A method for preparing gel microspheres

Abstract

The application discloses a preparation method of gel microspheres, which comprises the following steps: step one, preparing a hydrogel solution; step two, directly dropping the hydrogel solution prepared in step one into liquid nitrogen in the form of microdroplets to collect the hydrogel microspheres after quick freezing; and step three, collecting the hydrogel microspheres, solidifying, sterilizing and storing. The application directly uses liquid nitrogen as a collecting liquid. Due to the temperature difference between the hydrogel droplets and the liquid nitrogen, the gas on the surface of the liquid nitrogen evaporates to form an upward airflow, so that the hydrogel droplets float and wander on the liquid surface of the liquid nitrogen and quickly rotate into spherical shape. When the temperature of the small balls continuously decreases, the evaporation amount of the liquid nitrogen decreases, the formed gel microspheres gradually sink to the bottom of the collecting tank, and the gel microspheres after quick freezing are obtained. The method avoids the use of a solidifying liquid in the traditional method and limits the size and density of the gel microspheres. The prepared gel microspheres are uniform in particle size, smooth in surface, controllable in particle size in the range of 50-500 microns, and narrow in particle size distribution and small in particle size fluctuation range.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of gel microsphere preparation, and particularly relates to a gel microsphere preparation method. BACKGROUND

[0002] A hydrogel is a three-dimensional network polymer formed by cross-linking of linear polymer chains, which can swell in water and hold a large amount of water without dissolving. Because the molecular structure contains a large number of hydrophilic groups, it can absorb several hundred or even several thousand times its own weight of water, and the water retention capacity is also very strong, that is, it is not easy to dehydrate even under pressure. Due to the high water content, most hydrogels have excellent biological adaptability and are widely used in the fields of biological medicine, enzyme activity control, molecular separation, etc.

[0003] The preparation methods of hydrogel microspheres can be divided into batch emulsification method, microfluidic emulsion method, photolithography method, electrospraying method and mechanical crushing method. The batch emulsification method is to mix incompatible liquids (for example, water and oil) together to generate cross-linkable hydrogel droplets; the microfluidic emulsion method connects the incompatible liquids through a microfluidic channel, generates droplets at the intersection, and then cross-links the droplets to form hydrogel microspheres; the photolithography method focuses light on a mask or a mold to solidify and cross-link to form hydrogel microspheres; the electrospraying method applies a voltage between a needle and a receiving liquid, so that the applied voltage overcomes the surface tension at the needle tip to form a charged droplet jet, which is cross-linked in the receiving liquid to form hydrogel microspheres; in the mechanical crushing method, the pre-formed block-shaped hydrogel is mechanically crushed into hydrogel microspheres. The above methods all have certain defects in preparing gel microspheres with small particle size, small relative density and uniform particle size.

[0004] For example: Generally, the electrostatic droplet method (electrospraying method) is suitable for preparing gel microspheres with a particle size greater than 200 μm and a gel microsphere density greater than the density of the gel solidification liquid, but is not suitable for preparing gel microspheres with a particle size less than 200 μm and a relative density less than 1.02. Because the small droplets with a particle size less than 200 μm have very light quality, after being dropped into the gel bath, they initially float on the liquid surface, and due to the fact that the gel solidification reaction cannot occur sufficiently, they are mutually adhered to each other in a linear or flocculent shape, and finally form a large gel mass. Similarly, the sol drug liquid with a relative density less than 1.02 or close to the density of the gel solidification liquid is also not suitable for the electrostatic droplet method to prepare microspheres. When the density of the drug-containing sol liquid is close to or less than the density of the gel solidification liquid, the liquid droplets do not sink but float after being continuously dropped into the gel bath, and float on the surface of the gel bath for a long time. SUMMARY

[0005] The present application aims at the deficiencies in the prior art, and provides a gel microsphere preparation method.

[0006] To achieve the above object, the technical scheme adopted by the present application is as follows:

[0007] The first aspect of the present application provides a preparation method of gel microspheres, comprising the following steps:

[0008] Step one, preparing a hydrogel solution for standby;

[0009] Step two, directly dropping the hydrogel solution prepared in step one into liquid nitrogen in the form of microdroplets to collect, and obtaining hydrogel microspheres after rapid freezing;

[0010] Step three, collecting the hydrogel microspheres obtained in step two, solidifying, sterilizing and storing

[0011] Further, in step two, due to the temperature difference between the hydrogel droplets and the liquid nitrogen, the gas on the surface of the liquid nitrogen evaporates to form an upward airflow, so that the hydrogel droplets float and wander on the surface of the liquid nitrogen and quickly rotate into spherical shape; when the temperature of the small balls continues to decrease, the evaporation amount of the liquid nitrogen decreases, and the formed hydrogel microspheres gradually sink to the bottom of the collector containing the liquid nitrogen.

