CN114392384B - Method for preparing high drug-loading rate embolism microsphere and collecting device - Google Patents

Method for preparing high drug-loading rate embolism microsphere and collecting device Download PDF

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CN114392384B
CN114392384B CN202111594167.1A CN202111594167A CN114392384B CN 114392384 B CN114392384 B CN 114392384B CN 202111594167 A CN202111594167 A CN 202111594167A CN 114392384 B CN114392384 B CN 114392384B
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microspheres
weighing
phase
continuous phase
high drug
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CN114392384A (en
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李丹杰
郑亚楠
孟洁
程杰
秦长喜
崔景强
华静宇
夏凯丽
刘晓飞
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Henan Camel Medical Device Research Institute Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/08—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/12—Surgical instruments, devices or methods, e.g. tourniquets for ligaturing or otherwise compressing tubular parts of the body, e.g. blood vessels, umbilical cord
    • A61B17/12022—Occluding by internal devices, e.g. balloons or releasable wires
    • A61B17/12027—Type of occlusion
    • A61B17/12031—Type of occlusion complete occlusion
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/12—Surgical instruments, devices or methods, e.g. tourniquets for ligaturing or otherwise compressing tubular parts of the body, e.g. blood vessels, umbilical cord
    • A61B17/12022—Occluding by internal devices, e.g. balloons or releasable wires
    • A61B17/12099—Occluding by internal devices, e.g. balloons or releasable wires characterised by the location of the occluder
    • A61B17/12109—Occluding by internal devices, e.g. balloons or releasable wires characterised by the location of the occluder in a blood vessel
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A61L24/0015—Medicaments; Biocides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/06—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/0093—Microreactors, e.g. miniaturised or microfabricated reactors

Abstract

The invention discloses a method for preparing high drug-loading embolic microspheres and a collecting device, wherein the preparation method comprises a dispersion phase and a continuous phase, the dispersion phase and the continuous phase are subjected to two-phase speed regulation through a multi-channel microfluidic structure by an injection pump to obtain dropping liquid, and then the dropping liquid is subjected to curing reaction through the collecting device to obtain the high drug-loading embolic microspheres with proper size. The preparation method is simple and convenient to operate, the problem of low microsphere process yield can be solved, the prepared embolism microsphere has high drug-loading performance, and the collection device can realize high-throughput microsphere production.

Description

Method for preparing high drug-loading rate embolism microsphere and collecting device
Technical Field
The invention relates to the field of biomedical materials, in particular to a novel device for preparing, automatically collecting and curing embolism microspheres with high drug loading.
Background
The transcatheter embolism is one of three main techniques of intravascular interventional radiology, is an important technique for interventional therapy, and is characterized by that some artificial embolism material can be controllably injected into target supply blood vessel of pathological change tissue or organ to make it produce occlusion and block blood supply so as to attain the goal of controlling bleeding, curing vascular pathological change, eliminating function of pathological change organ and curing tumor.
Gelatin sponge and polyvinyl alcohol granules have been widely used as conventional granular embolizing agents since the 70's 20 th century, but the degree of embolization was unpredictable due to irregular and varying particle shapes. The spherical embolic agent is published in the 90 s of the 20 th century, so that the problem is solved. The microspheres have smooth surfaces, precise sizes and compressibility, and are not easy to agglomerate, so that blood vessels at the periphery of the tumor can be better embolized easily through the microcatheter, and the blood supply of the tumor can be more thoroughly reduced. The products widely applied at present are all prepared by a reversed-phase suspension copolymerization method, the wet microspheres soaked in a preservation solution are mostly used in clinical use states, the preparation method has the defects of long preparation period, wide microsphere size distribution, and complicated microsphere post-treatment (washing, screening and the like) operation, and the clinical medicine carrying time is long and the medicine carrying amount is not high; the last one is a copolymerization product of vinyl alcohol and acrylic acid, is in a powder state in clinical use, is directly used for carrying medicine, and has the defects of serious wall adhesion, deformation after medicine carrying and the like. At present, a novel high-drug-loading-rate embolic microsphere preparation and automatic collection and solidification device which can realize high drug loading, simple preparation and the like does not exist.
