A liposome polymer nanomicrosphere preparation system and method based on lavet nozzle collision injection technology

Abstract

The present application relates to liposome polymer nanoparticle mixed preparation technical field, disclose a kind of liposome polymer nanosphere preparation system and method based on lavall nozzle collision injection technology.The system includes jet mixer;Jet mixer includes collision mixing unit and at least two lavall nozzles;Collision mixing unit has mixing chamber in it, at least one liquid outlet channel and at least two liquid inlet channels are formed in collision mixing unit;Liquid inlet channel and liquid outlet channel are communicated with mixing chamber;Multiple lavall nozzles are correspondingly arranged in liquid inlet channel.Lavall nozzle can accelerate fluid to supersonic state to form high kinetic energy jet, high-speed jet is sprayed from different jet ports, and collision occurs in mixing chamber, increase the contact area of fluid, improve shear force and turbulent effect, improve the mixing uniformity of fluid, solve the problem of uneven particle size when liposome polymer nanoparticles are prepared by microfluidic system in prior art.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of liposome polymer nanoparticle hybrid preparation, and particularly relates to a liposome polymer nanomicrosphere preparation system and method based on a laval nozzle collision jet technology. BACKGROUND

[0002] Currently, liposome nanoparticles are generally prepared by a film hydration method, a reverse evaporation method and a microfluidic technology. The microfluidic technology is to form uniform hybrid microparticles by precisely controlling fluid through a microfluidic chip.

[0003] However, mixing two different fluids in microscale is one of the most basic processes in microfluidics. In microscale environment, the Reynolds number (Re) is usually small (Re<2000), and the effect of viscous force is much stronger than that of inertial force. Especially in the case of low to medium flow rate, the fluid mainly presents as laminar flow, and is mostly uniaxial flow. This phenomenon means that when two fluids converge in a microfluidic channel, they tend to flow side by side, forming a stable fluid interface, and the mixing process at this time mainly depends on molecular diffusion. The efficiency of diffusion mixing is usually low, and its mixing efficiency is mainly related to the diffusion distance, the diffusion coefficient of the fluid and the interface contact area. However, in a microfluidic chip, due to the small physical size of the channel, the diffusion path and time required to reach complete mixing under laminar flow state are usually far beyond the size limit of the chip, which makes it difficult to achieve rapid and efficient mixing through simple laminar flow mixing. In order to overcome the problem of low mixing efficiency in microfluidic systems, researchers have proposed various methods to enhance mixing. The core idea of these methods is to destroy the stable interface under laminar flow state, increase the contact area between different fluids, or promote the mutual stirring of fluids through external force to improve the mixing efficiency. Active mixing technology disturbs the fluid through external force (such as electromagnetic force, sound wave, mechanical force, etc.), but these technologies are usually complex in design and difficult to apply on a large scale. Passive mixing technology introduces microstructures (such as grooves, protrusions, etc.) into the channel to induce irregular flow of the fluid, thereby promoting mixing. However, these technologies can improve the mixing efficiency to a certain extent, but they are usually limited by the geometry of the microchannel and the complexity of the design, which cannot be realized for industrialized batch production.

[0004] Therefore, how to prepare liposome nanoparticles with uniform particle size is still a problem that needs to be solved in the industry. SUMMARY

[0005] The present application provides a liposome polymer nanomicrosphere preparation system and method based on a laval nozzle collision jet technology, which solves the problem of non-uniform microsphere particle size in the prior art when liposome polymer nanoparticles are prepared by a microfluidic system.

[0006] The first aspect of the present application provides a liposome polymer nanosphere preparation system based on a Laval nozzle collision jet technology, comprising a jet mixer, wherein the jet mixer comprises:

[0007] a collision mixing unit having a mixing cavity therein, at least one liquid outlet channel and at least two liquid inlet channels formed in the collision mixing unit, wherein the liquid inlet channels and the liquid outlet channel are in communication with the mixing cavity;

[0008] at least two Laval nozzles, each corresponding to one of the liquid inlet channels.

