Degradable embolism microsphere, preparation method and application
By designing biodegradable microspheres with a core-shell structure and utilizing esterification and double bond addition reactions, the toxicity and retention problems of traditional microspheres were solved, achieving complete and slow drug release and improving therapeutic efficacy.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-12-29
- Publication Date
- 2026-03-10
AI Technical Summary
Traditional cross-linking systems have problems with residual toxicity and difficulty in decomposition when preparing microspheres, which leads to the risk of drug retention in the body and uneven drug release.
A core-shell structure is formed by using a water-soluble polymer with hydroxyl groups and an amphiphilic crosslinking agent. The core forms a degradable network through esterification, while the shell forms a stable structure through double bond addition, enabling precise controlled release of the drug.
It achieves both complete and slow release of the drug, avoiding the initial burst release phenomenon and improving drug utilization and therapeutic effect.
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Figure CN121622970A_ABST
Abstract
Description
Technical Field
[0001] This application relates to the field of drug sustained-release technology, and in particular to a biodegradable embolic microsphere, its preparation method, and its application. Background Technology
[0002] Sustained-release microspheres, as a key component of drug delivery systems, significantly improve therapeutic efficacy and reduce adverse reactions by prolonging the drug's duration of action in vivo. The emergence of core-shell structured microspheres further optimizes drug release behavior. Their core mechanism lies in effectively suppressing the rapid release of drugs in the initial stages by regulating the material properties and permeability of the core and shell layers, thereby achieving a more stable and sustained release pattern. Traditional cross-linking systems often use reagents such as glutaraldehyde, whose residual toxicity not only poses a potential hazard to organisms but also results in carbon-carbon or ether bond cross-linking networks that are difficult to effectively decompose in vivo, potentially leading to long-term retention risks and hindering complete material metabolism. Summary of the Invention
[0003] The purpose of this application is to provide a biodegradable embolic microsphere, its preparation method, and its application to solve the above-mentioned problems.
[0004] To achieve the above objectives, this application adopts the following technical solution: In a first aspect, this application provides a biodegradable embolic microsphere comprising a core-shell structure formed by crosslinking a water-soluble polymer with hydroxyl groups, an amphiphilic crosslinking agent, and a water-soluble ionic monomer with double bonds. The amphiphilic crosslinking agent comprises hydrophobic segments with double bonds and hydrophilic segments with carboxyl groups. The core-shell structure comprises an outer shell and an inner shell. The outer shell comprises a cross-linked network formed by the polymerization of the hydrophobic segments with double bonds and the water-soluble ionic monomers with double bonds; The core comprises the hydrophilic segments with carboxyl groups and the water-soluble polymer with hydroxyl groups, which are esterified to form a degradable network structure.
[0005] This application provides a biodegradable embolic microsphere. By selecting an amphiphilic crosslinking agent with specific reactive functional groups, this application synthesizes biodegradable embolic microspheres with a core-shell structure. This application utilizes a water-soluble polymer with hydroxyl groups as the backbone. An esterification reaction occurs between the hydrophilic segments with carboxyl groups in the amphiphilic crosslinking agent and the hydroxyl groups on the water-soluble polymer, forming a biodegradable core network structure. The complete release of the drug in vivo is achieved through the degradation of the ester bonds in the core. Simultaneously, the hydrophobic segments with double bonds in the amphiphilic crosslinking agent and the water-soluble ionic monomers with double bonds undergo a double bond addition reaction, thereby endowing the microsphere with a stable outer shell structure. This core-shell structure is formed by the difference in the distribution of hydrophilic and hydrophobic segments in the amphiphilic crosslinking agent. The different hydrophilic and hydrophobic designs of the inner and outer layers enable precise control of drug release. The loose structure of the core ensures effective drug loading and initial diffusion, while the hydrophobic network of the shell acts as a barrier to slow down the drug release rate and avoid initial burst release. This allows for more controllable degradation-release synergistic therapeutic effects through biodegradable microspheres with a core-shell structure.