Disclosure of Invention
Based on this, aiming at the defects of the prior art, the technical problem to be solved by those skilled in the art is to provide a novel device for preparing embolization microspheres with high drug loading and automatically collecting and solidifying the embolization microspheres.
In order to overcome the technical defects, the invention adopts the following technical scheme:
a method for preparing embolization microspheres with high drug loading, comprising the following steps:
(1) Preparation of dispersed phase:
the method comprises the following steps: weighing quantitative starch, dissolving at 30-60 deg.C, gelatinizing for 5-35min, and cooling to obtain starch with concentration of 5-20wt%;
step two: weighing a certain amount of comonomer containing unsaturated double bonds and carboxyl, adding water to dissolve the comonomer, wherein the concentration is 0.5-1.5wt%;
step three: weighing quantitative benzaldehyde-2-sodium sulfonate, adding water to dissolve, wherein the concentration is 2-8wt%;
step four: weighing a quantitative initiator, namely ceric ammonium sulfate, and dissolving the initiator in water to obtain a solution with the concentration of 0.05-1.5wt%;
step five: weighing 10-20g of starch, 5-10g of comonomer solution and 3-8g of benzaldehyde-2-sodium sulfonate solution in a beaker, uniformly stirring, adding 3-6mL of initiator ammonium ceric sulfate solution and 1-3mL of concentrated sulfuric acid, and uniformly stirring;
(2) Preparation of a continuous phase: weighing a certain amount of emulsifier in a beaker, adding a certain amount of continuous phase main body to enable the emulsifier to account for 15-25wt%, and uniformly stirring;
(3) Preparing a carrying phase: adding concentrated sulfuric acid into the continuous matching prescription in the step (2) in a proportion of 0.5-1.5wt%, uniformly stirring, and transferring the mixture into a receiving tray 8 to serve as a receiving phase;
(4) Adding the dispersion phase and the continuous phase solution obtained in the steps (1) and (2) into a multi-channel micro-fluidic structure for regulating the speeds of the dispersion phase and the continuous phase by using an injection pump to obtain liquid drops with different sizes;
(5) Dripping the dropping liquid in the step (4) into the solution placed in the N 2 Solidifying the mixture by a collecting device in the atmosphere, and heating and reacting for 3-6h to obtain microspheres;
(6) And (4) filtering, and washing the microspheres obtained in the step (5) by one of petroleum ether, tween or physiological saline to obtain the target embolism microspheres.
Further, the comonomer containing the unsaturated double bond and the carboxyl in the step (1) is one or more of sodium acrylate, vinyl acetate, acrylic acid or methacrylic acid.
Further, the emulsifier in step (2) is one or more of Span80, cellulose acetate, tween 20 or EM 90.
Further, the main component of the continuous phase in the step (2) is any one of liquid paraffin, dimethicone, mineral oil, butyl acetate, n-octane, n-heptane, ethyl acetate, and butyl acetate.
Further, the multi-channel microfluidic structure in the step (4) is a group of microfluidic chips, two groups of microfluidic chips, four groups of microfluidic chips, eight groups of microfluidic chips and more than eight groups of microfluidic chips, which are formed by laser engraving according to a three-dimensional design by using any one of PMMA, PC, PTFE, ABS, PE and PET materials.
Preferably, the flow rate of the disperse phase in the step (4) is 1-80mL/h, and the flow rate of the continuous phase is 10-600mL/h.
The invention also provides an automatic collecting and curing device used in the scheme, which comprises an upper cover 1 and a lower cover 4 which are mainly used for preparing the embolism microsphere and comprise a rotating shaft 6, wherein the upper cover 1 and the lower cover 4 and an adjacent heating cylinder 3 form a cylindrical structure, and one side of the heating cylinder 3 is provided with an inlet of a multi-channel microfluidic structure 9; and a nitrogen port 2 is formed in one side of the rotating shaft 6, which is close to the upper cover 1, and the rotating shaft 6 is close to the lower cover 4 and is provided with a motor assembly 5.
