Polyglyoxylic acid ethyl ester microsphere, preparation method thereof and embolization agent
Through the self-degradation characteristics and solid-liquid ratio optimization of the end-capped polyethyl glycoloxylate, the ectopic embolization problem caused by slow degradation of degradable embolization microspheres is solved, and rapid degradation and accurate amount of embolization maintenance time judgment is achieved.
Patent Information
- Application Number
- CN202411672352.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-11-21
- Publication Date
- 2025-01-10
AI Technical Summary
The existing degradable embolization microspheres are slow to degrade, resulting in ectopic embolization problems, and it is difficult to judge the embolization maintenance time for a long time.
The end-capped polyethyl glycoloxylate is used as the oil-phase component, and the resulting fragments are gradually degraded by the end-end encapsulation group, forming soluble small molecules, improving the problem of residual fragments after degradation, and limiting the solid-liquid ratio and volume ratio optimize microsphere spherical properties and dispersion.
It effectively improves the problem of ectopic embolism after degradation, shortens the degradation time, and facilitates the judgment of the embolism maintenance time.
Smart Images
Figure CN119280458A_ABST
Abstract
Description
Technical Field
[0001] The present application relates to the technical field of embolic microsphere manufacturing, and in particular to a polyethyl glyoxylate microsphere and a preparation method thereof, and an embolic agent. Background Art
[0002] Transarterial embolization (TAE) is a method of delivering embolic materials directly to diseased blood vessels through a catheter, with the aim of blocking blood flow to achieve the effect of treating tumors, controlling bleeding or reducing blood supply. In clinical practice, embolic microspheres have been used in a variety of situations, including liver cancer, uterine fibroids, and traumatic bleeding. Its clinical application success rate is high, and the postoperative recovery time is short. Among them, degradable embolic microspheres have been increasingly widely used in clinical practice due to their good biocompatibility and the ability to degrade in vivo. However, the current degradable embolic microspheres degrade slowly, and degradation easily leads to ectopic embolism problems, which in turn limits the promotion and application of such embolic microspheres. Summary of the invention
[0003] The purpose of the present application is to provide a polyethyl glyoxylate microsphere and a preparation method thereof, and an embolic agent. The polyethyl glyoxylate microsphere prepared by the method can improve the problem that the degradable embolic microsphere is prone to ectopic embolism after degradation, and at the same time, it is also helpful to determine the embolic maintenance time of the degradable embolic microsphere.
[0004] The embodiment of the present application is implemented as follows:
[0005] In a first aspect, the present invention provides a method for preparing polyethyl glyoxylate microspheres, comprising the following steps:
[0006] Polyethyl glyoxylate is dispersed in an organic solvent to obtain an oil phase solution, wherein the polyethyl glyoxylate is a capped polyethyl glyoxylate; the oil phase solution is added into an aqueous phase solution and mixed for reaction to obtain polyethyl glyoxylate microspheres.
[0007] In the prior art, conventional degradable embolic microspheres are usually of the type that undergo random bond breakage and gradual degradation. Such degradable embolic microspheres have a slow degradation rate and a long degradation time, so that some fragments remain after degradation. Due to their small particle size, these fragments are easily distributed in a new space through the flow of blood, thereby embolizing to more distal blood vessels or even flowing back to the venous network through the capillary network, leading to serious non-target embolic side effects (i.e., ectopic embolism, such as pulmonary embolism, etc.); and, due to the long degradation time of such degradable embolic microspheres, it is difficult to effectively determine their corresponding embolic maintenance time. In the present application, end-capped polyethyl glyoxylate with self-degradation properties is used as an oil phase component and is used to prepare degradable embolic microspheres. The degradation form is starting from the encapsulation group at the end and undergoing gradual degradation from beginning to end. The fragments generated during the degradation process will quickly undergo a self-elimination phenomenon, thereby rapidly degrading the entire chain segment of the polymer into soluble small molecules, so that basically no small-particle fragments will remain after degradation, thereby improving the problem that the degradable embolic microspheres are prone to ectopic embolism after degradation; in addition, since the degradation time of the end-capped polyethyl glyoxylate with self-degradation properties is short, it also has the advantage of being easy to judge the maintenance time of embolism.
