Nano mesoporous embolism particle and preparation method thereof

Abstract

The invention provides nano mesoporous embolism particles and a preparation method thereof. The preparation method comprises the following steps: preparing a gelatin solution; the gelatin solution is subjected to ultrasonic foaming for a first preset time under first ultrasonic power, and gelatin foam is obtained; dropwise adding a cross-linking agent into the gelatin foam, and carrying out a cross-linking reaction for a second preset time under second ultrasonic power to obtain an intermediate product; and quenching the intermediate product by adopting liquid nitrogen to instantaneously cure the intermediate product, and carrying out wet material crushing, cleaning and freeze drying on the cured intermediate product to obtain the embolism particles. According to the nano-mesoporous embolism particle and the preparation method thereof, the embolism particle with nano-mesopores and uniform mesopore diameter distribution can be obtained, and the suspension property, the conduit passing ability, the water absorption rate and other properties of the embolism particle are improved.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine technology, and in particular to nano-mesoporous embolic particles and a preparation method thereof. Background Art

[0002] Liver cancer is the fourth most common malignant tumor in my country, and its case fatality rate ranks second among all malignant tumors. Surgical resection is the main treatment for liver cancer patients, but there are problems such as low postoperative survival rate and high recurrence rate. As interventional therapy becomes more and more mature, embolic granules are often used in clinical practice to block the blood supply to tumor tissue. However, the existing embolic granules on the market are prone to catheter blockage and poor particle strength in actual use due to their poor suspension performance.

[0003] In addition, the common method of preparing embolic particles is to mechanically stir and foam them and then place them in a freezer for freezing and solidification. The particles prepared in this way will have uneven internal foaming due to inconsistent stirring shear force. At the same time, due to fluctuations in freezer temperature control, some products will experience defoaming. Conventional freezing and solidification requires a long time for the product to be finalized, which greatly limits the production efficiency of traditional sponge particles. Summary of the invention

[0004] The present invention proposes a nano-mesoporous embolic particle and a preparation method thereof. Through the nano-mesoporous embolic particle and the preparation method thereof provided by the present invention, embolic particles with nano-mesopores and uniform mesopore size distribution can be obtained, thereby improving the suspension, catheter permeability and water absorption properties of the embolic particles and at the same time improving production efficiency.

[0005] In order to solve the above technical problems, an embodiment of the present invention provides a method for preparing nano-mesoporous embolic particles, which at least comprises the following steps:

[0006] Prepare gelatin solution;

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

[0008] adding a crosslinking agent dropwise to the gelatin foam, and performing a crosslinking reaction at a second ultrasonic power for a second preset time to obtain an intermediate product;

[0009] The intermediate product is quenched by liquid nitrogen to solidify the intermediate product instantaneously, and the solidified intermediate product is wet-ground, cleaned and freeze-dried to obtain embolic particles.

[0010] In one embodiment of the present invention, the first ultrasonic power is 100 watts to 200 watts, and the first preset time is 8 minutes to 15 minutes.

[0011] In one embodiment of the present invention, the second ultrasonic power is 30 watts to 50 watts, and the second preset time is 15 minutes to 20 minutes.

[0012] In one embodiment of the present invention, the cross-linking 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 a solvent, and after fully swelling, it is stirred and dissolved at a 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 cross-linking reaction are performed at the first temperature.

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

[0018] An embodiment of the present invention further provides a nano-mesoporous embolic particle obtained by the above-mentioned preparation method, wherein the embolic particle is a porous body with an irregular shape obtained by cross-linking gelatin molecules with a cross-linking agent; wherein the pore size of the mesopores in the embolic particle is less than 200 nm.

[0019] In one embodiment of the present invention, the most probable pore size of the embolic particles is in the range of 50 nm to 100 nm.

[0020] In one embodiment of the present invention, the packing density of the embolic particles is 25 mg / ml-29 mg / ml.