Further, the cylindrical structure passing through the rotating shaft 6 comprises a threaded washer 7 for fixing a receiving disc 8, and the receiving disc 8 is used for receiving the embolism microspheres flowing through the multi-channel microfluidic structure 9.
Furthermore, the concave part of the receiving disc 8 is provided with a plurality of circular grooves which are annularly arranged and combined and used for collecting the embolism microspheres.
Further, the inlet of the multi-channel microfluidic structure 9 is matched with the receiving disc 8.
The invention has the following beneficial effects:
1. the preparation method is simple and easy to operate;
2. according to the invention, a plurality of embolism microspheres with uniform particle size can be prepared at one time by using a multi-channel micro-fluidic structure;
3. the collecting device designed by the invention can realize high-flux production of the microspheres, avoid manual receiving and reduce the complexity of the preparation process.
Drawings
FIG. 1 is a schematic view of the structure of the collecting device of the present invention;
FIG. 2 is a schematic view of the construction of a receiving tray in the collecting apparatus of the present invention;
FIG. 3 is a schematic view of a multi-channel microfluidic structure in the collection device of the present invention;
in the figure: 1 is the upper cover, 2 is the nitrogen gas mouth, 3 is the cartridge heater, 4 is the lower cover, 5 is motor element, 6 is the pivot, 7 is the screw washer, 8 is the receiving disc, 9 is multichannel micro-fluidic structure.
Detailed description of the preferred embodiments
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. It is to be understood that the described embodiments are merely exemplary of the invention, and not restrictive of the full scope of the invention. All other embodiments, which can be obtained by a person skilled in the art without making any creative effort based on the embodiments in the present invention, belong to the protection scope of the present invention.
The invention provides a method for preparing embolism microsphere with high drug loading capacity, which is characterized by comprising the following steps (1) of preparing dispersed phase:
the method comprises the following steps: weighing quantitative starch, dissolving at 30-60 deg.C, gelatinizing for 5-35min, and cooling to obtain starch with concentration of 5-20wt%;
step two: weighing a certain amount of comonomer containing unsaturated double bonds and carboxyl groups, and adding water to dissolve the comonomer with the concentration of 0.5-1.5wt%;
step three: weighing quantitative benzaldehyde-2-sodium sulfonate, adding water to dissolve, wherein the concentration is 2-8wt%;
step four: weighing a quantitative initiator, namely ceric ammonium sulfate, and dissolving the initiator in water to obtain a solution with the concentration of 0.05-1.5wt%;
step four: weighing 10-20g of starch, 5-10g of comonomer solution and 3-8g of benzaldehyde-2-sodium sulfonate solution in a beaker, uniformly stirring, adding 3-6mL of initiator ammonium ceric sulfate solution and 1-3mL of concentrated sulfuric acid, and uniformly stirring;
(2) Preparation of a continuous phase: weighing a certain amount of emulsifier in a beaker, adding a certain amount of continuous phase main body to enable the emulsifier to account for 15-25wt%, and uniformly stirring;
(3) Preparing a carrying phase: adding concentrated sulfuric acid into the continuous matching prescription in the step (2) in a proportion of 0.5-1.5wt%, uniformly stirring, and transferring the mixture into a receiving tray 8 to serve as a receiving phase;
(4) Obtaining liquid drops with different sizes by using a multi-channel micro-fluidic structure for regulating the speeds of the dispersed phase and the continuous phase solution in the steps (1) and (2) through an injection pump;
(5) Dripping the dropping liquid in the step (4) into the solution placed in the N 2 And curing the mixture by a collecting device in the atmosphere, and heating and reacting for 3-6h to obtain the target microspheres.
(6) And (5) filtering, and washing the microspheres obtained in the step (5) by using petroleum ether, tween and normal saline to obtain the embolism microspheres.
Further, the comonomer containing unsaturated double bonds and carboxyl groups in the step (1) is one or more of sodium acrylate, vinyl acetate, acrylic acid or methacrylic acid.
