-way valve 2314 is an electromagnetic three-way valve, which facilitates automated control.

[0104] Furthermore, the circulating power source 232 includes a circulating pump 2321 and a flow detection unit 2322; the flow detection unit 2322 is located at the outlet of the circulating pump 2321 and is used to detect the flow rate of the continuous phase.

[0105] Optionally, the flow detection unit 2322 includes a flow meter.

[0106] In some embodiments, the system for preparing liposome polymer microspheres using a perforated tubular filter membrane further includes a third valve unit 260; an emulsion storage device 240 is connected to the outlet of an inner flow channel 213; the third valve unit 260 has a fifth open state and a sixth open state; in the fifth open state, a continuous phase supply device 230 is connected to the inner flow channel 213 to form a continuous phase circulation loop; in the sixth open state, the inlet of the inner flow channel 213 is connected to the emulsion storage device 240 for discharging the emulsion.

[0107] Specifically, the third valve body unit 260 includes a fifth three-way valve; the inlet of the fifth three-way valve is connected to the outlet of the inner flow channel 213, the first outlet of the fifth three-way valve is connected to the emulsion storage device 240, and the second outlet of the fifth three-way valve is connected to the inlet of the fourth three-way valve 2314.

[0108] Optionally, the fifth three-way valve can be a solenoid three-way valve for easy automated control.

[0109] It should be noted that liposome polymer microspheres are an advanced drug delivery carrier that combines the advantages of both liposomes and polymer microspheres, possessing a unique "core-shell" or "hybrid network" structure. Liposome polymer microspheres consist of a liposome portion and a polymer portion.

[0110] like Figure 5 As shown, a specific embodiment of the second aspect of the present invention provides a controlled method for preparing liposome polymer microspheres using a porous tubular filter membrane. This controlled method employs the system for preparing liposome polymer microspheres using a porous tubular filter membrane as described in any of the above embodiments. The method includes: S10. Inject the dispersed phase into the outer channel 212 and inject the continuous phase into the inner channel 213.

[0111] Specifically, the dispersed phase in the dispersed phase storage module is circulated and injected into the outer flow channel 212 to fill the outer flow channel 212; the circulation power source 232 is started to circulate and inject the continuous phase in the continuous phase storage module 231 into the inner flow channel 213.

[0112] S20. A protective gas is introduced into the outer flow channel 212 to push the dispersed phase through the micropores 214, forming droplets in the inner flow channel 213, and mixing with the continuous phase to form an emulsion.

[0113] Specifically, when the pressure supply device 250 is turned on, protective gas enters the outer flow channel 212. The dispersed phase will pass through the micropores 214 under the push of the high-pressure gas, form droplets in the inner flow channel 213, and disperse into the continuous phase under the scouring of the continuous phase to form an emulsion.

[0114] S30. After emulsification is completed, the emulsion in the inner channel 213 is discharged into the emulsion storage device 240 for storage.

[0115] Specifically, after emulsification is completed, the circulating power source 232 is stopped, the conduction state of the third valve body unit 260 is switched, and the emulsion in the inner flow channel 213 is discharged into the emulsion storage device 240 for storage.

[0116] S40. The emulsion is stirred, the solvent is evaporated, and the emulsion is freeze-dried to obtain liposome polymer microspheres.

[0117] Specifically, the emulsion storage device 240 stirs the emulsion at low speed, evaporates the solvent, and finally freeze-dries it to obtain microspheres.

[0118] In this embodiment, the system for preparing liposome polymer microspheres using a porous tubular filter membrane according to any of the above embodiments has at least the aforementioned advantages. Furthermore, the system for preparing liposome polymer microspheres using a porous tubular filter membrane according to any of the above embodiments can also successfully prepare liposome polymer microspheres with uniform particle size.

[0119] Example 1 In the dispersed phase supply device, prepare the dispersed phase: dissolve polylactic acid (PLA) in an appropriate amount of solvent (such as dichloromethane), and stir until completely transparent to form a PLA solution. Place the PLA solution at room temperature to avoid PLA degradation caused by high temperatures.

[0120] It should be noted that the molecular weight of PLA can be between 50,000 and 100,000. In other words, this embodiment uses polylactic acid with a molecular weight of 50,000 to 100,000. The mass-volume concentration of the PLA solution is between 5% and 10%, and the specific concentration can be adjusted according to experimental requirements. In this embodiment, the mass-volume concentration of the PLA solution is 8%.

[0121] To prepare the continuous phase in the continuous phase supply device, add an appropriate amount of surfactant (such as polyvinyl alcohol or hexadecyltrimethylammonium bromide) to deionized water to improve the stability of the aqueous phase and prevent the aggregation of PLA microspheres. A typical surfactant concentration is 1% (w / v), which can be adjusted according to experimental needs. Stir with a stirrer until the surfactant is completely dissolved in the deionized water to obtain the aqueous phase.

[0122] The air pump delivers protective gas into the first dispersed phase storage unit of the dispersed phase supply device, injects the PLA solution in the first dispersed phase storage unit into the outer channel of the membrane emulsification device, and fills the outer channel with PLA solution; the circulation power source is started, and the continuous phase stored in the second continuous phase storage unit is pumped into the inner channel to form a continuous phase circulation loop.

