Embolic microspheres, a preparation method thereof and drug-loaded embolic microspheres

Abstract

The application provides an embolization microsphere, a preparation method thereof and a drug-loaded embolization microsphere, and belongs to the technical field of embolization microsphere manufacturing. The preparation method of the embolization microsphere comprises the following steps: dispersing first photosensitive end-capped polyglycolic acid ethyl ester and second photosensitive end-capped polyglycolic acid ethyl ester in an organic solvent to obtain an oil phase solution; wherein the number average molecular weight of the first photosensitive end-capped polyglycolic acid ethyl ester is different from the number average molecular weight of the second photosensitive end-capped polyglycolic acid ethyl ester; and adding the oil phase solution into an aqueous phase solution and mixing to react, to obtain the embolization microsphere. The embolization microsphere prepared by the method contains photosensitive end-capped polyglycolic acid ethyl esters with different number average molecular weights, so that the microsphere has excellent stability under light-proof conditions and can be quickly and completely degraded after light excitation, thereby being capable of terminating embolization in real time and controllably according to clinical imaging or changes in the disease condition after surgery, and also capable of improving the problem of ectopic embolization of blood vessel distal ends caused by microsphere degradation.

Description

Technical Field

[0001] This application relates to the field of embolization microsphere manufacturing technology, and more specifically, to an embolization microsphere, a method for preparing the same, and a drug-loaded embolization microsphere. Background Technology

[0002] Transarterial embolization (TAE) is an important clinical treatment for tumors (such as liver cancer and uterine fibroids) and for controlling bleeding. Biodegradable embolic microspheres have attracted considerable attention due to their potential to improve complications associated with long-term placement of materials. Self-degradable polymers (SIPs), after the removal of unstable end-capping groups, undergo a complete depolymerization cascade, exhibiting an extremely rapid acute degradation curve. However, most commercially available biodegradable microspheres (such as PLGA, gelatin, and starch microspheres) are passively degraded (e.g., passive hydrolysis or passive enzymatic hydrolysis). This passive degradation method is closely related to the local tissue fluid environment, pH value, and enzyme concentration in the patient's body. The degradation process and rate cannot be artificially intervened, making it impossible to terminate embolization in a real-time and controllable manner based on clinical angiography or changes in the patient's condition after surgery. Furthermore, commonly used biodegradable embolic materials such as PLGA and gelatin are prone to generating micron-sized fragments during degradation, which can easily trigger ectopic embolism in peripheral blood vessels. Summary of the Invention

[0003] The purpose of this application is to provide an embolization microsphere, a method for preparing the same, and a drug-loaded embolization microsphere. The embolization microsphere prepared by this method contains photosensitive end-capped polyglyoxylate with different number-average molecular weights, which makes the microsphere have excellent stability under light-protected conditions and can rapidly and completely degrade after photoexcitation. This allows for real-time and controllable termination of embolization based on clinical angiography or changes in the patient's condition after surgery, and can also improve the problem of ectopic embolism in the distal blood vessels caused by microsphere degradation.

[0004] The embodiments of this application are implemented as follows: In a first aspect, embodiments of this application provide a method for preparing embolization microspheres, comprising the following steps: dispersing a first photosensitive end-capped poly(ethylene glyoxylate) and a second photosensitive end-capped poly(ethylene glyoxylate) in an organic solvent to obtain an oil phase solution; wherein the number-average molecular weight of the first photosensitive end-capped poly(ethylene glyoxylate) and the number-average molecular weight of the second photosensitive end-capped poly(ethylene glyoxylate) are different; adding the oil phase solution to an aqueous phase solution and mixing and reacting to obtain embolization microspheres.

[0005] In the above technical solution, the oil phase solution simultaneously contains a first photosensitive end-capped polyethylene glycol (PEG) and a second photosensitive end-capped PEG with different number-average molecular weights. The combined use of high and low number-average PEGs effectively maintains the stability of the microspheres in the unexcited state (high and low molecular weight PEGs can form an interpenetrating and entangled dense network, significantly improving the mechanical strength and anti-swelling stability of the microspheres, thus enhancing their stability in the unexcited state), and also allows the microspheres to completely degrade within a suitable timeframe after photoexcitation (after photoexcitation). The low molecular weight component completes the cascade depolymerization first, forming a large number of pores and degradation channels inside the microspheres, which greatly improves the contact efficiency between water molecules and degradation active sites. On this basis, the high molecular weight component, which originally took a very long time to degrade when it existed alone, can simultaneously promote depolymerization by relying on the degradation channels formed inside. The overall complete degradation time is compressed to a clinically acceptable range, meeting the need for rapid termination of embolization as needed after embolization. Thus, embolization can be terminated in real time and in a controllable manner according to clinical angiography or changes in the condition after the operation. It can also improve the problem of ectopic embolization in the terminal blood vessels caused by microsphere degradation.

[0006] In some alternative embodiments, the number-average molecular weight difference between the first photosensitive end-capped polyacetallate and the second photosensitive end-capped polyacetallate is 45 kDa to 90 kDa.

[0007] In the above technical solution, the difference in number-average molecular weight between the first photosensitive end-capped polyoxyethylene ester and the second photosensitive end-capped polyoxyethylene ester is precisely limited within the above range, which has many advantages: (1) Within this difference range, the two types of photosensitive end-capped polyoxyethylene esters with different molecular weights can achieve good miscibility in organic solvents, and it is not easy to have phase separation problems caused by excessive molecular weight difference, so as to form high-quality microspheres with high sphericity, relatively uniform particle size, adhesion and few irregular defects. (2) Within this difference range, the high and low molecular weight photosensitive end-capped polyoxyethylene esters can form a more suitable interpenetrating entangled network. The high molecular weight long chain can fully bind the spontaneous movement of the low molecular weight short chain, thereby effectively blocking the unexpected spontaneous cascade depolymerization of the low molecular weight component, which greatly improves the stability of the microspheres at room temperature and greatly reduces the risk of premature degradation during in vivo storage. (3) Within this difference range, the pore channel size formed after photolysis of low molecular weight components is more suitable, allowing water molecules to quickly penetrate into the core area of ​​microspheres. The cascade depolymerization of high molecular weight components can be promoted simultaneously, and the overall complete degradation time can be stably controlled within the appropriate range for clinical use, so as to better adapt to the personalized embolization time requirements of different TAE scenarios such as liver cancer, uterine fibroids, and trauma hemostasis.

[0008] In some alternative embodiments, the first photosensitive end-capped polyoxyethylene ester has a number-average molecular weight of 30 kDa to 45 kDa, and the second photosensitive end-capped polyoxyethylene ester has a number-average molecular weight of 90 kDa to 120 kDa.

