Polyhydroxy long-chain polymer embolization microsphere and preparation method thereof

Abstract

The invention relates to a polyhydroxy long-chain polymer embolization microsphere and a preparation method thereof, and belongs to the technical field of medical instruments. The invention provides a polyhydroxy long-chain polymer embolization microsphere. The polyhydroxy long-chain polymer embolization microsphere is prepared from a polyhydroxy long-chain polymer and a cross-linking agent of which the end group is epoxypropane through epoxy ring-opening cross-linking polymerization. The microspheres are formed by epoxy ring-opening cross-linking of hydroxyl groups on polyhydroxy long-chain macromolecules and epoxy groups on the cross-linking agent, the preparation method is simple and efficient, and product instability caused by introduction of monomers with double bonds in a conventional synthesis method is avoided.

Description

Technical Field

[0001] The present application relates to the technical field of medical devices, and in particular to a polyhydroxy long-chain polymer embolic microsphere and a preparation method thereof. Background Art

[0002] In recent years, embolic microspheres have received extensive attention as an important drug carrier and tumor treatment method, especially in the treatment of unresectable tumors such as hepatocellular carcinoma. Existing microsphere preparation technologies usually rely on the introduction of unsaturated bonds (such as carbon-carbon double bonds and triple bonds) on monomers or long polymer chains, followed by copolymerization with other monomers or polymers to form microspheres with specific functions. However, the complexity and high cost of this preparation method have hindered the promotion of embolic microspheres in clinical applications. Summary of the invention

[0003] In view of the deficiencies in the prior art, the purpose of the embodiments of the present application includes providing a polyhydroxy long-chain polymer embolic microsphere and a preparation method thereof. The microsphere has good mechanical properties and the preparation method is simple and efficient, so that the embolic microsphere can be better used in clinical applications.

[0004] The embodiment of the present application is implemented as follows:

[0005] In a first aspect, an embodiment of the present application provides a polyhydroxy long-chain polymer embolic microsphere, comprising: a polyhydroxy long-chain polymer and a cross-linking agent having a terminal epoxy group are polymerized through epoxy ring-opening cross-linking.

[0006] In the above technical scheme, the present application uses a polyhydroxy long-chain polymer as a raw material, and forms embolic microspheres with embolic function through epoxy ring-opening cross-linking polymerization with a cross-linking agent having an epoxy propene group at the end.

[0007] In the second aspect, an embodiment of the present application provides a method for preparing the above-mentioned polyhydroxy long-chain polymer embolic microspheres, comprising: S1. adding an alkaline catalyst and a polyhydroxy long-chain polymer into water to form an alkaline aqueous solution, and then adding a cross-linking agent, stirring the reaction, and obtaining an aqueous phase solution; S2. adding the aqueous phase solution to an oil phase solution containing a dispersant under stirring to obtain an oil-in-water reverse suspension polymerization system; S3. maintaining the stirring state, heating, purifying and collecting the oil-in-water reverse suspension polymerization system to obtain polyhydroxy long-chain polymer embolic microspheres.

[0008] In the above technical scheme, the polyhydroxy long-chain polymer reacts with the cross-linking agent under the action of an alkaline catalyst to form embolic microspheres through epoxy ring-opening cross-linking polymerization. The preparation method is simple and efficient, and avoids the introduction of double-bond monomers in the prior art, thereby introducing unsaturated chains to produce self-polymerization and ultimately causing product instability, thereby improving the stability of the embolic microspheres. BRIEF DESCRIPTION OF THE DRAWINGS

[0009] In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings required for use in the embodiments will be briefly introduced below. It should be understood that the following drawings only show certain embodiments of the present application and therefore should not be regarded as limiting the scope. For ordinary technicians in this field, other related drawings can be obtained based on these drawings without paying creative work.