[0006] Secondly, this application also provides a method for preparing biodegradable embolic microspheres, comprising: S1. Preparation of aqueous solution: Dissolve water-soluble polymer in water, heat and stir to dissolve, add amphiphilic crosslinking agent and acidic catalyst, carry out the first heating reaction under a protective atmosphere, add water-soluble ionic monomer aqueous solution to obtain aqueous solution; S2. Preparation of oil phase solution: Dissolve the oily dispersant in an oily solvent to obtain an oil phase solution; S3. Microsphere synthesis: The aqueous phase solution is slowly added dropwise to the oil phase solution under stirring to form a water-in-oil system. An oil-soluble initiator is added, and a second heating reaction is carried out. After the reaction is completed, the microspheres are washed and dried to obtain the biodegradable embolic microspheres.
[0007] This application also provides a method for preparing biodegradable embolic microspheres; wherein, a one-step core-shell structure is constructed: the amphiphilicity of 8-vinyl-10-octadecenoic acid is cleverly utilized, allowing it to self-assemble with PVA in an aqueous phase to form a core-shell precursor, eliminating the need for complex multiple emulsion techniques, resulting in a simple process with good reproducibility. The use of an oil-soluble initiator (AIBN) concentrates the initiation sites at the oil-water interface, effectively limiting and guiding the polymerization reaction of water-soluble ionic monomers to the oil-water interface, greatly reducing homopolymerization side reactions of ionic monomers in the aqueous phase, thereby significantly increasing the grafting density of anionic groups in the final microsphere product. Thirdly, this application also provides a drug-loaded biodegradable embolic microsphere, comprising the aforementioned biodegradable embolic microspheres, wherein the biodegradable embolic microspheres can be loaded with hydrophobic drugs and / or cationic drugs to obtain the drug-loaded biodegradable embolic microspheres.
[0008] Optionally, the hydrophobic drug includes at least one of doxorubicin, irinotecan, topotecan, and paclitaxel.
[0009] Optionally, the cationic drug includes at least one of doxorubicin, arubibin, epirubibin, idarubibin, penrubibin, irinotecan, topotecan, vinorelbine, vindesin, gemcitabine, and capecitabine.
[0010] The drug-loaded biodegradable embolic microspheres provided in this application have a core cross-linked network composed of hydrolyzable ester bonds, possessing inherent biodegradability. When introduced into the target site, the loose structure of the core allows for the gradual release of drug molecules, and the complete drug release is achieved through the degradation of the core ester bonds. Meanwhile, the outer shell, rich in hydrophobic polymer networks, effectively suppresses initial burst release by regulating the permeation rate. Attached Figure Description
[0011] To more clearly illustrate the technical solutions of the embodiments of this application, the accompanying drawings used in the embodiments will be briefly described below. It should be understood that the following drawings only show some embodiments of this application and should not be regarded as a limitation on the scope of this application.
[0012] Figure 1 A schematic diagram of the process flow for the preparation method of the biodegradable embolic microspheres provided in this application; Figure 2 The appearance of the biodegradable embolic microspheres provided in Example 1 after drug loading under a microscope; Figure 3 The appearance of the biodegradable embolic microspheres provided in Example 2 after drug loading under a microscope; Figure 4 The appearance of the biodegradable embolic microspheres provided in Example 3 after microscopic drug loading; Figure 5 The appearance of the biodegradable embolic microspheres provided in Example 4 after drug loading under a microscope; Figure 6 The appearance of the biodegradable embolic microspheres provided in Example 5 after drug loading under a microscope; Figure 7 The appearance of the biodegradable embolic microspheres provided in Comparative Example 1 after microscopic drug loading. Detailed Implementation
[0013] The embodiments of this application will be described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and should not be considered as limiting the scope of this application. Unless otherwise specified in the examples, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products.