[0009] In the above technical solution, when the difference in number-average molecular weight of the two photosensitive end-capped polyoxyethylene esters is in the range of 45 kDa to 90 kDa, limiting the number-average molecular weight of the two photosensitive end-capped polyoxyethylene esters to the above range has many effects: (1) The two photosensitive end-capped polyoxyethylene esters can achieve uniform miscibility in organic solvents, without layering or precipitation, and the oil phase is uniform and stable, so as to emulsify and prepare microspheres with high sphericity, relatively uniform particle size, adhesion and few irregular defects. (2) The molecular chains of high and low molecular weight can form a more suitable interpenetrating entangled network, and the high molecular weight long chain can fully bind the spontaneous movement of the low molecular weight short chain, thereby more effectively blocking the unexpected spontaneous cascade depolymerization of the low molecular weight component, which greatly improves the stability of the microspheres at room temperature storage and greatly reduces the risk of premature degradation during in vivo storage. (3) The pore channel size formed by the photolysis of low molecular weight photosensitive end-capped polyacetal ethyl ester is more suitable, allowing water molecules to quickly penetrate into the core area of ​​the microspheres. The cascade depolymerization of high molecular weight components can be promoted simultaneously, and the overall complete degradation time can be stably controlled within the appropriate range for clinical use, so as to better adapt to the personalized embolization time requirements of different TAE scenarios such as liver cancer, uterine fibroids, and trauma hemostasis.

[0010] In some alternative implementations, the feed mass of the first photosensitive end-capped polyoxyethylene ester is higher than that of the second photosensitive end-capped polyoxyethylene ester.

[0011] In the above technical solutions, the low molecular weight first photosensitive end-capped polyoxyethylene ester has a higher mass and has many advantages: (1) The low molecular weight photosensitive end-capped polyoxyethylene ester has a higher proportion, the viscosity of the oil phase solution is more suitable for the low shear emulsification process, the sphere formation process is more gentle, and embolization microspheres with more uniform particle size and less adhesion can be prepared. (2) The low molecular weight component has a higher proportion, the degradation products of low molecular weight polyoxyethylene ester have smaller molecular weights, faster in vivo metabolism, and are less likely to form large molecular residues in local tissues. This can effectively reduce the probability of local inflammatory reactions caused by large molecular foreign body residues, and can also better improve the problem of ectopic embolism in the terminal blood vessels caused by microsphere degradation. (3) The low molecular weight component has a higher proportion, the response threshold of the light signal that triggers microsphere degradation is lower, the response speed is faster, and it can better meet the need for rapid termination of embolism as needed after embolization.

[0012] In some alternative embodiments, the ratio of the mass of the first photosensitive end-capped polyethylene glyoxylate to the mass of the second photosensitive end-capped polyethylene glyoxylate is (2~10):1.

[0013] In the above technical solution, when there is more low molecular weight photosensitive end-capped polyoxyethylene ester, the mass ratio of the two is further limited to the above range, which has many effects: (1) The viscosity of the oil phase solution is more suitable for the low shear emulsification process, the spheroidization process is more gentle, and embolization microspheres with more uniform particle size, higher sphericity and less adhesion can be prepared. (2) The system still retains a sufficient proportion of high molecular weight photosensitive end-capped polyoxyethylene ester, which is sufficient to form a continuous molecular entanglement network, which can effectively restrain the spontaneous movement of low molecular weight short chains, thereby improving the stability of microspheres in the unexcited state. (3) With this precise range ratio, the total density of low molecular weight photosensitive end-capped sites is in a better range, the response sensitivity is higher, and the cascade depolymerization can be quickly started after photoexcitation. Moreover, after photoexcitation, the time for complete degradation of microspheres can be precisely controlled within 3 h to 12 h, which is perfectly suitable for clinical emergency scenarios such as traumatic massive hemorrhage and postoperative temporary hemostasis that require rapid embolization relief. (4) The degradation products are small molecule glyoxylate derivatives (which do not produce micron-sized polymer fragments). They are metabolized quickly in the body and can be completely excreted through the human body circulation in a short time. This effectively reduces the chance of local inflammatory reactions caused by the residue of large molecule foreign substances, and can also improve the problem of ectopic embolism in the peripheral blood vessels caused by microsphere degradation.

[0014] In some optional embodiments, the preparation steps of photosensitive end-capped polyethyl glyoxylate include: a polymerization step: under light-protected conditions, adding ethyl glyoxylate monomer and initiator to an anhydrous organic solvent, mixing and carrying out a polymerization reaction at -18°C to -22°C; an end-capping step: adding a photosensitive end-capping agent and initiator to the reaction system, then heating to 35°C to 45°C and reacting for 10 h to 20 h; wherein, in the polymerization step, controlling the molar ratio of ethyl glyoxylate monomer to initiator to be different, to obtain a first photosensitive end-capped polyethyl glyoxylate and a second photosensitive end-capped polyethyl glyoxylate respectively.

[0015] In the above technical solutions, the preparation methods of the first photosensitive end-capped poly(ethylene glyoxylate) and the second photosensitive end-capped poly(ethylene glyoxylate) are highly consistent. The only difference between the two processes is the molar ratio of the glyoxylate monomer and the initiator. This preparation process has many advantages: (1) The core operating parameters of the two preparation processes are highly consistent. Only the molar ratio of the monomer and the initiator needs to be adjusted according to the number average molecular weight required for the two photosensitive end-capped poly(ethylene glyoxylate) to produce two types of target products simultaneously on the same production equipment, which greatly reduces the production control cost. (2) The polymerization environment of light-proof and low temperature throughout the process can reduce the probability of unexpected side reactions of the glyoxylate monomer, thereby preparing photosensitive end-capped poly(ethylene glyoxylate) with high molecular chain structure regularity and no obvious chain branching defects, thus laying the foundation for the subsequent formation of a stable interpenetrating entangled network. (3) Adding an initiator during the end-capping process of the photosensitive end-capping agent can activate the active end groups of polyacetylacetate molecules more efficiently and thoroughly, and greatly improve the grafting rate of the photosensitive end-capping agent. At the same time, the constant temperature reaction at 35℃~45℃ for 10 h~20 h is suitable for the reactivity of most o-nitrobenzyl and coumarin photosensitive end-capping agents. The end-capping groups are firmly grafted and are not easy to fall off prematurely during storage.

