Apparatus for preparing lipid nanoparticles
By designing a jetting needle at an angle to the swirling liquid surface in the equipment for preparing lipid nanoparticles, the shear force is increased, which solves the problem of uneven size of liposome particles and improves the uniformity of liposome particles and product quality.
Patent Information
- Application Number
- CN202411573069.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-11-05
- Publication Date
- 2025-01-10
AI Technical Summary
In existing technologies, the liposome particles are not uniform in size, resulting in poor quality of the prepared liposome drugs.
An apparatus for preparing lipid nanoparticles is used, which includes a dissolving device, an emulsifying device, an input pipe, a first stirrer, and a jet needle. The jet needle is provided with multiple jet holes, and the orientation of the jet holes forms an angle of 60°-90° with the vortex surface of the emulsion mixture, thereby promoting thorough mixing of the aqueous and oil phase solutions by increasing the shear force.
It significantly improved the size uniformity of lipid nanoparticles and product quality, resulting in uniformly sized liposomes and a marked improvement in product quality.
Smart Images
Figure CN119281188A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the field of liposome drug preparation, in particular to a device for preparing lipid nanoparticles. Background Art
[0002] When preparing liposome drugs, it is necessary to mix an oil phase solution with an aqueous phase solution for emulsification to form liposomes. However, the problem that often occurs when the oil phase solution is mixed and emulsified with the aqueous phase solution is that the size of the obtained liposome particles is uneven, resulting in poor quality of the obtained liposome drugs. For this reason, people have tried to adopt various methods, such as increasing the pressure of the oil phase solution and the aqueous phase solution when mixing, raising the temperature when mixing, keeping the mixing temperature constant, increasing the ejection speed of the oil phase solution, etc., but the effect is not satisfactory. Summary of the invention
[0003] The purpose of the present invention is to provide a device for preparing lipid nanoparticles, which at least to some extent solves the problem of uneven size of liposome particles in the prior art.
[0004] The above object is achieved by the device for preparing lipid nanoparticles proposed according to the present invention. The device of the present invention comprises: a dissolving device, in which an oil phase solution is contained; an emulsifying device, in which an aqueous phase solution is contained; an input pipeline, in which the dissolving device is connected with the emulsifying device, and is used to input the oil phase solution from the dissolving device into the emulsifying device; a first agitator, which is arranged in the emulsifying device and is used to stir and mix the aqueous phase solution and the oil phase solution, so as to obtain an emulsion mixture. It is stipulated in the present invention that the device also comprises at least one injection needle, which is arranged in the emulsifying device and is connected to the input pipeline, and has at least one layer of injection holes, wherein the direction of the injection holes forms an angle with the liquid surface of the vortex caused by the emulsion mixture when it is stirred by the first agitator, and the angle is 60°-90°.
[0005] Through the present invention, the aqueous phase solution and the oil phase solution are fully mixed, and the obtained lipid nanoparticles are uniform in size, thereby significantly improving the product quality.
[0006] In one embodiment of the present invention, the diameter of the injection hole is 0.1-0.5 mm, preferably 0.3 mm, so that the diameter of the oil phase jet ejected from the injection hole can be controlled, so that it is easy to fully mix with the liquid phase solution, which is conducive to making the generated liposome particles small enough.
[0007] In one embodiment of the present invention, at least one layer of injection holes includes a first layer of injection holes at a first distance from the top of the injection needle head and a second layer of injection holes at a second distance from the top of the injection needle head, wherein the second distance is different from the first distance. Here, the first distance differs from the second distance by 0.5-1.5 mm. In this way, the aqueous phase solution and the oil phase solution can be fully mixed at different depths in the emulsion mixture, and a relatively homogeneous emulsion mixture is obtained after mixing, which is conducive to making the size of the generated liposome particles uniform.
