Microsphere preparation device

Abstract

The utility model provides a microsphere preparation device. The microsphere preparation device comprises a coagulation tank, a solidification tank, a shearing machine, a flow speed regulator, a first control valve and a second control valve, the condensation tank is provided with a first feed port, a return port and a discharge port, the solidification tank is provided with a second feed port, the discharge port, the shearing machine and the return port are sequentially connected to form a condensation liquid drop circulation pipeline, and the discharge port, the shearing machine and the second feed port are sequentially connected to form a condensation liquid drop output pipeline; according to the device disclosed by the utility model, microspheres with uniform particle size and narrower particle size distribution range are obtained by circularly shearing condensed liquid drops formed in the condensation tank; the speed of adding the condensed liquid drops into the curing tank can be controlled through a flow speed regulator, so that the microspheres are prevented from gathering in the curing process; and the inclined blades are arranged, so that upward thrust can be generated when the stirring paddle rotates, and the condensed liquid drops are prevented from being gathered and precipitated.

Description

Technical Field

[0001] This utility model relates to the field of pharmaceutical preparation equipment, and in particular to a microsphere preparation device. Background Technology

[0002] Microspheres are tiny spherical polymers with particle sizes ranging from a few micrometers to several hundred micrometers, prepared from polymer materials, and encapsulating one or more drugs. Compared with traditional injections, they can reduce fluctuations in blood drug concentrations, decrease side effects, and allow drug release to continue for weeks to months, thereby reducing the frequency of administration and improving patient compliance.

[0003] The preparation process of microspheres is relatively complex. Currently, industrially feasible methods for microsphere preparation include phase separation, solvent evaporation, spray drying, and hot melt extrusion. The basic principle of phase separation microsphere preparation involves adding a coagulant to a drug-polymer carrier-organic solvent system under stirring. The coagulant slowly extracts the solvent from the polymer carrier material, reducing its solubility and creating a new phase in the solution, forming drug-loaded droplets. This system is then transferred to another organic non-solvent curing agent, causing the microspheres to solidify and obtain the final product. Common problems in the phase separation microsphere preparation process include easy aggregation during solidification, wide microsphere size distribution, and non-uniform particle size. Utility Model Content

[0004] The technical problem to be solved by this invention is to overcome the defects of existing technology in the preparation of drug microspheres, such as easy aggregation, wide particle size distribution, and non-uniform particle size. The invention provides a microsphere preparation device that can obtain microspheres of different particle sizes by adjusting the rotation speed of the online shearing machine, and obtain microspheres with uniform particle size and narrow distribution by circulating shearing of the coagulation liquid.

[0005] The present invention solves the above-mentioned technical problems through the following technical solution:

[0006] This utility model provides a microsphere preparation device, which includes a coagulation tank, a solidification tank, a shearing machine, a flow rate regulator, a first control valve, and a second control valve;

[0007] The condensation tank is provided with a first inlet, a return outlet and an outlet, and the solidification tank is provided with a second inlet. The outlet, the shearing machine and the return outlet are connected in sequence to form a condensate droplet circulation pipeline. The outlet, the shearing machine and the second inlet are connected in sequence to form a condensate droplet output pipeline. The first control valve is provided on the condensate droplet circulation pipeline, and the second control valve and the flow rate regulator are provided on the condensate droplet output pipeline.

[0008] Both the coagulation tank and the solidification tank are equipped with a stirring paddle. The stirring paddle includes at least two sets of blade units, which are arranged sequentially along the axial direction of the stirring paddle's rotation axis. Each set of blade units includes multiple inclined blades arranged sequentially along the circumference of the rotation axis. The multiple inclined blades in each set of blade units are rotationally symmetrical about the rotation axis. The inclination angle of the inclined blades is 20~60°, and the inclination angle refers to the angle between the inclined blade and the horizontal plane.

[0009] The microsphere preparation device of this invention obtains microspheres with uniform particle size and narrow particle size distribution by circulating and shearing the condensed droplets formed in the coagulation tank; and the flow rate regulator can control the speed at which the condensed droplets are added to the curing tank to prevent the microspheres from agglomerating during the curing process; moreover, the inclined blades help to generate an upward thrust when the stirring paddle rotates, avoiding the agglomerated droplets from agglomerating and settling.