[0009] According to the liposome polymer nanosphere preparation system based on the Laval nozzle collision jet technology, one liquid outlet channel and two liquid inlet channels are formed in the collision mixing unit, the liquid outlet channel and the two liquid inlet channels are arranged in a circumferential direction of the collision mixing unit, and the two liquid inlet channels are symmetrically arranged along a central axis of the liquid outlet channel.

[0010] According to the liposome polymer nanosphere preparation system based on the Laval nozzle collision jet technology, the system further comprises:

[0011] an oil phase supply device for storing an oil phase, wherein the oil phase supply device is in communication with a liquid inlet of one of the Laval nozzles;

[0012] a water phase supply device for storing a water phase, wherein the water phase supply device is in communication with a liquid inlet of another Laval nozzle.

[0013] The second aspect of the present application provides a liposome polymer nanosphere preparation method based on a Laval nozzle collision jet technology, which utilizes the liposome polymer nanosphere preparation system based on the Laval nozzle collision jet technology according to any one of the above aspects, and the preparation method comprises the following steps:

[0014] feeding an oil phase to one Laval nozzle and feeding a water phase to another Laval nozzle, wherein the oil phase and the water phase form high-speed jets through the corresponding Laval nozzles, and the two high-speed jets collide and mix in the mixing cavity to obtain liposome polymer nanospheres.

[0015] The third aspect of the present application provides a liposome polymer nanosphere prepared by the liposome polymer nanosphere preparation method based on the Laval nozzle collision jet technology.

[0016] The liposome polymer nanosphere provided by the application, wherein the oil phase comprises at least one of hydrogenated lecithin, 1,2-distearoyl-sn-glycero-3-phosphocholine or cholesterol; and the water phase comprises at least one of polyethyleneimine, polyhexamethylene biguanide, benzalkonium chloride or chitosan.

[0017] The liposome polymer nanosphere provided by the application, wherein the oil phase comprises hydrogenated lecithin, 1,2-distearoyl-sn-glycero-3-phosphocholine and cholesterol; and the molar ratio of the hydrogenated lecithin, the 1,2-distearoyl-sn-glycero-3-phosphocholine and the cholesterol is (45-55):(8-12):(35-45).

[0018] The liposome polymer nanosphere provided by the application, wherein the molar ratio of the hydrogenated lecithin, the 1,2-distearoyl-sn-glycero-3-phosphocholine and the cholesterol is 50:10:40.

[0019] The liposome polymer nanosphere provided by the application, wherein the water phase comprises polyethyleneimine, polyhexamethylene biguanide and benzalkonium chloride; and the mass ratio of the polyethyleneimine, the polyhexamethylene biguanide and the benzalkonium chloride is (0.5-3):(1-5):(2-8).

[0020] The liposome polymer nanosphere provided by the application, wherein the mass ratio of the polyethyleneimine, the polyhexamethylene biguanide and the benzalkonium chloride is 2.5:2.5:5.

[0021] Or;

[0022] The mass ratio of the polyethyleneimine, the polyhexamethylene biguanide and the benzalkonium chloride is 1:4:4.

[0023] The liposome polymer nanosphere preparation system based on the collision jet technology of the Laval nozzle provided by the application, wherein the Laval nozzle is arranged in the liquid inlet channel, and the Laval nozzle can accelerate the fluid passing through the Laval nozzle to a supersonic state through the contraction and expansion structure of the Laval nozzle, so that a high-energy jet is formed, two high-speed jets are sprayed from different jet ports, and the two high-speed jets meet and collide violently in the mixing cavity, so that the contact area of the fluid is increased, and the shear force and the turbulent effect are greatly improved, so that the stable interface in the laminar flow can be rapidly destroyed, the nanoscale dispersion of the fluid is realized, and the mixing uniformity of the fluid is significantly improved. In addition, the instantaneous nature (usually completed in milliseconds) of the jet mixing avoids the batch difference of the traditional drop-by-drop addition, and is suitable for continuous production. Therefore, the liposome polymer nanosphere with uniform particle size can be prepared by using the preparation system provided by the application, and the problem of uneven particle size of the liposome polymer nanoparticles prepared by using the microfluidic system in the prior art can be solved.