[0016] In some alternative embodiments, the photosensitive end-capped polyethylene glyoxylate is a first photosensitive end-capped polyethylene glyoxylate, in which the molar ratio of glyoxylate monomer to initiator in the polymerization step is 1:(0.0008~0.0015); the photosensitive end-capped polyethylene glyoxylate is a second photosensitive end-capped polyethylene glyoxylate, in which the molar ratio of glyoxylate monomer to initiator in the polymerization step is 1:(0.0002~0.0005).

[0017] In the above technical solution, by controlling the molar ratio of glyoxylate monomer and initiator within the above range, the number-average molecular weight of the prepared first photosensitive end-capped polyglyoxylate can be accurately placed in the range of 30 kDa to 45 kDa. At the same time, the number-average molecular weight of the prepared first photosensitive end-capped polyglyoxylate can also be accurately placed in the range of 90 kDa to 120 kDa. Two photosensitive end-capped poly(ethylene glyoxylate) molecules with similar number-average molecular weights are well-compatible and miscible in organic solvents, minimizing the risk of phase separation due to large molecular weight differences. This results in the formation of high-quality microspheres with high sphericity, uniform particle size, minimal adhesion, and few irregular defects. Furthermore, they form well-matched interpenetrating entangled networks, where the high-molecular-weight long chains effectively restrain the spontaneous movement of the low-molecular-weight short chains, thus effectively blocking the unexpected spontaneous cascade depolymerization of low-molecular-weight components. This significantly improves the stability of the microspheres during room temperature storage and greatly reduces the risk of premature degradation during in vivo placement. In addition, the complete degradation time of the microspheres after photoexcitation can be stably controlled within the clinically appropriate range, better adapting to the personalized embolization duration requirements of different TAE scenarios such as liver cancer, uterine fibroids, and trauma hemostasis. It also effectively mitigates the problem of ectopic embolism in peripheral blood vessels caused by microsphere degradation.

[0018] In some alternative embodiments, the photosensitive end-capping agent is selected from at least one of o-nitrobenzyl chloroformate, o-nitrobenzyl alcohol, o-nitrobenzyl ether derivatives, bromohydroxycoumarin, and 7-aminocoumarin-4-acetic acid.

[0019] In the above technical solutions, there are many types of photosensitive capping agents that can be applied, providing a wide range of feasible implementation schemes, which facilitates the promotion and application of the technical solutions provided in the embodiments of this application. At the same time, the rich variety of optional capping agents can flexibly adapt to different clinical light source scenarios. Corresponding capping agents can be found from conventional ultraviolet light to near-infrared light bands, further expanding the promotion space of the product in different clinical scenarios. Moreover, the above-mentioned photosensitive capping agents are all medical-grade photoresponsive materials with good biocompatibility.

[0020] Secondly, embodiments of this application provide an embolization microsphere, which is prepared by the same preparation method as provided in the first aspect embodiment, and the average particle size of the embolization microsphere is 20 μm to 300 μm.

[0021] In the above technical solution, the embolization microspheres are prepared by the preparation method provided in the first aspect embodiment. The embolization microspheres prepared by this method contain photosensitive end-capped polyacetallate with different number average molecular weights. By photocontrolled removal of the photosensitive end-capping groups, the cascade depolymerization of the embolization microspheres from beginning to end can be triggered, thereby enabling real-time and controllable termination of embolization according to clinical angiography or changes in the patient's condition after surgery. More importantly, limiting the average particle size of the embolization microspheres to the above range has many advantages: (1) Microspheres in this particle size range can pass smoothly through the 2.7F~3F interventional microcatheters commonly used in clinical practice. The pushing process is less prone to blockage and microsphere breakage, greatly improving the smoothness of interventional operations. In addition, this particle size range can accurately target and embolize the target vascular bed of solid tumors such as liver cancer and uterine fibroids. (2) The light signal inside the microspheres in this particle size range can be fully penetrated, and the photosensitive end cap groups can be uniformly activated, which can effectively improve the problem of insufficient light signal in the core area of ​​the microsphere, which leads to degradation obstruction. In addition, the degradation channel generated after photoexcitation can quickly penetrate the entire microsphere at this particle size scale, ensuring the smooth progress of the cascade depolymerization process and effectively reducing the probability of local inflammatory reactions caused by large-sized foreign body residues.

[0022] Thirdly, embodiments of this application provide a drug-loaded embolization microsphere, comprising a drug and an embolization microsphere as provided in the second aspect embodiment, wherein the drug is loaded onto the embolization microsphere. Attached Figure Description

[0023] To more clearly illustrate the technical solutions of the embodiments of this application, the accompanying drawings used in the embodiments will be briefly introduced below. It should be understood that the following drawings only show some embodiments of this application and should not be regarded as a limitation of the scope. For those skilled in the art, other related drawings can be obtained based on these drawings without creative effort.

[0024] Figure 1 A process flow diagram of a method for preparing embolization microspheres provided in this application embodiment; Figure 2 This is a schematic diagram of the degradation of the embolization microspheres provided in the embodiments of this application under photoexcitation. Detailed Implementation

[0025] To make the objectives, technical solutions, and advantages of the embodiments of this application clearer, the technical solutions in the embodiments of this application will be clearly and completely described below. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased commercially.

[0026] It should be noted that the terms "and / or" in this application, such as "feature 1 and / or feature 2", all refer to the three cases of "feature 1" alone, "feature 2" alone, and "feature 1" plus "feature 2".

[0027] In addition, in the description of this application, unless otherwise stated, "one or more" means two or more; the range of "numerical value a to numerical value b" includes the two endpoints "a" and "b"; and "unit of measurement" in "numerical value a to numerical value b + unit of measurement" represents the "unit of measurement" of both "numerical value a" and "numerical value b".

[0028] The following is a detailed description of an embolization microsphere, its preparation method, and a drug-loaded embolization microsphere according to an embodiment of this application.

[0029] In a first aspect, embodiments of this application provide a method for preparing embolization microspheres, comprising the following steps: dispersing a first photosensitive end-capped poly(ethylene glyoxylate) and a second photosensitive end-capped poly(ethylene glyoxylate) in an organic solvent to obtain an oil phase solution; wherein the number-average molecular weight of the first photosensitive end-capped poly(ethylene glyoxylate) and the number-average molecular weight of the second photosensitive end-capped poly(ethylene glyoxylate) are different; adding the oil phase solution to an aqueous phase solution and mixing and reacting to obtain embolization microspheres.