Further, the emulsifier in step (2) is one or more of Span80, cellulose acetate, tween 20 or EM 90.
Further, the main component of the continuous phase in the step (2) is any one of liquid paraffin, dimethicone, mineral oil, butyl acetate, n-octane, n-heptane, ethyl acetate, and butyl acetate.
Further, the multichannel microfluidic structure in the step (4) is a group of microfluidic chips, two groups of microfluidic chips, four groups of microfluidic chips, eight groups of microfluidic chips and more than eight groups of microfluidic chips, which are formed by laser engraving according to a three-dimensional design by using any one of PMMA, PC, PTFE, ABS, PE and PET materials.
Further, the flow rate of the dispersed phase in the step (4) is 1-80mL/h, and the flow rate of the continuous phase is 10-600mL/h.
The invention also provides a collecting device used in the scheme, which comprises an upper cover 1 and a lower cover 4 which pass through a rotating shaft 6 and are used for preparing the embolism microsphere, wherein the upper cover 1 and the lower cover 4 and an adjacent heating cylinder 3 form a cylindrical structure, and one side of the heating cylinder 3 is provided with an inlet of a multi-channel microfluidic structure 9; and the rotating shaft 6 is close to one side of the upper cover 1 and is provided with a nitrogen port 2, and the rotating shaft 6 is close to the lower cover 4 and is provided with a motor component 5.
As an embodiment of the present invention, further, the cylindrical structure passing through the rotating shaft 6 comprises a threaded washer 7 for fixing a receiving disc 8, and the receiving disc 8 is used for receiving the plug microspheres flowing through the multi-channel microfluidic structure 9.
As an embodiment of the invention, further, the concave part of the receiving disc 8 is provided with a plurality of circular grooves which are combined in a ring-shaped arrangement and used for collecting the embolism microspheres.
As an embodiment of the present invention, further, the inlet of the multi-channel microfluidic structure 9 is configured with the receiving tray 8.
The following are examples:
example 1
A method for preparing high drug-loading rate embolization microspheres comprises the following steps:
the method comprises the following steps: weighing 5g of starch, adding 100g of water, sufficiently dissolving at 35 ℃, gelatinizing for 5min, and cooling for later use, wherein the starch concentration is 5wt%;
step two: weighing 0.05g of sodium acrylate, adding 10g of water for dissolving, wherein the concentration is 0.5wt%;
step three: weighing 0.32g of benzaldehyde-2-sodium sulfonate, adding 16g of water to dissolve, wherein the concentration is 2wt%;
step four: weighing 0.025g of ammonium ceric sulfate, adding 50g of water to dissolve, wherein the concentration is 0.05wt%;
step five: weighing 10g of starch, 5g of sodium acrylate solution and 8g of benzaldehyde-2-sodium sulfonate solution in a beaker, uniformly stirring, adding 5mL of initiator ammonium ceric sulfate solution and 3mL of concentrated sulfuric acid, and uniformly stirring to obtain a dispersion phase for later use;
step six: 40g of Span80 is weighed in a beaker, 230g of liquid paraffin is added, and the mixture is uniformly stirred to be used as a continuous phase for later use; 4.05mL of concentrated sulfuric acid is added into the continuous matching method, and after being uniformly stirred, the concentrated sulfuric acid is transferred into a receiving tray 8 to be used as a receiving phase;
step seven: using an injection pump to make the solution of the dispersion phase and the continuous phase pass through a multi-channel microfluidic structure, wherein the flow rate of the dispersion phase is 1mL/h, the flow rate of the continuous phase is 25mL/h, the rotating speed of a motor is 3rpm, and after collecting droplets, N is obtained 2 Heating and reacting for 2.5h at 45 ℃ in the atmosphere;
step eight: and filtering the collected microspheres, and washing the microspheres with petroleum ether, tween and normal saline to obtain the microspheres with the particle size of 100-150 mu m and the average particle size of 120 mu m.
