Preparation method and use method of hydrogel vascular embolism material
Through the low-temperature vacuum dispersion method and the on-site mixed use method, the problems of uneven dispersion of hydrogel vascular embolization materials and drug failure are solved, and uniform dispersion and efficient drug dispersion are achieved for small blood vessels.
Patent Information
- Application Number
- CN202411841389.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-13
- Publication Date
- 2025-03-18
AI Technical Summary
The existing hydrogel vascular embolization materials are unevenly dispersed during the preparation process, resulting in the formation of gel blocks and cannot be used for tiny vascular embolization. It is difficult to control the drug loading, and the drug is prone to failure.
The low-temperature vacuum dispersion method is used to form a hydrogel vascular embolization material without gel blocks by stirring the mixing of material A (thickener) and material B (nano-silicate thixotropic agent) at 0 to 3°C. Meanwhile, a method of use is provided that allows mixing hydrogel embolization materials with sterilized injection water to adjust viscosity and dispersion properties on site.
The homogeneous dispersion of hydrogel vascular embolization materials is achieved, and it is suitable for tiny vascular embolization, reducing the risk of drug failure, and improving the dispersion and therapeutic effect of the drug.
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Figure CN119633161A_ABST
Abstract
Description
Technical Field
[0001] The present invention belongs to the technical field of vascular embolic materials, and in particular relates to a preparation method and a use method of a hydrogel vascular embolic material. Background Art
[0002] Vascular embolization surgery is mainly a surgery to embolize the target blood vessels with embolic materials through the use of catheters and guide wires. It is an effective treatment for aneurysms, malformed blood vessels, hemorrhages, and hypervascular tumors. Currently, the commonly used embolic materials in clinical practice include spring coils, embolic microspheres, iodine, gelatin sponges, and hydrogel embolic materials.
[0003] Among them, hydrogel embolic materials are widely used due to their adjustable gel time, mechanical properties, shear viscosity, good biocompatibility, excellent embolic performance and intravascular diffusion. However, the existing hydrogel embolic materials use conventional dispersion methods during the preparation process, and the thixotropic agent materials they contain are difficult to disperse evenly, forming small gel blocks that cannot be broken up and evenly dispersed in the embolic material, and cannot be used for small vascular embolization treatment.
[0004] At the same time, uneven dispersion will also affect the viscosity of the vascular embolic material. If the viscosity of the hydrogel embolic material is too high when entering the human body, it will be difficult to enter small blood vessels; if the viscosity is too low, it will easily affect the embolic effect due to insufficient viscosity.
[0005] In clinical use, due to the different diameters of the embolized blood vessels, the embolization materials are often required to have different diffusion properties, but in the prior art, they are generally pre-prepared in advance and there is no choice. At the same time, when the hydrogel embolization material needs to be loaded with drugs, it is usually pre-prepared in advance, but the type and dosage of the pre-prepared drugs are difficult to control, and the effectiveness of the drugs cannot be guaranteed. Many drugs will react with the components of the hydrogel embolization material during long-term storage, resulting in drug failure.
[0006] Therefore, there is an urgent need for a preparation method that can evenly disperse the components of a hydrogel embolic material and a method for using a hydrogel embolic material that can effectively load drugs and is suitable for various application conditions. Summary of the invention
[0007] The purpose of the present invention is to provide a preparation method and use method of a hydrogel vascular embolic material to solve the problems of uneven dispersion, difficult control of drug loading during use, and easy drug failure in conventional preparation methods.
[0008] The purpose of the present invention can be achieved through the following technical solutions:
[0009] In a first aspect, the present invention provides a method for preparing a hydrogel vascular embolic material, comprising the following process steps:
[0010] S101. Material A is mixed with a portion of sterile water for injection at 40-70°C to obtain a pre-dissolved product, which is kept warm for later use;
[0011] S102. The temperature of the remaining sterile water for injection is adjusted to 0-10° C., the pre-dissolved material, material B and developer are added, and vacuum dispersed to obtain a hydrogel vascular embolization material;
[0012] The material A is a thickener; the material B is a thixotropic agent.