[0030] In this application, the oil phase solution simultaneously contains a first photosensitive end-capped polyethylene glycol (PEG) and a second photosensitive end-capped PEG with different number-average molecular weights. The combined use of high and low number-average PEGs effectively maintains the stability of the microspheres in the unexcited state (high and low molecular weight PEGs can form an interpenetrating entangled dense network, significantly improving the mechanical strength and anti-swelling stability of the microspheres, thus enhancing their stability in the unexcited state), and also allows the microspheres to completely degrade within a suitable timeframe after photoexcitation (low molecular weight PEGs after photoexcitation...). The molecular weight components first complete cascade depolymerization, forming numerous pores and degradation channels within the microspheres, significantly improving the contact efficiency between water molecules and degradation active sites. Based on this, the high molecular weight components, which originally took a very long time to degrade when existing alone, can simultaneously depolymerize through the degradation channels already formed inside. The overall complete degradation time is compressed to a clinically acceptable range, meeting the need for rapid termination of embolization as needed after embolization. This allows for real-time and controllable termination of embolization based on clinical angiography or changes in the patient's condition after surgery, and can also improve the problem of ectopic embolization in the distal blood vessels caused by microsphere degradation.

[0031] It should be noted that the core reason for using two different number-average molecular weight photosensitive end-capped polyethylene glycol (PEG) esters in combination is that the inventors discovered that if only a single low-molecular-weight PEG ester is used, it is prone to spontaneous depolymerization without photoexcitation, resulting in poor stability of the microspheres in the untriggered state, which is insufficient to meet the basic requirements for use. Conversely, if only a single high-molecular-weight PEG ester is used, the time required for complete degradation after photoexcitation is too long, making it difficult to meet the requirement for rapid degradation after clinical embolization. Therefore, this application is the first to combine two number-average molecular weight PEG esters in combination to construct an embolic microsphere more suitable for clinical needs.

[0032] As an example, the number-average molecular weight difference between the first photosensitive end-capped polyoxyethylene and the second photosensitive end-capped polyoxyethylene is 45 kDa to 90 kDa, for example, but not limited to any one of the differences of 45 kDa, 50 kDa, 60 kDa, 70 kDa, 80 kDa and 90 kDa or any range between the two.

[0033] In this embodiment, the difference in number-average molecular weight between the first and second photosensitive end-capped polyoxyethylene esters is precisely limited to the above-mentioned range, which has many advantages: (1) Within this difference range, the two types of photosensitive end-capped polyoxyethylene esters can achieve good miscibility in organic solvents, and it is not easy to have phase separation problems caused by excessive molecular weight difference, thereby forming high-quality microspheres with high sphericity, relatively uniform particle size, adhesion and few irregular defects. (2) Within this difference range, the high and low molecular weight photosensitive end-capped polyoxyethylene esters can form a more suitable interpenetrating entangled network. The high molecular weight long chain can fully bind the spontaneous movement of the low molecular weight short chain, thereby effectively blocking the unexpected spontaneous cascade depolymerization of the low molecular weight component, which greatly improves the stability of the microspheres at room temperature and greatly reduces the risk of premature degradation during in vivo storage. (3) Within this difference range, the pore channel size formed after photolysis of low molecular weight components is more suitable, allowing water molecules to quickly penetrate into the core area of ​​microspheres. The cascade depolymerization of high molecular weight components can be promoted simultaneously, and the overall complete degradation time can be stably controlled within the appropriate range for clinical use, so as to better adapt to the personalized embolization time requirements of different TAE scenarios such as liver cancer, uterine fibroids, and trauma hemostasis.

[0034] As an example, the first photosensitive end-capped polyoxyethylene ester has a number average molecular weight of 30 kDa to 45 kDa (e.g., but not limited to any one of 30 kDa, 32 kDa, 34 kDa, 36 kDa, 38 kDa, 40 kDa, 42 kDa, 44 kDa and 45 kDa or any range between the two), and the second photosensitive end-capped polyoxyethylene ester has a number average molecular weight of 90 kDa to 120 kDa (e.g., but not limited to any one of 90 kDa, 95 kDa, 100 kDa, 105 kDa, 110 kDa, 115 kDa and 120 kDa or any range between the two).

[0035] In this embodiment, when the difference in number-average molecular weight of the two photosensitive end-capped polyoxyethylene esters is in the range of 45 kDa to 90 kDa, limiting the number-average molecular weight of the two photosensitive end-capped polyoxyethylene esters to the above range has many advantages: (1) The two photosensitive end-capped polyoxyethylene esters can achieve uniform miscibility in organic solvents, without layering or precipitation, and the oil phase is uniform and stable, thereby enabling the preparation of microspheres with high sphericity, relatively uniform particle size, adhesion, and few irregular defects through emulsification. (2) The molecular chains of high and low molecular weights can form a more suitable interpenetrating entangled network, and the high molecular weight long chain can fully bind the spontaneous movement of the low molecular weight short chain, thereby more effectively blocking the unexpected spontaneous cascade depolymerization of the low molecular weight component, which greatly improves the stability of the microspheres during room temperature storage and greatly reduces the risk of premature degradation during in vivo storage. (3) The pore channel size formed by the photolysis of low molecular weight photosensitive end-capped polyacetal ethyl ester is more suitable, allowing water molecules to quickly penetrate into the core area of ​​the microspheres. The cascade depolymerization of high molecular weight components can be promoted simultaneously, and the overall complete degradation time can be stably controlled within the appropriate range for clinical use, so as to better adapt to the personalized embolization time requirements of different TAE scenarios such as liver cancer, uterine fibroids, and trauma hemostasis.

[0036] It is understandable that, since the embodiments of this application use two photosensitive end-capped polyacetalates with different number-average molecular weights in combination, the stability of the microspheres in the unexcited state and the complete degradation time after photoexcitation are closely related not only to the number-average molecular weight but also to the mass ratio of the two.

[0037] As an example, the feed mass of the first photosensitive end-capped polyoxyethylene ester is higher than that of the second photosensitive end-capped polyoxyethylene ester.

[0038] In this embodiment, the low molecular weight first photosensitive end-capped polyoxyethylene ester has a higher mass and has many advantages: (1) The high proportion of low molecular weight photosensitive end-capped polyoxyethylene ester makes the viscosity of the oil phase solution more suitable for low-shear emulsification process, and the spheroidization process is more gentle, which can produce embolization microspheres with more uniform particle size and less adhesion. (2) The high proportion of low molecular weight component makes the degradation products of low molecular weight polyoxyethylene ester smaller in molecular weight, and the metabolism rate in vivo is faster. It is not easy to form large molecular residues in local tissues, which can effectively reduce the probability of local inflammatory reactions caused by large molecular foreign body residues, and can also better improve the problem of ectopic embolism in the terminal blood vessels caused by microsphere degradation. (3) The high proportion of low molecular weight component makes the response threshold of the light signal that triggers microsphere degradation lower, the response speed is faster, and it can better meet the need for rapid termination of embolism as needed after embolization.