[0014] This application provides a biodegradable embolic microsphere comprising a core-shell structure formed by crosslinking a hydroxyl-containing water-soluble polymer, an amphiphilic crosslinking agent, and a water-soluble ionic monomer with double bonds. The amphiphilic crosslinking agent comprises hydrophobic segments with double bonds and hydrophilic segments with carboxyl groups. The core-shell structure comprises an outer shell and an inner shell. The outer shell comprises a crosslinked network formed by polymerizing hydrophobic segments with double bonds and water-soluble ionic monomers with double bonds. The inner shell comprises a biodegradable network structure formed by esterification of hydrophilic segments with carboxyl groups and a water-soluble polymer with hydroxyl groups.
[0015] The biodegradable embolic microspheres provided in this application have a carefully designed structure and composition to achieve specific functions. This application synthesizes biodegradable embolic microspheres with a core-shell structure by selecting amphiphilic crosslinking agents with specific reactive functional groups. This application utilizes a water-soluble polymer with hydroxyl groups as the backbone. An esterification reaction occurs between the hydrophilic segments with carboxyl groups in the amphiphilic crosslinking agent and the hydroxyl groups on the water-soluble polymer, forming a biodegradable core network structure. The complete release of drugs in vivo is achieved through the degradation of the ester bonds in the core. Simultaneously, the hydrophobic segments with double bonds in the amphiphilic crosslinking agent and the water-soluble ionic monomers with double bonds undergo a double bond addition reaction, thereby endowing the microspheres with a stable outer shell structure. This core-shell structure is formed by the difference in the distribution of hydrophilic and hydrophobic segments in the amphiphilic crosslinking agent. The different hydrophilic and hydrophobic properties of the inner and outer layers enable precise control of drug release. The loose structure of the core ensures effective drug loading and initial diffusion, while the hydrophobic network of the shell acts as a barrier to slow down the drug release rate and avoid initial burst release. This allows for more controllable degradation-release synergistic therapeutic effects through biodegradable microspheres with a core-shell structure.
[0016] This application also provides a method for preparing biodegradable embolic microspheres, the process flow diagram of which is shown below. Figure 1 As shown, it includes: S1. Preparation of aqueous solution: Dissolve water-soluble polymer in water, heat and stir to dissolve, add amphiphilic crosslinking agent and acidic catalyst, carry out the first heating reaction under a protective atmosphere, add water-soluble ionic monomer aqueous solution to obtain aqueous solution; In one alternative embodiment, the hydroxyl-containing water-soluble polymer includes at least one of polyvinyl alcohol, sodium alginate, sodium hyaluronate, sodium carboxymethyl cellulose, and water-soluble chitosan.
[0017] Optionally, the amphiphilic crosslinking agent includes 8-vinyl-10-octadecenoic acid, which is a dicarboxylic acid containing vinyl functional groups. The molecular chain segments have hydrophilic carboxyl groups on both sides and a hydrophobic long alkane chain without double bonds in the middle part of the molecular chain segments. The carboxylic acid groups on both sides of the crosslinking agent can undergo esterification with the hydroxyl groups on the water-soluble polymer to generate degradable ester bonds. Due to the strong hydrophilicity of the carboxylic acid and the water-soluble polymer, the esterification reaction is concentrated in the core region of the water-in-oil system, thereby giving the core a degradable network structure. On the other hand, in the hydrophilic system of the water-soluble polymer, the hydrophobic long alkane chain in the amphiphilic crosslinking agent spontaneously aggregates into hydrophobic microregions, moving away from the hydrophilic system of the core and approaching the oil-water interface in the water-in-oil system, thereby forming a stable shell with the ionic monomer with double bonds through an addition reaction.
[0018] In this application, the biodegradable core network enables complete drug release and enhances the utilization rate of the loaded drug; while the stable outer shell forms a sustained-release barrier, enhancing the sustained-release effect of the drug.
[0019] In an optional embodiment, the water-soluble ionic monomer with double bonds includes at least one of an alkene compound with a carboxylic acid group and an alkene compound with a sulfonic acid group.
[0020] In an optional embodiment, the alkene compound with a carboxylic acid group includes at least one of acrylic acid, methacrylic acid, and their derivatives.