[0123] By adjusting the conduction state of the sixth three-way valve, the gas path is switched, allowing protective gas to enter the outer flow channel to increase the pressure in the outer flow channel. This causes the dispersed phase to pass through the micropores and form droplets, while the continuous phase in the inner flow channel scours and disperses the droplets into the continuous phase.

[0124] After the dispersed phase in the first dispersed phase storage unit is used up, switch the fifth three-way valve to connect the outlet of the inner flow channel with the emulsion storage device and store the emulsion in the emulsion storage device.

[0125] The emulsion was transferred to a vacuum environment and solvent was evaporated at 0°C to 8°C to prevent PLA degradation; finally, vacuum drying was performed to obtain liposome polymer microspheres.

[0126] The liposome polymer microspheres were tested, and the results are as follows: Figure 6 As shown, the system for preparing liposome polymer microspheres using a porous tubular filter membrane in this embodiment successfully prepared liposome polymer microspheres with a diameter of 2 micrometers, and the particle size distribution of the liposome polymer microspheres was uniform.

[0127] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A system for preparing liposome polymer microspheres using a porous tubular filter membrane, characterized in that, Includes a membrane emulsification device (210); the membrane emulsification device (210) includes: Multiple tubular filter membranes (211) are arranged in parallel; an outer flow channel (212) is formed between two adjacent tubular filter membranes (211); an inner flow channel (213) is formed inside the tubular filter membrane (211) along its own axial direction; multiple micropores (214) are opened on the tube wall of the tubular filter membrane (211); the outer flow channel (212) is connected to the inner flow channel (213) through the micropores (214).

2. The system for preparing liposome polymer microspheres using a porous tubular filter membrane according to claim 1, characterized in that, Also includes: A dispersed phase supply device (220), connected to the outer flow channel (212), is used to inject a dispersed phase into the outer flow channel (212); A continuous phase supply device (230) is connected to the inner flow channel (213) to form a continuous phase circulation loop.

3. The system for preparing liposome polymer microspheres using a porous tubular filter membrane according to claim 2, characterized in that, The dispersed phase supply device (220) includes: Both the first dispersed phase storage unit (221) and the second dispersed phase storage unit (222) are used to store the dispersed phase; The first valve body unit (223) has a first conducting state and a second conducting state; In the first conducting state, the first dispersed phase storage unit (221) injects the dispersed phase into the outer channel (212); in the second conducting state, the second dispersed phase storage unit (222) injects the dispersed phase into the outer channel (212).

4. The system for preparing liposome polymer microspheres using a porous tubular filter membrane according to claim 3, characterized in that, The first valve body unit (223) includes: The first three-way valve connects the external flow channel (212) to the first dispersed phase storage unit (221) and the second dispersed phase storage unit (222) respectively.

5. The system for preparing liposome polymer microspheres using a porous tubular filter membrane according to claim 2, characterized in that, The continuous phase supply device (230) includes: A continuous phase storage module (231) is used to store the continuous phase; the inlet of the continuous phase storage module (231) is connected to the outlet of the inner flow channel (213), and the outlet of the continuous phase supply device (230) is connected to the inlet of the inner flow channel (213) to form the continuous phase circulation loop. A circulating power source (232) is provided in the continuous phase circulating loop.

6. The system for preparing liposome polymer microspheres using a porous tubular filter membrane according to claim 5, characterized in that, The continuous phase storage module (231) includes: The first continuous phase storage unit (2311) and the second continuous phase storage unit (2312) are both used to store the continuous phase; The second valve body unit has a third conduction state and a fourth conduction state; In the third conducting state, the first continuous phase storage unit (2311) injects the continuous phase into the inner flow channel (213); in the fourth conducting state, the second continuous phase storage unit (2312) injects the continuous phase into the inner flow channel (213).

7. The system for preparing liposome polymer microspheres using a porous tubular filter membrane according to claim 6, characterized in that, The second valve body unit includes: The inlet of the inner flow channel (213) is connected to the outlet of the first continuous phase storage unit (2311) and the outlet of the second continuous phase storage unit (2312) through the second three-way valve (2313); The fourth three-way valve (2314) connects the outlet of the inner flow channel (213) to the inlet of the first continuous phase storage unit (2311) and the inlet of the second continuous phase storage unit (2312) respectively.

8. The system for preparing liposome polymer microspheres using a porous tubular filter membrane according to any one of claims 1 to 7, characterized in that, Also includes: An emulsion storage device (240), connected to the inner flow channel (213), is used to store the emulsion discharged from the inner flow channel (213).

9. The system for preparing liposome polymer microspheres using a porous tubular filter membrane according to claim 8, characterized in that, Also includes: A pressure supply device (250) is connected to the outer channel (212) for introducing protective gas into the outer channel (212) to push the dispersed phase through the micropores (214) to form droplets in the inner channel (213).

10. A controlled method for preparing liposome polymer microspheres using a porous tubular filter membrane, characterized in that, The system for preparing liposome polymer microspheres using a porous tubular filter membrane according to any one of claims 1 to 9, the method comprising: The dispersed phase is injected into the outer channel (212), and the continuous phase is injected into the inner channel (213). A protective gas is introduced into the outer channel (212) to push the dispersed phase through the micropores (214) to form droplets in the inner channel (213) and mix with the continuous phase to form an emulsion; After emulsification is completed, the emulsion in the inner channel (213) is discharged into the emulsion storage device (240) for storage; The emulsion was stirred, the solvent was evaporated, and the mixture was freeze-dried to obtain microspheres.

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