A kind of nano-mesoporous embolization particle and its preparation method

Abstract

The present invention provides a nano-mesoporous embolization particle and a preparation method thereof. The preparation method includes: preparing a gelatin solution; subjecting the gelatin solution to ultrasonic foaming for a first preset time under a first ultrasonic power to obtain gelatin foam; dropping a crosslinking agent into the gelatin foam and performing a crosslinking reaction for a second preset time under a second ultrasonic power to obtain an intermediate product; quenching the intermediate product with liquid nitrogen to instantaneously solidify the intermediate product, and subjecting the solidified intermediate product to wet material crushing, washing, and freeze-drying to obtain the embolization particle. Through the nano-mesoporous embolization particle and the preparation method thereof provided by the present invention, embolization particles with nano-mesopores and a uniform mesopore pore size distribution can be obtained, and the properties such as the suspension property, catheter passing property, and water absorption rate of the embolization particles can be improved.

Description

Technical Field

[0001] The present invention relates to the field of biomedical technologies, and particularly to a nano-mesoporous embolization particle and a preparation method thereof. Background Art

[0002] With the increasing maturity of interventional therapies, embolization granules are commonly used clinically to block the blood supply of tumor tissues. However, the existing embolization granules on the market are prone to catheter blockage and poor particle strength due to poor suspension performance during actual use.

[0003] In addition, the common preparation methods of current embolization granules are mostly to mechanically stir and foam and then place them in a freezer for freezing and curing. The granules prepared in this way will have uneven internal foaming due to inconsistent stirring shear forces. At the same time, due to fluctuations in the temperature control of the freezer, defoaming occurs in some products, and conventional freezing and curing requires a long time to complete the shaping of the product, greatly limiting the production efficiency of traditional sponge particles. Summary of the Invention

[0004] The present invention provides a nano-mesoporous embolization particle and a preparation method thereof. Through the nano-mesoporous embolization particle and the preparation method provided by the present invention, embolization particles with nano-mesopores and uniform mesopore size distributions can be obtained, improving the performance of embolization particles such as suspension, catheter passing ability, and water absorption rate, and at the same time improving production efficiency.

[0005] To solve the above technical problems, an embodiment of the present invention provides a preparation method of a nano-mesoporous embolization particle, which at least includes the following steps:

[0006] Prepare a gelatin solution;

[0007] Ultrasonically foam the gelatin solution at a first ultrasonic power for a first preset time to obtain gelatin foam;

[0008] Drop a crosslinking agent into the gelatin foam and carry out a crosslinking reaction at a second ultrasonic power for a second preset time to obtain an intermediate product;

[0009] Quench the intermediate product with liquid nitrogen to instantaneously solidify the intermediate product, and wet-mill, wash, and freeze-dry the solidified intermediate product to obtain embolization particles.

[0010] In an embodiment of the present invention, the first ultrasonic power is 100 W - 200 W, and the first preset time is 8 minutes - 15 minutes.

[0011] In an embodiment of the present invention, the second ultrasonic power is 30 W - 50 W, and the second preset time is 15 minutes - 20 minutes.

[0012] In one embodiment of the present invention, the crosslinking agent includes one or a combination of formaldehyde, glutaraldehyde or n-butyraldehyde.

[0013] In one embodiment of the present invention, the liquid nitrogen quenching time is 4 minutes to 8 minutes.

[0014] In one embodiment of the present invention, when preparing the gelatin solution, gelatin is added to the solvent, and after sufficient swelling, it is stirred and dissolved at the first temperature to obtain the gelatin solution at the first temperature.

[0015] In one embodiment of the present invention, the solvent is water for injection, and the mass ratio of the gelatin to the solvent is 1:(8 - 20).

[0016] In one embodiment of the present invention, the first temperature is 45°C to 55°C, and the ultrasonic foaming and the crosslinking reaction are carried out at the first temperature.

[0017] In one embodiment of the present invention, the mass ratio of the crosslinking agent to the gelatin is 1:5 to 20.

[0018] One embodiment of the present invention further provides a nano-mesoporous embolization particle, which is obtained by the above-mentioned preparation method. The embolization particle is a porous body with an irregular shape obtained by crosslinking gelatin molecules and a crosslinking agent; wherein, the pore diameter of the mesopores in the embolization particle is less than 200 nm.

[0019] In one embodiment of the present invention, the most probable pore diameter of the embolization particle is in the range of 50 nm to 100 nm.