Example 2
A method for preparing embolization microspheres with high drug loading comprises the following steps:
the method comprises the following steps: weighing 10g of starch, adding 100g of water, fully dissolving at 35 ℃, gelatinizing for 5min, and cooling for later use, wherein the starch concentration is 10wt%;
step two: weighing 0.1g of vinyl acetate, adding 10g of water for dissolving, wherein the concentration is 1wt%;
step three: weighing 0.32g of benzaldehyde-2-sodium sulfonate, adding 10g of water to dissolve, wherein the concentration is 3.2wt%;
step four: 0.025g of ammonium ceric nitrate is weighed and dissolved in 50g of water, and the concentration is 0.05wt%;
step five: weighing 12g of starch, 6g of vinyl acetate solution and 5g of benzaldehyde-2-sodium sulfonate solution in a beaker, uniformly stirring, adding 3mL of initiator ammonium ceric nitrate solution and 1mL of nitric acid, and uniformly stirring to obtain a dispersion phase for later use;
step six: weighing 50g of Span80 in a beaker, adding 200g of liquid paraffin, and uniformly stirring to obtain a continuous phase for later use; adding 1.35mL of nitric acid into the continuous matching formula, uniformly stirring, and transferring the mixture into a receiving tray 8 to serve as a receiving phase;
step seven: using an injection pump to make the solution of the dispersion phase and the continuous phase pass through a multi-channel microfluidic structure, wherein the flow rate of the dispersion phase is 5mL/h, the flow rate of the continuous phase is 23mL/h, the rotating speed of a motor is 4rpm, and after collecting droplets, N is obtained 2 Heating and reacting for 2.5h at 55 ℃ in the atmosphere;
step eight: and filtering the collected microspheres, and washing the microspheres with petroleum ether, tween and normal saline to obtain the microspheres with the particle size of 380-425 mu m and the average particle size of 405 mu m.
Example 3
A method for preparing embolization microspheres with high drug loading comprises the following steps:
the method comprises the following steps: weighing 15g of starch, adding 100g of water, fully dissolving at 55 ℃, gelatinizing for 15min, and cooling for later use, wherein the starch concentration is 15wt%;
step two: weighing 0.10g of methacrylic acid, adding 10g of water for dissolving, wherein the concentration is 1wt%;
step three: weighing 0.32g of benzaldehyde-2-sodium sulfonate, adding 16g of water to dissolve, wherein the concentration is 2wt%;
step four: weighing 0.025g of ammonium ceric sulfate, adding 50g of water to dissolve, wherein the concentration is 0.05wt%;
step five: weighing 15g of starch, 5g of methacrylic acid solution and 8g of benzaldehyde-2-sodium sulfonate solution in a beaker, uniformly stirring, adding 3mL of initiator ammonium ceric sulfate solution and 1mL of concentrated sulfuric acid, and uniformly stirring to obtain a dispersion phase for later use;
step six: weighing 40g of EM90 in a beaker, adding 160g of simethicone, and uniformly stirring to obtain a continuous phase for later use; adding 1.5mL of concentrated sulfuric acid into the continuous matching method, uniformly stirring, and transferring the mixture into a receiving tray 8 to serve as a receiving phase;
step seven: using an injection pump to make the solution of the dispersion phase and the continuous phase pass through a multi-channel microfluidic structure, wherein the flow rate of the dispersion phase is 7mL/h, the flow rate of the continuous phase is 23mL/h, the rotating speed of a motor is 5rpm, and after collecting droplets, N is obtained 2 Heating and reacting for 3h at 45 ℃ in the atmosphere;
step eight: and filtering the collected microspheres, and washing the microspheres with petroleum ether, tween and normal saline to obtain the microspheres with the particle size of 490-590 mu m and the average particle size of 550 mu m.