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

[0022] In summary, the present invention proposes a nano-mesoporous embolic particle and a preparation method thereof, which can obtain embolic particles with nano-mesoporous and uniform mesopore size distribution. By controlling the pore size of the nano-mesoporous, the embolic particles have a high specific surface area and uniform nano-micropores inside, which can accommodate more water molecules to enter, and have good water absorption performance and embolic effect. At the same time, because it has good swelling properties, it can be suspended in the contrast agent for a long time to achieve the purpose of better passing through the catheter during use, which is more helpful for the clinical use of doctors and realizes embolic treatment in the lesion area. The frozen shaping of the gelatin sponge is efficiently achieved by liquid nitrogen quenching, which improves production efficiency, reduces the defoaming phenomenon in the preparation process of traditional embolic products, and makes the sponge have a lower bulk density, so that the product has good industrial application prospects and medical performance. The present application can obtain embolic particles with excellent suspension, catheter passability and water absorption, improve the treatment effect, and at the same time, the embolic particles have good biocompatibility, and the blood vessels can be re-canalized after degradation, and repeated embolic treatments can be performed. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings required for describing the embodiments will be briefly introduced below. Obviously, the accompanying drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other accompanying drawings can be obtained based on these accompanying drawings without paying creative work.

[0024] Figure 1 This is a scanning electron microscope image of the embolic particles obtained in Example 1.

[0025] Figure 2 This is a scanning electron microscope image of the embolic particles obtained in Example 2.

[0026] Figure 3 This is a scanning electron microscope image of the embolic particles obtained in Comparative Example 1.

[0027] Figure 4 This is a scanning electron microscope image of the embolic particles obtained in Comparative Example 2.

[0028] Figure 5 Scanning electron micrograph of the embolic particles provided for Comparative Example 3.

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

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

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

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

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

[0034] The following uses specific specific examples to illustrate the implementation manners 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 implementation manners. 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 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; subjecting the gelatin solution to ultrasonic foaming for a first preset time at 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 at 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, cleaning, and freeze-drying to obtain embolization particles.

[0038] In one 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 solvent is, for example, 1: (8~20). Specifically, gelatin is added to water for injection, and after sufficient swelling, it is stirred at a first temperature at a speed of 50r / min (revolutions / minute) to 60r / min for 0.5h (hour) to 1.5h to dissolve, and then allowed to stand to remove bubbles to prepare a gelatin solution with a first temperature, and the first temperature is, for example, 45°C to 55°C. By selecting gelatin as the base material, the obtained embolic particles are biodegradable and can be gradually degraded under the action of enzymes in the body. After degradation, the recanalization of blood vessels can effectively reduce tissue necrosis, have good biocompatibility, and will not cause severe inflammatory reactions, so that repeated embolization treatments can be performed.

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

[0040] In one embodiment of the present invention, after obtaining gelatin foam, a crosslinking agent is added to the gelatin foam to perform a crosslinking reaction, wherein after the gelatin foam is obtained after the first preset time, it is necessary to immediately and rapidly add a crosslinking agent to the gelatin foam to reduce the defoaming of the gelatin foam. And the crosslinking reaction is carried out under ultrasound, for example, after foaming in an ultrasonic device such as an ultrasonic crusher, the ultrasound is turned off, and after the crosslinking agent is immediately added, the power of the ultrasonic device is adjusted to a second ultrasonic power, and the crosslinking reaction is carried out under the second ultrasonic power for a second preset time 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 crosslinking agent includes, for example, one or more combinations of aldehyde crosslinking agents such as formaldehyde, glutaraldehyde or n-butyraldehyde. Among them, when the crosslinking agent selects formaldehyde, for example, a formaldehyde aqueous solution is used for crosslinking, and the mass fraction of the formaldehyde aqueous solution is, for example, 3wt%~6wt%. Specifically, for example, a formaldehyde solution with a mass fraction of 37% is mixed with water for injection to obtain a formaldehyde aqueous solution with a preset mass fraction. The mass ratio of the crosslinking agent to the gelatin is, for example, 1:5 to 20. In this embodiment, the foaming and crosslinking steps are both completed at the first temperature. Crosslinking under ultrasonic conditions can ensure the uniformity of crosslinking and prevent defoaming. By controlling the second ultrasonic power and the second preset time, the uniform distribution of foam pore size in the intermediate product is ensured.