[0020] In one embodiment of the present invention, the bulk density of the embolization particle is 25 mg / ml to 29 mg / ml.

[0021] In one embodiment of the present invention, the water absorption rate of the embolization particle is greater than 2000%.

[0022] In summary, the present invention provides a nano-porous embolization particle and a preparation method thereof, which can obtain embolization particles with nano-pores and a uniform mesopore size distribution. By controlling the pore size of the nano-pores, the embolization particles have a high specific surface area and uniform nano-micropores inside, which can accommodate more water molecules, resulting in good water absorption performance and embolization effect. At the same time, due to its good swelling characteristics, it can be suspended in the contrast agent for a long time, so as to better pass through the catheter during use, which is more conducive to the clinical use of doctors and realizes embolization treatment in the lesion area. The freezing and shaping of gelatin sponge is efficiently achieved by liquid nitrogen quenching, which improves the production efficiency and reduces the defoaming phenomenon in the preparation process of traditional embolization agents at the same time, making the sponge have a lower bulk density, and endowing the product with good industrial application prospects and medical performance. This application can obtain embolization particles with excellent suspension, catheter passing ability and water absorption rate, etc., improving the treatment effect. At the same time, the embolization particles have good biocompatibility, can be degraded and the blood vessels can be recanalized, enabling repeated embolization treatments. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following will briefly introduce the drawings required for the description of the embodiments. Obviously, the drawings in the following description are only some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can be obtained based on these drawings.

[0024] Figure 1 Scanning electron microscope image of the embolization particles obtained in Example 1.

[0025] Figure 2 Scanning electron microscope image of the embolization particles obtained in Example 2.

[0026] Figure 3 Scanning electron microscope image of the embolization particles obtained in Comparative Example 1.

[0027] Figure 4 Scanning electron microscope image of the embolization particles obtained in Comparative Example 2.

[0028] Figure 5 Scanning electron microscope image of the embolization particles provided in Comparative Example 3.

[0029] Figure 6 Schematic diagram of the pore size distribution of the embolization particles obtained in Example 1.

[0030] Figure 7 Schematic diagram of the pore size distribution of the embolization particles obtained in Example 2.

[0031] Figure 8 Schematic diagram of the pore size distribution of the embolization particles obtained in Comparative Example 1.

[0032] Figure 9 Schematic diagram of the pore size distribution of the embolization particles obtained in Comparative Example 2.

[0033] Figure 10 Schematic diagram of the pore size distribution of the embolization particles provided in Comparative Example 3. Specific embodiments

[0034] The following specific examples illustrate the embodiments of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments. Various details in this specification can also be modified or changed based on different viewpoints and applications without departing from the spirit of the present invention.

[0035] It should be understood that the present invention can be implemented in different forms and should not be construed as limited to the embodiments presented herein. On the contrary, providing these embodiments will make the disclosure thorough and complete, and will fully convey the scope of the present invention to those skilled in the art.

[0036] The technical solutions of the present invention will be further described in detail below in conjunction with the embodiments. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts belong to the scope of protection of the present invention.

[0037] The present invention provides a method for preparing nano-mesoporous embolization particles. The preparation method at least includes: preparing a gelatin solution; performing ultrasonic foaming on the gelatin solution at a first ultrasonic power for a first preset time to obtain gelatin foam; dropping a crosslinking agent into the gelatin foam and performing a crosslinking reaction at a second ultrasonic power for a second preset time to obtain an intermediate product; quenching the intermediate product with liquid nitrogen to instantaneously solidify the intermediate product, and performing wet material pulverization, cleaning, and freeze-drying on the solidified intermediate product to obtain embolization particles.

[0038] In an embodiment of the present invention, when preparing the gelatin solution, the solvent is, for example, water for injection, and the mass ratio of gelatin to the solvent is, for example, 1:(8 - 20). Specifically, gelatin is added to water for injection. After sufficient swelling, it is stirred at a speed of 50 r / min (revolutions per minute) - 60 r / min for 0.5 h (hours) - 1.5 h at the first temperature for dissolution, and then the bubbles are removed by standing to prepare a gelatin solution with the first temperature, and the first temperature is, for example, 45°C - 55°C. By selecting gelatin as the base material, the obtained embolization particles are biodegradable, can be gradually degraded under the action of enzymes in the body, and the recanalization of blood vessels after degradation can effectively reduce tissue necrosis. They have good biocompatibility and will not cause serious inflammatory reactions, so multiple repeated embolization treatments can be carried out.