[0008] In one embodiment of the present invention, the first layer of injection holes is evenly distributed along the peripheral surface of the head of the injection needle, and the second layer of injection holes is evenly distributed along the peripheral surface of the head of the injection needle. In other words, the multiple injection holes in the first layer are spaced at the same angle from each other, and similarly, the multiple injection holes in the second layer are spaced at the same angle from each other. Thus, the oil phase solution can be ejected from the injection holes from multiple different directions at the same interval angle. This further improves the mixing uniformity of the aqueous phase solution and the oil phase solution, making the resulting emulsion mixture more homogeneous, and further improving the size uniformity of the generated liposome particles.
[0009] In one embodiment of the present invention, the first layer of injection holes and the second layer of injection holes are staggered at the same angle. This means that the first layer of injection holes and the second layer of injection holes are staggered at different heights so that they are spaced at the same angle in vertical projection. In this way, the aqueous solution and the oily solution are mixed more evenly, thereby obtaining a more homogeneous emulsion mixture, further improving the size uniformity of the produced liposome particles.
[0010] In one embodiment of the present invention, a vertical third layer injection hole is provided at the top of the head of the injection needle. There is usually only one third layer injection hole, but multiple injection holes are not excluded. The oil phase solution is ejected vertically downward through the vertical third layer injection hole. This allows the aqueous phase solution and the oil phase solution to be fully mixed in the vertical downward direction, thereby making the obtained emulsion phase mixture more homogeneous, and ultimately improving the size uniformity of the generated liposome particles.
[0011] In one embodiment of the present invention, a compressed air pipeline is provided on the dissolving device for introducing compressed air into the dissolving device. The introduced compressed air is helpful for fully mixing the components of the oil phase solution on the one hand, and is also helpful for the oil phase solution to be ejected from the ejection hole of the ejection needle through the input pipeline, thereby increasing its ejection speed, thereby facilitating the full mixing of the aqueous phase solution and the oil phase solution.
[0012] In one embodiment of the present invention, the speed of the first stirrer can be adjusted according to the pressure of the compressed air. Specifically, when the pressure of the compressed air increases, the speed of the first stirrer is also increased accordingly, and vice versa. In this way, the dissolving device and the emulsifying device can work in coordination with each other, and the effects of the increase in the pressure of the compressed air and the increase in the speed of the stirrer are superimposed on each other, so that the aqueous solution and the oily solution are fully and evenly mixed.
[0013] In one embodiment of the present invention, the number of injection needles can be changed according to the volume of the emulsion mixture. It goes without saying that if the volume of the emulsion mixture is large, the number of injection needles can be increased accordingly, and vice versa. In this way, the aqueous solution and the oil solution are fully mixed, and redundant injection needles are avoided, thereby reducing costs.
[0014] In one embodiment of the present invention, a plurality of injection needles are evenly distributed in the emulsification device, which is conducive to the uniform mixing of the aqueous phase solution and the oil phase solution, and improves the uniformity of the size of the generated liposome particles.
[0015] In one embodiment of the present invention, a second stirrer is provided in the dissolving device for stirring and mixing the components of the oil phase solution. The oil phase solution is composed of a phospholipid solution and ethanol, for example, and the second stirrer can facilitate the dissolution of the phospholipid solution in the ethanol. BRIEF DESCRIPTION OF THE DRAWINGS
[0016] In order to better understand the above and other purposes, features, advantages and functions of the present application, reference may be made to the preferred embodiments shown in the accompanying drawings. The same reference numerals in the accompanying drawings represent the same components. It should be understood by those skilled in the art that the accompanying drawings are intended to schematically illustrate the preferred embodiments of the present application and have no limiting effect on the scope of the present application, and the components in the drawings are not drawn to scale.
[0017] Figure 1 is an overall schematic diagram of a device for preparing lipid nanoparticles according to the present invention;
[0018] Figure 2 Shows Figure 1 The injection needle of the device;
[0019] Figure 3 yes Figure 2 A schematic cross-sectional view of the injection needle is shown;
[0020] Figure 4 yes Figure 2 A partial view of the head of the injection needle;
[0021] Figure 5 Shown in Figure 2 The spray hole layout on the spray needle head; and
[0022] Figure 6 The orientation of the injection hole on the injection needle head is shown. DETAILED DESCRIPTION
[0023] The specific implementation of the present application is now described in detail with reference to the accompanying drawings. What is described here is only the preferred implementation of the present application. Those skilled in the art can think of other ways to implement the present application based on the preferred implementation, and other ways also fall within the scope of the present application.