[0008] In some optional embodiments, the ratio of the solid content in the oil phase solution to the solid content in the water phase solution is 1:(8-12).
[0009] In the above technical solution, the ratio of the solid content in the oil phase solution to the solid content in the water phase solution is limited within a specific range, so that the prepared polyethyl glyoxylate microspheres have better sphericity and better dispersibility.
[0010] In some optional embodiments, the ratio of the solid content in the oil phase solution to the solid content in the water phase solution is 1:10.
[0011] In the above technical solution, the ratio of the solid content in the oil phase solution to the solid content in the water phase solution is limited to a specific value, so that the prepared polyethyl glyoxylate microspheres have better sphericity and better dispersibility.
[0012] In some optional embodiments, the solid content in the oil phase solution is 5-15%.
[0013] In the above technical solution, the solid content in the oil phase solution is limited to a specific range, so as to facilitate the subsequent mixing with the water phase solution to form high-quality polyethyl glyoxylate microspheres.
[0014] In some alternative embodiments, the organic solvent comprises dichloromethane.
[0015] In the above technical solution, the organic solvent contains dichloromethane, which helps polyethyl glyoxylate to be well dissolved and evenly dispersed, and further helps to subsequently mix with the aqueous phase solution to form high-quality polyethyl glyoxylate microspheres.
[0016] In some optional embodiments, the volume ratio of the oil phase solution to the water phase solution is (8-12):1.
[0017] In the above technical solution, the volume ratio of the oil phase solution to the water phase solution is limited within a specific range, so that the prepared polyethyl glyoxylate microspheres have better sphericity and better dispersibility.
[0018] In some optional embodiments, the volume ratio of the oil phase solution to the water phase solution is 10:1.
[0019] In the above technical solution, the volume ratio of the oil phase solution to the water phase solution is limited to a specific value, so that the prepared polyethyl glyoxylate microspheres have better sphericity and better dispersibility.
[0020] In some optional embodiments, the step of preparing the aqueous phase solution includes: dispersing polyvinyl alcohol in water to obtain an aqueous phase solution.
[0021] In the above technical solution, polyvinyl alcohol is used as the main component in the water phase, which can be easily mixed with polyethyl glyoxylate to form high-quality polyethyl glyoxylate microspheres.
[0022] In a second aspect, an embodiment of the present application provides a polyethyl glyoxylate microsphere, which is prepared using the preparation method provided in the embodiment of the first aspect.
[0023] In the above technical scheme, the polyethyl glyoxylate microspheres prepared by the preparation method provided in the first aspect of the embodiment can improve the problem that the degradable embolic microspheres are prone to ectopic embolism after degradation, and at the same time, it is also helpful to determine the embolism maintenance time of the degradable embolic microspheres.
[0024] In a third aspect, an embodiment of the present application provides an embolic agent, comprising the polyethyl glyoxylate microspheres provided in an embodiment of the second aspect. BRIEF DESCRIPTION OF THE DRAWINGS
[0025] In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings required for use in the embodiments will be briefly introduced below. It should be understood that the following drawings only show certain embodiments of the present application and therefore should not be regarded as limiting the scope. For ordinary technicians in this field, other related drawings can be obtained based on these drawings without paying creative work.