[0039] In an embodiment of the present invention, the gelatin solution is foamed. Specifically, the gelatin solution is, for example, placed in an ultrasonic device such as an ultrasonic crusher, and, for example, the ultrasonic probe is placed at one-half to two-thirds of the gelatin solution, and ultrasonic foaming is carried out at the first ultrasonic power for the first preset time to obtain gelatin foam. Among them, the first ultrasonic power is, for example, 100 W (watts) - 200 W, and the first preset time is, for example, 8 min (minutes) - 15 min. Through ultrasonic foaming, uniform nano-foams can be formed. By adjusting the first ultrasonic power and the first preset time of ultrasonic foaming, the density and pore size of the nano-foams can be controlled. By controlling the position of the ultrasonic probe in the gelatin solution, the complete foaming of the gelatin solution can be ensured, and the utilization rate of raw materials can be improved.

[0040] In one embodiment of the present invention, after obtaining the gelatin foam, a cross-linking agent is dropped into the gelatin foam for cross-linking reaction. Among them, after obtaining the gelatin foam at the end of the first preset time, it is necessary to immediately and rapidly drop the cross-linking agent into the gelatin foam to reduce the defoaming of the gelatin foam. And the cross-linking reaction is carried out, for example, under ultrasonic conditions. For example, after foaming in an ultrasonic device such as an ultrasonic crusher, the ultrasonic is turned off, and immediately after dropping the cross-linking agent, the power of the ultrasonic device is adjusted to the second ultrasonic power, and the cross-linking reaction is carried out for the second preset time under the second ultrasonic power to obtain an intermediate product. In this embodiment, the second ultrasonic power is, for example, 30W - 50W, the second preset time is, for example, 15min - 20min, and the cross-linking agent includes, for example, one or several combinations of aldehyde cross-linking agents such as formaldehyde, glutaraldehyde or n-butyraldehyde. Among them, when the cross-linking agent is selected as formaldehyde, for example, formaldehyde aqueous solution is used for cross-linking, and the mass fraction of the formaldehyde aqueous solution is, for example, 3wt% - 6wt%. Specifically, for example, a 37% formaldehyde solution is mixed with injection water to obtain a formaldehyde aqueous solution with a preset mass fraction. Among them, the mass ratio of the cross-linking agent to gelatin is, for example, 1:5 - 20. In this embodiment, both the foaming and cross-linking steps are completed at the first temperature. Carrying out cross-linking under ultrasonic conditions can ensure the uniformity of cross-linking and prevent defoaming at the same time. By controlling the second ultrasonic power and the second preset time, it is ensured that the pore size distribution of the foam in the intermediate product is uniform.

[0041] In one embodiment of the present invention, after obtaining the intermediate product, that is, after turning off the ultrasonic device, the intermediate product is immediately collected and transferred into a low-temperature resistant container, such as a stainless steel vessel, a low-temperature resistant plastic vessel or a low-temperature resistant glass vessel, etc., and sealed. After sealing, the low-temperature resistant container is placed in a Dewar cup for fixation, and the Dewar cup is placed in a liquid nitrogen tank for quenching. The quenching time is, for example, 4min - 8min to quench and solidify the intermediate product. By quenching and solidifying the intermediate product with liquid nitrogen, the time required for freezing and solidification in the traditional process is greatly reduced, the production efficiency is improved, and the defoaming situation of the intermediate product is also reduced, obtaining an intermediate product with a nano-porous structure having a uniform pore size.

[0042] In one embodiment of the present invention, after the quenched and solidified intermediate product is thawed in normal-temperature injection water, the sample is cut into small pieces, for example, wet material pulverization is carried out using a pulverizer. After wet material pulverization, it is washed multiple times with injection water. After washing, the product is taken out, an appropriate amount of water is added, and it is placed in a -40°C refrigerator for pre-freezing. When the refrigerator temperature drops to -40°C, the completely frozen sample is placed in a freeze dryer, the cabin of the freeze dryer is evacuated to vacuum, and freeze drying is carried out until the sample is completely dry to obtain embolization particles. Through freeze drying, the stability of the embolization particles can be ensured, and high-quality embolization particles can be obtained.