[0041] In one embodiment of the present invention, after obtaining the intermediate product, that is, after turning off the ultrasonic equipment, the intermediate product is immediately collected and transferred to a low-temperature resistant container, such as a stainless steel container, a low-temperature resistant plastic container or a low-temperature resistant glass container, and sealed. After sealing, the low-temperature resistant container is placed in a Dewar cup for fixing, and the Dewar cup is placed in a liquid nitrogen tank for quenching, and 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 of the intermediate product is reduced, and an intermediate product with a nano-mesoporous structure with uniform pore size is obtained.

[0042] In one embodiment of the present invention, the intermediate product after quenching and solidification is placed in water for injection at room temperature for thawing, and then the sample is cut into small pieces, for example, the wet material is crushed using a pulverizer, and after the wet material is crushed, it is washed several times with water for injection, and after washing, the product is taken out, added with an appropriate amount of water, and placed in a -40°C refrigerator for pre-freezing. When the refrigerator is cooled to -40°C, the completely frozen sample is placed in a freeze dryer, the freeze dryer cabin is evacuated, and freeze-dried until the sample is completely dry to obtain embolic particles. By freeze drying, the stability of the embolic particles can be ensured, and high-quality embolic particles can be obtained.

[0043] The present invention also proposes a nano-mesoporous embolic particle, the embolic particle is obtained by the above method, and the embolic particle with an irregularly shaped porous body is obtained by crosslinking gelatin molecules with a crosslinking agent, wherein the pore size of the mesopore in the embolic particle is, for example, less than 200nm. In this embodiment, by adjusting the ultrasonic conditions during the foaming and crosslinking process, the most probable pore size of the embolic particles obtained in different embodiments is, for example, in the range of 50nm~100nm, and the most probable pore size refers to the area in the porous material where the pore size of the material being tested is most concentrated. By controlling the pore size of the embolic particles, the dispersibility of the embolic particles is improved, thereby improving the suspension of the embolic particles. In the present application, the packing density of the embolic particles is, for example, 25mg / ml~29mg / ml, and the water absorption rate of the embolic particles is, for example, greater than 2000%, thereby improving the catheter passability and water absorption rate of the embolic particles, that is, the present application can obtain embolic particles with excellent suspension, catheter passability and water absorption rate, etc., and improve the therapeutic effect.

[0044] Hereinafter, the present invention will be explained in more detail by citing examples, which should not be construed as limiting. Appropriate modifications may be made within the scope consistent with the gist of the present invention, all of which fall within the technical scope of the present invention.

[0045] Example 1

[0046] Add 45 g of gelatin into 455 g of water for injection, and after it is fully swollen, stir and dissolve it at 50°C at a speed of 50 r / min for 1 hour, let it stand to remove bubbles, and prepare a gelatin solution at the first temperature.

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

[0048] Open the ultrasonic crusher cabin, 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 200W, close the cabin, turn on the equipment to start ultrasound, turn off the ultrasonic probe after 15 minutes, and obtain ultrasonically foamed gelatin foam.

[0049] Open the ultrasonic crusher cabin, immediately add the above-prepared formaldehyde aqueous solution to the gelatin foam, maintain the first temperature, adjust the ultrasonic probe power to 50W, close the cabin, turn on the equipment to start ultrasonication, and turn off the ultrasonic probe after 20 minutes to obtain the intermediate product of the cross-linking reaction.