[0013] Preferably, in step S102, the temperature of the remaining sterile water for injection is adjusted to 0-3°C.
[0014] Preferably, the vacuum degree of vacuum dispersion in step S102 is -0.1 to 0.08 MPa.
[0015] Preferably, material A comprises a combination of one or more of gelatin, xanthan gum, carbomer gum, chitosan and sodium alginate.
[0016] More preferably, material A is gelatin.
[0017] Preferably, material B is a nano-silicate thixotropic agent.
[0018] Preferably, the nano-silicate thixotropic agent includes one or a combination of nano-lithium magnesium silicate and nano-aluminum magnesium silicate.
[0019] More preferably, the nano-silicate thixotropic agent is nano-lithium magnesium silicate.
[0020] Preferably, the mass ratio of material A to material B is 1:(2-4).
[0021] Preferably, the added amount of material A and material B is 5-10 wt % of the total mass of material A, material B and sterile water for injection.
[0022] Preferably, the developer includes a combination of one or more of an iodine reagent, barium sulfate and tantalum powder.
[0023] Preferably, the amount of developer added is 20-45 wt % of the total mass of the sterile water for injection.
[0024] In a second aspect, the present invention provides a method for using a hydrogel vascular embolic material, comprising the following steps:
[0025] S201. Loading the above-prepared hydrogel vascular embolic material into syringe A;
[0026] S202. Loading sterile water for injection into syringe B;
[0027] S203. Connect syringe A and syringe B through a three-way valve, push and pull the push rods of syringe A and syringe B back and forth to mix the hydrogel embolic material and sterile water for injection evenly;
[0028] The volume ratio of the hydrogel vascular embolization material to the sterile injection water is (1-5):1.
[0029] Preferably, in step S203, the pushing and pulling are repeated 10 to 50 times.
[0030] Preferably, in step S202, syringe B is loaded with a drug solution.
[0031] Beneficial effects of the present invention:
[0032] 1. In the preparation method of the hydrogel vascular embolic material of the present invention, a low-temperature dispersion method is mainly used. Furthermore, the present invention finds that a hydrogel vascular embolic material without gel blocks can be obtained by rapid dispersion at 0-3°C. Under low temperature conditions, the dispersion system is more stable. The thixotropic agent will first be evenly dispersed in water to form a suspension to avoid agglomeration. In the subsequent stirring process, it will dissolve in water to form a uniform gel, which will help the thixotropic agent to form a more uniform dispersion state in the matrix material. The prepared hydrogel vascular embolic material can enter smaller blood vessels in the human body and is suitable for various application environments.
[0033] 2. The hydrogel vascular embolic material of the present invention is preferably nano-lithium magnesium silicate. Compared with other types of thixotropic agents, nano-lithium magnesium silicate has the characteristics of colorless transparency, strong thixotropy and chemical stability. It can also better adapt to the environment during low-temperature dispersion, quickly disperse in water, and then form a gel, which helps to obtain a hydrogel embolic material with excellent performance and uniform dispersion.
[0034] 3. The present invention provides a new method for using a hydrogel vascular embolic material. The hydrogel embolic material is first prefabricated and then mixed at the site of use, which can reduce the shear viscosity and modulus of the hydrogel during transportation, allowing the hydrogel vascular embolic material to diffuse into smaller blood vessels, and the sample remixed on site can reach the same strength as the prefabricated hydrogel embolic material, and the reliable embolic strength helps to achieve better treatment effects. At the same time, when mixing on site, the viscosity and diffusion properties of the hydrogel vascular embolic material can be adjusted at any time according to the patient's condition and actual conditions to adapt to different blood vessels; when mixing, a shear mixing method is also adopted to mix the hydrogel vascular embolic material and sterile injection water evenly in a reciprocating shear motion, which can reduce the shear viscosity and modulus of the hydrogel during transportation, allowing the hydrogel vascular embolic material to diffuse into smaller blood vessels. Compared with general hydrogel vascular embolic materials, it can reduce storage costs and surgical difficulties, reduce the failure problems that may occur in long-term storage of hydrogels, and greatly reduce the risk of ectopic embolism.