[0024] The liposome polymer nanomicrosphere and the preparation method of the liposome polymer nanomicrosphere based on the collision jet technology of the Laval nozzle provided by the application can prepare the polymer nanomicrosphere with uniform particle size distribution by using the preparation system. BRIEF DESCRIPTION OF DRAWINGS

[0025] In order to more clearly illustrate the technical solutions of the application or the prior art, the drawings needed to be used in the embodiments or the prior art description will be briefly introduced. Obviously, the drawings in the following description are some embodiments of the application, and other drawings can be obtained by those skilled in the art without creative labor.

[0026] Figure 1 is a structural schematic diagram of the preparation system of the liposome polymer nanomicrosphere based on the collision jet technology of the Laval nozzle provided by the application.

[0027] Figure 2 is a structural schematic diagram of the jet mixer of the preparation system of the liposome polymer nanomicrosphere based on the collision jet technology of the Laval nozzle provided by the application.

[0028] Figure 3 is a structural schematic diagram of the jet mixer of the preparation system of the liposome polymer nanomicrosphere based on the collision jet technology of the Laval nozzle provided by the application.

[0029] Figure 4 is a photo of the nanomicrosphere of Example 1.

[0030] Figure 5 is a particle size distribution diagram of the nanomicrosphere of Example 1, Example 2 and Example 3.

[0031] Figure 6 is a diagram of the relationship between the particle size and the pH of the nanomicrosphere of Example 1.

[0032] Figure 7 is a diagram of the relationship between the Zeta potential and the pH of the nanomicrosphere of Example 1.

[0033] Figure 8 is a diagram of the relationship between the encapsulation efficiency and the pH of the nanomicrosphere of Example 1.

[0034] Reference signs:

[0035] 310, jet mixer; 311, collision mixing unit; 312, Laval nozzle;

[0036] 320, oil phase supply device;

[0037] 330、water phase supply device. DETAILED DESCRIPTION

[0038] In order to make the objects, technical solutions and advantages of the present application clearer, the technical solutions in the present application will be described clearly and completely below with reference to the drawings in the present application. Obviously, the described embodiments are only part of, rather than all of, the embodiments of the present application. Based on the embodiments in the present application, all other embodiments obtained by a person of ordinary skill in the art without creative work fall within the protection scope of the present application.

[0039] Compared with microfluidic systems, the collision jet mixer has significant advantages in improving mixing efficiency and realizing large-scale preparation. The collision jet mixer sprays different fluids (such as aqueous solutions of biological macromolecules and ethanol solutions of liposomes) into the mixing chamber at high speed from different directions through high-speed jet spraying. Due to the collision of the jet in the mixing chamber, strong turbulent flow effect is generated, thereby greatly improving the mixing efficiency of the fluids. In this process, positively charged liposomes can quickly and efficiently encapsulate negatively charged biological macromolecules through electrostatic adsorption mechanism, thereby forming stable structure and uniform size lipid nanoparticles (LNPs). This collision-induced turbulent mixing enables the two fluids to reach sufficient mixing in a very short time and space, providing an effective way for batch preparation of LNPs.

[0040] The core advantage of the collision jet mixer lies in its ability to generate strong turbulence through jet collision. Unlike microfluidic technology which relies on mainly laminar diffusion mixing mechanism, the jet mixer makes the fluids collide in the mixing chamber through jet spraying, forming complex turbulent and shear flow. This turbulent mixing effect greatly increases the contact area between the fluids and significantly shortens the mixing time, enabling different fluid components to be fully mixed within milliseconds. In addition, the jet mixer has high jet speed, and the inertial force of the jet significantly enhances the convective mixing effect of the fluids, further improving the binding efficiency of liposomes and biological macromolecules. In contrast, the diffusion mixing in the microfluidic system relies on the molecular diffusion at the fluid interface, and the diffusion speed is usually slow, so the mixing efficiency is limited by the diffusion path and fluid diffusion coefficient. Microfluidic chips need to have extremely complex channel designs (such as stacked structures, fishbone-shaped mixers, etc.) to increase the contact area and flow complexity of the fluids, thereby enhancing the mixing effect, but these designs are usually difficult to meet the needs of batch preparation.