Example 4
A method for preparing high drug-loading rate embolization microspheres comprises the following steps:
the method comprises the following steps: weighing 20g of starch, adding 100g of water, fully dissolving at 55 ℃, gelatinizing for 15min, and cooling for later use, wherein the starch concentration is 20wt%;
step two: weighing 0.150g of acrylic acid, adding 10g of water for dissolving, wherein the concentration is 1.5wt%;
step three: weighing 1.6g of benzaldehyde-2-sodium sulfonate, adding 20g of water to dissolve, wherein the concentration is 8wt%;
step four: weighing 0.75g of ammonium ceric sulfate, adding 50g of water to dissolve, wherein the concentration is 1.5wt%;
step five: weighing 18g of starch, 7g of acrylic acid solution and 8g of benzaldehyde-2-sodium sulfonate solution in a beaker, uniformly stirring, adding 5mL of initiator ammonium ceric sulfate solution and 2.5mL of concentrated sulfuric acid, and uniformly stirring to obtain a dispersion phase for later use;
step six: 40g of Span 20 is weighed in a beaker, 160g of mineral oil is added, and the mixture is uniformly stirred to be used as a continuous phase for standby; adding 1.5mL of concentrated sulfuric acid into the continuous matching formula, uniformly stirring, and transferring the mixture into a receiving tray 8 to serve as a receiving phase;
step seven: using an injection pump to make the solution of the dispersion phase and the continuous phase pass through a multi-channel microfluidic structure, wherein the flow rate of the dispersion phase is 12mL/h, the flow rate of the continuous phase is 18mL/h, the rotating speed of a motor is 7rpm, and after collecting droplets, N is obtained 2 Heating and reacting for 3h at 45 ℃ in the atmosphere;
step eight: filtering the collected microspheres, and washing with petroleum ether, tween and normal saline to obtain microspheres with a particle size of 690-750 μm and an average particle size of 724 μm.
Example 5
A method for preparing high drug-loading rate embolization microspheres comprises the following steps:
the method comprises the following steps: weighing 20g of starch, adding 100g of water, fully dissolving at 55 ℃, gelatinizing for 15min, and cooling for later use, wherein the starch concentration is 20wt%;
step two: weighing 0.150g of sodium acrylate, adding 10g of water for dissolving, wherein the concentration is 1.5wt%;
step three: weighing 1.6g of benzaldehyde-2-sodium sulfonate, adding 20g of water to dissolve, wherein the concentration is 8wt%;
step four: weighing 0.75g of ammonium ceric sulfate, adding 50g of water to dissolve, wherein the concentration is 1.5wt%;
step five: weighing 18g of starch, 7g of sodium acrylate solution and 8g of benzaldehyde-2-sodium sulfonate solution in a beaker, uniformly stirring, adding 5mL of initiator ammonium ceric sulfate solution and 2.5mL of concentrated sulfuric acid, and uniformly stirring to obtain a dispersion phase for later use;
step six: 40g of Span80 is weighed in a beaker, 160g of liquid paraffin is added, and the mixture is uniformly stirred to be used as a continuous phase for later use; adding 1.5mL of concentrated sulfuric acid into the continuous matching method, uniformly stirring, and transferring the mixture into a receiving tray 8 to serve as a receiving phase;
step seven: using an injection pump to make the solution of the dispersion phase and the continuous phase pass through a multi-channel microfluidic structure, wherein the flow rate of the dispersion phase is 12mL/h, the flow rate of the continuous phase is 18mL/h, the rotating speed of a motor is 7rpm, and after collecting droplets, N is obtained 2 Heating and reacting for 3h at 45 ℃ in the atmosphere;
step eight: and filtering the collected microspheres, and washing the microspheres with petroleum ether, tween and normal saline to obtain the microspheres with the particle size of 950-1000 mu m and the average particle size of 970 mu m.