[0010] Figure 1 The results of the drug loading rate determination of doxorubicin hydrochloride loaded on the embolic microspheres prepared in Examples 1-6 of the present application;

[0011] Figure 2 The results of the drug loading rate determination of irinotecan hydrochloride loaded on the embolic microspheres prepared in Examples 1-6 of the present application;

[0012] Figure 3 These are the results of drug loading rate determination of lenvatinib mesylate loaded on the embolic microspheres prepared in Examples 1-6 of the present application. DETAILED DESCRIPTION

[0013] In order to make the purpose, technical scheme and advantages of the embodiments of the present application clearer, the technical scheme in the embodiments of the present application will be described clearly and completely below. If the specific conditions are not specified in the embodiments, they are carried out according to the conventional conditions or the conditions recommended by the manufacturer. If the manufacturer is not specified for the reagents or instruments used, they are all conventional products that can be purchased commercially.

[0014] The following is a detailed description of a polyhydroxy long-chain polymer embolic microsphere and a preparation method thereof according to an embodiment of the present application.

[0015] The embodiment of the present application provides a polyhydroxy long-chain polymer embolic microsphere, comprising: a polyhydroxy long-chain polymer and a cross-linking agent having a terminal epoxy group through epoxy ring-opening cross-linking polymerization.

[0016] Among them, the crosslinking agent includes a glycidyl ether compound with a terminal group of propylene oxide. As an example, the glycidyl ether compound includes but is not limited to polyethylene glycol diglycidyl ether, glycerol triglycidyl ether, glycerol diglycidyl ether, polypropylene glycol diglycidyl ether, 1,4-butanediol diglycidyl ether, resorcinol diglycidyl ether, bisphenol A diglycidyl ether, 1,6-hexanediol diglycidyl ether, neopentyl glycol diglycidyl ether, PEG 500 - one or more of diglycidyl ether and pentaerythritol glycidyl ether.

[0017] By selecting long-chain glycidyl ether compounds as crosslinking agents, the strength and elasticity of microspheres can be comprehensively adjusted. Due to the presence of multiple active epoxy groups, they can undergo effective crosslinking reactions with polyhydroxy long-chain polymers during the polymerization process. This crosslinking can form a stable three-dimensional network structure, enhance the mechanical properties and durability of the microspheres, and enable them to exhibit better stability and reliability in biomedical applications. The selection of a series of glycidyl ether compounds (such as polyethylene glycol diglycidyl ether, propylene glycol triglycidyl ether, etc.) provides a wealth of options for adjusting the performance of microspheres.

[0018] In the present application, by way of example, the polyhydroxy long-chain polymer includes, but is not limited to, one or more of polyvinyl alcohol, starch, gelatin, ethylene vinyl alcohol copolymer, hyaluronic acid, chitosan, sodium alginate, dextran, polyquaternium-10, polyglycerol, cellulose, hydroxymethyl cellulose and hydroxyethyl cellulose.

[0019] In the present application, the embolic microspheres are formed by epoxy ring-opening cross-linking of hydroxyl groups on polyhydroxy long-chain polymers and epoxy groups on cross-linking agents. While being formed by epoxy ring-opening polymerization, hydroxyl groups are simultaneously generated on the hydroxyl long-chain polymer chains, thereby enhancing the hydrophilicity and making the synthesized microspheres have good mechanical properties and suspension properties.

[0020] The present application avoids the conventional synthesis method of introducing unsaturated bonds (carbon-carbon double bonds, carbon-carbon triple bonds, etc.) on monomers or polymer long chains, and then copolymerizing the modified monomers or polymer long chains with charged monomers, because the introduction of unsaturated chains in conventional synthesis methods not only causes the substance to self-polymerize, resulting in instability of the product, but the introduction of charged monomers, unsaturated bonds and initiators also increases the purification and manufacturing costs of microspheres, all of which are not conducive to the production of microsphere products. The present application is simple and efficient through the epoxy ring-opening cross-linking polymerization preparation method, which is conducive to the stable production of microsphere products. In some embodiments of the present application, the embolic microspheres also include sulfonic acid groups, which are obtained by bonding a compound containing a sulfonic acid group to a hydroxyl group on a polyhydroxy long-chain polymer.