[0043] The present invention also provides a nano-mesoporous embolization particle. The embolization particle is obtained by the above method, and is a porous embolization particle with an irregular shape obtained by crosslinking gelatin molecules with a crosslinking agent. Among them, the pore diameter of the mesopores in the embolization particle is, for example, less than 200 nm. In this embodiment, by adjusting the ultrasonic conditions during the foaming and crosslinking processes, the most probable pore diameter of the embolization particles obtained in different embodiments is, for example, in the range of 50 nm to 100 nm. The most probable pore diameter refers to the region in the porous material where the pore sizes of the measured material are most concentrated. By controlling the pore diameter of the embolization particle, the dispersibility of the embolization particle is improved, thereby improving the suspension property of the embolization particle. In this application, the bulk density of the embolization particle is, for example, 25 mg / ml to 29 mg / ml, and the water absorption rate of the embolization particle is, for example, greater than 2000%, thereby improving the catheter passing property and water absorption rate of the embolization particle, etc. That is, this application can obtain embolization particles with excellent suspension property, catheter passing property, water absorption rate and other properties, improving the treatment effect.

[0044] Hereinafter, the present invention will be more specifically explained by referring to examples, which should not be construed as restrictive. Within the scope consistent with the gist of the present invention, appropriate modifications can be made, and all of them fall within the technical scope of the present invention.

[0045] Example 1

[0046] Add 45 g of gelatin to 455 g of water for injection. After sufficient swelling, stir and dissolve at 50 °C at a speed of 50 r / min for 1 h, and let it stand to remove air bubbles to prepare a gelatin solution at the first temperature.

[0047] Add 19 ml of 37 wt% formaldehyde to 191 ml of water for injection, fully dissolve and stir evenly to prepare an aqueous formaldehyde solution.

[0048] Open the chamber of the ultrasonic crusher, place the gelatin solution in the ultrasonic crusher, immerse the ultrasonic probe at two-thirds of the gelatin solution, maintain the first temperature, adjust the equipment power to 200 W, close the chamber, turn on the equipment to start ultrasonic treatment, and turn off the ultrasonic probe after 15 min to obtain ultrasonic foamed gelatin foam.

[0049] Open the chamber of the ultrasonic crusher, immediately add the above-prepared aqueous formaldehyde solution dropwise to the gelatin foam rapidly, maintain the first temperature, adjust the power of the ultrasonic probe to 50 W, close the chamber, turn on the equipment to start ultrasonic treatment, and turn off the ultrasonic probe after 20 min to obtain an intermediate product of the crosslinking reaction.

[0050] Immediately collect the intermediate product in a stainless steel container and seal it. After sealing, fix it in a Dewar cup, place the Dewar cup in a liquid nitrogen tank for quenching, and take it out after reacting for 8 min.

[0051] After thawing the intermediate product quenched with liquid nitrogen in normal temperature injection water, cut the sample into small pieces, for example, use a pulverizer to crush the wet material. After wet material crushing, wash it several times with injection water. After washing, take out the product, add an appropriate amount of water, and then place it in a -40 °C refrigerator for pre-freezing. When the refrigerator temperature drops to -40 °C, put the completely frozen sample into a freeze dryer, evacuate the freeze dryer cabin to vacuum, and freeze-dry until the sample is completely dry to obtain embolization particles.

[0052] Example 2

[0053] Add 45 g of gelatin to 455 g of injection water. After sufficient swelling, stir and dissolve at 50 °C at a speed of 50 r / min for 1 h, and let it stand to remove air bubbles to prepare a gelatin solution at the first temperature.

[0054] Add 19 ml of 37 wt% formaldehyde to 191 ml of injection water, fully dissolve and stir evenly to prepare an aqueous formaldehyde solution.

[0055] Open the cabin of the ultrasonic crusher, place the gelatin solution in the ultrasonic crusher, immerse the ultrasonic probe at two-thirds of the gelatin solution, maintain the first temperature, adjust the equipment power to 100 W, close the cabin, turn on the equipment to start ultrasonic treatment, and turn off the ultrasonic probe after 8 min to obtain ultrasonic foamed gelatin foam.

[0056] Open the cabin of the ultrasonic crusher, immediately quickly drop the above-prepared aqueous formaldehyde solution into the gelatin foam, maintain the first temperature, adjust the power of the ultrasonic probe to 30 W, close the cabin, turn on the equipment to start ultrasonic treatment, and turn off the ultrasonic probe after 15 min to obtain an intermediate product of cross-linking reaction.

[0057] Immediately collect the intermediate product with a stainless steel container and seal it. After sealing, fix it in a Dewar cup, place the Dewar cup in a liquid nitrogen tank for quenching, and take it out after reacting for 4 min.