[0021] In an optional embodiment, the alkene compound with a sulfonic acid group includes at least one of 2-acrylamido-2-methylpropanesulfonic acid, sodium allyl sulfonate, or sodium methpropylene sulfonate and its derivatives.
[0022] This application introduces ionic monomers with anionic groups such as sulfonic acid groups or carboxylic acid groups. After the ionic monomers form a shell network structure through double bond addition, they can effectively load cationic drugs, thus achieving high-efficiency drug loading.
[0023] In some embodiments, the water-soluble polymer accounts for 10-20% of the mass percentage of the aqueous solution; the amphiphilic crosslinking agent accounts for 1-5% of the mass percentage of the water-soluble polymer; and the water-soluble ionic monomer accounts for 5-15% of the mass percentage of the aqueous solution. By controlling the different proportions of the polymer, crosslinking agent, and ionic monomer, it is beneficial to form a stable core-shell structure.
[0024] Optionally, the mass percentage of the water-soluble polymer in the aqueous solution can be 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, or any value between 10% and 20%.
[0025] Optionally, the amphiphilic crosslinking agent may be 1%, 2%, 3%, 4%, 5% by mass of the water-soluble polymer, or any value between 1% and 5%.
[0026] Optionally, the mass percentage of water-soluble ionic monomers in the aqueous solution can be 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, or any value between 5% and 15%.
[0027] In addition, the acidic catalyst includes at least one of toluenesulfonic acid or p-toluenesulfonic acid, and the acidic catalyst accounts for 1-3% of the mass percentage of the amphiphilic crosslinking agent, which can effectively enhance the efficiency of the reaction system.
[0028] Optionally, the acid catalyst accounts for 1%, 2%, or 3% of the mass percentage of the amphiphilic crosslinking agent, or any value between 1% and 3%.
[0029] In some embodiments, step S1 includes dissolving the amphiphilic crosslinking agent in an organic solvent first, and then adding it to an aqueous solution of a water-soluble polymer.
[0030] In one alternative embodiment, the mass ratio of the organic solvent to the amphiphilic crosslinking agent is 1-5:1.
[0031] Optionally, the mass ratio of the organic solvent to the amphiphilic crosslinking agent is 1:1, 2:1, 3:1, 4:1, 5:1, or any value between 1 and 5:1.
[0032] In an optional embodiment, the organic solvent includes ethanol and / or acetone.
[0033] Optionally, the conditions for the first heating reaction are: reacting at 60-70℃ for 2-4 hours; the temperature of the first heating reaction can be 60℃, 62℃, 62℃, 63℃, 64℃, 65℃, 66℃, 67℃, 68℃, 69℃, 70℃, or any value between 60-70℃; the time of the first heating reaction can be 2 hours, 3 hours, or 4 hours.
[0034] S2. Preparation of oil phase solution: Dissolve the oily dispersant in an oily solvent to obtain an oil phase solution; In an optional embodiment, the oily solvent includes at least one of liquid paraffin, n-heptane, cyclohexane, and butyl acetate; the oily dispersant includes at least one of Tween-60, Tween-80, Span-60, Span-80, OP-10, OP-20, and cellulose acetate butyrate, and is used in an amount of 1-4% of the mass of the oily solvent; the polarity index P of the oily solvent satisfies 0.01≤P≤5.
[0035] Optionally, the amount of oily dispersant can be 1%, 2%, 3%, or 4% of the mass of the oily solvent, or any value between 1% and 4%.
[0036] S3. Microsphere synthesis: The aqueous solution is slowly added dropwise to the oil solution under stirring to form a water-in-oil system. An oil-soluble initiator is added, and a second heating reaction is carried out. After the reaction is completed, the microspheres are washed and dried to obtain biodegradable embolic microspheres.
[0037] In this application, the oil-soluble initiator is configured to generate free radicals in the oil phase, which can efficiently diffuse to the oil-water interface, causing the initiation sites to concentrate at the oil-water interface. The polymerization reaction of the water-soluble ionic monomer is effectively restricted and guided to the oil-water interface, greatly reducing the homopolymerization side reaction of the ionic monomer in the aqueous phase, thereby significantly increasing the grafting density of anionic groups in the final microsphere product. At the same time, it promotes the full reaction of the hydrophobic segments with double bonds of the crosslinking agent with the water-soluble ionic monomer to form the shell.