[0026] Figure 1A process flow chart of a method for preparing polyethyl glyoxylate microspheres provided in an embodiment of the present application;
[0027] Figure 2 This is an optical microscope image of polyethyl glyoxylate microspheres provided in an embodiment of the present application before degradation;
[0028] Figure 3 This is an optical microscope image of the polyethyl glyoxylate microspheres provided in the examples of the present application after degradation;
[0029] Figure 4 This is an optical microscope image of the gelatin microspheres provided in the examples of the present application before degradation;
[0030] Figure 5 This is an optical microscope image of the gelatin microspheres provided in the examples of the present application after degradation;
[0031] Figure 6 This is a summary of the degradation curves of the polyethyl glyoxylate microspheres and gel microspheres provided in the examples of the present application. DETAILED DESCRIPTION
[0032] In order to make the purpose, technical scheme and advantages of the embodiments of the present application clearer, the technical scheme in the embodiments of the present application will be described clearly and completely below. If the specific conditions are not specified in the embodiments, they are carried out according to the conventional conditions or the conditions recommended by the manufacturer. If the manufacturer is not specified for the reagents or instruments used, they are all conventional products that can be purchased commercially.
[0033] It should be noted that “and / or” in this application, such as “Feature 1 and / or Feature 2”, refers to the three situations of “Feature 1” alone, “Feature 2” alone, or “Feature 1” plus “Feature 2”.
[0034] In addition, in the description of the present application, unless otherwise specified, the meaning of "multiple" in "one or more" refers to two or more; the range of "value a ~ value b" includes the two end values "a" and "b", and the "unit" in "value a ~ value b + unit of measurement" represents the "unit of measurement" of both "value a" and "value b".
[0035] The following is a detailed description of a polyethyl glyoxylate microsphere and its preparation method and embolic agent according to an embodiment of the present application.
[0036] In a first aspect, the present invention provides a method for preparing polyethyl glyoxylate microspheres, comprising the following steps:
[0037] Polyethyl glyoxylate is dispersed in an organic solvent to obtain an oil phase solution, wherein the polyethyl glyoxylate is a capped polyethyl glyoxylate; the oil phase solution is added into an aqueous phase solution and mixed for reaction to obtain polyethyl glyoxylate microspheres.
[0038] In the prior art, conventional degradable embolic microspheres are usually of the type that undergo random bond breakage and gradual degradation. Such degradable embolic microspheres have a slow degradation rate and a long degradation time, so that some fragments remain after degradation. Due to their small particle size, these fragments are easily distributed in a new space through the flow of blood, thereby embolizing to more distal blood vessels or even flowing back to the venous network through the capillary network, leading to serious non-target embolic side effects (i.e., ectopic embolism, such as pulmonary embolism, etc.); and, due to the long degradation time of such degradable embolic microspheres, it is difficult to effectively determine their corresponding embolic maintenance time. In the present application, end-capped polyethyl glyoxylate with self-degradation characteristics is used as an oil phase component and is used to prepare degradable embolic microspheres. The degradation form is starting from the encapsulation group at the end and undergoing gradual degradation from beginning to end. The fragments generated during the degradation process will quickly undergo a self-elimination phenomenon, thereby rapidly degrading the entire chain segment of the polymer into soluble small molecules, so that basically no small-particle fragments will remain after degradation, thereby improving the problem that the degradable embolic microspheres are prone to ectopic embolism after degradation; in addition, the degradation time of the end-capped polyethyl glyoxylate with self-degradation characteristics is short, and it also has the advantage of being easy to judge the maintenance time of embolism.
[0039] It should be emphasized that the main innovation of the present application is that polyethyl glyoxylate with self-degradable properties is introduced into the technical field of degradable embolic microsphere manufacturing, and acutely degradable degradable microspheres are obtained through simple ester bond capping, thereby improving the problem that degradable embolic microspheres are prone to ectopic embolism after degradation. At the same time, it is also helpful to determine the embolic maintenance time of the degradable embolic microspheres.
[0040] It should be noted that the source of the end-capped polyethyl glyoxylate is not limited, for example, it can be purchased from the market, or it can be prepared by itself. The examples of the present application take the self-preparation as an example for auxiliary explanation.