[0035] 4. In the method for using the hydrogel vascular embolic material of the present invention, the sterile injection water can be replaced by a drug-loaded solution to be shear-mixed with the hydrogel vascular embolic material. This can significantly improve the dispersibility of the drug in the hydrogel vascular embolic material and achieve a high efficiency of the drug on the human body. On the other hand, it can accurately control the drug dosage and type, reduce storage costs and production costs, better adapt to different application scenarios, and effectively avoid drug failure, so that the drug can effectively and efficiently act on the human body and improve the surgical effect. BRIEF DESCRIPTION OF THE DRAWINGS
[0036] The present invention will be further described below in conjunction with the accompanying drawings.
[0037] Figure 1 This is a diagram showing the effect of embolizing the bilateral renal arteries of a pig according to Example 1 of the present invention;
[0038] Figure 2 This is a diagram showing the effect of embolizing the porcine hepatic artery in comparative example 3 of the present invention;
[0039] Figure 3 is a comparison diagram of hepatic artery embolization in Example 1 of the present invention and Comparative Example 3;
[0040] Figure 4 is a graph showing the modulus variation of Example 1 of the present invention and Comparative Example 1;
[0041] Figure 5 1 is a shear viscosity change diagram of Example 1 of the present invention and Comparative Example 1. DETAILED DESCRIPTION
[0042] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.
[0043] Example
[0044] Example 1, a hydrogel vascular embolic material, prepared and used according to the following method:
[0045] Preparation method of hydrogel vascular embolic material:
[0046] Add 4.5 g of gelatin and 25 g of sterile water for injection into a flask, stir at 70°C and 200 rpm for 30 min to obtain a gelatin predissolved product, and keep it at 70°C for later use;
[0047] Add 156.8 g of sterile water for injection into a stirring tank, adjust the temperature to 2°C, add 80 g of tantalum powder, 13.2 g of nano-lithium magnesium silicate and 26.7 g of the above-obtained gelatin predissolved material, stir for 5 min at a vacuum degree of -0.1 MPa and a rotation speed of 1800 rpm to obtain a hydrogel vascular embolization material.
[0048] Methods of using hydrogel vascular embolization materials:
[0049] 0.6 mL of the hydrogel vascular embolic material obtained above was loaded into syringe A, and 0.3 mL of sterile water for injection was loaded into syringe B;
[0050] Connect syringe A and syringe B through a three-way valve. When the valve core of the three-way valve is deflected, syringe A is only connected to syringe B. Push and pull the push rods of syringe A and syringe B back and forth 20 times to mix the hydrogel embolic material with sterile water for injection evenly before use.
[0051] Example 2, a hydrogel vascular embolic material, is different from Example 1 only in that during the use of the hydrogel vascular embolic material, the sterile water for injection is replaced by an equal amount of loaded drug solution, and the loaded drug solution is a mixed solution of sterile water for injection dispersed with 50 mg of cisplatin.
[0052] Example 3, a hydrogel vascular embolic material, is different from Example 1 only in that syringe A is loaded with 0.3 mL of the hydrogel vascular embolic material obtained above.
[0053] Example 4, a hydrogel vascular embolic material, is different from Example 1 only in that syringe A is loaded with 0.9 mL of the hydrogel vascular embolic material obtained above.
[0054] Example 5, a hydrogel vascular embolic material, is different from Example 1 only in that, in the preparation method of the hydrogel vascular embolic material, the dispersion temperature is adjusted to 0°C.