[0021] In the present application, by introducing sulfonic acid groups into polyhydroxy long-chain polymer microspheres by ionization modification in advance, the drug loading performance and mechanical properties of embolic microspheres can be increased. Among them, the introduction of sulfonic acid groups significantly enhances the hydrophilicity of the microspheres, giving the microspheres a higher charge density, on the one hand, enhancing the drug loading, the sulfonic acid groups can form electrostatic interactions with positively charged drug molecules, enhance the binding ability of the drugs, thereby improving the drug loading rate of the microspheres; on the other hand, improve the mechanical strength and stability of the microspheres. Therefore, the present application cross-links polyhydroxy long-chain polymers modified with sulfonic acid groups with glycidyl ether compounds with propylene oxide at the end groups, and forms embolic microspheres with drug loading performance through epoxy ring-opening cross-linking polymerization, and the microspheres have excellent mechanical properties and stability.

[0022] As an example, the compound containing a sulfonic acid group includes, but is not limited to, one or more of 1,4-butane sultone, 1,3-propane sultone, and sodium 2-chloroethyl sulfonate.

[0023] The present application sulfonates the polyhydroxy long-chain polymer by using the above-mentioned compound containing sulfonic acid groups, and introduces sulfonic acid groups by reacting with the hydroxyl groups on the polyhydroxy long-chain polymer to form ether bonds. The sulfonic acid groups are more stable in structure connected by ether bonds, thereby giving the embolic microspheres more stable functional groups, which can more stably load and release drugs in human applications.

[0024] The preparation method of the above-mentioned polyhydroxy long-chain polymer embolic microspheres is described below.

[0025] A method for preparing polyhydroxy long-chain polymer embolic microspheres comprises the following steps:

[0026] (1) Preparation of aqueous solution

[0027] The alkaline catalyst and the polyhydroxy long-chain polymer are added into water to dissolve to form an alkaline aqueous solution, and finally a cross-linking agent is added and stirred for 1-120 minutes to obtain an aqueous phase solution.

[0028] Wherein, the alkaline catalyst includes KOH and / or NaOH, and specifically, the mass concentration of the aqueous solution or organic solution of the alkaline catalyst is 5-25%. High concentration of alkaline catalyst can effectively increase the reaction rate, and the strong alkaline environment helps to promote the dissolution and cross-linking reaction of polyhydroxy long-chain polymers, so that the reactants are evenly mixed, thereby accelerating the cross-linking polymerization. KOH and NaOH, as alkaline catalysts, have good catalytic effect and economy. The reaction environment under strong alkaline conditions can improve the selectivity of the cross-linking reaction and reduce the occurrence of side reactions, thereby improving the yield and purity of the final microspheres.

[0029] In some embodiments of the present application, under stirring conditions, an alkaline catalyst is first added to water to prepare an alkaline aqueous solution, the polyhydroxy long-chain polymer is dissolved in the alkaline aqueous solution, and then a cross-linking agent is added and mixed uniformly to obtain an aqueous phase solution.

[0030] After the alkaline catalyst is first added to water, the alkaline aqueous solution formed provides an ideal environment for the dissolution of the polyhydroxy long-chain polymer, promotes its full dissolution and uniform distribution, and can effectively increase the reaction rate; moreover, the alkaline environment helps to activate the polyhydroxy long-chain polymer and enhance its reactivity with the cross-linking agent.

[0031] Wherein, the mass percentage of the polyhydroxy long-chain polymer in the aqueous phase solution is 1-10%. As an example, the mass percentage of the polyhydroxy long-chain polymer in the aqueous phase solution includes but is not limited to 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%.

[0032] By limiting the mass percentage of the polyhydroxy long-chain polymer in the aqueous solution to 1-10%, it helps to promote the full dissolution of the polyhydroxy long-chain polymer in the aqueous phase; within this mass concentration range, the particle size and morphology of the microspheres can be effectively controlled, which helps to obtain a uniform particle size distribution, thereby improving the controllability of the drug release behavior.

[0033] Wherein, the cross-linking agent accounts for 5 to 30% of the feed weight of the polyhydroxy long-chain polymer. As an example, the cross-linking agent accounts for 5% to 30% of the feed weight of the polyhydroxy long-chain polymer, including but not limited to 5%, 6%, 8%, 10%, 12%, 15%, 17%, 19%, 21%, 22%, 25%, 27%, 29%, 30%.