[0041] Another significant advantage is that the processing capacity of impact jet mixers is significantly superior to that of microfluidic technology. Microfluidic chips, due to their small channel size, have limited fluid throughput, making large-scale production difficult in a short time. In contrast, jet mixers, through high-speed jet injection, can handle larger volumes of fluid, significantly increasing the production rate of LNPs per unit time. This is particularly crucial in lipid nanoparticle preparation, as large-scale production requires equipment capable of processing large volumes of solution quickly while ensuring uniform and consistent mixing. Impact jet mixers, through their simple structural design (i.e., simultaneously injecting fluid through multiple jet nozzles), can achieve high-throughput production while maintaining effective mixing, meeting the demands of industrial-grade production. Furthermore, impact jet mixers offer better operability compared to microfluidic technology. Microfluidic chips typically place extremely high demands on manufacturing processes due to the complexity of their channel structure and their tiny size, and are highly sensitive to changes in parameters such as flow rate, pressure, and fluid viscosity during practical use. Therefore, the production and operation of microfluidic chips are more difficult and costly. Jet mixers are relatively simple in design, with easily adjustable jet nozzle sizes, low manufacturing costs, and flexible operation, adaptable to the physicochemical properties of different solutions. In the preparation of lipid nanoparticles, impact jet mixers allow for flexible control of mixing efficiency and particle physical properties (such as size and surface charge) by adjusting parameters like jet velocity, jet angle, and mixing chamber volume, thus enabling personalized and customized nanoparticle preparation. This flexibility gives jet mixers a significant advantage in industrial applications.

[0042] like Figures 1 to 3 As shown, a specific embodiment of the first aspect of the present invention provides a liposome polymer nanosphere preparation system based on Laval nozzle collision jet technology. The preparation system includes a jet mixer 310; the jet mixer 310 includes a collision mixing unit 311 and at least two Laval nozzles 312; the collision mixing unit 311 has a mixing chamber, and at least one outlet channel and at least two inlet channels are formed within the collision mixing unit 311; both the inlet and outlet channels are connected to the mixing chamber; a plurality of Laval nozzles 312 are correspondingly arranged in the inlet channels.

[0043] In the present embodiment, by arranging the Laval nozzle 312 in the liquid inlet channel, the Laval nozzle 312 can accelerate the passing fluid to supersonic speed through its own converging-diverging structure, forming high kinetic energy jets. Two high-speed jets are ejected from different jet ports and meet in the mixing chamber to collide violently. Not only does this increase the contact area of the fluid, but it also significantly improves the mixing efficiency through shear force and turbulent effects, rapidly destroys the stable interface in laminar flow, and achieves nanoscale dispersion of the fluid, significantly improving the uniformity of the fluid mixture. In addition, the instantaneous nature of jet mixing (usually completed in milliseconds) avoids the batch differences of traditional drop-by-drop addition, making it suitable for continuous production. Therefore, the preparation system of the present embodiment can prepare lipid-polymer nanospheres with uniform particle size, solving the problem of uneven particle size of lipid-polymer nanospheres prepared by microfluidic systems in the prior art.

[0044] By directly embedding the Laval nozzle 312 into the liquid inlet channel, the external booster equipment (such as a high-pressure pump) is eliminated, the number of pipeline connections is reduced, the risk of leakage is reduced, and the compactness of the system is improved. By arranging at least two liquid inlet channels, the Laval nozzle 312 corresponds to each liquid inlet channel and is arranged in the liquid inlet channel, which can support flexible configuration of multiple liquid inlet channels and simultaneously process multiple raw materials (such as lipid phase, aqueous phase, and drug solution), adapting to complex formula requirements.

[0045] The Laval nozzle 312 converts fluid pressure energy into kinetic energy, which is more energy-efficient than mechanical stirring and has no moving parts to wear out, resulting in low maintenance costs. The improved mixing efficiency also reduces the amount of surfactant used, meeting the low-cost pharmaceutical requirements. The jet mixing process does not have a significant temperature rise, avoiding the inactivation of heat-sensitive drugs (such as proteins), and the number of metal contact surfaces is reduced, reducing the risk of heavy metal contamination.