[0050] The intermediate product was immediately collected with a stainless steel container and sealed. After sealing, it was placed in a Dewar cup and fixed. The Dewar cup was placed in a liquid nitrogen tank for quenching and taken out after reacting for 8 minutes.

[0051] After the intermediate product quenched by liquid nitrogen is thawed in injection water at room temperature, the sample is cut into small pieces, for example, the wet material is crushed by a pulverizer, and after the wet material is crushed, it is washed several times with injection water. After washing, the product is taken out, added with an appropriate amount of water, and placed in a -40°C refrigerator for pre-freezing. When the refrigerator is cooled to -40°C, the completely frozen sample is placed in a freeze dryer, the freeze dryer cabin is evacuated, and freeze-dried until the sample is completely dry to obtain embolic particles.

[0052] Example 2

[0053] Add 45 g of gelatin into 455 g of water for injection, and after it is fully swollen, stir and dissolve it at 50°C at a speed of 50 r / min for 1 hour, let it stand to remove bubbles, and prepare a gelatin solution at the first temperature.

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

[0055] Open the ultrasonic crusher cabin, 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 ultrasound, turn off the ultrasonic probe after 8 minutes, and obtain ultrasonically foamed gelatin foam.

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

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

[0058] After the intermediate product quenched by liquid nitrogen is thawed in injection water at room temperature, the sample is cut into small pieces, for example, the wet material is crushed by a pulverizer, and after the wet material is crushed, it is washed several times with injection water. After washing, the product is taken out, added with an appropriate amount of water, and placed in a -40°C refrigerator for pre-freezing. When the refrigerator is cooled to -40°C, the completely frozen sample is placed in a freeze dryer, the freeze dryer cabin is evacuated, and freeze-dried until the sample is completely dry to obtain embolic particles.

[0059] Comparative Example 1

[0060] Add 45 g of gelatin into 455 g of water for injection, and after it is fully swollen, stir and dissolve it at 50°C at a speed of 50 r / min for 1 hour, let it stand to remove bubbles, and prepare a gelatin solution at the first temperature.

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

[0062] The gelatin solution was transferred to a reaction kettle, maintained at the first temperature, and stirred at 700 r / min for 8 minutes to obtain stirred and foamed gelatin foam.

[0063] The above-prepared formaldehyde aqueous solution is immediately and rapidly added dropwise to the gelatin foam, and stirring and the first temperature are maintained until the cross-linking reaction is completed to obtain an intermediate product of the cross-linking reaction.

[0064] The intermediate product was immediately collected with a stainless steel container and sealed. After sealing, it was placed in a Dewar cup and fixed. The Dewar cup was placed in a liquid nitrogen tank for quenching and taken out after reacting for 8 minutes.

[0065] After the intermediate product quenched by liquid nitrogen is thawed in injection water at room temperature, the sample is cut into small pieces, for example, the wet material is crushed by a pulverizer, and after the wet material is crushed, it is washed several times with injection water. After washing, the product is taken out, added with an appropriate amount of water, and placed in a -40°C refrigerator for pre-freezing. When the refrigerator is cooled to -40°C, the completely frozen sample is placed in a freeze dryer, the freeze dryer cabin is evacuated, and freeze-dried until the sample is completely dry to obtain embolic particles.

[0066] Comparative Example 2

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

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

[0069] Open the ultrasonic crusher cabin, 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 200W, close the cabin, turn on the equipment to start ultrasound, turn off the ultrasonic probe after 15 minutes, and obtain ultrasonically foamed gelatin foam.

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

[0071] The intermediate product was immediately collected and transferred to a -40°C freezer for freeze solidification and taken out after 96 hours of reaction.

[0072] After the frozen solidified intermediate product is thawed in injection water at room temperature, the sample is cut into small pieces, for example, the wet material is crushed by a grinder, and after the wet material is crushed, it is washed several times with injection water. After washing, the product is taken out, added with an appropriate amount of water, and placed in a -40°C refrigerator for pre-freezing. When the refrigerator is cooled to -40°C, the completely frozen sample is placed in a freeze dryer, the freeze dryer cabin is evacuated, and freeze-dried until the sample is completely dry to obtain embolic particles.