[0024] See first Figure 1 , which schematically shows an apparatus 100 for preparing lipid nanoparticles according to the present invention as a whole. Figure 1 It can be seen that the device 100 includes a dissolving device 10, an emulsifying device 20 and an input pipe 30, and the input pipe 30 connects the dissolving device 10 with the emulsifying device 20. The dissolving device 10 contains an oil phase solution, the emulsifying device 20 contains an aqueous phase solution, and the input pipe 30 is used to input the oil phase solution from the dissolving device 10 into the emulsifying device 20. Then, the aqueous phase solution in the emulsifying device 20 is fully mixed with the oil phase solution to obtain an emulsion mixture, which is drawn out via an output pipe 50 for subsequent further processing, such as extracting and recovering the ethanol contained therein, dehydrating, and finally obtaining a solid liposome freeze-dried powder injection that is easy to store. Ethanol is initially present in the oil phase solution in the dissolving device 10, and is used to dissolve the main drug and phospholipids under heating. The main drug is difficult to dissolve in water or insoluble in water, and the phospholipids are used as auxiliary agents here, that is, the components of the oil phase solution are mainly the main drug, phospholipids and ethanol used to dissolve them. The aqueous phase solution in the emulsifying device 20 is mainly water and a phosphate buffer for adjusting the pH value.
[0025] As mentioned above, in the prior art, the size of the liposome particles obtained is not uniform enough, resulting in low product quality. Although various methods have been used in the prior art, the effect is still unsatisfactory. In order to solve this technical problem, the present invention utilizes shearing force to improve uniformity. Specifically, the oil phase solution is subjected to shearing force when it meets the aqueous phase solution. The present invention increases the shearing force, fundamentally making the emulsion mixture particles obtained after the aqueous phase solution is mixed with the oil phase solution significantly reduced, and then making the liposome particles finally produced significantly reduced, such as obtaining liposome nanoparticles of 130-250nm, thereby greatly improving the uniformity of the liposome particle size, and significantly improving the product quality. The working method of the device 100 for preparing lipid nanoparticles of the present invention is described in detail below.
[0026] Continue to see Figure 1, a first agitator 21 is provided in the emulsifying device 20. Preferably, a second agitator 11 is provided in the dissolving device 10, and the second agitator 11 is used to stir and mix the components of the oil phase solution in the dissolving device 10, specifically, to facilitate the dissolution of the main drug and phospholipids in ethanol, so as to quickly obtain the oil phase solution. In order to speed up the acquisition of the oil phase solution, a compressed air pipeline 12 is preferably provided on the dissolving device 10 for introducing compressed air into the dissolving device 10, as shown by arrow F, and the pressure of the compressed air is, for example, 0.12MPA. The obtained oil phase solution is input into the emulsifying device 20 via the input pipeline 30. For this purpose, a pump 31 for sucking the oil phase solution is provided on the input pipeline 30.
[0027] According to the present invention, at least one injection needle 40 is provided in the emulsification device 20. Figure 1 2 shows two injection needles 40 by way of example, preferably three injection needles 40 are provided, but a plurality of injection needles 40 may also be provided. The specific number of the injection needles 40 may be changed according to the volume of the emulsion phase mixture in the emulsification device 20, that is, if the volume of the emulsion phase mixture in the emulsification device 20 is large, more injection needles 40 may be used, otherwise the number of the injection needles 40 may be reduced. In the case where a plurality of injection needles 40 are provided, the injection needles 40 are preferably evenly distributed in the emulsification device 20 to facilitate sufficient mixing of the aqueous phase solution and the oil phase solution.