[0055] Example 6, a hydrogel vascular embolic material, is different from Example 1 only in that, in the preparation method of the hydrogel vascular embolic material, the dispersion temperature is adjusted to 3°C.
[0056] Example 7, a hydrogel vascular embolic material, is different from Example 1 only in that, in the preparation method of the hydrogel vascular embolic material, the dispersion temperature is adjusted to 4°C.
[0057] Example 8, a hydrogel vascular embolic material, is different from Example 1 only in that, in the preparation method of the hydrogel vascular embolic material, the dispersion temperature is adjusted to 10°C.
[0058] Comparative Example
[0059] Comparative Example 1, a hydrogel vascular embolic material, prepared and used according to the following method:
[0060] Preparation method of hydrogel vascular embolic material:
[0061] Add 4.5 g of gelatin and 25 g of sterile water for injection into a flask, stir at 70°C and 200 rpm for 30 min to obtain a gelatin predissolved product, and keep it at 70°C for later use;
[0062] Add 280.1 g of sterile water for injection into a stirring tank, adjust the temperature to 2°C, add 80 g of tantalum powder, 13.2 g of nano-lithium magnesium silicate and 26.7 g of the above-obtained gelatin predissolved material, stir for 5 min at a vacuum degree of -0.1 MPa and a rotation speed of 1800 rpm to obtain a hydrogel vascular embolization material.
[0063] Methods of using hydrogel vascular embolization materials:
[0064] The hydrogel vascular embolization material is vacuum-filled into a 1 mL syringe for direct use.
[0065] Comparative Example 2 is a hydrogel vascular embolic material, which is different from Example 1 only in that in the preparation method of the hydrogel vascular embolic material, the dispersion temperature is adjusted to 40°C.
[0066] Comparative Example 3, a hydrogel vascular embolic material, is different from Example 1 only in that it is used according to the following method:
[0067] 0.6 mL of the obtained hydrogel vascular embolization material was directly mixed with 0.3 mL of sterile water for injection and then vacuum-filled into a 1 mL syringe for direct use.
[0068] Comparative Example 4, a hydrogel vascular embolic material, prepared and used according to the following method:
[0069] Preparation method of hydrogel vascular embolic material:
[0070] Add 4.5 g of gelatin and 25 g of sterile water for injection into a flask, stir at 70°C and 200 rpm for 30 min to obtain a gelatin predissolved product, and keep it at 70°C for later use;
[0071] Add 156.8 g of sterile water for injection and 123.3 g of drug-loaded solution, i.e., a mixed solution of sterile water for injection in which 20.55 mg of cisplatin is dispersed, into a stirring tank, adjust the temperature to 2°C, add 80 g of tantalum powder, 13.2 g of nano-lithium magnesium silicate and 26.7 g of the above-obtained gelatin predissolved material, and stir for 5 min at a vacuum degree of -0.1 MPa and a rotation speed of 1800 rpm to obtain a hydrogel vascular embolization material.
[0072] Methods of using hydrogel vascular embolization materials:
[0073] The hydrogel vascular embolization material is vacuum-filled into a 1 mL syringe for direct use.
[0074] Performance testing:
[0075] 1. Extrusion force test: Prepare a 130 cm long, 2.8 F microcatheter, and inject the hydrogel vascular embolic material to be used in the embodiment and the comparative example into the microcatheter before the test. Connect the microcatheter filled with vascular embolic agent to the syringe head through the Luer connector, fix the syringe with a clamp, set the pushing speed to 30 mm / min, and the test distance to 20 mm. Record the maximum and average pushing force of the syringe handle during the test, accurate to 0.1 N. The test results are shown in Table 1.
[0076] 2. Modulus change test: Under the conditions of 1% strain and 1 Hz frequency, the test was conducted for 30 minutes to analyze the relationship between the modulus change of the hydrogel vascular embolic material in Example 1 and Comparative Example 1 and the time.