[0058] After thawing the intermediate product quenched with liquid nitrogen in normal temperature injection water, cut the sample into small pieces, for example, use a pulverizer to crush the wet material. After wet material crushing, wash it several times with injection water. After washing, take out the product, add an appropriate amount of water, and then place it in a -40 °C refrigerator for pre-freezing. When the refrigerator temperature drops to -40 °C, put the completely frozen sample into a freeze dryer, evacuate the freeze dryer cabin to vacuum, and freeze-dry until the sample is completely dry to obtain embolization particles.

[0059] Comparative Example 1

[0060] Add 45 g of gelatin to 455 g of injection water. After sufficient swelling, stir and dissolve at 50 °C at a speed of 50 r / min for 1 h, and let it stand to remove air bubbles to prepare a gelatin solution at the first temperature.

[0061] Add 19 ml of 37 wt% formaldehyde to 191 ml of water for injection, dissolve it fully and stir evenly to prepare an aqueous formaldehyde solution.

[0062] Transfer the gelatin solution to a reaction kettle, maintain the first temperature, stir and foam for 8 min at 700 r / min to obtain gelatin foam with stirred foaming.

[0063] Immediately add dropwise the above-prepared aqueous formaldehyde solution to the gelatin foam rapidly, maintain stirring and the first temperature until the cross-linking reaction ends to obtain an intermediate product of the cross-linking reaction.

[0064] Immediately collect the intermediate product using a stainless-steel container and seal it. After sealing, fix it in a Dewar cup, place the Dewar cup in a liquid nitrogen tank for quenching, and take it out after reacting for 8 min.

[0065] After thawing the intermediate product quenched with liquid nitrogen in water for injection at room temperature, cut the sample into small pieces, for example, use a pulverizer to crush the wet material. After wet material crushing, wash it several times with water for injection. After washing, take out the product, add an appropriate amount of water and place it in a -40 °C refrigerator for pre-freezing. When the refrigerator cools down to -40 °C, put the completely frozen sample into a freeze dryer, evacuate the freeze dryer chamber to vacuum, and freeze-dry until the sample is completely dry to obtain embolization particles.

[0066] Comparative Example 2

[0067] Add 45 g of gelatin to 455 g of water for injection, fully swell it, stir and dissolve it at 50 °C at a speed of 50 r / min for 1 h, and let it stand to remove air bubbles to prepare a gelatin solution at the first temperature.

[0068] Add 19 ml of 37 wt% formaldehyde to 191 ml of water for injection, dissolve it fully and stir evenly to prepare an aqueous formaldehyde solution.

[0069] Open the chamber of the ultrasonic crusher, place the gelatin solution in the ultrasonic crusher, immerse the ultrasonic probe at two-thirds of the gelatin solution, maintain the first temperature, adjust the equipment power to 200 W, close the chamber, turn on the equipment to start ultrasonic treatment, and turn off the ultrasonic probe after 15 min to obtain gelatin foam with ultrasonic foaming.

[0070] Open the chamber of the ultrasonic crusher, immediately add dropwise the above-prepared aqueous formaldehyde solution to the gelatin foam rapidly, maintain the first temperature, adjust the power of the ultrasonic probe to 50 W, close the chamber, turn on the equipment to start ultrasonic treatment, and turn off the ultrasonic probe after 20 min to obtain an intermediate product of the cross-linking reaction.

[0071] Immediately collect the intermediate product and transfer it to a -40 °C freezer for freezing and solidifying, and take it out after reacting for 96 h.

[0072] After thawing the frozen and solidified intermediate product in normal temperature injection water, cut the sample into small pieces. For example, use a pulverizer to crush the wet material. After wet material crushing, wash it multiple times with injection water. After washing, take out the product, add an appropriate amount of water, and then place it in a -40°C refrigerator for pre-freezing. When the temperature of the refrigerator drops to -40°C, put the completely frozen sample into a freeze dryer, evacuate the freeze dryer chamber to vacuum, and freeze-dry until the sample is completely dry to obtain embolization particles.

[0073] Comparative Example 3

[0074] The material used in Comparative Example 3 is the gelatin sponge particle embolization agent sold by Hangzhou Alikon Medical Technology Co., Ltd., batch number: 30132428; specification: Gelfoam-150.

[0075] Among them, the preparation method of the product provided by Comparative Example 3 includes: preparing a gelatin aqueous solution, transferring the gelatin aqueous solution to a reaction kettle for foaming, adding a formaldehyde solution for cross-linking reaction, transferring the reactant to a refrigerator for freezing and solidifying, washing the frozen and solidified product, and freeze-drying the washed product to obtain a comparative product. Compared with Example 1, the foaming and solidifying processes in Comparative Example 1 are different, and the rest of the production processes can be repeated with Example 1.