[0073] Comparative Example 3

[0074] The material used in Comparative Example 3 is the gelatin sponge granule embolic agent sold by Hangzhou Ailikang Pharmaceutical Technology Co., Ltd., with batch number: 30132428 and specification: Gelfoam-150.

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

[0076] In one embodiment of the present invention, the embolic particles in Examples 1-2 and Comparative Examples 1-3 were subjected to a scanning electron microscope (SEM) test to observe the pore size and distribution of the embolic particles. The test results are as follows: Figures 1 to 5 shown.

[0077] In one embodiment of the present invention, the pore size distribution of the embolic particles in Examples 1-2 and Comparative Examples 1-3 is tested, and the pore size distribution is tested, for example, using a mercury intrusion instrument (model: AutoPore IV 9500). Specifically, 2 g of the samples of Example 1, Example 2, Comparative Example 1, Comparative Example 2, and Comparative Example 3 are respectively taken and placed in an oven for 2 hours to remove moisture, and then the samples are placed in an expansion agent and sealed, the expansion agent is, for example, mercury (Hg), and then the expansion agent is sequentially placed in a low pressure station and a high pressure station for pore size analysis. The test results are as follows: Figures 6 to 10 shown.

[0078] In one embodiment of the present invention, the suspension test is to weigh 100 mg of samples of Example 1, Example 2, Comparative Example 1, Comparative Example 2 and Comparative Example 3 respectively and transfer them into a 20 ml syringe, draw 10 ml of contrast agent through a three-way valve and add it to the embolic particles in the 20 ml syringe, the contrast agent is, for example, iohexol, etc., expel the air from the syringe, repeatedly invert the syringe until a stable particle suspension is observed, start timing, and start until the suspension disappears, wherein, when the volume of the embolic particles in the syringe is less than 2 / 3, it is considered that the suspension disappears, and the corresponding disappearance time is recorded. The test results are shown in Table 1.

[0079] Table 1. Suspension performance test results of embolic particles in Examples 1-2 and Comparative Examples 1-3

[0080]

[0081] In one embodiment of the present invention, the water absorption test includes: weighing W1 weight of gelatin sponge particles and putting them into a test tube, then weighing the total weight as W2, adding 10 ml of purified water, removing the free water after complete swelling, weighing the weight of the swollen sample as W3, and calculating the water absorption of the sample according to the following formula.

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

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

[0084]

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

[0086] ρb=W / V;

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

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

[0089]

[0090] See also Figures 1 to 5 As shown, comparing Example 1-2 and Example 1-3, as Figure 1 As shown in FIG. 1 , the pore sizes of the nano-mesopores of the embolic 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. Figure 2As shown in the figure, the pore sizes of the nano-mesopores of the embolic particles obtained in Example 2 are mostly distributed in the range of 70nm to 80nm, and the morphology of the nano-mesopores is close to circular, with clear boundaries and dense distribution of nano-mesopores. Figure 3 As shown in FIG. 1 , the pore sizes of the mesopores of the embolic particles obtained in Comparative Example 1 are mostly distributed in the range of 700 nm to 900 nm, and the shapes of the mesopores are irregular with unclear boundaries. Figure 4 As shown, the maximum pore size of the mesopores of the embolic 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 size distribution is seriously uneven, and the shape of the mesopores is irregular and the boundaries are unclear. Figure 5 As shown, the pore size of the mesopores of the embolic particles obtained in Comparative Example 3 ranges from about 100 nm to about 800 nm, the pore size distribution is seriously uneven, and the shape of the mesopores is irregular with unclear boundaries. That is, the embolic particles obtained by the preparation method of the present application include a plurality of nano-mesopores, and the pore size of the nano-mesopores is small, and the pore size distribution is dense, the pore size of each mesopore is roughly equal, the embolic particles are uniform in pore size, and the morphology of the nano-mesopores is close to circular with clear boundaries. The pore size of the embolic particles in Comparative Examples 1-3 is large, and the pore size distribution is uneven, and the pore size morphology is poor. Therefore, the embolic 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 embolic effect.