[0028] Depend on Figure 1 It can be seen that the injection needle 40 is connected to the input pipe 30 and has at least one layer of injection holes. Thus, the oil phase solution enters the injection needle 40 through the input pipe 30, and then ejects from the injection hole set on the head of the injection needle 40, and enters the emulsification device 20. Under the stirring of the first agitator 21 in the emulsification device 20, the aqueous phase solution and the oil phase solution are mixed to obtain an emulsion mixture. In order to drive the first agitator 21 to rotate and stir, the first agitator 21 is connected to the motor 22 through a connecting rod 23. The rotation speed of the first agitator 21 is preferably adjustable, for example, according to the pressure of the compressed air. Specifically, when the pressure of the compressed air supplied through the compressed air pipe 12 increases, the injection speed of the oil phase solution ejected from the injection hole will also increase. Correspondingly, the rotation speed of the first agitator 21 is increased, so that the effects of the increase in the pressure of the compressed air and the increase in the rotation speed of the agitator are superimposed on each other, so that the dissolution device 10 and the emulsification device 20 work in coordination with each other, which helps to fully and evenly mix the aqueous phase solution and the oil phase solution.
[0029] In order to reduce the particles of the emulsion mixture obtained after the aqueous phase solution and the oil phase solution are mixed, and ultimately improve the uniformity of the liposome particle size, the injection needle 40 is specially designed in the present invention. Figure 2 and Figure 3The injection needle 40 includes a head 41, a rod 42, a transition portion 43, a connecting portion 44 and a connecting hole 45 located in the connecting portion 44. The connecting portion 44 is, for example, threaded and used to connect with the input pipeline 30 so that the oil phase solution enters the connecting hole 45 via the input pipeline 30. Other connection methods can also be used for connection. The inner diameter of the connecting hole 45 is smaller than that of the input pipeline 30, and after passing through the transition portion 43, it transitions to a smaller inner hole located in the rod 42, and the diameter of the inner hole is, for example, 1 mm. The inner hole in the rod 42 leads to the injection hole on the head 41, so that the oil phase solution is finally ejected from the injection hole. The diameter of the injection hole is 0.1-0.5 mm, preferably 0.3 mm. In this way, the diameter of the oil phase jet ejected from the injection hole can be controlled to be small enough, so that the oil phase solution and the liquid phase solution are fully mixed, and then sufficiently small liposome particles can be produced.
[0030] See also Figure 4 and Figure 5 At least one layer of injection holes is provided on the head 41 of the injection needle 40, and the at least one layer of injection holes includes, for example, a first layer of injection holes 1, a second layer of injection holes 2 and an optional third layer of injection holes 3. That is, the third layer of injection holes 3 is not necessarily present, but is optional. Figure 4 and Figure 5 The third layer of injection holes 3 is located at the top of the head 41. When the injection needle 40 is vertically installed in the working state, the third layer of injection holes 3 is vertically downward. Figure 5 Thus, the oil phase solution is sprayed vertically downward through the third layer spray hole 3, so that the water phase solution and the oil phase solution at the bottom of the emulsification device 20 can be fully mixed in the vertical downward direction, thereby making the obtained emulsion mixture more homogeneous, and finally improving the size uniformity of the generated liposome particles. Figure 4 and Figure 5 As can be seen in the figure, the third layer of injection holes 3 is only one, but the third layer of injection holes 3 can also include multiple injection holes, such as two, three, etc., and is not limited to one. The first layer of injection holes 1, the second layer of injection holes 2 and the third layer of injection holes 3 are preferably the same size, but can also be different in size.
[0031] Continue to see Figure 4 and Figure 5 In the working state of the vertically installed injection needle 40, the first layer injection hole 1 is a first distance d1 from the top of the head 41 of the injection needle 40, and the second layer injection hole 2 is a second distance d2 from the top of the head 41 of the injection needle 40, wherein the second distance d2 is different from the first distance d1. Here, for example, it is provided that the difference between the first distance d1 and the second distance d2 is 0.5-1.5 mm, preferably 1 mm, Figure 4The second distance d2 between the second layer of injection holes 2 located below and the top of the head 41 is 1 mm-1.5 mm. Figure 5 Since multiple layers of injection holes are arranged at different distances from the top of the head 41 of the injection needle 40, the oil phase solution is ejected from the injection holes of each layer located at different depths of the emulsion mixture, thereby being fully mixed with the water phase solution at different depths of the emulsion mixture. After mixing, the emulsion mixture is more homogeneous, which helps to make the size of the generated liposome particles uniform.