[0012] Further, the hydrogel solution prepared in step one is a drug-loaded hydrogel, or a first hydrogel and a second hydrogel.

[0013] Further preferably, when the hydrogel solution is a drug-loaded hydrogel, a single-channel dropping method is adopted.

[0014] Further preferably, when the hydrogel solution is a first hydrogel and a second hydrogel, a double-channel mixed dropping method is adopted.

[0015] Further, the liquid outlet pipe of the dropping device of the hydrogel solution is provided with a heat preservation device outside.

[0016] Further preferably, the liquid outlet end of the liquid outlet pipe is 3-30 cm away from the surface of the liquid nitrogen.

[0017] Further, the solidification is photocuring or coagulation bath solidification.

[0018] Further, the particle size of the gel microspheres is 50 μm-1000 μm.

[0019] The second aspect of the present application provides an injectable drug gel microsphere prepared by the above preparation method.

[0020] The present application adopts the above technical scheme, and has the following technical effects compared with the prior art:

[0021] The present application directly uses liquid nitrogen as the collecting liquid. Due to the temperature difference between the hydrogel droplets and the liquid nitrogen, the gas on the surface of the liquid nitrogen evaporates to form an upward gas flow, so that the hydrogel droplets float and walk on the liquid surface of the liquid nitrogen and quickly rotate into spherical shape. When the temperature of the small balls continuously decreases, the evaporation amount of the liquid nitrogen decreases, and the formed gel microspheres gradually sink to the bottom of the collecting tank to obtain the gel microspheres after quick freezing. The present application avoids the use of solidification liquid in the traditional method and limits the size and density of the gel microspheres. The gel microspheres prepared by the method of the present application have uniform particle size, smooth surface, adjustable and controllable particle size in the range of 50 μm-500 μm, narrow particle size distribution, and small particle size fluctuation range. BRIEF DESCRIPTION OF DRAWINGS

[0022] Figure 1 FIG. 1 is a schematic diagram of a gel microsphere preparation device in Example 1 of the present application;

[0023] Figure 2 FIG. 2 is a schematic diagram of a gel microsphere preparation device in Example 2 of the present application. DETAILED DESCRIPTION

[0024] The present application will be further described below in conjunction with the drawings and specific examples, but is not limited by the examples and the features in the examples in the present application can be combined with each other without conflict. EXAMPLE

[0025] The present embodiment provides a preparation method of gel microspheres, comprising the following steps:

[0026] Step one, prepare a hydrogel liquid for standby use;

[0027] Step two, directly drop the hydrogel liquid prepared in step one into liquid nitrogen in the form of small droplets for collection. Due to the temperature difference between the hydrogel droplets and the liquid nitrogen, the gas on the surface of the liquid nitrogen evaporates to form an upward gas flow, so that the hydrogel droplets float and walk on the liquid surface of the liquid nitrogen and quickly rotate into spherical shape. When the temperature of the small balls continuously decreases, the evaporation amount of the liquid nitrogen decreases, and the formed hydrogel microspheres gradually sink to the bottom of the collector containing the liquid nitrogen to obtain the hydrogel microspheres after quick freezing;

[0028] Step three, collect the hydrogel microspheres obtained in step two, solidify, sterilize and store.

[0029] The hydrogel liquid prepared in the present embodiment is a drug-loaded hydrogel, a single-channel dropping method is used, and a gel microsphere preparation device as shown in FIG. 1 is used. Figure 1 The gel microsphere preparation device described above (1) is used to prepare the gel microspheres.

[0030] Figure 1 ​The device includes a tubing 1, an infusion pump 2, a high-voltage electrostatic generator 3, a wetting electrode 4, a low-temperature electrode 5, an ultrasonic transducer 6, a collection tank 7, and a heat preservation device 9. The tubing 1 contains a drug-loaded hydrogel. A nozzle 8, with an inner diameter of 100-600 μm, is located at the bottom of the tubing 1 and communicates with the inner cavity. A heat preservation device 9 is installed on the outside of the nozzle 8 to prevent the drug-loaded hydrogel inside the nozzle from becoming too cold. An annular, thin-film wetting electrode 4 is located at the bottom of the inner cavity of the tubing 1. The tube 1 is connected to the negative terminal of the high-voltage electrostatic generator 3; the upper part of the tube body 1 has a liquid inlet, which is connected to the output end of the syringe pump 2. The input end of the syringe pump 2 is connected to the sol storage device. An ultrasonic transducer 6 is installed in the sol storage device, and its ultrasonic probe is located in the sol liquid; the collection tank 7 contains liquid nitrogen, and the tip of the nozzle 8 is 3-30 cm away from the liquid nitrogen surface in the collection tank 7; a ring-shaped thin-film low-temperature electrode 5 is installed in the upper part of the inner cavity of the collection tank 7, and the low-temperature electrode 5 is connected to the positive terminal of the high-voltage electrostatic generator 3.