[0010] The microsphere preparation device of this invention is mainly applicable to the process of preparing microspheres by phase separation method.

[0011] In this invention, the coagulation vessel is used to hold the drug, carrier material, solvent, and coagulant. Inside the coagulation vessel, the coagulant slowly extracts the solvent from the carrier material to reduce its solubility, generating a new phase in the solution and forming coagulated droplets. The curing vessel is used to hold the drug-loaded droplets and the hardener. Inside the curing vessel, the microspheres are cured under the action of the hardener to obtain the final product.

[0012] In this invention, the shearing machine is an online shearing machine, which can realize the shearing of materials in a flowing state.

[0013] The online shearing machine can be a conventional shearing machine capable of performing shearing operations in real time during material conveying. An online shearing machine generally consists of a motor, housing, stator, rotor, and sealing mechanism. The housing has an inlet and an outlet, while the stator and rotor are housed within the housing. The motor provides power to the shearing machine and controls the shearing speed. The sealing mechanism ensures that the condensate does not leak, allowing for pressurized operation of the condensate, such as Fluko's FDC1 / 40 online shearing machine. During operation, the condensate continuously flows into the housing cavity from the inlet. Through the close cooperation between the high-speed rotating rotor and stator, and relying on the shearing and centrifugal extrusion generated by the high linear velocity, the material is fully collided, mixed, and pulverized before entering the next process through the outlet.

[0014] In this invention, the flow rate regulator is preferably also provided on the circulating pipeline of the condensed droplets, so as to further control the flow rate of the condensed liquid during the circulating shearing and improve the uniformity of the particle size distribution of the condensed liquid.

[0015] In this invention, the microsphere preparation device generally further includes pipelines for forming the condensed droplet circulation pipeline and the condensed droplet output pipeline. The pipelines preferably include a main pipe, a first branch pipe, and a second branch pipe. One end of the main pipe is connected to the discharge port, and the first branch pipe and the second branch pipe are connected in parallel to the other end of the main pipe. The flow rate regulator and the shearing machine are sequentially arranged on the main pipe. The first branch pipe is provided with a first control valve, and the second branch pipe is provided with a second control valve. The main pipe and the first branch pipe form the condensed droplet circulation pipeline, and the main pipe and the second branch pipe form the condensed droplet output pipeline.

[0016] In this invention, the first feed inlet is preferably located at the top of the condensing tank. The return outlet is preferably located at the top of the condensing tank. The discharge outlet is preferably located at the bottom of the condensing tank.

[0017] In this invention, the flow rate regulator preferably includes a flow meter and a proportional control valve, which are sequentially arranged on the condensate droplet output pipeline. The proportional control valve can adjust the valve opening in real time via a flow meter control signal, thereby adjusting the pipeline opening. This facilitates control of the speed at which the condensate droplets flow through the shearing machine and into the solidification tank. Simultaneously, the flow meter can display the specific flow rate.

[0018] In this invention, the tilt angle is preferably 40°.

[0019] In this invention, the axial distance between two adjacent sets of blade units is 10-30 cm. When the axial distance between two adjacent sets of blade units is within the preferred range, the material can be further thoroughly stirred and mixed, reducing or preventing the aggregation or precipitation of microspheres.

[0020] In this invention, the stirring paddle preferably includes a motor, a speed regulating device, a rotating shaft, and inclined blades disposed on the rotating shaft. One end of the speed regulating device is connected to the rotating shaft, and the other end of the speed regulating device is connected to the motor. The stirring speed is adjusted by the speed regulating device, which is conventional in the art, such as a gear reduction mechanism.

[0021] In this invention, the number of blade units can be 2 to 3. Within each blade unit, the number of inclined blades can be 3 to 4.

[0022] In this invention, the distance between the bottommost blade unit and the bottom of the coagulation tank is preferably 1-5 cm. The distance between the bottommost blade unit and the bottom of the solidification tank is also preferably 1-5 cm. This preferred distance allows for thorough stirring and mixing of the material, further reducing or preventing the aggregation or sedimentation of microspheres.