[0039] As an example, the ratio of the mass of the first photosensitive end-capped polyoxyethylene ester to the mass of the second photosensitive end-capped polyoxyethylene ester is (2~10):1, for example, but not limited to any one of the ratios 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1 and 10:1 or any range between the two.

[0040] In this embodiment, when there is more low molecular weight photosensitive end-capped polyoxyethylene ester, the mass ratio of the two is further limited to the above range, which has many effects: (1) The viscosity of the oil phase solution is more suitable for the low shear emulsification process, the spheroidization process is more gentle, and embolization microspheres with more uniform particle size, higher sphericity and less adhesion can be prepared. (2) A sufficient proportion of high molecular weight photosensitive end-capped polyoxyethylene ester is still retained in the system, which is sufficient to form a continuous molecular entanglement network, which can effectively restrain the spontaneous movement of low molecular weight short chains, thereby improving the stability of microspheres in the unexcited state. (3) With this precise range ratio, the total density of low molecular weight photosensitive end-capped sites is in a better range, the response sensitivity is higher, and the cascade depolymerization can be quickly started after photoexcitation. Moreover, after photoexcitation, the time for complete degradation of microspheres can be precisely controlled within 3 h to 12 h, which is perfectly suitable for clinical emergency scenarios such as traumatic massive hemorrhage and postoperative temporary hemostasis that require rapid embolization relief. (4) The degradation products are small molecule glyoxylate derivatives (which do not produce micron-sized polymer fragments). They are metabolized quickly in the body and can be completely excreted through the human body circulation in a short time. This effectively reduces the chance of local inflammatory reactions caused by the residue of large molecule foreign substances, and can also improve the problem of ectopic embolism in the peripheral blood vessels caused by microsphere degradation.

[0041] In other possible implementations, the ratio of the mass of the first photosensitive end-capped polyoxyethylene ester and the mass of the second photosensitive end-capped polyoxyethylene ester can be flexibly adjusted according to actual application requirements.

[0042] As an example, the preparation steps of photosensitive capped poly(glyoxylate) include: a polymerization step: under light-protected conditions, adding glyoxylate monomer and initiator to an anhydrous organic solvent and mixing, and carrying out a polymerization reaction at -18°C to -22°C (e.g., but not limited to any one of -18°C, -19°C, -20°C, -21°C, and -22°C, or any range between any two); a capping step: adding a photosensitive capping agent and initiator to the reaction system, then heating to 35°C to 45°C (e.g., but not limited to any one of 35°C, 37°C, 39°C, 40°C, 42°C, and 45°C, or any range between any two) and reacting for 10 h to 20 h (e.g., but not limited to 10 h, 12 h, 14 h, 16 h, 18 h, and 20 h). (Any point value in h or any range value between two); wherein, in the polymerization step, the molar ratio of glyoxylate monomer to initiator is controlled to be different, so as to obtain the first photosensitive end-capped polyglyoxylate and the second photosensitive end-capped polyglyoxylate respectively.

[0043] In this embodiment, the preparation methods of the first and second photosensitive end-capped poly(ethylene glyoxylate) are highly consistent. The only difference between the two processes is the molar ratio of ethylene glyoxylate monomer and initiator. This preparation process has many advantages: (1) The core operating parameters of the two preparation processes are highly consistent. Only the molar ratio of monomer to initiator needs to be adjusted according to the number average molecular weight required for the two types of photosensitive end-capped poly(ethylene glyoxylate) to produce two types of target products simultaneously on the same production equipment, which greatly reduces the production control cost. (2) The polymerization environment of light-proof and low temperature throughout the process can reduce the probability of unexpected side reactions of ethylene glyoxylate monomer, thereby preparing photosensitive end-capped poly(ethylene glyoxylate) with high molecular chain structure regularity and no obvious chain branching defects, thus laying the foundation for the subsequent formation of a stable interpenetrating entangled network. (3) Adding an initiator during the end-capping process of the photosensitive end-capping agent can activate the active end groups of polyacetylacetate molecules more efficiently and thoroughly, and greatly improve the grafting rate of the photosensitive end-capping agent. At the same time, the constant temperature reaction at 35℃~45℃ for 10 h~20 h is suitable for the reactivity of most o-nitrobenzyl and coumarin photosensitive end-capping agents. The end-capping groups are firmly grafted and are not easy to fall off prematurely during storage.

[0044] It should be noted that the type of initiator used in the preparation of photosensitive end-capped polyacetal is not limited and can be carried out according to conventional processes in the field. In this application, triethylamine is used as an example for illustration.

[0045] It should be noted that the molar ratio of ethyl glyoxylate monomer and initiator is not limited and can be flexibly adjusted according to the required number-average molecular weight.

[0046] As an example, the photosensitive end-capped polyglyoxylate is the first photosensitive end-capped polyglyoxylate. In the polymerization step, the molar ratio of glyoxylate monomer to initiator is 1:(0.0008~0.0015), for example, but not limited to, any one or any two of the following molar ratios: 1:0.0008, 1:0.0009, 1:0.0010, 1:0.0011, 1:0.0012, 1:0.0013, 1:0.0014, and 1:0.0015. The range of values ​​between; the photosensitive end-capped polyglyoxylate is the second photosensitive end-capped polyglyoxylate. In the polymerization step, the molar ratio of glyoxylate monomer to initiator is 1:(0.0002~0.0005), for example, but not limited to any one of the molar ratios of 1:0.0002, 1:0.00025, 1:0.0003, 1:0.00035, 1:0.0004, 1:0.00045 and 1:0.0005, or any range of values ​​between two of them.

[0047] In this embodiment, by controlling the molar ratio of glyoxylate monomer and initiator within the above-mentioned range, the number-average molecular weight of the prepared first photosensitive end-capped polyglyoxylate can be accurately placed within the range of 30 kDa to 45 kDa. At the same time, the number-average molecular weight of the prepared first photosensitive end-capped polyglyoxylate can also be accurately placed within the range of 90 kDa to 120 kDa. Two photosensitive end-capped poly(ethylene glyoxylate) molecules with similar number-average molecular weights are well-compatible and miscible in organic solvents, minimizing the risk of phase separation due to large molecular weight differences. This results in the formation of high-quality microspheres with high sphericity, uniform particle size, minimal adhesion, and few irregular defects. Furthermore, they form well-matched interpenetrating entangled networks, where the high-molecular-weight long chains effectively restrain the spontaneous movement of the low-molecular-weight short chains, thus effectively blocking the unexpected spontaneous cascade depolymerization of low-molecular-weight components. This significantly improves the stability of the microspheres during room temperature storage and greatly reduces the risk of premature degradation during in vivo placement. In addition, the complete degradation time of the microspheres after photoexcitation can be stably controlled within the clinically appropriate range, better adapting to the personalized embolization duration requirements of different TAE scenarios such as liver cancer, uterine fibroids, and trauma hemostasis.