[0076] In an embodiment of the present invention, the embolization particles in Examples 1-2 and Comparative Examples 1-3 are tested by a Scanning Electron Microscope (SEM) to observe the pore size and distribution of the embolization particles. The test results are as Figures 1 to 5 shown.

[0077] In an embodiment of the present invention, the pore size distribution of the embolization particles in Examples 1-2 and Comparative Examples 1-3 is tested, and the pore size distribution is tested by, for example, a Micromeritics mercury porosimeter (model: AutoPore IV 9500). Specifically, take 2 g samples of Example 1, Example 2, Comparative Example 1, Comparative Example 2, and Comparative Example 3 and place them in an oven to dry for 2 h to remove moisture. Then seal the samples in an expander. The expander is, for example, mercury (Hg). Then load the expander into the low-pressure station and the high-pressure station in sequence for pore size analysis. The test results are as Figures 6 to 10 shown.

[0078] In an embodiment of the present invention, for the suspension test, 100 mg samples of Example 1, Example 2, Comparative Example 1, Comparative Example 2, and Comparative Example 3 were weighed separately and transferred to a 20 ml syringe. 10 ml of a contrast agent, such as iohexol, was aspirated and added to the embolization particles in the 20 ml syringe through a three-way valve. The air was expelled from the syringe, and the syringe was repeatedly inverted until a stable particle suspension was observed. Timing was started until the suspension disappeared. Among them, when the volume of the syringe containing the embolization particles was less than 2 / 3, it was considered that the suspension disappeared, and the corresponding disappearance time was recorded. The test results are shown in Table 1.

[0079] Table 1. Test results of the suspension performance of the embolization particles in Examples 1-2 and Comparative Examples 1-3

[0080]

[0081] In an embodiment of the present invention, the water absorption test includes: weighing gelatin sponge particles with a weight of W1 and putting them into a test tube. Then, the total weight was weighed as W2, and 10 ml of purified water was added. After complete swelling, the free water was removed, and the weight of the swollen sample was weighed as W3. The water absorption of the sample was calculated according to the following formula.

[0082] Water absorption = (W3 - W2) / W1 × 100%.

[0083] Table 2. Water absorption of the embolization particles in Examples 1-2 and Comparative Examples 1-3

[0084]

[0085] In an embodiment of the present invention, the bulk density test includes: weighing a sample with a weight of W and putting it into a graduated cylinder, reading the volume V of the sample, and calculating the bulk density of the sample according to the following formula.

[0086] ρb = W / V;

[0087] Among them, ρb is the bulk density; W is the mass; V is the volume.

[0088] Table 3. Bulk density of the embolization particles in Examples 1-2 and Comparative Examples 1-3

[0089]

[0090] Please refer to Figures 1 to 5 As shown, comparing Examples 1-2 and Examples 1-3, as Figure 1 shown, the pore diameters of the nano-mesopores of the embolization particles obtained in Example 1 are mostly distributed in the range of 50 nm to 60 nm, and the morphology of the nano-mesopores is close to circular with clear boundaries. As Figure 2As shown, most of the pore diameters of the nano-mesopores of the embolization particles obtained in Example 2 are distributed in the range of 70 nm to 80 nm, and the morphology of the nano-mesopores is close to circular, with clear boundaries and dense distribution of nano-mesopores. As Figure 3 shown, most of the pore diameters of the mesopores of the embolization particles obtained in Comparative Example 1 are distributed in the range of 700 nm to 900 nm, and the shapes of the mesopores are irregular and the boundaries are not clear. As Figure 4 shown, the maximum pore diameter of the mesopores of the embolization particles obtained in Comparative Example 2 is about 1 μm, and small pores of about 100 nm are distributed around the large pores. The pore diameter distribution is seriously uneven, and the shapes of the mesopores are irregular and the boundaries are not clear. As Figure 5 shown, the pore diameters of the mesopores of the embolization particles obtained in Comparative Example 3 range from about 100 nm to about 800 nm. The pore diameter distribution is seriously uneven, and the shapes of the mesopores are irregular and the boundaries are not clear. That is, the embolization particles obtained by the preparation method of the present application include a plurality of nano-mesopores, and the pore diameters of the nano-mesopores are small, and the pore diameter distribution is dense. The pore diameter of each mesopore is approximately equal, and the embolization particles have uniformity in pore diameter. The morphology of the nano-mesopores is close to circular and the boundaries are clear. The pore diameters of the embolization particles in Comparative Examples 1-3 are large, and the pore diameter distribution is uneven, and the pore diameter morphology is poor. Therefore, the embolization particles obtained by the preparation method of the present application have a high specific surface area and uniform nano-micropores, can accommodate more water molecules to enter, and have good water absorption performance and embolization effect.