[0046] In addition, the design of the Laval nozzle 312 can accurately control the flow state of the fluid as needed. For example, the conversion between subsonic and supersonic flow can be achieved by changing the geometric parameters of the Laval nozzle 312 (such as the throat diameter, the ratio of the inlet and outlet cross-sectional areas, etc.). Through precise control, the jet mixer 310 can optimize the jet speed and turbulent intensity, thereby optimizing the mixing and formation process of the lipid-polymer nanospheres. The diverging section of the Laval nozzle 312 helps to alleviate the back pressure generated by the high-speed jet. Generally, the high-speed jet in the mixer can cause an increase in local pressure, affecting the flow and mixing efficiency of subsequent fluids. Through the gradual diverging section design of the Laval nozzle 312, the back pressure can be eliminated to some extent, making the fluid flow more stable and the mixing effect more uniform. Therefore, the preparation system of the present embodiment can prepare lipid-polymer nanospheres with uniform particle size.

[0047] It should be noted that subsonic can refer to a Mach number less than 1, and the speed is lower than the local sound speed. Supersonic can refer to a Mach number greater than 1, and the speed is higher than the local sound speed.

[0048] Further, the collision mixing unit 311 is formed with one liquid outlet flow channel and two liquid inlet flow channels; the liquid outlet flow channel and the two liquid inlet flow channels are arranged at intervals along the circumference of the collision mixing unit 311; the two liquid inlet flow channels are symmetrically arranged along the central axis of the liquid outlet flow channel. The two liquid inlet flow channels are symmetrically distributed along the circumference, and the two liquid inlet flow channels are symmetrically arranged along the central axis of the liquid outlet flow channel, so that the high-speed jet flow forms a head-on collision in the mixing chamber, generating stronger turbulence and shear force, and significantly improving the dispersion uniformity of the lipids and polymers. The liquid outlet flow channel and the liquid inlet flow channel are at a certain angle, which can quickly guide the mixed product out, prevent the retention of insufficiently mixed materials, and ensure the stability of continuous flow. The circumferential layout shortens the path of the jet flow from the liquid inlet to the collision, reduces the pressure loss, and can reduce energy consumption compared with the linear flow channel. The symmetric liquid inlet flow channels balance the jet flow pressure, avoiding uneven mixing caused by one-sided flow. By independently regulating the flow rates of the two liquid inlet jet flows, gradient mixing can be achieved to adapt to complex process requirements. The circumferential liquid outlet design shortens the residence time of the product in the chamber.

[0049] Optionally, the expansion ratio of the expansion section of the Laval nozzle 312 is 2 to 3. Such design not only has a direct impact on the maximum Mach number that the flow rate in the Laval nozzle 312 can reach, but also affects the distribution of the Mach number and the stability of the axial Mach number and speed change. At this time, the flow field in the Laval nozzle 312 can have better results, and the larger the value deviates from this range, the worse the quality of the entire flow field.

[0050] Preferably, the expansion ratio of the expansion section of the Laval nozzle 312 is 2 or 3.

[0051] It should be noted that the expansion ratio of the expansion section of the Laval nozzle 312 for the jet flow oil phase can be the same as or different from the expansion ratio of the expansion section of the Laval nozzle 312 for the jet flow water phase.

[0052] It can be understood that the expansion ratio of the expansion section of the Laval nozzle 312 is the ratio of the area of the cross section at the outlet of the expansion section of the Laval nozzle 312 to the area of the smallest cross section at the throat.

[0053] It can be understood that the pipe section of the Laval nozzle 312 close to the mixing chamber is the expansion section, the pipe section far from the mixing chamber is the contraction section, and the expansion section and the contraction section are the throat.

[0054] As Figure 1As shown, in some embodiments, the liposome polymer nanomicrosphere preparation system based on the Laval nozzle collision jet technology further comprises an oil phase supply device 320 and a water phase supply device 330; the oil phase supply device 320 is used for storing the oil phase; the oil phase supply device 320 is in communication with the liquid inlet of one Laval nozzle 312; the water phase supply device 330 is used for storing the water phase; the water phase supply device 330 is in communication with the liquid inlet of another Laval nozzle 312. By arranging the oil phase supply device 320 and the water phase supply device 330, continuous production can be realized, and the production efficiency is improved.