[0038] In an oil-water two-phase system, when aqueous droplets are dispersed in the oil phase, crosslinking agents and water-soluble ionic monomers can accumulate and polymerize at the interface between the droplets and the oil phase. Due to the interfacial effect, this polymerization reaction can form a dense and highly crosslinked polymer network, thus constituting the outer shell of the microspheres. The core consists of a loose structure formed by the homopolymerization and / or copolymerization of water-soluble polymer chains and water-soluble ionic monomers. In the aqueous environment inside the microspheres, the polymerization reaction between the water-soluble polymer chains and water-soluble ionic monomers results in a relatively low degree of crosslinking in the core, thus forming a more loose structure.
[0039] In one optional embodiment, the volume ratio of the aqueous phase to the oil phase is 1:4-6; the stirring speed is 300-800 rpm; the temperature of the second heating reaction is 60-80℃, and the time is 2-6 h.
[0040] Optionally, the volume ratio of the aqueous phase to the oil phase can be 1:4, 1:5, 1:6, or any value between 1:4 and 6.
[0041] Optionally, the stirring speed can be 300 rpm, 400 rpm, 500 rpm, 600 rpm, 700 rpm, 800 rpm, or any value between 300 and 800 rpm.
[0042] Optionally, the temperature of the second heating reaction can be 60℃, 62℃, 64℃, 66℃, 68℃, 70℃, 72℃, 74℃, 76℃, 78℃, 80℃, or any value between 60℃ and 80℃; the time of the second heating reaction can be 2h, 3h, 4h, 5h, 6h, or any value between 2h and 6h.
[0043] In an optional embodiment, the oil-soluble initiator includes benzoyl peroxide and / or azobisisobutyronitrile, and the amount of the oil-soluble initiator is 0.5-2.0% of the total mass of the water-soluble ionic monomer and the amphiphilic crosslinking agent.
[0044] Optionally, the amount of oil-soluble initiator can be 0.5%, 1%, 1.5%, or 2% of the total mass of water-soluble ionic monomers and amphiphilic crosslinking agents, or any value between 0.5% and 2%.
[0045] The above technical solution allows for precise control of the aqueous solution preparation conditions in the method for preparing biodegradable embolic microspheres, resulting in a homogeneous aqueous solution with suitable reactivity. This optimization significantly improves the stability and reproducibility of the subsequent microsphere synthesis process. The resulting biodegradable embolic microspheres exhibit superior structural uniformity, size distribution, and performance stability, thereby enhancing their reliability and effectiveness in applications such as drug sustained release.
[0046] This application also provides a drug-loaded biodegradable embolization microsphere, comprising the biodegradable embolization microsphere, wherein the biodegradable embolization microsphere can be loaded with hydrophobic drugs and / or cationic drugs to obtain the drug-loaded biodegradable embolization microsphere.
[0047] In an optional embodiment, the hydrophobic drug includes at least one of doxorubicin, irinotecan, topotecan, and paclitaxel.
[0048] In an optional embodiment, the cationic arubibrine, epirubibrine, idarubibrine, pentorubibrine, irinotecan, topotecan, vinorelbine, vindesin, gemcitabine, and capecitabine are all selected.
[0049] The implementation schemes of this application will be described in detail below with reference to specific embodiments. However, those skilled in the art will understand that the following embodiments are only for illustrating this application and should not be regarded as limiting the scope of this application. Unless otherwise specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments used without specified manufacturers are all conventional products that can be purchased commercially.
[0050] Example 1 This embodiment provides a biodegradable embolization microsphere: Its raw materials include: polyvinyl alcohol, 8-vinyl-10-octadecenoic acid, and 2-acrylamido-2-methylpropanesulfonic acid.