[0034] Limiting the mass percentage of the cross-linking agent to the polyhydroxy long-chain polymer to 5-30% can not only control the cross-linking degree and mechanical properties of the microspheres, reduce the risk of side reactions, but also improve the uniformity of the microspheres.

[0035] In another preparation method of the present application, before the cross-linking agent is added, a modifier is added to the alkaline aqueous solution, wherein the modifier includes a compound containing a sulfonic acid group.

[0036] The modifier containing sulfonic acid group can react with polyhydroxy long-chain polymer, thereby introducing sulfonic acid group on polyhydroxy long-chain polymer, so as to sulfonic acid modify polyhydroxy long-chain polymer, form a more hydrophilic surface, and then improve the surface properties of microspheres; moreover, sulfonic acid group can form electrostatic interaction with drug molecules, enhance the binding ability of drugs, and then increase the loading capacity of drugs. In addition, the introduction of sulfonic acid group can also improve the mechanical properties of microspheres, such as improving the elasticity and strength of microspheres. That is to say, the present application first sulfonates polyhydroxy long-chain polymers, and then adds a cross-linking agent to carry out polymerization reaction, so as to regulate the density of sulfonation, so that the density of sulfonic acid group introduction of synthesized embolic microspheres is differentiated, and then the hydrophilic strength of microspheres can be adjusted, and the drug loading performance and mechanical properties of microspheres can be improved. Therefore, the introduction of sulfonic acid group in the present application can not only increase the drug loading capacity of microspheres, but also because the present application needs to further form microsphere structure after sulfonating polyhydroxy long-chain polymers, and polyhydroxy long-chain polymers have better mechanical properties after sulfonation.

[0037] Wherein, the feed mass ratio of the modifier to the polyhydroxy long-chain polymer is (1-5): 1. As an example, the feed mass ratio of the modifier to the polyhydroxy long-chain polymer includes but is not limited to 1: 1, 1.2: 1, 1.4: 1, 1.5: 1, 1.7: 1, 1.9: 1, 2: 1, 2.4: 1, 2.6: 1, 2.8: 1, 3: 1, 3.4: 1, 3.7: 1, 4: 1, 4.3: 1, 4.8: 1, 5: 1.

[0038] A moderate feed ratio (1-5):1 can enable sufficient reaction between the modifier and the polyhydroxy long-chain polymer. Within this ratio range, multiple hydroxyl groups can be effectively activated to form a sufficient number of sulfonic acid groups, thereby significantly improving the surface properties and hydrophilicity of the microspheres; it can also effectively control the physicochemical properties of the microspheres, thereby improving the drug loading capacity and release characteristics of the microspheres.

[0039] As an example, the compound containing a sulfonic acid group includes, but is not limited to, one or more of 1,4-butane sultone, 1,3-propane sultone, and sodium 2-chloroethyl sulfonate.

[0040] Selecting compounds containing sulfonic acid groups such as 1,4-butane sultone, 1,3-propane sultone and sodium 2-chloroethyl sulfonate can not only improve the hydrophilicity and biocompatibility of the microspheres, but also enhance the drug loading capacity.

[0041] (2) Preparation of oil phase solution

[0042] Under stirring, an oil-soluble dispersant is added to the oil phase solvent to obtain an oil phase solution.

[0043] Wherein, the dispersant includes Tween series compounds and / or Span series compounds, such as Tween 20 and Span 80. As an example, the mass ratio of Tween 20 to Span 80 is 1:(1-5). The mass ratio of Tween 20 to Span 80 includes but is not limited to 1:1, 1:2, 1:3, 1:4, and 1:5.

[0044] Wherein, the oil phase solvent includes but is not limited to at least one of liquid paraffin, liquid alkane solvent series compounds such as n-heptane, ethyl acetate and butyl acetate. In some embodiments of the present application, the mass percentage of the dispersant in the oil phase solution is 0.5-5%. As an example, the mass percentage of the dispersant in the oil phase solution includes but is not limited to 0.5%, 0.7%, 1%, 0.5%, 1.3%, 1.5%, 1.8%, 2%, 2.5%, 2.7%, 3%, 3.4%, 3.8%, 4%, 4.3%, 4.5%, 4.7%, 5%.