[0055] Further, the oil phase supply device 320 comprises at least two oil phase storage tanks; the two oil phase storage tanks are in communication with the liquid inlet of one Laval nozzle through a first three-way valve. After the oil phase in one of the oil phase storage tanks is used up, the oil phase in the other oil phase storage tank can be transported to the liquid inlet of the Laval nozzle by switching the first three-way valve.

[0056] Further, the water phase supply device 330 comprises at least two water phase storage tanks; the two water phase storage tanks are in communication with the liquid inlet of another Laval nozzle through a second three-way valve. After the water phase in one of the water phase storage tanks is used up, the water phase in the other water phase storage tank can be transported to the liquid inlet of the Laval nozzle by switching the second three-way valve.

[0057] Specific embodiments of the second aspect of the present application provide a liposome polymer nanomicrosphere preparation method based on the Laval nozzle collision jet technology. The preparation method uses the liposome polymer nanomicrosphere preparation system based on the Laval nozzle collision jet technology in any of the above embodiments, and the preparation method comprises: transporting the oil phase to one Laval nozzle 312 and transporting the water phase to another Laval nozzle 312; the oil phase and the water phase form high-speed jets through the corresponding Laval nozzles 312, and the two high-speed jets collide and mix in the mixing chamber to obtain the liposome polymer nanomicrosphere.

[0058] The third aspect of the present application provides a liposome polymer nanomicrosphere. The liposome polymer nanomicrosphere is prepared by using the liposome polymer nanomicrosphere preparation method based on the Laval nozzle collision jet technology in any of the above embodiments.

[0059] Further, the oil phase of the liposome polymer nanomicrosphere comprises at least one of oil phase hydrogenated lecithin, 1,2-distearoyl-sn-glycero-3-phosphocholine or cholesterol; and the water phase of the liposome polymer nanomicrosphere comprises at least one of polyethyleneimine, polyhexamethylene biguanide, benzalkonium chloride or chitosan.

[0060] Optionally, the oil phase comprises hydrogenated lecithin, 1,2-distearoyl-sn-glycero-3-phosphocholine and cholesterol; the molar ratio of hydrogenated lecithin, DSPC and the cholesterol is (45-55):(8-12):(35-45).

[0061] Optionally, the molar ratio of hydrogenated lecithin, 1,2-distearoyl-sn-glycero-3-phosphocholine and cholesterol is 45:8:35.

[0062] Optionally, the molar ratio of hydrogenated lecithin, 1,2-distearoyl-sn-glycero-3-phosphocholine and cholesterol is 55:12:45.

[0063] Optionally, the molar ratio of hydrogenated lecithin, 1,2-distearoyl-sn-glycero-3-phosphocholine and cholesterol is 50:10:40.

[0064] It should be noted that DSPC is the abbreviation of 1,2-distearoyl-sn-glycero-3-phosphocholine, which belongs to phospholipid compounds.

[0065] Optionally, the water phase comprises polyethyleneimine, polyhexamethylene biguanide and benzalkonium chloride; the mass ratio of polyethyleneimine, polyhexamethylene biguanide and benzalkonium chloride is (0.5-3):(1-5):(2-8).

[0066] Optionally, the mass ratio of polyethyleneimine, polyhexamethylene biguanide and benzalkonium chloride is 2.5:2.5:5.

[0067] Optionally, the mass ratio of polyethyleneimine, polyhexamethylene biguanide and benzalkonium chloride is 1:4:4.

[0068] Optionally, the mass ratio of polyethyleneimine, polyhexamethylene biguanide and benzalkonium chloride is 0.5:1:2.

[0069] Optionally, the mass ratio of polyethyleneimine, polyhexamethylene biguanide and benzalkonium chloride is 3:5:8.