[0048] As an example, the photosensitive end-capping agent is selected from at least one of o-nitrobenzyl chloroformate, o-nitrobenzyl alcohol, o-nitrobenzyl ether derivatives, bromohydroxycoumarin, and 7-aminocoumarin-4-acetic acid.

[0049] In this embodiment, there are many types of photosensitive capping agents that can be applied, providing a wide range of feasible solutions, which facilitates the promotion and application of the technical solutions provided in this application. At the same time, the rich variety of optional capping agents can flexibly adapt to different clinical light source scenarios. Applicable capping agents can be found from conventional ultraviolet light to near-infrared light bands, further expanding the promotion space of the product in different clinical scenarios. In addition, the above-mentioned types of photosensitive capping agents also have the advantages of good biocompatibility and high safety.

[0050] It should be noted that in the preparation of the first and second photosensitive end-capped polyglyoxylates, the photosensitive end-capping agents used in the end-capping step can be the same (using monochromatic light excitation during degradation) or different (using composite light or multiple light excitation during degradation). The specific process can be adapted according to actual needs.

[0051] As an example, in the capping step, the molar ratio of ethyl glyoxylate monomer to photosensitive capping agent is 1:(0.0018~0.0022), for example, but not limited to any one of the molar ratios of 1:0.0018, 1:0.0019, 1:0.002, 1:0.0021 and 1:0.0022, or any range between the two.

[0052] As an example, in the capping step, the molar ratio of the photosensitive capping agent to the initiator is 1:(0.9~1.1), for example, but not limited to any one of 1:0.9, 1:1 and 1:1.1 or any range between the two.

[0053] Understandably, after the capping reaction is completed, there is a post-processing step, which includes: transferring the solution system to anhydrous ethanol for precipitation and filtration, then washing and filtering the precipitate multiple times with anhydrous methanol, and finally vacuum drying the collected precipitate to obtain a white photosensitive capped polyacetal ethyl ester solid.

[0054] As an example, in the step of the mixed reaction, the volume ratio of the oil phase solution to the aqueous phase solution is 1:(8~12), for example, but not limited to, any one of 1:8, 1:9, 1:10, 1:11 and 1:12 or any range between the two.

[0055] In this embodiment, the volume ratio of the oil phase solution to the aqueous phase solution is limited to the above range. A large proportion of aqueous phase allows the oil phase droplets to be fully dispersed and have a suitable viscosity, which can prepare microspheres with good sphericity, relatively uniform particle size and less adhesion.

[0056] It should be noted that the type of organic solvent used in the preparation of the oil phase solution is not limited and can be carried out in accordance with conventional processes in the field. Anhydrous dichloromethane is used as an example in the embodiments of this application.

[0057] It should be noted that there are no limitations on the preparation method of the aqueous solution, and it can be carried out in accordance with conventional processes in this field.

[0058] As an example, the preparation steps of an aqueous solution include: dissolving polyvinyl alcohol in water to obtain an aqueous solution.

[0059] As an example, in the oil phase solution, the amount of photosensitive end-capped polyoxyethylene ester added is A g / mL; in the aqueous phase solution, the amount of polyvinyl alcohol added is B g / mL, and the ratio of A to B is (8~12):1, for example, but not limited to, any one of 8:1, 9:1, 10:1, 11:1 and 12:1 or any range between the two.

[0060] In this embodiment, the amount of substances added during the preparation of the two solutions is limited to the above range, which can be combined with a large proportion of aqueous phase system of 1: (8~12). This ratio allows photosensitive end-capped polyoxyethylene ester to maintain a regular spherical morphology during the droplet solidification process, and finally obtain finished microspheres with excellent sphericity, narrow particle size distribution and almost no adhesion.

[0061] As an example, after the oil phase solution and aqueous phase solution are mixed and reacted, the resulting microspheres are alternately washed with ultrapure water and anhydrous ethanol, and then dried and sieved to obtain dried microspheres of the target particle size.

[0062] It should be noted that, unless otherwise specified or limited, any process or step in the preparation of the microspheres can be carried out in accordance with conventional processes in this field.

[0063] As an example, a process flow diagram of the preparation method of embolic microspheres is exemplarily provided. Figure 1 .

[0064] Secondly, embodiments of this application provide an embolization microsphere, which is prepared by the same preparation method as provided in the first aspect embodiment, and the average particle size of the embolization microsphere is 20 μm to 300 μm, for example, but not limited to, any one of 20 μm, 40 μm, 60 μm, 80 μm, 100 μm, 150 μm, 200 μm, 250 μm and 300 μm or any range between two of them.

[0065] In this application, the embolization microspheres are prepared using the preparation method provided in the first aspect embodiment. The embolization microspheres prepared by this method contain photosensitive end-capped polyacetallate with different number average molecular weights. By photocontrolled removal of the photosensitive end-capping groups, the cascade depolymerization of the embolization microspheres from start to finish can be triggered, thereby enabling real-time and controllable termination of embolization according to clinical angiography or changes in the patient's condition after surgery. More importantly, limiting the average particle size of the embolization microspheres to the above range has many advantages: (1) Microspheres in this particle size range can pass smoothly through the 2.7F~3F interventional microcatheters commonly used in clinical practice. The pushing process is less prone to blockage and microsphere breakage, greatly improving the smoothness of interventional operations. In addition, this particle size range can accurately target and embolize the target vascular bed of solid tumors such as liver cancer and uterine fibroids. (2) The light signal inside the microspheres in this particle size range can be fully penetrated, and the photosensitive end cap groups can be uniformly activated, which can effectively improve the problem of insufficient light signal in the core area of ​​the microsphere, which leads to degradation obstruction. In addition, the degradation channel generated after photoexcitation can quickly penetrate the entire microsphere at this particle size scale, ensuring the smooth progress of the cascade depolymerization process and effectively reducing the probability of local inflammatory reactions caused by large-sized foreign body residues.

[0066] Thirdly, embodiments of this application provide a drug-loaded embolization microsphere, comprising a drug and an embolization microsphere as provided in the second aspect embodiment, wherein the drug is loaded onto the embolization microsphere.