[0032] See also Figure 5 The first layer of injection holes 1 and the second layer of injection holes 2 respectively include a plurality of injection holes, for example, four injection holes. Figure 5 It is preferably provided that the first layer of injection holes 1 are evenly distributed along the peripheral surface of the head 41 of the injection needle 40, and the second layer of injection holes 2 are also evenly distributed along the peripheral surface of the head 41 of the injection needle 40. Figure 4 In the example shown, the four injection holes of the first layer are located on a circle and spaced 90° apart from each other, and the four injection holes of the second layer are located on another circle and spaced 90° apart from each other. This allows the oil phase solution to be ejected from the injection holes of each layer from multiple different directions at the same interval angle, thereby further improving the mixing uniformity of the aqueous phase solution and the oil phase solution, making the resulting emulsion mixture more homogeneous, and further improving the size uniformity of the generated liposome particles.
[0033] Continue to see Figure 5 In the present invention, it is preferably provided that the first layer of injection holes 1 and the second layer of injection holes 2 are staggered at the same angle. Specifically, Figure 5 As shown, the four injection holes of the first layer and the four injection holes of the second layer are evenly distributed on a circle in vertical projection, that is, the projections of the eight injection holes on the circle are spaced at the same angle θ, that is, θ=45°. It can be understood that this will make the aqueous phase solution and the oil phase solution more evenly mixed, so that a more homogeneous emulsion mixture can be obtained, and the size uniformity of the generated liposome particles can be further improved.
[0034] See below Figure 6 On the one hand, when the aqueous phase solution and the oil phase solution are mixed in the emulsifying device 20, their mixing is promoted by the stirring of the first stirrer 21. The rotation direction of the first stirrer 21 is as follows: Figure 6As shown by the arrow R in . Thus, in the direction shown by the arrow R, a vortex of an emulsion mixture consisting of an aqueous solution and an oily solution is generated. Obviously, the liquid surface M of the vortex is not horizontal, but inclined, in other words, it forms a certain angle relative to the horizontal plane. On the other hand, when the oily solution sprayed from the injection hole meets the original aqueous solution in the emulsifying device 20, the oily solution will be subjected to shear force. This shear force will cause the component of the main drug in the oily solution to be crushed to form nano-scale particles. Therefore, the greater the shear force, the more it helps to crush the main drug in the oily solution, and thus helps to improve the uniformity of the generated liposome particles.
[0035] It is based on this understanding that the present invention attempts to maximize the shear force, while various methods in the prior art do not take this shear force into consideration. Therefore, the present invention stipulates that the direction N of the injection hole forms an angle α with the liquid surface M of the vortex caused by the first agitator 21 when the emulsion mixture is stirred. The angle α is 60°-90°, preferably 90°. That is to say, in the present invention, the direction N of the injection hole is nearly perpendicular to the liquid surface M of the vortex. Figure 6 It is schematically shown that the direction N of the first layer of injection holes 1 and the second layer of injection holes 2, that is, the direction N of the oil phase solution jets ejected from the first layer of injection holes 1 and the second layer of injection holes 2, is substantially perpendicular to the liquid surface M of the vortex of the emulsion mixture. At this time, the shear force on the oil phase solution ejected from the first layer of injection holes 1 and the second layer of injection holes 2 is the greatest.
[0036] In the present invention, the shear force exerted on the jet of the oil phase solution ejected from the first layer injection hole 1 and the second layer injection hole 2 is increased, so that the aqueous phase solution and the oil phase solution are fundamentally fully mixed, so that the obtained emulsion mixture is more homogeneous, the uniformity of the produced liposome nanoparticles is significantly improved, and finally the product quality is significantly improved.