[0023] In this invention, the ratio of the diameter of each blade unit to the inner diameter of the condensation tank is preferably 0.3 to 0.6, where the diameter of the blade unit refers to the diameter of the circle formed by the farthest point of the blade. The ratio of the diameter of each blade unit to the inner diameter of the solidification tank is also preferably 0.3 to 0.6. The ratio of the diameter of each blade unit to the height of the condensation tank is preferably 0.2 to 0.6. The ratio of the diameter of each blade unit to the height of the solidification tank is also preferably 0.2 to 0.6. In each blade unit, the ratio of the width of the inclined blade to the diameter of the blade unit is preferably 0.1 to 0.2. These parameters, within this preferred range, allow for thorough stirring and mixing of the material, further reducing or preventing the aggregation or sedimentation of microspheres.

[0024] The positive and progressive effects of this utility model are as follows:

[0025] This invention relates to a microsphere preparation apparatus. Microspheres of different sizes can be obtained by adjusting the rotation speed of the shearing machine, and microspheres with uniform size and narrow distribution can be obtained through circulating shearing of the coagulation liquid. Furthermore, the flow rate regulator can control the rate at which the coagulation liquid is added to the solidification tank, preventing microsphere aggregation during solidification. The inclined blades also help generate upward thrust when the agitator rotates, avoiding aggregation and sedimentation of the coagulated liquid droplets. This invention provides a new approach to the design of industrial-scale equipment for phase separation microsphere production. Attached Figure Description

[0026] Figure 1 This is a schematic diagram of the overall structure of the microsphere preparation device described in the embodiments of this utility model.

[0027] Figure 2 This is a schematic diagram of the structure of the stirring paddle described in an embodiment of the present invention.

[0028] Figure 3 This is an enlarged view of the layout of the inclined blades and rotating shaft described in the embodiment of this utility model.

[0029] Explanation of reference numerals in the attached figures:

[0030] 1-Coagulation tank, 2-Cure tank, 3-Shearing machine, 4-First control valve, 5-Second control valve, 6-Main pipe, 7-First branch pipe, 8-Second branch pipe, 9-Flow meter, 10-Proportional regulating valve, 11-Agitator;

[0031] 101 - First feed inlet, 102 - Return feed inlet, 103 - Discharge outlet;

[0032] 201 - Second feed inlet;

[0033] 1101 - Shaft, 1102 - Inclined blade, 1103 - Blade unit. Detailed Implementation

[0034] The present invention will be described more clearly and completely below with reference to the accompanying drawings, using a preferred embodiment.

[0035] Example 1

[0036] This embodiment discloses a microsphere preparation apparatus, which includes a coagulation tank 1, a curing tank 2, pipelines, a shearing machine 3, a flow rate regulator, a first control valve 4, and a second control valve 5. The coagulation tank 1 is provided with a first inlet 101, a return inlet 102, and an outlet 103. The curing tank 2 is provided with a second inlet 201. The first inlet 101 and the return inlet 102 are both located at the top of the coagulation tank 1, and the outlet 103 is located at the bottom of the coagulation tank 1. The outlet 103 is also provided with a discharge valve. The coagulation tank 1 is used to hold drugs, carrier materials, solvents, and coagulants, while the curing tank 2 is used to hold drug-loaded droplets and a hardening agent. The outlet 103, the shearing machine 3, and the return inlet 102 are connected in sequence to form a coagulated droplet circulation pipeline, and the outlet 103, the shearing machine 3, and the second inlet 201 are connected in sequence to form a coagulated droplet output pipeline.

[0037] In this embodiment, the pipeline includes a main pipe 6, a first branch pipe 7, and a second branch pipe 8. One end of the main pipe 6 is connected to the discharge port 103. The first branch pipe 7 and the second branch pipe 8 are connected in parallel at the other end of the main pipe 6. A flow rate regulator and a shearing machine 3 are sequentially installed on the main pipe 6. A first control valve 4 is installed on the first branch pipe 7, and a second control valve 5 is installed on the second branch pipe 8. The main pipe 6 and the first branch pipe 7 form a condensed droplet circulation pipeline, and the main pipe 6 and the second branch pipe 8 form a condensed droplet output pipeline.

[0038] In this embodiment, the shearing machine 3 is an online shearing machine, purchased from Fluko, model FDC1 / 40. The flow rate regulator includes a flow meter 9 (Linuo Tiansheng T713-KP sanitary liquid turbine flow meter) and a proportional control valve 10 (Siemens DN25 PID control valve), which are sequentially installed on the main pipe 6.