[0067] It should be noted that there are no restrictions on the specific types of drugs and loading methods. They can be set in accordance with conventional forms in the field. For example, the drugs may include at least one of doxorubicin, arubicin, epirubicin, idarubicin, and pentorubicin; the loading method is physical blending.

[0068] The features and performance of this application will be further described in detail below with reference to the embodiments.

[0069] Example 1 This application provides a method for preparing embolic microspheres, comprising the following steps: Preparation of the first photosensitive end-capped polyacetal: Under anhydrous and light-protected conditions, ethyl glyoxylate monomer (C4H6O3) was dissolved in anhydrous dichloromethane (DCM) to prepare a 10 mol / L first monomer solution. 50 mL of the first monomer solution (500 mmol, 1.0 equivalent) was placed at -20°C and stirred for 1 h. After the temperature stabilized, 35 μL of triethylamine (250 μmmol, 0.0008 equivalent) was added dropwise as the first initiator, and the mixture was stirred at -20°C for 1 h to initiate the anionic polymerization of ethyl glyoxylate monomer. Subsequently, a photosensitizing end-capping agent (1 mmol, 0.002 equivalent of o-nitrobenzyl chloroformate) and 0.002 equivalent of triethylamine were added to the reaction system. The reaction temperature was then raised to 40°C and stirred for 16 hours under light-protected conditions. h was used to perform the end-capping reaction; after the end-capping reaction was completed, the solution system was transferred to anhydrous ethanol for precipitation and filtration, and then the precipitate was washed and filtered multiple times with anhydrous methanol. Finally, the collected precipitate was vacuum dried to obtain a white first photosensitive end-capped polyacetal ethyl ester solid (number average molecular weight of 30 kDa).

[0070] To better understand the entire reaction process, a synthetic route for a first photosensitive end-capped polyacetal is provided here for further explanation.

[0071]

[0072] The first reaction stage (i.e., -20℃, 1 h) refers to the polymerization stage; the second reaction stage (i.e., 40℃, 16 h) refers to the end-capping stage.

[0073] Preparation of the second photosensitive end-capped polyacetal: Under anhydrous and light-protected conditions, ethyl glyoxylate monomer was dissolved in anhydrous dichloromethane (DCM) to prepare a 10 mol / L second monomer solution. 50 mL of the second monomer solution (500 mmol, 1.0 equivalent) was placed at -20°C and stirred for 1 h. After the temperature stabilized, 17.5 μL of triethylamine (125 μmmol, 0.00025 equivalent) was added dropwise as a second initiator, and the mixture was stirred at -20°C for 1 h to initiate the anionic polymerization of ethyl glyoxylate monomer. Subsequently, a photosensitizing end-capping agent (1 mmol, 0.002 equivalent of o-nitrobenzyl chloroformate) and 0.002 equivalent of triethylamine were added to the reaction system. The reaction temperature was then raised to 40°C and stirred for 16 hours under light-protected conditions. h was used to carry out the end-capping reaction; after the end-capping reaction was completed, the solution system was transferred to anhydrous ethanol for precipitation and filtration, and then the precipitate was washed and filtered multiple times with anhydrous methanol. Finally, the collected precipitate was vacuum dried to obtain a white second photosensitive end-capped polyacetal ethyl ester solid (number average molecular weight of 90 kDa).

[0074] Microsphere preparation: A total of 10 g of first and second photosensitive end-capped polyethylene glyoxylate (PEG) was dissolved in 100 mL of dichloromethane, with the mass ratio of PEG to PEG being 2:1, to obtain an oil phase solution. 10 g of polyvinyl alcohol (PVA1788) was dissolved in 1000 mL of ultrapure water to obtain an aqueous phase solution.

[0075] Under light-protected conditions, 100 mL of oil phase solution was slowly added to 1000 mL of aqueous phase solution, maintaining an emulsification speed of 500 rpm and stirring at 25 °C for 24 h to fully evaporate the organic solvent. After the reaction was completed, the obtained microspheres were washed alternately with ultrapure water and anhydrous ethanol, and then dried and sieved to obtain dried microspheres with an average particle size of 200 μm.

[0076] Example 2 This application provides a method for preparing embolization microspheres, which differs from Example 1 only in that: the first photosensitive end-capped poly(ethylene glyoxylate) has a number-average molecular weight of 30 kDa, the second photosensitive end-capped poly(ethylene glyoxylate) has a number-average molecular weight of 120 kDa, and the mass ratio of the first photosensitive end-capped poly(ethylene glyoxylate) to the second photosensitive end-capped poly(ethylene glyoxylate) is 3:1.

[0077] Example 3 This application provides a method for preparing embolization microspheres, which differs from Example 1 only in that: the first photosensitive end-capped poly(ethylene glyoxylate) has a number-average molecular weight of 35 kDa, the second photosensitive end-capped poly(ethylene glyoxylate) has a number-average molecular weight of 110 kDa, and the mass ratio of the first photosensitive end-capped poly(ethylene glyoxylate) to the second photosensitive end-capped poly(ethylene glyoxylate) is 4:1.

[0078] Example 4 This application provides a method for preparing embolization microspheres, which differs from Example 1 only in that: the first photosensitive end-capped poly(ethylene glyoxylate) has a number-average molecular weight of 45 kDa, the second photosensitive end-capped poly(ethylene glyoxylate) has a number-average molecular weight of 115 kDa, and the mass ratio of the first photosensitive end-capped poly(ethylene glyoxylate) to the second photosensitive end-capped poly(ethylene glyoxylate) is 5:1.

[0079] Example 5 This application provides a method for preparing embolization microspheres, which differs from Example 1 only in that: the first photosensitive end-capped poly(ethylene glyoxylate) has a number-average molecular weight of 40 kDa, the second photosensitive end-capped poly(ethylene glyoxylate) has a number-average molecular weight of 110 kDa, and the mass ratio of the first photosensitive end-capped poly(ethylene glyoxylate) to the second photosensitive end-capped poly(ethylene glyoxylate) is 10:1.

[0080] Example 6 This application provides a method for preparing embolization microspheres, which differs from Example 1 only in that: the first photosensitive end-capped poly(ethylene glyoxylate) has a number-average molecular weight of 35 kDa, the second photosensitive end-capped poly(ethylene glyoxylate) has a number-average molecular weight of 100 kDa, and the mass ratio of the first photosensitive end-capped poly(ethylene glyoxylate) to the second photosensitive end-capped poly(ethylene glyoxylate) is 15:1.

[0081] Comparative Example 1 This application provides a method for preparing embolized microspheres, which differs from Example 1 only in that only first photosensitive end-capped polyacetallate is used.