[0031] The aforementioned tube 1 also has a lifting and adjusting device ( Figure 1 (Not shown in the image).

[0032] In this invention, the cryogenic electrode 5 is located above the liquid nitrogen surface in the collection tank 7.

[0033] As a preferred example, the output voltage of the high-voltage electrostatic generator 3 is 3000-8000 volts and the frequency is 40-100 Hz.

[0034] Adopting such Figure 1 The apparatus shown is used to prepare drug-loaded hydrogel microspheres, with rifapentine powder as the loaded drug. The specific steps are as follows:

[0035] Step 1: Add liquid nitrogen to the collection tank 7 so that the liquid nitrogen level is lower than the level of the cryogenic electrode 5. Adjust the lifting adjustment device of the tube body 1 so that the tip of the nozzle 8 is 3-30cm away from the liquid nitrogen level in the collection tank 7 and the tip of the nozzle 8 is above the cryogenic electrode 5.

[0036] Step 2: Activate the ultrasonic transducer 6. Under the action of ultrasound, the solid drug powder (rifapentine powder) is uniformly dispersed into the sol solution to form a drug-loaded sol solution; wherein, the particle size of rifapentine powder can be reduced to 2-10μm.

[0037] Step 3: Start the syringe pump 2 and the high-voltage electrostatic generator 3. The syringe pump 2 outputs a drug-loaded sol solution at a flow rate of 80 ml / h, and the high-voltage electrostatic generator 3 outputs a voltage of 6000 volts. The drug-loaded sol solution enters the tube 1, and the drug-loaded sol solution in contact with the wetting electrode 4 carries a negative charge. The cryogenic electrode 5 is connected to the positive terminal of the high-voltage electrostatic generator 3. Under the action of the high-voltage electrostatic field, the tiny droplets of drug-loaded sol solution continuously generated by the nozzle 8 fall into the liquid nitrogen. The inner diameter of the nozzle 8 is 300 μm.

[0038] Due to the temperature difference between the drug-loaded gel droplets and liquid nitrogen, the gas on the surface of the liquid nitrogen evaporates, forming an upward airflow, allowing the drug-loaded gel droplets to float and wander on the surface of the liquid nitrogen and quickly rotate into a spherical shape; as the temperature of the wandering small balls continues to decrease, the evaporation of liquid nitrogen decreases, and the formed gel microspheres gradually sink to the bottom of the collection tank 7, obtaining the rapidly frozen gel microspheres;

[0039] Step four, collect the gel microspheres, solidify, sterilize and store.

[0040] The particle size of the gel microspheres is observed under an optical microscope to be 100-300 μm. Embodiment

[0041] The embodiment provides a preparation method of gel microspheres, comprising the following steps:

[0042] Step one, prepare a hydrogel solution for standby;

[0043] Step two, drop the hydrogel solution prepared in step one into liquid nitrogen in the form of small droplets for collection; due to the temperature difference between the hydrogel droplets and liquid nitrogen, the gas on the surface of the liquid nitrogen evaporates, forming an upward airflow, allowing the hydrogel droplets to float and wander on the surface of the liquid nitrogen and quickly rotate into a spherical shape; as the temperature of the wandering small balls continues to decrease, the evaporation of liquid nitrogen decreases, and the formed hydrogel microspheres gradually sink to the bottom of the collector containing liquid nitrogen, obtaining the rapidly frozen hydrogel microspheres;

[0044] Step three, collect the hydrogel microspheres obtained in step two, solidify, sterilize and store.

[0045] The hydrogel solution prepared in the embodiment is a first hydrogel and a second hydrogel, wherein the first hydrogel is a drug-loaded hydrogel, and the second hydrogel contains a pore-forming agent and a coagulant; a double-channel dropping method is adopted, and a gel microsphere preparation device as shown in Figure 2 is adopted.