[0091] See also Figures 6 to 10 As shown in FIG. 1 , by comparing Examples 1-2, it can be seen that the pore size of the nano-mesopores in the embolic particles can be controlled by controlling the power and time of ultrasound during the foaming and cross-linking of the gelatin solution, and as the ultrasound power and time increase, the pore size of the nano-mesopores becomes smaller, as shown in FIG. Figure 6 As shown in FIG. 1 , the most probable pore size of the nano-mesopores of the embolic particles obtained in Example 1 is 55 nm. Figure 7 As shown in FIG. 2 , the most probable pore size of the nano-mesopores of the embolic particles obtained in Example 2 is 80 nm. By comparing Example 1 with Comparative Example 1, it can be seen that the pores in the embolic particles formed by stirring and foaming are relatively large, and the effect in the application process is relatively poor. Figure 8 As shown in FIG. 1 , the most probable pore size of the mesopores of the embolic particles obtained in Comparative Example 1 is 880 nm. By comparing Example 1 and Comparative Example 2, it can be seen that by ultrasonic foaming but freezing solidification, the solidification time is increased, resulting in partial defoaming of the mesopores, and the distribution uniformity of the formed mesopore size is poor, such as Fig. 9 As shown in FIG. 2 , the pore sizes of the mesopores of the embolic particles obtained in Comparative Example 2 are mostly distributed around 120 nm, 780 nm and 960 nm. By comparing Examples 1-2 and Example 3, it can be seen that without using ultrasonic foaming and freezing solidification at the same time, the mesopores of the embolic particles obtained have larger pore sizes and uneven distribution, resulting in partial defoaming of the mesopores, and the distribution uniformity of the formed mesopores is poor, such as Fig.10As shown, the pore sizes of the mesopores of the embolic particles in Comparative Example 3 are mostly distributed around 620nm, 780nm and 960nm. That is, the embolic particles obtained by the preparation method of the present application have a pore size of nano-mesopores less than 200nm, and the pore size of the nano-mesopores is 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, ultrasonic bubbling and liquid nitrogen quenching are used simultaneously to obtain nano-mesopore embolic particles with small pore size and uniform distribution.

[0092] Please refer to Table 1. By comparing Examples 1-2 and Comparative Examples 1-3, it can be seen that the embolic particles obtained by the present application have good suspension properties. This is because the nano-mesopores of the embolic particles have a small pore size and are evenly distributed, which gives them good swelling properties, thereby improving the suspension of the embolic particles, so as to achieve the purpose of better passing through the catheter during use, which is more helpful for doctors' clinical use and realizes embolic treatment in the lesion area.

[0093] Please refer to Table 2. By comparing Examples 1-2 and Comparative Examples 1-3, it can be seen that the water absorption rate of the embolic particles obtained in the present application is greater than 2000%. This is because the embolic particles have a high specific surface area and uniform nano-mesopores, which can accommodate more water molecules and thus have better water absorption and swelling properties, thereby improving the embolic effect.

[0094] Please refer to Table 3. By comparing Examples 1-2 and Comparative Examples 1-3, it can be seen that the packing density of the embolic particles obtained in the present application is smaller than that in the comparative examples. This is because compared with the traditional freezing solidification method, the freezing and shaping of the gelatin sponge is more efficiently achieved by liquid nitrogen quenching, which reduces the defoaming phenomenon that is easy to occur in traditional embolic products, and makes the sponge have a lower packing density, so that the product has both industrialization capabilities and good medical properties.