[0070] Example 1

[0071] The embodiment provides a liposome polymer nanomicrosphere. The oil phase liquid of the liposome polymer nanomicrosphere comprises hydrogenated lecithin, DSPC and cholesterol, and the molar ratio of the hydrogenated lecithin, the DSPC and the cholesterol is 50:10:40. The water phase liquid comprises polyethyleneimine (PEI), polyhexamethylene biguanide (PHMB) and benzalkonium chloride (BC), and the mass ratio of the PEI, the PHMB and the BC is 2.5:2.5:5; the PEI is obtained by compounding PEI with a molecular weight of 3000 and PEI with a molecular weight of 18000 at a mass ratio of 1:1.

[0072] The oil phase liquid and the water phase liquid are respectively introduced into two Laval nozzles at a flow ratio of 1:3 to form two high-speed jets, and the two high-speed jets collide in a mixing chamber to synthesize nanometer particles. The electron microscope image of the nanometer particles is shown in Figure 4 The particle size distribution is shown in Figure 5 It can be seen from Figure 4 and Figure 5 that the average particle size of the nanometer particles is 45 nanometers, and the particle size distribution PDI is 0.09. It is shown that the microspheres of nanometer size and uniform particle size are successfully prepared by the method of the embodiment.

[0073] In addition, the influence of the pH value on the particle size of the nanometer particles is also studied, as shown in Figure 6 It can be known from Figure 6 that the particle size of the nanometer particles can be adjusted by adjusting the pH value of the oil phase or / and the water phase.

[0074] The influence of the pH value on the Zeta potential of the nanometer particles is also studied, as shown in Figure 7 It can be known from Figure 7 that the Zeta potential of the nanometer particles can be adjusted by adjusting the pH value of the oil phase or / and the water phase.

[0075] The influence of the pH value on the encapsulation efficiency of the nanometer particles is also studied, as shown in Figure 8 It can be known from Figure 8 that the influence of the pH value on the encapsulation efficiency of the nanometer particles is limited. In other words, the nanometer particles of the embodiment can adjust the particle size and the Zeta potential of the nanometer particles by adjusting the pH value while ensuring that the change in the encapsulation efficiency is small.

[0076] Embodiment 2

[0077] The embodiment provides a liposome polymer nanomicrosphere. The oil phase solution of the liposome polymer nanomicrosphere comprises hydrogenated lecithin, DSPC and cholesterol, and the molar ratio of the hydrogenated lecithin, the DSPC and the cholesterol is 50:10:40. The water phase solution comprises polyethyleneimine (PEI), polyhexamethylene biguanide (PHMB) and benzalkonium chloride (BC), and the mass ratio of the PEI, the PHMB and the BC is 2.5:2.5:5; the molecular weight of the PEI is 25000.

[0078] The oil phase solution and the water phase solution are respectively introduced into two Laval nozzles at a flow ratio of 1:3 to form two high-speed jets, and the two high-speed jets collide in a mixing chamber to synthesize nanometer particles. Figure 5 It can be seen that the average particle size of the nanometer particles in the embodiment is 45nm, and the particle size distribution PDI is 0.09. It is illustrated that the microspheres with nanometer size and uniform particle size distribution are successfully prepared by the method in the embodiment.

[0079] Embodiment 3

[0080] The embodiment provides a liposome polymer nanomicrosphere. The oil phase solution of the liposome polymer nanomicrosphere comprises hydrogenated lecithin, DSPC and cholesterol, and the molar ratio of the hydrogenated lecithin, the DSPC and the cholesterol is 50:10:40. The water phase solution comprises polyethyleneimine (PEI), polyhexamethylene biguanide (PHMB) and benzalkonium chloride (BC), and the mass ratio of the PEI, the PHMB and the BC is 1:4:4; the PEI is obtained by compounding PEI with a molecular weight of 3000 and PEI with a molecular weight of 18000 according to a mass ratio of 1:1.

[0081] The oil phase solution and the water phase solution are respectively introduced into two Laval nozzles at a flow ratio of 1:3 to form two high-speed jets, and the two high-speed jets collide in a mixing chamber to synthesize nanometer particles. Figure 5 It can be seen that the average particle size of the nanometer particles in the embodiment is 45nm, and the particle size distribution PDI is 0.09. It is illustrated that the microspheres with nanometer size and uniform particle size distribution are successfully prepared by the method in the embodiment.