[0045] (3) Inverse suspension polymerization

[0046] Under the condition of stirring rate of 100-500r / min, the aqueous phase solution in step (1) is slowly dripped into the oil phase solution in step (2) to form an oil-in-water reverse suspension polymerization system. After the dripping is completed, the reverse suspension polymerization system is heated to 30-90°C, kept in heating and stirring state, and heated reaction is carried out, and the reaction time is 5-36h.

[0047] A stable microsphere structure can be formed through inverse suspension polymerization. By controlling the stirring rate to 100-500r / min, the particle size and morphology of the microspheres can be effectively adjusted to meet the needs of different applications. Reacting the inverse suspension polymerization system at 30-90°C for 5-36h can enhance the cross-linking reaction and form more stable microspheres.

[0048] (4) Microsphere purification and collection

[0049] After the reaction is completed, stirring and heating are stopped, the layers are allowed to stand, the oil phase is separated, the microspheres are collected, and the microspheres are washed with petroleum ether, butyl acetate, sodium bicarbonate aqueous solution and ultrapure water in turn. After sieving, polyhydroxy long-chain polymer embolic microspheres with different particle size distributions are obtained.

[0050] Among them, static stratification can effectively separate the oil phase and the water phase, so as to enable efficient collection of the microspheres; then by using petroleum ether, butyl acetate, sodium bicarbonate aqueous solution and ultrapure water to wash the microspheres in sequence, the unreacted raw materials, residual modifiers and cross-linking agents can be removed to improve the purity of the microspheres; the screening step can effectively separate microspheres of different particle sizes to meet various application requirements.

[0051] The features and performance of the present application are further described in detail below in conjunction with the embodiments.

[0052] Example 1

[0053] This embodiment provides a polyhydroxy long-chain polymer embolic microsphere, which can be prepared by the following synthetic route:

[0054]

[0055] The preparation method comprises the following steps:

[0056] (1) Preparation of aqueous solution

[0057] Under stirring conditions, a 10wt% NaOH solution was prepared, and then polyvinyl alcohol (PVA) was dissolved in the NaOH solution. After the solution was clarified, propylene glycol triglycidyl ether was added and stirred for 1 hour to obtain an aqueous phase solution; the mass fraction of PVA in the aqueous phase solution was 5%, and the molar ratio of PVA to propylene glycol triglycidyl ether was 6:1.

[0058] (2) Preparation of oil phase solution

[0059] Under stirring, Tween 20 and Span 80 were added to liquid paraffin in a mass ratio of 1:3 (mass percentage of the dispersant was 3%) to obtain an oil phase solution.

[0060] (3) Inverse suspension polymerization

[0061] Under the condition of stirring rate of 300r / min, the aqueous phase solution in step (1) is slowly dripped into the oil phase solution in step (2) to form an oil-in-water reverse suspension polymerization system; wherein, after the dripping is completed, the reverse suspension polymerization system is heated to 70°C and maintained in a heating and stirring state to carry out a heating reaction, and the stirring and heating are stopped after the reaction for 16 hours.

[0062] (4) Microsphere purification and collection

[0063] After the reaction is completed, stirring and heating are stopped, the layers are allowed to stand, the oil phase is separated, the microspheres are collected, and the microspheres are washed with petroleum ether, butyl acetate, sodium bicarbonate aqueous solution and ultrapure water in turn. After sieving, polyhydroxy long-chain polymer embolic microspheres with different particle size distributions are obtained.

[0064] Example 2

[0065] This embodiment provides a polyhydroxy long-chain polymer embolic microsphere, which can be prepared by the following synthetic route:

[0066]

[0067] The preparation method comprises the following steps:

[0068] (1) Preparation of sulfonated PVA (polyvinyl alcohol)

[0069] At 100°C, a 25wt% NaOH solution was prepared, and then PVA was added for activation for 2 hours, and then 1,3-propane sultone was added to react at 80°C for 16 hours. The molar ratio of 1,3-propane sultone to PVA was 1:2.5. Finally, sulfonated PVA was obtained after purification and drying.