[0041] As an example, the preparation method of end-capped polyethyl glyoxylate comprises the following steps:
[0042] Under anhydrous conditions, ethyl glyoxylate monomer is dissolved in dichloromethane to obtain a 10mol / L monomer solution. Take 50mL monomer solution (500mmol, 1.0 equivalent) and place it at -20°C and stir for 1 hour. After the solution temperature stabilizes, 35μL of triethylamine (250μmmol, 0.0005 equivalent) is added dropwise and kept at -20°C and stirred for 1 hour to initiate the polymerization of ethyl glyoxylate. Subsequently, 710μL of acetyl chloride (1mmol, 0.002 equivalent) is added to the solution, the reaction temperature is raised to room temperature and stirred for 48 hours to end-cap polyethyl glyoxylate. After the reaction is completed, the reaction solution is poured into ethanol for precipitation, and the solid collected after filtration is washed with methanol to obtain end-capped polyethyl glyoxylate.
[0043] It should be noted that in the preparation process of end-capped polyethyl glyoxylate, the relevant process parameters involved (such as raw material type, dosage ratio, reaction temperature and time, etc.) are not fixed values, but can be adaptively adjusted according to actual needs. The embodiment of the present application only provides a specific method that can be implemented as an example.
[0044] It should be noted that the oil phase solution and the water phase solution may be prepared simultaneously, or the water phase solution may be prepared first and then the oil phase solution, or the oil phase solution may be prepared first and then the water phase solution.
[0045] As an example, the ratio of the solid content in the oil phase solution to the solid content in the water phase solution is 1:(8-12), for example but not limited to, the solid content ratio is any one of 1:8, 1:9, 1:10, 1:11 and 1:12 or a range between any two of them.
[0046] In this embodiment, the ratio of the solid content in the oil phase solution to the solid content in the water phase solution is limited to a specific range, so that the prepared polyethyl glyoxylate microspheres have better sphericity and better dispersibility.
[0047] As an example, the ratio of the solid content in the oil phase solution to the solid content in the water phase solution is 1:10.
[0048] In this embodiment, the ratio of the solid content in the oil phase solution to the solid content in the water phase solution is limited to a specific value, so that the prepared polyethyl glyoxylate microspheres have better sphericity and better dispersibility.
[0049] As an example, the solid content in the oil phase solution is 5-15%, for example but not limited to any point value among 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, and 15%, or a range value between any two of the solid content.
[0050] In this embodiment, the solid content in the oil phase solution is limited to a specific range, so as to facilitate subsequent mixing with the water phase solution to form high-quality polyethyl glyoxylate microspheres.
[0051] It should be noted that the type of organic solvent is not limited and can be selected according to routine practices in the art.
[0052] As an example, the organic solvent includes dichloromethane.
[0053] In this embodiment, the organic solvent contains dichloromethane, which helps the polyethyl glyoxylate to be well dissolved and evenly dispersed, and further helps to subsequently mix with the aqueous phase solution to form high-quality polyethyl glyoxylate microspheres.
[0054] As an example, the volume ratio of the oil phase solution to the water phase solution is (8-12):1, such as but not limited to any one of 8:1, 9:1, 10:1, 11:1 and 12:1 or a range between any two of the volume ratios.
[0055] In this embodiment, the volume ratio of the oil phase solution to the water phase solution is limited to a specific range, so that the prepared polyethyl glyoxylate microspheres have better sphericity and better dispersibility.
[0056] As an example, the volume ratio of the oil phase solution to the water phase solution is 10:1.
[0057] In this embodiment, the volume ratio of the oil phase solution to the water phase solution is limited to a specific value, so that the prepared polyethyl glyoxylate microspheres have better sphericity and better dispersibility.
[0058] As an example, the step of preparing the aqueous phase solution includes: dispersing polyvinyl alcohol in water to obtain an aqueous phase solution.
[0059] In this embodiment, polyvinyl alcohol is used as the main component in the water phase, which can be easily mixed with polyethyl glyoxylate to form high-quality polyethyl glyoxylate microspheres.
[0060] It should be noted that any process or step not specifically described or limited in the preparation of polyethyl glyoxylate microspheres may be arranged according to conventional selection in the art.