[0077] 3. Shear viscosity change test: at a shear rate of 0.01s -1 Under the conditions of , the test was conducted for 30 min to analyze the relationship between the shear viscosity of the hydrogel vascular embolic materials in Example 1 and Comparative Example 1 and the change over time.
[0078] The experimental results of Experiment 2 and Experiment 3 are shown in Table 2.
[0079] 4. Embolism test: Select pig kidney or pig liver as the embolism model to compare the visualization, embolism effect and diffusion of the hydrogel vascular embolization material after embolism. Figure 1 , Figure 2 and Figure 3 shown.
[0080] 5. Drug sustained release test: 0.5 mL of the hydrogel vascular embolic material samples of Example 2 and Comparative Example 4 were added to 200 mL of normal saline, kept warm at 37°C, and the drug concentration in the normal saline was tested at different time points and converted into drug release ratio. The test results are shown in Table 3.
[0081] Table 1 Extrusion force test results
[0082]
[0083] Table 2 Test results of modulus and shear viscosity change of Example 1 and Comparative Example 1
[0084]
[0085] Table 3 Drug sustained release test results
[0086]
[0087] According to Table 1 and Table 2, combined with Example 1, Comparative Example 1 and other examples and comparative examples, it can be seen that Comparative Example 1 and Comparative Example 2 require a greater extrusion force, which is not conducive to delivering the embolic material to farther and thinner blood vessels during clinical use. And the change in Comparative Example 2 is more obvious than that in Example 1. The reason is that in Comparative Example 2, a common preparation method in the prior art is used to prepare the hydrogel embolic material at 40°C, resulting in the formation of small gel blocks by the thixotropic agent, which is not easy to break and disperse. The presence of these small gel blocks will affect the continuity of delivery and the development effect, which is not conducive to the hydrogel embolic material embolizing small blood vessels; while in the low temperature environment of Example 1, nano-magnesium lithium silicate will first form a uniform suspension in water to avoid agglomeration, and dissolve in water to form a uniform gel during the subsequent stirring process.
[0088] It can be found from Table 2 that at 30 minutes, the storage modulus and loss modulus of Example 1 are equivalent to those of Comparative Example 1. Comparative Example 1 adopts a pre-mixing method to obtain a hydrogel vascular embolic material that can be directly used, indicating that after stabilization, Example 1 can provide an embolic strength equivalent to that of Comparative Example 1 in the blood vessel. The reason is that, through the use method provided in Example 1, the shearing action will break the card house structure of nano magnesium lithium silicate during use, resulting in a decrease in the initial state modulus and shear viscosity, which will enable the hydrogel vascular embolic material to better enter the small blood vessels during the hydrogel delivery process. After the delivery, the modulus of the hydrogel vascular embolic material in the blood vessel will return to the normal value, and the embolic strength will not be affected. In addition, the shear viscosity and extrusion force in Example 1 are lower than those in Comparative Example 1, which also shows that Example 1 is more conducive to delivery than Comparative Example 1. It can be seen that the preparation method and use method provided by the present invention can more effectively promote the uniform dispersion of the hydrogel vascular embolic material and improve the continuity of delivery.
[0089] according to Figure 1 , Figure 2 and Figure 3 , Figure 1 This is a picture showing the effect of embolizing the bilateral renal arteries of a pig in Example 1. It can be seen that the imaging of Example 1 is clear and visible, with good diffusion effect in the blood vessels, and a good filling and embolization effect is achieved in both the main trunk and the lower branches of the renal artery. Figure 2 This is the effect picture of embolization of the pig hepatic artery in Example 3. It can be seen that Example 3 only completed the embolization of the main trunk of the hepatic artery and failed to diffuse to the branches of the hepatic artery. In addition, due to the large extrusion force and difficult delivery, the hydrogel vascular embolization material suddenly gushed out during the doctor's strong pushing and delivery process, resulting in segmented embolization, and a section in the middle of the hepatic artery failed to achieve embolization. Figure 3 is Figure 2 Based on the experiment, a comparison diagram of the embolic materials of Example 1 and Comparative Example 3 was provided on both sides of the same hepatic artery. The left side is the embolization area of Example 1. It can be seen that Example 1 completed the embolization of the main trunk and small branches of the hepatic artery compared with Comparative Example 3, and the delivery was smooth, which was convenient for the doctor's surgical operation. However, the right side obviously did not deliver to the small branches, and the embolization segmentation phenomenon also occurred.