[0070] (2) Preparation of aqueous solution

[0071] Under stirring conditions, the sulfonated PVA in step (1) is first dissolved in deionized water to obtain a sulfonated PVA solution (wherein the mass fraction of the sulfonated PVA is 50%); then a NaOH solution with a mass concentration of 25% is added, and after the solution is clarified, propylene glycol triglycidyl ether is added, and stirred for 1 hour to obtain an aqueous phase solution; the feeding molar ratio of propylene glycol triglycidyl ether to sulfonated PVA is 1:6.

[0072] (3) Preparation of oil phase solution

[0073] Under stirring, Tween 20 and Span 80 were added to liquid paraffin in a mass ratio of 1:3 (mass percentage of the dispersant was 3%) to obtain an oil phase solution.

[0074] (4) Inverse suspension polymerization

[0075] Under the condition of stirring rate of 300r / min, the aqueous phase solution in step (2) is slowly dripped into the oil phase solution in step (3) to form an oil-in-water reverse suspension polymerization system; wherein, after the dripping is completed, the reverse suspension polymerization system is heated to 70°C and maintained in a heating and stirring state to carry out a heating reaction, and the stirring and heating are stopped after the reaction for 16 hours.

[0076] (5) Microsphere purification and collection

[0077] After the reaction is completed, stirring and heating are stopped, the layers are allowed to stand, the oil phase is separated, the microspheres are collected, and the microspheres are washed with petroleum ether, butyl acetate, sodium bicarbonate aqueous solution and ultrapure water in turn. After sieving, polyhydroxy long-chain polymer embolic microspheres with different particle size distributions are obtained.

[0078] Example 3

[0079] This embodiment provides a polyhydroxy long-chain polymer embolic microsphere, which can be prepared by the following synthetic route:

[0080]

[0081] The preparation method comprises the following steps:

[0082] (1) Preparation of sulfonated PVA (polyvinyl alcohol)

[0083] At 100°C, prepare a 25wt% NaOH solution and then add PVA. After activation for 2 hours, add 1,4-butanesulfonate and react for 16 hours at 80°C. The molar ratio of 1,4-butanesulfonate to PVA is 1:2. Finally, sulfonated PVA can be obtained after purification and drying.

[0084] (2) Preparation of aqueous solution

[0085] Under stirring conditions, the sulfonated PVA in step (1) is first dissolved in deionized water to obtain a sulfonated PVA solution (wherein the mass fraction of the sulfonated PVA is 50%); then a NaOH solution with a mass concentration of 25% is added, and after the solution is clarified, propylene glycol triglycidyl ether is added, and stirred for 1 hour to obtain an aqueous phase solution; the feeding molar ratio of propylene glycol triglycidyl ether to sulfonated PVA is 1:6.

[0086] Steps (3), (4) and (5) are the same as in Example 2.

[0087] Example 4

[0088] This embodiment provides a polyhydroxy long-chain polymer embolic microsphere, which can be prepared by the following synthetic route:

[0089]

[0090] The preparation method comprises the following steps:

[0091] (1) Preparation of sulfonated PVA (polyvinyl alcohol)

[0092] At 100°C, prepare a 25wt% NaOH solution and then add PVA. After activation for 2 hours, add 1,3-propane sultone and react at 80°C for 16 hours. The molar ratio of 1,3-propane sultone to PVA is 1:2. Finally, sulfonated PVA can be obtained after purification and drying.

[0093] (2) Preparation of aqueous solution

[0094] Under stirring conditions, the sulfonated PVA in step (1) is first dissolved in deionized water to obtain a sulfonated PVA solution (wherein the mass fraction of the sulfonated PVA is 50%); then a KOH solution with a mass concentration of 25% is added, and after the solution is clarified, ethylene glycol diglycidyl ether is added, and stirred for 1 hour to obtain an aqueous phase solution; the feeding molar ratio of ethylene glycol diglycidyl ether to sulfonated PVA is 1:5.

[0095] Steps (3), (4) and (5) are the same as in Example 2.