Comparative example 1
A method for preparing high drug-loading rate embolization microspheres comprises the following steps:
the method comprises the following steps: weighing 10g of starch, adding 100g of water, fully dissolving at 35 ℃, gelatinizing for 5min, and cooling for later use, wherein the starch concentration is 10wt%;
step two: weighing 0.1g of sodium acrylate, adding 10g of water for dissolving, wherein the concentration is 1wt%;
step three: 0.025g of ammonium ceric nitrate is weighed and dissolved in 50g of water, and the concentration is 0.05wt%;
step four: weighing 12g of starch and 6g of sodium acrylate solution in a beaker, uniformly stirring, adding 3mL of initiator ammonium ceric nitrate solution and 1mL of nitric acid, and uniformly stirring to obtain a dispersion phase for later use;
step five: weighing 50g of Span80 in a beaker, adding 200g of liquid paraffin, and uniformly stirring to obtain a continuous phase for later use; the continuous matching party is simultaneously used as a receiving phase;
step six: using an injection pump to make the solution of the dispersion phase and the continuous phase pass through a multi-channel microfluidic structure, wherein the flow rate of the dispersion phase is 5mL/h, the flow rate of the continuous phase is 23mL/h, the rotating speed of a motor is 4rpm, and after collecting droplets, N is obtained 2 Heating and reacting for 2.5h at 55 ℃ in the atmosphere;
step seven: and filtering the collected microspheres, and washing the microspheres with petroleum ether, tween and normal saline to obtain the microspheres with the particle size of 410-510 mu m and the average particle size of 452 mu m.
Comparative example 2
A method for preparing embolization microspheres with high drug loading comprises the following steps:
the method comprises the following steps: weighing 10g of starch, adding 100g of water, fully dissolving at 35 ℃, gelatinizing for 5min, and cooling for later use, wherein the starch concentration is 10wt%;
step two: weighing 0.32g of benzaldehyde-2-sodium sulfonate, adding 10g of water to dissolve, wherein the concentration is 3.2wt%;
step three: weighing 12g of starch and 5g of benzaldehyde-2-sodium sulfonate solution in a beaker, and uniformly stirring the starch and the solution to be used as a dispersion phase for later use;
step four: weighing 50g of Span80 in a beaker, adding 200g of liquid paraffin, and uniformly stirring to obtain a continuous phase for later use; adding 1.35mL of nitric acid into the continuous matching formula, uniformly stirring, and transferring the mixture into a receiving tray 8 to serve as a receiving phase;
step five: using an injection pump to make the solution of the dispersion phase and the continuous phase pass through a multi-channel microfluidic structure, wherein the flow rate of the dispersion phase is 5mL/h, the flow rate of the continuous phase is 23mL/h, the rotating speed of a motor is 4rpm, and after collecting droplets, N is obtained 2 Heating and reacting for 2.5h at 55 ℃ in the atmosphere;
step six: filtering the collected microspheres, and washing with petroleum ether, tween and normal saline to obtain microspheres with the particle size of 420-530 μm and the average particle size of 465 μm.
1g of microspheres obtained in the previous example and subjected to surface moisture removal are weighed respectively, 4mL of 25mg/mL of doxorubicin hydrochloride is added, and the drug loading concentration results are as follows:
group of Drug loading capacity (mg/g) for 10min Drug loading capacity (mg/g) for 20min
Example 1 79 85
Example 2 73 82
Example 3 65 72
Example 4 57 63
Example 5 53 60
Comparative example 1 35 40
Comparative example 2 28 35
As can be seen from the comparison, the embolization microsphere containing two electronegative groups can realize higher drug loading by the preparation method provided by the invention. The accurate control of the particle size of the microspheres can be realized through a multi-channel micro-fluidic structure, the flow velocity of a dispersed phase and a continuous phase is regulated and controlled, and the microspheres with different specifications and models of 100-300 mu m, 300-500 mu m, 500-700 mu m, 700-900 mu m, 900-1200 mu m and the like can be obtained. Meanwhile, by regulating the number of channels in the microfluidic chip and the rotating speed of the automatic collecting device, automatic collection and solidification can be realized, manual operation is reduced, and production efficiency is improved.
Finally, it should also be noted that, herein, relational terms such as first and second, and the like may be used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any actual such relationship or order between such entities or actions. Also, the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus. Without further limitation, an element defined by the phrase "comprising a … …" does not exclude the presence of another identical element in a process, method, article, or apparatus that comprises the element.