[0039] In this embodiment, both the coagulation tank 1 and the solidification tank 2 are equipped with a stirring paddle 11. The stirring paddle 11 includes a motor, a speed regulating device, a rotating shaft 1101, and two sets of blade units 1103 arranged sequentially along the axial direction of the rotating shaft 1101. One end of the speed regulating device is connected to the rotating shaft 1101, and the other end is connected to the motor. The speed regulating device is a gear reduction mechanism used to adjust the rotational speed of the rotating shaft 1101. Each set of blade units 1103 includes four inclined blades 1102 evenly distributed circumferentially along the rotating shaft 1101. The four inclined blades 1102 in each set of blade units 1103 are rotationally symmetrical about the rotating shaft 1101, and the inclination angle α of the inclined blades is 40°. Figure 3 As shown.

[0040] In this embodiment, the axial spacing between the two sets of blade units 1103 is 20 cm. The ratio of the diameter D of each set of blade units 1103 to the inner diameter of the condensation tank 1 and the curing tank 2 is 0.5. The distance between the bottommost blade unit 1103 and the bottom of the condensation tank 1 and the curing tank 2 is 2-4 cm. The ratio of the diameter D of each set of blade units 1103 to the height of the condensation tank 1 and the curing tank 2 is 0.48. In each set of blade units 1103, the ratio of the width d of the inclined blade 1102 to the diameter D of the blade unit 1103 is 0.13.

[0041] Example 2

[0042] This embodiment uses the microsphere preparation apparatus described in Example 1 to prepare microspheres, and the specific steps include:

[0043] (1) Add the drug (2.2 g exenatide), polymer carrier material (83 g PLGA model 75:25), and organic solvent (1.5 L dichloromethane) into the coagulation tank 1 through the first feed port 101, start the stirring device 11 to dissolve the polymer carrier material, and add the coagulant (1.15 kg polydimethylsiloxane) into the coagulation tank 1 at a flow rate of 152 g / min. Stir for 5 min after adding the coagulant.

[0044] (2) Open the discharge valve at the discharge port 103. The condensed droplets flow into the shearing machine 3 at a flow rate of 1~2 L / min through the proportional regulating valve 10 and the flow meter 9. Open the first control valve 4. The condensed droplets enter the first branch pipe 7 from the shearing machine 3 and return to the condensing tank 1 from the return port 102. The shearing is cyclical for 5~10 min.

[0045] (3) Close the first control valve 4 and open the second control valve 5. The condensed droplets are injected into the solidification tank 2 containing 55 L of n-heptane at a flow rate of 1~2 L / min to obtain exenatide microspheres.

[0046] The results showed that the exenatide microspheres were well dispersed. The particle size of the exenatide microspheres measured by laser particle size analyzer was 10-13 μm for D10, 35-40 μm for D50, 50-55 μm for D90, and the span was 0.6-1.0.

[0047] Comparative Example 1

[0048] The microsphere preparation device of this comparative example is basically the same as that of Example 1, except that the microsphere preparation device of this comparative example does not have a first branch pipe 7 and a first control valve 4 (i.e., it does not have a condensed droplet circulation pipeline).

[0049] The microspheres were prepared using the microsphere preparation apparatus described in this comparative example. The specific steps included:

[0050] (1) Add 2.2 g exenatide, 83 g PLGA (model 75:25) and 1.5 L dichloromethane into coagulation tank 1 through the first feed port 101, start the stirring device 11 to dissolve the polymer carrier material, add 1.15 kg polydimethylsiloxane into coagulation tank 1 at a constant rate of 152 g / min, and continue stirring for 5 min after the addition is complete;

[0051] (2) Open the discharge valve at the discharge port 103. The condensed droplets flow into the shearing machine 3 at a flow rate of 1~2 L / min through the proportional regulating valve 10 and the flow meter 9. Open the second control valve 5. The condensed droplets enter the second branch pipe 8 at a flow rate of 1~2 L / min and are pumped into the solidification tank 2 containing 55 L of n-heptane from the second feed port 201 to obtain exenatide microspheres.

[0052] The results showed that some of the exenatide microspheres exhibited significant aggregation. The measured particle sizes of the exenatide microspheres were 24–26 μm (D10), 47–50 μm (D50), 120–125 μm (D90), and 1.9–2.1 μm (span).