[0091] Please refer to Figures 6 to 10 shown. Comparing Comparative Examples 1-2, it can be seen that by controlling the power and time of ultrasound during the foaming and crosslinking of the gelatin solution, the pore diameter of the nano-mesopores in the embolization particles can be controlled. As the power and time of ultrasound increase, the pore diameter of the nano-mesopores becomes smaller. As Figure 6 shown, the most probable pore diameter of the nano-mesopores of the embolization particles obtained in Example 1 is 55 nm. As Figure 7 shown, the most probable pore diameter of the nano-mesopores of the embolization particles obtained in Example 2 is 80 nm. Comparing Example 1 and Comparative Example 1, it can be seen that by stirring and foaming, the pores in the formed embolization particles are larger and the effect during application is poorer. As Figure 8 shown, the most probable pore diameter of the mesopores of the embolization particles obtained in Comparative Example 1 is 880 nm. Comparing Example 1 and Comparative Example 2, it can be seen that by ultrasonic foaming but freezing and curing, increasing the curing time results in partial defoaming of the mesopores, and the uniformity of the pore diameter distribution of the formed mesopores is poor. As Figure 9 shown, most of the pore diameters of the mesopores of the embolization particles obtained in Comparative Example 2 are near 120 nm, 780 nm, and 960 nm. Comparing Examples 1-2 and Example 3, it can be seen that without using ultrasonic foaming and freezing and curing at the same time, the pore diameters of the mesopores of the obtained embolization particles are large and the distribution is uneven, resulting in partial defoaming of the mesopores, and the uniformity of the pore diameter distribution of the formed mesopores is poor. As Figure 10As shown, the pore diameters of the mesopores of the embolization particles in Comparative Example 3 are mostly distributed around 620 nm, 780 nm, and 960 nm. That is, for the embolization particles obtained by the preparation method of the present application, the pore diameters of the nano-mesopores in the embolization particles are less than 200 nm, and the pore diameters of the nano-mesopores are relatively concentrated, which can break through the size limitation of the mesopores in the prior art and improve the uniformity of the mesopore distribution. Therefore, only by simultaneously using ultrasonic foaming and liquid nitrogen quenching can nano-mesoporous embolization particles with small pore diameters and uniform distribution be obtained.

[0092] As shown in Table 1, by comparing Examples 1-2 and Comparative Examples 1-3, it can be seen that the embolization particles obtained by the present application have good suspension performance. This is because the pore diameters of the nano-mesopores of the embolization particles are small and uniformly distributed, endowing them with good swelling characteristics, thereby improving the suspension of the embolization particles, so as to better pass through the catheter during use, which is more conducive to the clinical use of doctors and realizes embolization treatment in the lesion area.

[0093] As shown in Table 2, by comparing Examples 1-2 and Comparative Examples 1-3, it can be seen that the water absorption rate of the embolization particles obtained by the present application is greater than 2000%. This is because the embolization particles have a high specific surface area and uniform nano-mesopores inside, which can accommodate more water molecules to enter, thus having good water absorption performance and swelling property, thereby improving the embolization effect.

[0094] As shown in Table 3, by comparing Examples 1-2 and Comparative Examples 1-3, it can be seen that the bulk density of the embolization particles obtained by the present application is less than that of the comparative examples. This is because compared with the traditional freezing and solidification method, the liquid nitrogen quenching method more efficiently realizes the freezing and shaping of the gelatin sponge, reduces the defoaming phenomenon that easily occurs in traditional embolization agent products, makes the sponge have a lower bulk density, and enables the product to have both industrialization ability and good medical performance at the same time.