[0051] This embodiment also provides a method for preparing the biodegradable embolic microspheres, the specific steps of which are as follows: S1. Prepare the aqueous solution: 10g of PVA was dissolved in 100g of water and heated to 90°C with stirring until dissolved. 1g of 8-vinyl-10-octadecenoic acid was dissolved in 2g of ethanol and then added to the PVA aqueous solution. 0.2g of acidic catalyst toluenesulfonic acid was added, and the mixture was reacted at 65°C for 2 hours under nitrogen protection. Subsequently, 10g of 2-acrylamido-2-methylpropanesulfonic acid was dissolved in water, and this AMPS aqueous solution was added to the PVA aqueous solution, mixing thoroughly to form an aqueous phase.
[0052] S2. Prepare the oil phase solution: Add Tween-80 to 1000 mL of liquid paraffin, stir at 35 °C to dissolve and form a homogeneous solution, thus obtaining the oil phase.
[0053] S3, Microsphere Synthesis: The aqueous phase was slowly added dropwise to the oil phase while stirring at 500 rpm. Then, 0.055 g of the oil-soluble initiator azobisisobutyronitrile (AIBN) was added to the system. The mixture was kept at 60°C for 4 hours under nitrogen protection. After the reaction was complete, heating and stirring were stopped, and the mixture was allowed to settle. The upper oil phase was discarded, and the remaining material was repeatedly washed with anhydrous ethanol and centrifuged. The washed gel microspheres were dried in a vacuum oven at 50°C to constant weight to obtain the final product.
[0054] Example 2 The only difference between this embodiment and Example 1 is that the initiator in step 3 is replaced with 0.055g (0.5%) of benzoyl dioxide (BPO).
[0055] Example 3 The only difference between this embodiment and Embodiment 2 is that the mass of the initiator BPO in step 3 is changed to 0.11g (1%).
[0056] Example 4 The only difference between this embodiment and Embodiment 1 is that, unlike Embodiment 2, the mass of initiator BPO in step 3 is changed to 0.22g (2%).
[0057] Example 5 The only difference between this embodiment and embodiment 4 is that, unlike embodiment 2, the oil phase solvent in step (2) is changed to 1000 mL butyl acetate.
[0058] Comparative Example 1 The only difference between this comparative example and Example 1 is that the initiator is replaced with a water-soluble initiator, 0.11g of ammonium persulfate.
[0059] The above embodiments and comparative examples were tested as follows: 1. Drug loading detection Test method: Prepare a 20 mg / mL doxorubicin hydrochloride solution. Take 1 mL of polyvinyl alcohol embolization microspheres, blot dry the surface moisture with filter paper, place them in a vial, add 2 mL of drug solution to the vial, shake for 30 min, and then aspirate the supernatant. Measure the absorbance at 233 nm using a UV spectrophotometer and substitute the absorbance into the drug concentration standard curve to calculate the drug loading.
[0060] 2. Drug release detection The drug-loaded microspheres were placed in a drug release bag, which was then placed in an Erlenmeyer flask. 100 mL of 0.9% NaCl was added to the flask, a rotor was placed inside, and the flask was sealed. The flask was then placed in a 37°C constant-temperature stirred water bath for release. Every so often, 5 mL of the released solution was pipetted out, and 5 mL of fresh 0.9% NaCl was added. The absorbance of the solution in the Erlenmeyer flask was periodically measured, and the data were substituted into a standard curve to calculate the cumulative drug release rate and recorded.
[0061] The formula for calculating the cumulative release rate is as follows: ; In the formula, Q represents the cumulative drug release rate (%), and M... D Where n is the quantity of drug loaded, and C is the number of times the drug is retrieved. n This is the nth time.
[0062] Drug sample concentration, V is the total volume of the release solution, C i V represents the concentration of the drug sample taken in the i-th sampling. i Let C0 and V0 be the volume of the sample taken in the i-th sampling, where both C0 and V0 are 0.