[0096] Example 5

[0097] This embodiment provides a polyhydroxy long-chain polymer embolic microsphere, which can be prepared by the following synthetic route:

[0098]

[0099] The preparation method comprises the following steps:

[0100] (1) Preparation of aqueous solution

[0101] Under stirring conditions, prepare a 25 wt% NaOH solution and then add hydroxyethyl cellulose, followed by 1,4-butanesulfonate, and finally add propylene glycol triglycidyl ether, and stir for 1 hour to obtain an aqueous phase solution; the molar ratio of propylene glycol triglycidyl ether to hydroxyethyl cellulose is 1:6.

[0102] The remaining steps (2), (3) and (4) are the same as those in Example 1.

[0103] Example 6

[0104] This embodiment provides a polyhydroxy long-chain polymer embolic microsphere, which can be prepared by the following synthetic route:

[0105]

[0106] The preparation method comprises the following steps:

[0107] (1) Preparation of aqueous solution

[0108] Under stirring conditions, NaOH is first added to water to prepare a NaOH solution (mass concentration is 10%), gelatin is dissolved in the solution, 1,4-butanesulfonic acid lactone is subsequently added, and finally propylene glycol triglycidyl ether is added, stirred for 1 hour, to obtain an aqueous phase solution; the molar ratio of propylene glycol triglycidyl ether to gelatin is 1:6.

[0109] The remaining steps (2), (3) and (4) are the same as those in Example 1.

[0110] Comparative Example 1

[0111] This comparative example uses commercially available embolic microspheres DC Bead (manufactured by Boston Scientific).

[0112] Comparative Example 2

[0113] This comparative example provides a polyhydroxy long-chain polymer embolic microsphere, the preparation method of which comprises the following steps:

[0114] (1) Preparation of sulfonated PVA

[0115] 3 g of PVA was added to 9 g of water and heated to 70°C for dissolution. Then 3 mL of concentrated sulfuric acid (density 1.83 g / mL, mass 5.49 g) was added and heated to 40°C for stirring reaction. After the reaction for 1 hour, the reaction solution was added dropwise to ethanol to obtain a precipitate. The precipitate was filtered and vacuum dried for 24 hours to obtain polyvinyl alcohol (SPVA) modified with sulfonate groups.

[0116] (2) Preparation of aqueous solution

[0117] Under stirring conditions, SPVA is first dissolved in deionized water to obtain an SPVA solution, in which the mass fraction of SPVA is 50%; then a NaOH solution with a mass concentration of 25% is added, and after the solution is clarified, propylene glycol triglycidyl ether is added, and the mixture is stirred for 1 hour to obtain an aqueous phase solution; the molar ratio of propylene glycol triglycidyl ether to SPVA is 1:6.

[0118] Steps (3), (4) and (5) are the same as in Example 2.

[0119] Comparative Example 3

[0120] This comparative example uses the embolic microspheres prepared by patent CN117771419A.

[0121] Test Example 1

[0122] In this test example, the embolic microspheres prepared in Examples 1-6 and Comparative Example 1 were tested for physical properties, including strength, elasticity and density.

[0123] The elasticity determination method is as follows: take the embolic microspheres prepared in Examples 1-6 and Comparative Example 1 respectively, spread them on a glass slide, place them under the probe of a texture analyzer (TAXT plusC), and select the Hold Compression mode for testing.

[0124] The density test method is: measure 1 mL of the embolic microspheres prepared in Examples 1-6 and Comparative Example 1, and weigh the mass. The ratio of the mass to the volume is the density of the microspheres.

[0125] Please see Table 1 for the above performance test results.

[0126] Table 1

[0127]

[0128]

[0129] As can be seen from Table 1, the PVA microspheres in Example 1 have high mechanical strength but poor elasticity. The strength of the PVA microspheres after ionization modification in Examples 2 to 4 is slightly reduced, but the elasticity is greatly improved, which shows that ionization modification can improve the mechanical properties of PVA microspheres. By comparing Example 2 and Example 4, it can be seen that although the mechanical strength of the long-chain cross-linking agent decreases, it can improve the elasticity of the microspheres, and the branched cross-linking agent has high mechanical strength but low elasticity. The cellulose microspheres in Example 5 have a higher strength than Examples 2 to 4 because the molecular chain has a rigid sugar ring structure. The gelatin microspheres in Example 6 have more hydrophilic groups in the molecular chain, so they have greater elasticity. In addition, compared with Comparative Example 1, the strength and elasticity of Examples 2 to 4 are improved, and the higher mechanical properties make the microspheres less likely to be damaged when passing through the catheter, which helps the delivery of the microspheres in the catheter.