[0061] As an example, the process flow chart of the preparation method of polyethyl glyoxylate microspheres is exemplarily referred to Figure 1 .
[0062] In a second aspect, an embodiment of the present application provides a polyethyl glyoxylate microsphere, which is prepared using the preparation method provided in the embodiment of the first aspect.
[0063] In the present application, the polyethyl glyoxylate microspheres prepared by the preparation method provided in the first embodiment can improve the problem that the degradable embolic microspheres are prone to ectopic embolism after degradation, and at the same time, it is also helpful to determine the embolism maintenance time of the degradable embolic microspheres.
[0064] In a third aspect, an embodiment of the present application provides an embolic agent, comprising the polyethyl glyoxylate microspheres provided in an embodiment of the second aspect.
[0065] It should be noted that the specific type of embolic agent is not limited and can be adaptively adjusted according to actual needs.
[0066] The features and performance of the present application are further described in detail below in conjunction with the embodiments.
[0067] Example 1
[0068] The present invention provides a method for preparing polyethyl glyoxylate microspheres, comprising the following steps:
[0069] Preparation of S1 polyethyl glyoxylate microspheres
[0070] Under anhydrous conditions, ethyl glyoxylate monomer is dissolved in dichloromethane to obtain a 10mol / L monomer solution. Take 50mL monomer solution (500mmol, 1.0 equivalent) and place it at -20°C and stir for 1 hour. After the solution temperature stabilizes, 35μL of triethylamine (250μmmol, 0.0005 equivalent) is added dropwise and kept at -20°C and stirred for 1 hour to initiate the polymerization of ethyl glyoxylate. Subsequently, 710μL of acetyl chloride (1mmol, 0.002 equivalent) is added to the solution, the reaction temperature is raised to room temperature and stirred for 48 hours to end-cap polyethyl glyoxylate. After the reaction is completed, the reaction solution is poured into ethanol for precipitation, and the solid collected after filtration is washed with methanol to obtain end-capped polyethyl glyoxylate.
[0071] Preparation of S2 polyethyl glyoxylate microspheres
[0072] 10 g of the blocked poly(ethyl glyoxylate) in S1 was dispersed in 100 mL of dichloromethane to obtain an oil phase solution; 10 g of poly(vinyl alcohol) (PVA1788) was dispersed in 1000 mL of deionized water and stirred at 500 rpm to obtain an aqueous phase solution; the oil phase solution was added dropwise to the aqueous phase solution and stirred at room temperature (25°C) for 24 hours. After the reaction, the mixture was washed with ultrapure water and ethanol and filtered to obtain poly(ethyl glyoxylate) microspheres.
[0073] Test example
[0074] 100 mg of each of the polyethyl glyoxylate microspheres with a particle size of 100 to 300 μm and the gelatin microspheres prepared by formaldehyde cross-linking (purchased from Hainan Biomaike Medical Technology Co., Ltd.) in Example 1 were added to 10 mL of normal saline and incubated in a 37°C water bath shaker. The initial morphology and the morphology after degradation of the microspheres were photographed under an optical microscope (200 times), and the particle size of the degraded fragments was statistically analyzed and summarized in Table 1; and the degradation curve was drawn by monitoring the mass changes of each group of microspheres.
[0075] The steps for monitoring the mass changes of each group of microspheres are as follows:
[0076] First, the initial mass of the microspheres is recorded, and then the remaining mass of the microspheres is measured every other day until the microspheres are completely degraded. Finally, all the measured data are summarized and the corresponding degradation curve is drawn.