[0090] According to Table 3, in combination with Example 2 and Comparative Example 4, it can be seen that after 6 hours of sustained release, the cisplatin release ratio of Example 2 reaches the maximum value, is basically completely released and tends to be stable within the next 24 hours. In Comparative Example 4, cisplatin is first mixed with the hydrogel vascular embolization material and stored. After refrigerated storage for 1 month, it is found that the maximum cisplatin release ratio is 64.5%, which is much lower than 95.1% of Example 2, indicating that a large amount of cisplatin is mixed in the hydrogel in advance and decomposes and fails during storage.
[0091] It should be noted that, in this article, relational terms such as first and second, etc. are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Moreover, the terms "include", "comprise" or any other variants thereof are intended to cover non-exclusive inclusion, so that a process, method, article or device including a series of elements includes not only those elements, but also other elements not explicitly listed, or also includes elements inherent to such process, method, article or device.
[0092] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.
Claims
1. A method for preparing a hydrogel vascular embolic material, characterized in that: The process steps include: S101. Material A is mixed with a portion of sterile water for injection at 40-70°C to obtain a pre-dissolved product, which is kept warm for later use; S102. The temperature of the remaining sterile water for injection is adjusted to 0-10° C., the pre-dissolved material, material B and developer are added, and vacuum dispersed to obtain a hydrogel vascular embolization material; The material A is a thickener; the material B is a thixotropic agent.
2. The method for preparing the hydrogel vascular embolic material according to claim 1, characterized in that: In the step S102, the temperature of the remaining sterile water for injection is adjusted to 0-3°C.
3. The method for preparing the hydrogel vascular embolic material according to claim 1, characterized in that: The material A comprises a combination of one or more of gelatin, xanthan gum, carbomer gum, chitosan and sodium alginate.
4. The method for preparing the hydrogel vascular embolic material according to claim 1, characterized in that: The material B is a nano-silicate thixotropic agent.
5. The method for preparing the hydrogel vascular embolic material according to claim 4, characterized in that: The nano-silicate thixotropic agent includes one or a combination of nano-lithium magnesium silicate and nano-aluminum magnesium silicate.
6. The method for preparing the hydrogel vascular embolic material according to claim 1, characterized in that: The mass ratio of the material A to the material B is 1:(2-4).
7. The method for preparing the hydrogel vascular embolic material according to claim 1, characterized in that: The total addition amount of the material A and the material B is 5-10 wt % of the total mass of the material A, the material B and the sterile water for injection.
8. The method for preparing the hydrogel vascular embolic material according to claim 1, characterized in that: The developer includes a combination of one or more of an iodine reagent, barium sulfate and tantalum powder.
9. A method for using a hydrogel vascular embolic material, characterized in that: The following steps are involved: S201. Loading the hydrogel vascular embolic material prepared by the method for preparing a hydrogel vascular embolic material according to any one of claims 1 to 8 into syringe A; S202. Loading sterile water for injection into syringe B; S203. Connect syringe A and syringe B through a three-way valve, push and pull the push rods of syringe A and syringe B back and forth to mix the hydrogel embolic material and sterile water for injection evenly; The volume ratio of the hydrogel vascular embolization material to the sterile injection water is (1-5):
1.
10. The method for using the hydrogel vascular embolic material according to claim 9, characterized in that: In step S202, syringe B is loaded with a drug solution.