[0063] 3. The appearance of the drug-loaded microspheres was observed under a microscope. The appearance of the drug-loaded biodegradable embolic microspheres provided in Examples 1-5 is shown below. Figure 2-7 As shown, the appearance of the embolic microspheres provided in Comparative Example 1 after drug loading is as follows: Figure 6 As shown in the figure; the drug loading and release results are shown in Table 1.
[0064] Table 1. Drug loading and release results
[0065] Drug loading analysis: Water-soluble free radicals cannot effectively enter the hydrophobic core, resulting in insufficient cross-linking of the core. They mainly polymerize in the aqueous shell layer and cannot form a stable core-shell structure. Therefore, the drug loading is the lowest and the drug release is the fastest.
[0066] Oil-soluble initiators AIBN and BPO decompose to generate free radicals. Due to their lipophilic nature, these free radicals can easily diffuse into the hydrophobic core of the emulsion droplets, efficiently initiating the copolymerization reaction between the vinyl groups on 8-vinyl-10-octadecenoic acid and the monomers diffused to the core-shell interface. Therefore, oil-soluble initiators are more effective than water-soluble initiators. The free radicals generated by the decomposition of oil-soluble initiator BPO have moderate reactivity, making them more suitable for graft copolymerization reactions. Therefore, the drug loading of the microspheres in Example 2 is higher than that in Example 1, resulting in better sustained-release performance. When the solvent in the oil phase is replaced with the more polar butyl acetate, the hydrophobic long chains in the crosslinking agent are closer to the oil-water interface, making it easier for them to contact the initiator in the oil phase system. This results in a higher degree of crosslinking of the microspheres and thus better drug loading.
[0067] Drug release analysis: Increasing the initiator concentration generates more free radicals, resulting in denser cross-linking of the core. Simultaneously, the shell becomes thicker due to a higher degree of graft polymerization. Therefore, increasing the initiator concentration in the reaction system prolongs the drug release time of the microspheres. Furthermore, the increased polarity of the oil phase solvent allows the hydrophobic long chains in the cross-linking agent to contact more initiators, leading to a higher degree of cross-linking of the microspheres, a denser inner shell, and a thicker outer shell due to the higher degree of graft polymerization, further slowing down drug release.
[0068] Appearance analysis of drug-loaded microspheres: Under a microscope, the drug-loaded microspheres all exhibited a core-shell structure on their surface. Furthermore, as the initiator concentration gradually increased in Examples 2-4, the core-shell structure of the microspheres became increasingly thicker. The increased solvent polarity in Example 5 also contributed to the increased core-shell thickness of the microspheres.
[0069] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of this application, and are not intended to limit them. Although this application has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of this application.
[0070] Furthermore, those skilled in the art will understand that although some embodiments herein include certain features included in other embodiments but not others, combinations of features from different embodiments are intended to be within the scope of this application and form different embodiments. For example, in the foregoing claims, any of the claimed embodiments can be used in any combination. The information disclosed in this background section is intended only to enhance the understanding of the general background of this application and should not be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.
Claims
1. A degradable embolizing microsphere, characterized in that, Comprise: A core-shell structure cross-linked by a water-soluble polymer with hydroxyl groups, an amphiphilic cross-linking agent and a water-soluble ionic monomer with double bonds, the amphiphilic cross-linking agent comprising a hydrophobic segment with double bonds and a hydrophilic segment with carboxyl groups, the core-shell structure comprising an outer shell and an inner core arranged in a covering manner; The outer shell comprises a cross-linked network formed by polymerization of the hydrophobic segment with double bonds and the water-soluble ionic monomer with double bonds; The inner core comprises a degradable network structure formed by esterification of the hydrophilic segment with carboxyl groups and the water-soluble polymer with hydroxyl groups.
2. The degradable embolizing microspheres according to claim 1, characterized in that, The water-soluble polymer with hydroxyl groups comprises at least one of polyvinyl alcohol, sodium alginate, sodium hyaluronate, sodium hydroxymethyl cellulose and water-soluble chitosan; And / or, The amphiphilic cross-linking agent comprises 8-vinyl-10-octadecene diacid.