[0095] In summary, the present invention proposes a nano-mesoporous embolic particle and a preparation method thereof, which can obtain embolic particles with nano-mesoporous and uniform mesopore size distribution. By controlling the pore size of the nano-mesoporous, the embolic particles have a high specific surface area and uniform nano-micropores inside, which can accommodate more water molecules to enter, and have good water absorption performance and embolic effect. At the same time, because it has good swelling properties, it can be suspended in the contrast agent for a long time to achieve the purpose of better passing through the catheter during use, which is more helpful for the clinical use of doctors and realizes embolic treatment in the lesion area. The frozen shaping of the gelatin sponge is efficiently achieved by liquid nitrogen quenching, which improves production efficiency, reduces the defoaming phenomenon in the preparation process of traditional embolic products, and makes the sponge have a lower bulk density, so that the product has good industrial application prospects and medical performance. The present application can obtain embolic particles with excellent suspension, catheter passability and water absorption, improve the treatment effect, and at the same time, the embolic particles have good biocompatibility, and the blood vessels can be re-canalized after degradation, and repeated embolic treatments can be performed.

[0096] The above description is only a preferred embodiment of the present application and an explanation of the technical principles used. 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 a specific combination of the above-mentioned technical features, but should also cover other technical solutions formed by any combination of the above-mentioned technical features or their equivalent features without departing from the inventive concept, such as a technical solution formed by replacing the above-mentioned features with (but not limited to) technical features with similar functions disclosed in this application.

[0097] Except for the technical features described in the specification, the remaining technical features are known technologies to those skilled in the art. In order to highlight the innovative features of the present invention, the remaining technical features will not be described here in detail.

Claims

1. A method for preparing nano-mesoporous embolic particles, characterized in that: At least the following steps are included: Prepare gelatin solution; subjecting the gelatin solution to ultrasonic foaming at a first ultrasonic power for a first preset time to obtain gelatin foam; adding a crosslinking agent dropwise to the gelatin foam, and performing a crosslinking reaction at a second ultrasonic power for a second preset time to obtain an intermediate product; The intermediate product is quenched by liquid nitrogen to solidify the intermediate product instantaneously, and the solidified intermediate product is wet-ground, cleaned and freeze-dried to obtain embolic particles.

2. The method for preparing nano-mesoporous embolic particles according to claim 1, characterized in that: The first ultrasonic power is 100 watts to 200 watts, and the first preset time is 8 minutes to 15 minutes.

3. The method for preparing nano-mesoporous embolic particles according to claim 1, characterized in that: The second ultrasonic power is 30 watts to 50 watts, and the second preset time is 15 minutes to 20 minutes.

4. The method for preparing nano-mesoporous embolic particles according to claim 1, characterized in that: The cross-linking agent includes one or a combination of formaldehyde, glutaraldehyde or n-butyraldehyde.

5. The method for preparing nano-mesoporous embolic particles according to claim 1, characterized in that: The liquid nitrogen quenching time is 4 minutes to 8 minutes.

6. The method for preparing nano-mesoporous embolic particles according to claim 1, characterized in that: When preparing the gelatin solution, gelatin is added to a solvent, and after fully swelling, it is stirred and dissolved at a first temperature to obtain the gelatin solution at the first temperature.

7. The method for preparing nano-mesoporous embolic particles according to claim 6, characterized in that: The solvent is water for injection, and the mass ratio of the gelatin to the solvent is 1:(8-20).

8. The method for preparing nano-mesoporous embolic particles according to claim 6, characterized in that: The first temperature is 45° C. to 55° C., and the ultrasonic foaming and the cross-linking reaction are performed at the first temperature.

9. The method for preparing nano-mesoporous embolic particles according to claim 6, characterized in that: The mass ratio of the cross-linking agent to the gelatin is 1:5-20.

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

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

12. The nano-mesoporous embolic particle according to claim 10, characterized in that: The packing density of the embolic particles is 25 mg / ml to 29 mg / ml.

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

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