[0082] In addition, by changing the component ratio, Figure 5 It can be seen that, in the case of changing the component ratio, the average particle size of the liposome polymer nanomicrosphere in the embodiment 1, the embodiment 2 and the embodiment 3, and the particle size distribution change little, and it is further illustrated that the liposome polymer nanomicrosphere with the average particle size close to and the particle size distribution stable can be prepared by using the preparation system provided in the embodiment, and the batch difference can be almost ignored.

[0083] It should be pointed out finally that the above embodiments are only used to illustrate the technical solutions of the present application, but not to limit the same; and although the present application has been described in detail with reference to the foregoing embodiments, it should be appreciated by those skilled in the art that the technical solutions recorded in the foregoing embodiments can be modified, or some technical features thereof can be replaced equivalently; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the spirit and scope of the technical solutions of the embodiments of the present application.

Claims

1. A method for preparing liposome polymer nanomicrospheres based on the collision jet technology of Laval nozzle, characterized in that, Liposome polymer nanosphere preparation system based on collision jet technology of Laval nozzle The preparation system comprises a fluidic mixer (310), wherein the fluidic mixer (310) comprises a collision mixing unit (311) and two Laval nozzles (312). The collision mixing unit (311) has a mixing cavity, at least one liquid outlet flow channel and two liquid inlet flow channels are formed in the collision mixing unit (311); the liquid inlet flow channels and the liquid outlet flow channel are in communication with the mixing cavity; the two Laval nozzles (312) are arranged one by one in the liquid inlet flow channels. The preparation method comprises: delivering an oil phase to one of the Laval nozzles (312) and delivering an aqueous phase to the other Laval nozzle (312); the oil phase and the aqueous phase form high-speed jets through the corresponding Laval nozzles (312), and the two high-speed jets collide and mix in the mixing cavity to obtain liposome polymer nanospheres; wherein the oil phase comprises hydrogenated lecithin, 1,2-distearoyl-sn-glycero-3-phosphocholine and cholesterol; the molar ratio of the hydrogenated lecithin, the 1,2-distearoyl-sn-glycero-3-phosphocholine and the cholesterol is (45-55):(8-12):(35-45); the aqueous phase comprises polyethyleneimine, polyhexamethylene biguanide and benzalkonium chloride; the mass ratio of the polyethyleneimine, the polyhexamethylene biguanide and the benzalkonium chloride is (0.5-3):(1-5):(2-8).

2. The method for preparing liposome polymer nanomicrospheres based on the Laval nozzle collision jet technology according to claim 1, characterized in that, The number of the liquid outlet flow channels is one, and the liquid outlet flow channel and the two liquid inlet flow channels are arranged at intervals along the circumference of the collision mixing unit (311); the two liquid inlet flow channels are symmetrically arranged along the central axis of the liquid outlet flow channel.

3. The method of claim 1, wherein the method is characterized by, The preparation system further comprises: an oil phase supply device (320) for storing the oil phase; the oil phase supply device (320) is in communication with the liquid inlet of one of the Laval nozzles (312); an aqueous phase supply device (330) for storing the aqueous phase; the aqueous phase supply device (330) is in communication with the liquid inlet of the other Laval nozzle (312).

4. The method of claim 1, wherein the method is characterized by, The molar ratio of the hydrogenated lecithin, the 1,2-distearoyl-sn-glycero-3-phosphocholine and the cholesterol is 50:10:

40.

5. The method of claim 1, wherein the method is characterized by, The mass ratio of the polyethyleneimine, the polyhexamethylene biguanide and the benzalkonium chloride is 2.5:2.5:5; or; The mass ratio of the polyethyleneimine, the polyhexamethylene biguanide and the benzalkonium chloride is 1:4:

4.

6. Liposome polymer nanospheres, characterized in that, The liposome polymer nanospheres are prepared by the liposome polymer nanosphere preparation method based on collision jet technology of Laval nozzle according to any one of claims 1 to 5.

Images