3. The degradable embolizing microspheres according to claim 1, characterized in that, The water-soluble ionic monomer with double bonds comprises at least one of an olefin compound with carboxylic acid groups and an olefin compound with sulfonic acid groups; Optionally, the olefin compound with carboxylic acid groups comprises at least one of acrylic acid, methacrylic acid and derivatives thereof; Optionally, the olefin compound with sulfonic acid groups comprises at least one of 2-acrylamido-2-methylpropane sulfonic acid, sodium allyl sulfonate or sodium methacrylate sulfonate and derivatives thereof.
4. A method of producing the degradable embolizing microspheres according to any one of claims 1 to 3, characterized by, Comprise: S1, configure an aqueous solution: dissolve a water-soluble polymer in water, heat and stir to dissolve, add an amphiphilic cross-linking agent and an acidic catalyst, after the first heating reaction in a protective atmosphere, add an aqueous solution of a water-soluble ionic monomer, to obtain an aqueous solution; S2, configure an oil phase solution: dissolve an oil dispersant in an oil solvent to obtain an oil phase solution; S3, microsphere synthesis: slowly drop the aqueous solution into the oil phase solution under stirring to form a water-in-oil system, add an oil-soluble initiator, and after the second heating reaction, wash and dry to obtain the degradable embolization microspheres.
5. The preparation method according to claim 4, characterized in that, Step S1 meets at least one of the following conditions: A. The first heating reaction conditions are: reacting at 60-70℃ for 2-4 hours; B. The water-soluble polymer accounts for 10-20% of the mass percentage of the aqueous solution; C. The amphiphilic cross-linking agent accounts for 1-5% of the mass percentage of the water-soluble polymer; D. The water-soluble ionic monomer accounts for 5-15% of the mass percentage of the aqueous solution; E. The acidic catalyst comprises at least one of toluenesulfonic acid or p-toluenesulfonic acid, and the acidic catalyst accounts for 1-3% of the mass percentage of the amphiphilic cross-linking agent.
6. The preparation method according to claim 4, characterized in that, In step S1, the amphiphilic cross-linking agent is first dissolved in an organic solvent, and then the aqueous solution of the water-soluble polymer is added; Optionally, the mass ratio of the organic solvent to the amphiphilic cross-linking agent is 1-5:1; Optionally, the organic solvent comprises ethanol and / or acetone.
7. The preparation method according to claim 4, characterized in that, Step S2 meets at least one of the following conditions: F. The oil solvent comprises at least one of liquid paraffin, n-heptane, cyclohexane and butyl acetate; G. the oily dispersant comprises at least one of Tween-60, Tween-80, Span-60, Span-80, OP-10, OP-20, cellulose acetate butyrate, and the amount is 1-4% of the mass of the oily solvent; H. the polarity index P of the oily solvent satisfies 0.01≤P≤5.
8. The method of any one of claims 4-7, wherein, Step S3 satisfies at least one of the following conditions: I. the volume ratio of the aqueous phase to the oily phase is 1:4-6; J. the stirring speed is 300-800 rpm; K. the temperature of the second heating reaction is 60-80℃, and the time is 2-6h.
9. The preparation method according to claim 8, characterized in that, The oil-soluble initiator comprises dibenzoyl peroxide and / or azobisisobutyronitrile, and the amount of the oil-soluble initiator is 0.5-2.0% of the total mass of the water-soluble ionic monomer and the amphiphilic crosslinking agent.
10. A drug-loaded degradable embolic microsphere, characterized in that, The degradable embolization microspheres of any one of claims 1-3 can load hydrophobic drugs and / or cationic drugs to obtain drug-loaded degradable embolization microspheres. Optionally, the hydrophobic drug comprises at least one of doxorubicin, irinotecan, topotecan, and paclitaxel. Optionally, the cationic drug comprises at least one of doxorubicin, aclarubicin, epirubicin, idarubicin, valrubicin, irinotecan, topotecan, vinorelbine, vindesine, gemcitabine, and capecitabine.