[0053] Comparative Example 2

[0054] The microsphere preparation apparatus of this comparative example is basically the same as that of Example 1, except that the blade 1102 on the stirring paddle 11 of this comparative example is horizontal.

[0055] The microsphere preparation method and process in this comparative example are the same as those in Example 2.

[0056] The results showed that significant aggregation and precipitation occurred during the experiment, and well-dispersed microspheres were not obtained.

Claims

1. A microsphere preparation apparatus, characterized in that, It includes a coagulation tank, a solidification tank, a shearing machine, a flow rate regulator, a first control valve, and a second control valve; The condensation tank is provided with a first inlet, a return outlet and an outlet, and the solidification tank is provided with a second inlet. The outlet, the shearing machine and the return outlet are connected in sequence to form a condensate droplet circulation pipeline. The outlet, the shearing machine and the second inlet are connected in sequence to form a condensate droplet output pipeline. The first control valve is provided on the condensate droplet circulation pipeline, and the second control valve and the flow rate regulator are provided on the condensate droplet output pipeline. Both the coagulation tank and the solidification tank are equipped with a stirring paddle. The stirring paddle includes at least two sets of blade units, which are arranged sequentially along the axial direction of the stirring paddle's rotation axis. Each set of blade units includes multiple inclined blades arranged sequentially along the circumference of the rotation axis. The multiple inclined blades in each set of blade units are rotationally symmetrical about the rotation axis. The inclination angle of the inclined blades is 20~60°, and the inclination angle refers to the angle between the inclined blade and the horizontal plane.

2. The microsphere preparation apparatus as described in claim 1, characterized in that, The shearing machine is an online shearing machine; And / or, the flow rate regulator is also provided on the condensed droplet circulation pipeline.

3. The microsphere preparation apparatus as described in claim 1, characterized in that, The microsphere preparation device further includes pipelines, which include a main pipe, a first branch pipe, and a second branch pipe. One end of the main pipe is connected to the discharge port, and the first branch pipe and the second branch pipe are connected in parallel to the other end of the main pipe. The flow rate regulator and the shearing machine are sequentially arranged on the main pipe. The first branch pipe is equipped with a first control valve, and the second branch pipe is equipped with a second control valve. The main pipe and the first branch pipe form the condensed droplet circulation pipeline, and the main pipe and the second branch pipe form the condensed droplet output pipeline.

4. The microsphere preparation apparatus according to any one of claims 1 to 3, characterized in that, The flow rate regulator includes a flow meter and a proportional control valve, which are sequentially installed on the condensate droplet output pipeline.

5. The microsphere preparation apparatus as described in claim 1, characterized in that, The first feed inlet is located at the top of the condensation tank; And / or, the return port is located at the top of the condensation tank; And / or, the discharge port is located at the bottom of the condensation tank.

6. The microsphere preparation apparatus as described in claim 1, characterized in that, The stirring paddle includes a motor, a speed regulating device, the rotating shaft, and the inclined blades disposed on the rotating shaft. One end of the speed regulating device is connected to the rotating shaft, and the other end of the speed regulating device is connected to the motor.

7. The microsphere preparation apparatus as described in claim 1 or 6, characterized in that, The tilt angle is 40°.

8. The microsphere preparation apparatus as described in claim 1 or 6, characterized in that, The axial spacing between two adjacent sets of blade units is 10~30 cm.

9. The microsphere preparation apparatus as described in claim 1, characterized in that, The distance between the bottommost blade unit and the bottom of the condenser is 1~5 cm; And / or, the distance between the bottommost blade unit and the bottom of the curing tank is 1~5 cm.

10. The microsphere preparation apparatus according to claim 1, characterized in that, The ratio of the diameter of each blade unit to the inner diameter of the condenser is 0.3 to 0.

6. The diameter of the blade unit refers to the diameter of the circle formed by the farthest end of the blade around the axis of rotation. And / or, the ratio of the diameter of each blade unit to the inner diameter of the curing tank is 0.3 to 0.6; And / or, the ratio of the diameter of each blade unit to the height of the condenser is 0.2 to 0.6; And / or, the ratio of the diameter of each blade unit to the height of the curing tank is 0.2 to 0.6; And / or, in each of the blade units, the ratio of the width of the inclined blade to the diameter of the blade unit is 0.1 to 0.2.

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