[0077] Table 1
[0078] sample Number of 10~20μm Number of 20~50μm Number of 50~100μm Polyethyl glyoxylate microspheres 0 0 0 Gelatin Microspheres 145 102 32
[0079] See also Figure 2 to Figure 5 (in, Figure 2 and Figure 3 Optical microscope images of polyethyl glyoxylate microspheres before and after degradation, Figure 4 and Figure 5 The optical microscope images (corresponding to the gelatin microspheres before and after degradation) and Table 1 show that a large number of insoluble fragments of 10 to 100 μm will remain after the degradation of the gelatin microspheres. These fragments may undergo a new spatial distribution through the flow of blood due to their small particle size, thereby embolizing to more distal blood vessels or even flowing back to the venous network through the capillary network, leading to serious non-target embolic side effects (such as pulmonary embolism). However, due to the self-degradation characteristics of polyethyl glyoxylate microspheres, their fragments will spontaneously self-degrade after degradation, thereby quickly degrading the polymer chain segments into soluble small molecules. This has also been verified in the observation results after degradation, that is, no insoluble fragments of 10 to 100 μm were observed, thereby improving the problem of ectopic embolism that the degradable embolic microspheres are prone to cause after degradation.
[0080] See also Figure 6It can be seen that the degradation curve of gelatin microspheres showed a gentle downward trend, and it took about 7 days for the mass to drop from 80% to 20%; while the mass of polyethyl glyoxylate microspheres began to drop suddenly on the 7th day, and it took about 2 days to drop from 80% to 20%, and it was completely degraded on the 11th day. From the structural composition of the two, the degradation of gelatin microspheres is caused by the gradual hydrolysis and cleavage of the amide bonds in the gelatin molecules. A single gelatin segment needs to hydrolyze a certain number of amide bonds to destroy the microsphere structure, resulting in slow degradation; and polyethyl glyoxylate, due to its self-degradation characteristics, will quickly undergo self-elimination after the acetate at the end group breaks, thereby degrading the entire polyethyl glyoxylate segment, thereby inducing rapid degradation. Affected by these two different forms of degradation modes, the embolization maintenance time of gelatin microspheres in vivo becomes difficult to predict, and may occur at any stage of the degradation process; and due to its rapid degradation characteristics, the degradation duration of polyethyl glyoxylate is very short, which can effectively judge its embolization maintenance time.
[0081] The embodiments described above are part of the embodiments of the present application, rather than all of the embodiments. The detailed description of the embodiments of the present application is not intended to limit the scope of the present application for protection, but merely represents the selected embodiments of the present application. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present application.
Claims
1. A method for preparing polyethyl glyoxylate microspheres, characterized in that: The following steps are involved: Dispersing poly(ethyl glyoxylate) in an organic solvent to obtain an oil phase solution, wherein the poly(ethyl glyoxylate) is a capped poly(ethyl glyoxylate); The oil phase solution is added into the water phase solution and mixed for reaction to obtain polyethyl glyoxylate microspheres.
2. The method for preparing polyethyl glyoxylate microspheres according to claim 1, characterized in that: The ratio of the solid content in the oil phase solution to the solid content in the water phase solution is 1:(8-12).
3. The method for preparing polyethyl glyoxylate microspheres according to claim 2, characterized in that: The ratio of the solid content in the oil phase solution to the solid content in the water phase solution is 1:
10.
4. The method for preparing polyethyl glyoxylate microspheres according to claim 2, characterized in that: The solid content of the oil phase solution is 5-15%.
5. The method for preparing polyethyl glyoxylate microspheres according to claim 1, characterized in that: The organic solvent includes dichloromethane.
6. The method for preparing polyethyl glyoxylate microspheres according to any one of claims 1 to 5, characterized in that: The volume ratio of the oil phase solution to the water phase solution is (8-12):
1.
7. The method for preparing polyethyl glyoxylate microspheres according to claim 6, characterized in that: The volume ratio of the oil phase solution to the water phase solution is 10:
1.
8. The method for preparing polyethyl glyoxylate microspheres according to any one of claims 1 to 5, characterized in that: The preparation step of the aqueous phase solution comprises: dispersing polyvinyl alcohol in water to obtain the aqueous phase solution.
9. A polyethyl glyoxylate microsphere, characterized in that: The method is prepared according to any one of claims 1 to 8.
10. An embolic agent, characterized in that: The invention comprises the polyethyl glyoxylate microspheres as claimed in claim 9.