The embodiments in the present description are described in a progressive manner, each embodiment focuses on differences from other embodiments, and the same and similar parts among the embodiments are referred to each other.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims (6)

1. A method for preparing embolization microspheres with high drug loading capacity is characterized by comprising the following steps:
(1) Preparation of dispersed phase:
the method comprises the following steps: weighing quantitative starch, dissolving at 30-60 deg.C, gelatinizing for 5-35min, and cooling to obtain starch with concentration of 5-20wt%;
step two: weighing a certain amount of comonomer containing unsaturated double bonds and carboxyl, adding water to dissolve the comonomer, wherein the concentration is 0.5-1.5wt%;
step three: weighing quantitative benzaldehyde-2-sodium sulfonate, adding water to dissolve, wherein the concentration is 2-8wt%;
step four: weighing a quantitative initiator, namely ceric ammonium sulfate, and dissolving the initiator in water to obtain a solution with the concentration of 0.05-1.5wt%;
step five: weighing 10-20g of starch, 5-10g of comonomer solution and 3-8g of benzaldehyde-2-sodium sulfonate solution in a beaker, uniformly stirring, adding 3-6mL of initiator ammonium ceric sulfate solution and 1-3mL of concentrated sulfuric acid, and uniformly stirring;
(2) Preparation of a continuous phase: weighing a quantitative emulsifier in a beaker, adding a quantitative continuous phase main body to enable the emulsifier to account for 15-25wt%, and uniformly stirring, wherein the continuous phase main body is any one of liquid paraffin, dimethyl silicone oil and mineral oil;
(3) Preparing a carrying phase: adding concentrated sulfuric acid in the proportion of 0.5-1.5wt% into the continuous matching party in the step (2), uniformly stirring, and transferring the mixture into a receiving tray to serve as a receiving phase;
(4) Adding the dispersed phase and continuous phase solution obtained in the steps (1) and (2) into a multi-channel microfluidic structure through an injection pump, and adjusting the speed of the dispersed phase and the continuous phase to obtain liquid drops with different sizes;
(5) Dripping the dropping liquid in the step (4) into the solution placed in the N 2 Solidifying by a collecting device in the atmosphere, and heating for reacting for 3-6h to obtain microspheres;
(6) And (3) filtering, and washing the microspheres obtained in the step (5) by one of petroleum ether, tween or physiological saline to obtain the target embolism microspheres.
2. The method for preparing high drug loading capacity embolization microspheres according to claim 1, wherein the comonomer containing unsaturated double bond and carboxyl in step (1) is one or more of sodium acrylate, acrylic acid or methacrylic acid.
3. The method for preparing high drug loading embolization microspheres according to claim 1, wherein the emulsifier in step (2) is one or more of Span80, cellulose acetate, tween 20 or EM 90.
4. The method for preparing high drug-loading rate embolization microspheres of claim 1, wherein the multichannel microfluidic structure in step (4) is a group of microfluidic chips, two groups of microfluidic chips, four groups of microfluidic chips, eight groups of microfluidic chips and more than eight groups of microfluidic chips, which are formed by laser engraving according to a three-dimensional design by using any one of PMMA, PC, PTFE, ABS, PE and PET materials.
5. The method for preparing high drug loading capacity embolization microspheres according to claim 1, wherein the flow rate of the dispersed phase in step (4) is 1-80mL/h, and the flow rate of the continuous phase is 10-600mL/h.
6. A collecting device for preparing the embolic microsphere of any one of claims 1 to 5, comprising an upper cover and a lower cover which pass through a rotating shaft, wherein the upper cover and the lower cover and an adjacent heating cylinder form a cylindrical structure, and one side of the heating cylinder is provided with an inlet of a multi-channel microfluidic structure; a nitrogen port is formed in one side, close to the upper cover, of the rotating shaft, and a motor assembly is mounted on the rotating shaft, close to the lower cover; the cylindrical structure passing through the rotating shaft comprises a threaded gasket for fixing a receiving disc, and the receiving disc is used for receiving the embolism microspheres flowing through the multi-channel microfluidic structure; the concave part of the receiving disc is provided with a plurality of circular grooves which are annularly arranged and combined and used for collecting embolism microspheres; the inlet of the multi-channel micro-fluidic structure is matched with the receiving disc.
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