[0082] Comparative Example 2 This application provides a method for preparing embolized microspheres, which differs from Example 1 only in that: only second photosensitive end-capped polyacetallate is used.

[0083] Test case In vitro degradation kinetics test Test methods: The microspheres from Examples 1-6 and Comparative Examples 1-2 were used as samples. Each sample was taken twice, with 100 mg taken each time. The two samples were dispersed in transparent vials containing 10 mL of physiological saline (37°C) and used as the light-protected group and the photo-excited group, respectively. Specifically, the light-protected group samples were incubated in a water bath shaker under no-light conditions, and the mass degradation rate of the microspheres was monitored over 30 days to determine the stability of the microspheres in the unexcited state. The photo-excited group was exposed to 365 nm ultraviolet light (irradiation intensity 20 mW / cm²). 2 Irradiate for 5 minutes, then record the time for complete degradation of the microspheres. The criterion for determining the time point of complete degradation is: under a microscope (magnification 200), there are no microsphere fragments of 2 μm to 100 μm in the field of view. A schematic diagram of the degradation of the embolic microspheres under photoexcitation can be found in [reference needed]. Figure 2 Finally, the test results are summarized in Table 1.

[0084] Table 1

[0085] Note: The light-protected group in Comparative Example 1 showed a quality degradation rate of up to 50% within 30 days, indicating that its stability in the unexcited state was poor and did not meet the basic requirements for use of embolized microspheres. Therefore, the photoexcited group was not tested subsequently.

[0086] Mechanical property testing Embolization microspheres from Examples 1 to 6 were taken as samples, and their strength and elasticity were tested. The test method was as follows: the sample was laid flat on a glass slide and placed under the probe of a texture analyzer (TA.XT PlusC). The HoldCompression mode was selected for testing. The test results are summarized in Table 2.

[0087] Table 2

[0088] Referring to Table 1, the test results of Examples 1-6 and Comparative Examples 1-2 show that the embolic microspheres prepared by using two photosensitive end-capped polyoxyethylene esters with different number-average molecular weights in accordance with the embodiments of this application have excellent stability in the unexcited state, and the complete degradation time after photoexcitation can be precisely controlled within 3 h to 20 h. In particular, by controlling the ratio of the mass of the first photosensitive end-capped polyoxyethylene ester to the mass of the second photosensitive end-capped polyoxyethylene ester within the range of (2-10):1, the complete degradation time of the microspheres after photoexcitation can be further precisely controlled within 3 h to 12 h, which is perfectly suited for clinical emergency scenarios such as traumatic massive hemorrhage and postoperative temporary hemostasis that require rapid embolization relief, thereby enabling real-time and controllable termination of embolization after surgery based on clinical angiography or changes in the patient's condition.

[0089] Referring to Table 2, the test results of Examples 1-5 and Example 6 show that when the ratio of the mass of the first photosensitive end-capped polyacetal ester to the mass of the second photosensitive end-capped polyacetal ester is controlled within the range of (2-10):1, the former also has superior strength and elasticity compared to the latter when it is not within the specified range.

[0090] The embodiments described above are some, but not all, of the embodiments of this application. The detailed description of the embodiments of this application is not intended to limit the scope of the claimed application, but merely to illustrate selected embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of this application without inventive effort are within the scope of protection of this application.

Claims

1. A method for preparing embolic microspheres, characterized in that, Includes the following steps: First photosensitive end-capped polyglyoxylate and second photosensitive end-capped polyglyoxylate are dispersed in an organic solvent to obtain an oil phase solution; wherein the number average molecular weight of the first photosensitive end-capped polyglyoxylate and the number average molecular weight of the second photosensitive end-capped polyglyoxylate are different. The oil phase solution was added to the aqueous phase solution and mixed to react, resulting in embolization microspheres.

2. The method for preparing embolic microspheres according to claim 1, characterized in that, The number-average molecular weight difference between the first photosensitive end-capped polyacetal and the second photosensitive end-capped polyacetal is 45 kDa to 90 kDa.

3. The method for preparing embolic microspheres according to claim 2, characterized in that, The first photosensitive end-capped polyoxyethylene has a number-average molecular weight of 30 kDa to 45 kDa, and the second photosensitive end-capped polyoxyethylene has a number-average molecular weight of 90 kDa to 120 kDa.

4. The method for preparing embolic microspheres according to claim 3, characterized in that, The feed mass of the first photosensitive end-capped polyglyoxylate is higher than that of the second photosensitive end-capped polyglyoxylate.

5. The method for preparing embolic microspheres according to claim 4, characterized in that, The ratio of the mass of the first photosensitive end-capped polyoxyethylene to the mass of the second photosensitive end-capped polyoxyethylene is (2~10):

1.

6. The method for preparing embolic microspheres according to any one of claims 1 to 5, characterized in that, The preparation steps of photosensitive end-capped polyacetal ester include: Polymerization steps: Under light-protected conditions, ethyl glyoxylate monomer and initiator are added to anhydrous organic solvent, mixed, and the polymerization reaction is carried out at -18℃ to -22℃; End-capping step: Add photosensitizing end-capping agent and initiator to the reaction system, then heat to 35℃~45℃ and react for 10 h~20 h; In the polymerization step, the molar ratio of the glyoxylate monomer to the initiator is controlled to be different, thereby obtaining the first photosensitive end-capped polyglyoxylate and the second photosensitive end-capped polyglyoxylate.

7. The method for preparing embolic microspheres according to claim 6, characterized in that, The photosensitive end-capped polyglyoxylate is the first photosensitive end-capped polyglyoxylate, and in the polymerization step, the molar ratio of the glyoxylate monomer to the initiator is 1:(0.0008~0.0015). The photosensitive end-capped polyglyoxylate is the second photosensitive end-capped polyglyoxylate, and in the polymerization step, the molar ratio of the glyoxylate monomer to the initiator is 1:(0.0002~0.0005).

8. The method for preparing embolic microspheres according to claim 6, characterized in that, The photosensitive end-capping agent is selected from at least one of o-nitrobenzyl chloroformate, o-nitrobenzyl alcohol, o-nitrobenzyl ether derivatives, bromohydroxycoumarin, and 7-aminocoumarin-4-acetic acid.

9. An embolic microsphere, characterized in that, The embolic microspheres are prepared by any one of the preparation methods described in claims 1 to 8, and the average particle size of the embolic microspheres is 20 μm to 300 μm.

10. A drug-loaded embolic microsphere, characterized in that, It includes a drug and the embolic microspheres as described in claim 9, wherein the drug is loaded onto the embolic microspheres.

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