[0095] In summary, the present invention provides a nano-mesoporous embolization particle and a preparation method thereof, capable of obtaining embolization particles with nano-mesopores and a uniform mesopore size distribution. By controlling the pore size of the nano-mesopores, the interior of the embolization particles has a high specific surface area and uniform nano-micropores, which can accommodate more water molecules to enter, having good water absorption performance and embolization effect. At the same time, due to its good swelling characteristics, it can be suspended in the contrast agent for a long time, so as to better pass through the catheter during use, which is more conducive to the clinical use of doctors and realizes the embolization treatment in the lesion area. The cryogenic setting of the gelatin sponge is efficiently achieved by liquid nitrogen quenching, improving the production efficiency. At the same time, the defoaming phenomenon in the preparation process of traditional embolization agent products is reduced, making the sponge have a lower bulk density, and endowing the product with good industrial application prospects and medical properties. This application can obtain embolization particles with excellent suspension, catheter passing ability, water absorption rate and other properties, improving the treatment effect. At the same time, the embolization particles have good biocompatibility, can be degraded and the blood vessels can be recanalized, enabling repeated embolization treatments.

[0096] The above description is only a preferred embodiment of the present application and an explanation of the applied technical principles. Those skilled in the art should understand that the scope of the invention involved in the present application is not limited to the technical solution formed by the specific combination of the above technical features. At the same time, it should also cover other technical solutions formed by any combination of the above technical features or their equivalent features without departing from the inventive concept. For example, the technical solution formed by mutually replacing the above features with the (but not limited to) technical features with similar functions disclosed in the present application.

[0097] Except for the technical features described in the specification, the remaining technical features are well-known to those skilled in the art. To highlight the innovative features of the present invention, the remaining technical features are not elaborated herein.

Claims

1. A preparation method of nano-mesoporous embolization particles, characterized in that, At least include the following steps: Prepare a gelatin solution; Place the gelatin solution in an ultrasonic crusher, immerse the ultrasonic probe at two-thirds of the gelatin solution, and perform ultrasonic foaming for a first preset time at a first ultrasonic power to obtain gelatin foam; Drop a crosslinking agent into the gelatin foam, and perform a crosslinking reaction for a second preset time at a second ultrasonic power to obtain an intermediate product; Quench the intermediate product with liquid nitrogen to instantaneously solidify the intermediate product, and perform wet material crushing, cleaning, and freeze-drying on the solidified intermediate product to obtain embolization particles, wherein, the pore diameter of the mesopores in the embolization particles is less than 200 nm.

2. The preparation method of the nano-mesoporous embolization particles according to claim 1, characterized in that, The first ultrasonic power is 100 W - 200 W, and the first preset time is 8 minutes - 15 minutes.

3. The preparation method of the nano-mesoporous embolization particles according to claim 1, characterized in that, The second ultrasonic power is 30 W - 50 W, and the second preset time is 15 minutes - 20 minutes.

4. The preparation method of the nano-mesoporous embolization particles according to claim 1, characterized in that, The crosslinking agent includes one or a combination of several of formaldehyde, glutaraldehyde, or n-butyraldehyde.

5. The preparation method of the nano-mesoporous embolization particles according to claim 1, wherein, The liquid nitrogen quenching time is 4 minutes - 8 minutes.

6. The preparation method of the nano-mesoporous embolization particles according to claim 1, wherein, When preparing the gelatin solution, add gelatin to a solvent, fully swell it, and then stir and dissolve it at a first temperature to obtain the gelatin solution at the first temperature.

7. The preparation method of the nano-mesoporous embolization particles according to claim 6, wherein The solvent is water for injection, and the mass ratio of gelatin to the solvent is 1:(8 - 20).

8. The preparation method of the nano-mesoporous embolization particles according to claim 6, characterized in that, The first temperature is 45°C - 55°C, and the ultrasonic foaming and the crosslinking reaction are carried out at the first temperature.

9. The preparation method of the nano-mesoporous embolization particles according to claim 6, wherein, The mass ratio of the crosslinking agent to the gelatin is 1:5 - 20.

10. A nano-mesoporous embolization particle, characterized in that, Obtained by the preparation method according to any one of claims 1 - 9, the embolization particles are porous bodies with irregular shapes obtained by crosslinking gelatin molecules and a crosslinking agent; wherein, the pore diameter of the mesopores in the embolization particles is less than 200 nm.

11. The nano-mesoporous embolization particles according to claim 10, characterized in that, The most probable pore diameter of the embolization particles is in the range of 50 nm - 100 nm.

12. The nano-mesoporous embolization particle according to claim 10, wherein The bulk density of the embolization particles is 25 mg / ml - 29 mg / ml.

13. The nano-mesoporous embolization particle according to claim 10, characterized in that, The water absorption rate of the embolization particles is greater than 2000%.

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