[0046] The above gel microsphere preparation device comprises a double-liquid dispensing mechanism 10, and the two storage cavities of the double-liquid dispensing mechanism 10 are connected with a first hydrogel storage tank 11 and a second hydrogel storage tank 14 through a first liquid pump 12 and a second liquid pump 13 respectively; a heat preservation device 9 is arranged outside the liquid outlet pipe at the bottom of the double-liquid dispensing mechanism 10 to prevent the temperature of the hydrogel in the liquid outlet pipe from being too low; wherein the double-liquid dispensing mechanism 10 can adopt a double-liquid dispensing machine provided in patent CN207605948U; liquid nitrogen is contained in a collection tank 7, and the tip of the liquid outlet pipe is 3-30 cm away from the liquid surface of the liquid nitrogen in the collection tank 7.

[0047] A gel microsphere preparation device as shown in Figure 2 is adopted to prepare drug-loaded hydrogel microspheres, and the specific steps are as follows:

[0048] Step one, add liquid nitrogen into the collecting tank 7, and make the tip of the outlet tube 3-30 cm away from the liquid nitrogen surface in the collecting tank 7;

[0049] Step two, before starting the first liquid pump 12, the second liquid pump 13 and the double-liquid dispensing mechanism 10, adjust the elements in the double-liquid dispensing mechanism 10 that control the outlet speed of the two gels, then start the first liquid pump 12, the second liquid pump 13 and the double-liquid dispensing mechanism 10, the first hydrogel and the second hydrogel are mixed and then stably discharged from the outlet tube, and the generated gel droplets fall into the liquid nitrogen;

[0050] Due to the temperature difference between the gel droplets and the liquid nitrogen, the gas on the surface of the liquid nitrogen evaporates, forming an upward airflow, which makes the gel droplets float and wander on the surface of the liquid nitrogen, and quickly rotate into spherical shape; when the temperature of the small ball decreases, the evaporation of the liquid nitrogen decreases, and the gel microspheres formed gradually sink to the bottom of the collecting tank 7, and the gel microspheres after quick freezing are obtained; among them, some substances with density greater than the hydrogel (such as pore-forming agents, larger particle drugs) will concentrate on the outer layer of the hydrogel microspheres under the centrifugal force of the high-speed rotation of the gel microspheres, forming a multi-layer structure of the hydrogel microspheres;

[0051] Step three, collect the gel microspheres, solidify, sterilize and store.

[0052] The above only describes the preferred embodiments of the present application, and does not limit the implementation and protection scope of the present application. For those skilled in the art, it should be realized that any equivalent replacement and obvious changes made according to the content of the present application and the drawings should be included in the protection scope of the present application.

Claims

1. A method for preparing gel microspheres, characterized by, The method comprises the following steps: Step 1: preparing a hydrogel solution; Step 2: directly dropping the hydrogel solution prepared in step 1 into liquid nitrogen in the form of microdroplets to collect hydrogel microspheres after rapid freezing; due to the temperature difference between the hydrogel droplets and the liquid nitrogen, the gas on the surface of the liquid nitrogen evaporates to form an upward airflow, so that the hydrogel droplets float and wander on the liquid nitrogen surface and quickly rotate into spherical shape; when the temperature of the small balls continues to decrease, the evaporation of the liquid nitrogen decreases, and the formed hydrogel microspheres gradually sink to the bottom of the collector containing the liquid nitrogen; Step 3: collecting the hydrogel microspheres obtained in step 2, solidifying, sterilizing and storing; the particle size of the gel microspheres is 50-1000 μm.

2. The method of claim 1, wherein the gel microspheres are prepared by the process of: The hydrogel solution prepared in step 1 is a drug-loaded hydrogel, or a first hydrogel and a second hydrogel.

3. The method of claim 2, wherein the gel microspheres are prepared by the process of: When the hydrogel solution is a drug-loaded hydrogel, a single-channel dropping method is used.

4. The method of claim 2, wherein the gel microspheres are prepared by the process of: When the hydrogel solution is a first hydrogel and a second hydrogel, a double-channel mixed dropping method is used.

5. The method for preparing gel microspheres according to claim 1, characterized in that, The liquid outlet pipe of the dropping device is provided with a heat preservation device outside.

6. The method of claim 5, wherein the gel microspheres are prepared by the process of: The liquid outlet end of the liquid outlet pipe is 3-30 cm away from the liquid nitrogen surface.

7. The method of claim 1, wherein the gel microspheres are prepared by a process comprising: The solidification is photocuring or coagulation bath solidification.

8. An injectable drug gel microsphere prepared by the method according to any one of claims 1-7.

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