[0037] It should be pointed out that the vortex of the emulsion mixture is generated when it is stirred by the first agitator 21, and the size of the vortex depends on the rotation speed of the first agitator 21. The greater the rotation speed, the larger the vortex, and vice versa. The inclination degree of the liquid surface M of the vortex of different sizes is also different. In normal operation, the rotation speed of the first agitator 21 is usually 600-900 rpm, that is, the orientation of the first layer of injection holes 1 and the second layer of injection holes 2 in the present invention is determined by precise measurement when the rotation speed of the first agitator 21 is 600-900 rpm. Since the inclination degree of the liquid surface M of the vortex is also affected by various factors such as the volume, viscosity, temperature, pressure, etc. of the emulsion mixture in the emulsifying device 20, it is impossible to clearly and specifically specify the angle of the first layer of injection holes 1 and the second layer of injection holes 2 relative to the horizontal plane or the vertical line. However, the unique design of the injection hole of the injection needle 40 of the present invention, that is, the direction N of the injection hole forms a nearly vertical angle α with the liquid surface M of the vortex caused by the emulsion mixture when it is stirred by the first agitator 21, is the inventive concept of the present invention and remains unchanged and is the core of the present invention.
[0038] Some embodiments of the present application have been introduced for the purpose of illustration, but the present application is not limited to these embodiments. Those skilled in the art may also think of many modifications and variations. Therefore, these embodiments are selected and described in order to better illustrate the principles and practical applications of the present application and to enable those skilled in the art to understand the content thereof, that is, without departing from the spirit of the present application, all modifications and variations made will fall within the scope of protection of the present application as defined by the appended claims.
Claims
1. A device (100) for preparing lipid nanoparticles, wherein: The device (100) comprises: A dissolving device (10), wherein the dissolving device (10) contains an oil phase solution; an emulsifying device (20), wherein the emulsifying device (20) contains an aqueous solution; an input pipe (30), the input pipe (30) connecting the dissolving device (10) and the emulsifying device (20) and used for inputting the oil phase solution from the dissolving device (10) into the emulsifying device (20); a first stirrer (21), the first stirrer (21) being disposed in the emulsifying device (20) and used for stirring and mixing the aqueous phase solution and the oil phase solution to obtain an emulsion mixture; and At least one injection needle (40), the injection needle (40) is arranged in the emulsifying device (20) and connected to the input pipe (30), and has at least one layer of injection holes, wherein the direction (N) of the injection holes forms an angle (α) with the liquid surface (M) of the vortex (W) caused by the emulsion mixture when being stirred by the first agitator (21), and the angle (α) is 60°-90°.
2. The device (100) according to claim 1, wherein The diameter of the injection hole is 0.1-0.5 mm.
3. The device (100) according to claim 1 or 2, wherein: At least one layer of the injection holes comprises a first layer of injection holes (1) at a first distance (d1) from the top of the head (41) of the injection needle (40) and a second layer of injection holes (2) at a second distance (d2) from the top of the head (41) of the injection needle (40), wherein the second distance (d2) is different from the first distance (d1).
4. The device (100) according to claim 3, wherein: The first distance (d1) and the second distance (d2) differ by 0.5-1.5 mm.
5. The device (100) according to claim 4, wherein The first layer of injection holes (1) are evenly distributed along the peripheral surface of the head (41) of the injection needle (40), and the second layer of injection holes (2) are evenly distributed along the peripheral surface of the head (41) of the injection needle (40).
6. The device (100) according to claim 5, wherein: The first layer of injection holes (1) and the second layer of injection holes (2) are staggered at the same angle.
7. The device (100) according to claim 6, wherein A vertical third layer of injection holes (3) is provided at the top end of the head (41) of the injection needle (40).
8. The device (100) according to any one of claims 4 to 7, wherein: The dissolving device (10) is provided with a compressed air pipeline (12) for introducing compressed air into the dissolving device (10).
9. The device (100) according to claim 8, wherein The rotation speed of the first stirrer (21) can be adjusted according to the pressure of the compressed air.
10. The device (100) according to any one of claims 4 to 7, wherein: The number of the injection needles (40) can be varied according to the volume of the emulsion mixture.
11. The device (100) according to any one of claims 4 to 7, wherein: The plurality of injection needles (40) are evenly distributed in the emulsification device (20).
12. The device (100) according to any one of claims 4 to 7, wherein: A second stirrer (11) is provided in the dissolving device (10) for stirring and mixing the components of the oil phase solution.