[0130] Test Example 2

[0131] In this test example, the drug loading performance of the embolic microspheres prepared in Examples 1-6 and Comparative Examples 1-3 was tested respectively, and the drugs used included doxorubicin hydrochloride, irinotecan hydrochloride and lenvatinib mesylate.

[0132] Test method: Take three groups (1 mL for each group) of the embolic microspheres prepared in Examples 1-6 and Comparative Examples 1-3 and number them, remove moisture from the surface of the microspheres with filter paper, transfer the microspheres into a vial, add 5 mL of doxorubicin hydrochloride solution (20 mg / mL), irinotecan hydrochloride solution (20 mg / mL) and lenvatinib mesylate solution (10 mg / mL), respectively, mix and shake, and test the solution concentration at 5 min, 30 min and 60 min, respectively, calculate the drug loading rate of the embolic microspheres and draw drug loading curves of each drug corresponding to Examples 1-6 and Comparative Examples 1-3.

[0133] Please see Table 2 for the above mentioned drug loading rate results of embolic microspheres.

[0134] Table 2

[0135]

[0136]

[0137] Figure 1 The results of the drug loading rate determination of doxorubicin hydrochloride loaded on the embolic microspheres prepared in Examples 1-6 of the present application; Figure 2 The results of the drug loading rate determination of irinotecan hydrochloride loaded on the embolic microspheres prepared in Examples 1-6 of the present application; Figure 3 These are the results of drug loading rate determination of lenvatinib mesylate loaded on the embolic microspheres prepared in Examples 1-6 of the present application.

[0138] From Table 2 and Figure 1-Figure 3 It can be seen that the embolic microspheres prepared in Example 1 without ionization modification have almost no adsorption capacity for drugs, and the embolic microspheres of Examples 2-6 have excellent loading efficiency for the above three drugs, while the loading amount of the above three drugs in Comparative Example 1 is low and the loading speed is slow. The loading speed of the embolic microspheres of Examples 2 and 3 for the above three drugs is faster than that of Example 4. This is mainly because in the embolic microspheres prepared in Examples 2 and 3, the cross-linking agent is propylene glycol triglycidyl ether, and the molecular skeleton is relatively rigid. When interacting with the drug, the pores in the microspheres are not easy to collapse, ensuring the smooth flow of drug molecules, so the loading speed is faster; while in Example 4, the cross-linking agent is ethylene glycol diglycidyl ether, and the molecular skeleton is relatively soft. As the drug is loaded, the positive and negative charges are neutralized, the volume of the microspheres is reduced, and the pores become smaller, so the loading speed is slow. In the cellulose embolic microspheres in Example 5, the main chain of the molecule has a sugar ring structure, which is relatively rigid as a whole, ensuring the circulation of the drug and having a good drug loading effect. The gelatin embolic microspheres in Example 6 have strong hydrophilicity and thus have a good drug loading effect on hydrophilic cationic drugs.

[0139] Although the embolic microspheres in Comparative Example 2 are also sulfonated, the sulfate bonds formed are easily hydrolyzed, so the drug loading amount decreases in the later stage of the test; the embolic microspheres in Comparative Example 3 are cage-like structures with large spaces, which are suitable for loading rigid macromolecular drugs. When loading small molecule drugs, the drugs are easy to escape, which is not conducive to its practical application.

[0140] The embodiments described above are part of the embodiments of the present application, rather than all of the embodiments. The detailed description of the embodiments of the present application is not intended to limit the scope of the present application for protection, but merely represents the selected embodiments of the present application. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present application.

Claims

1. A polyhydroxy long-chain polymer embolic microsphere, characterized in that: include: It is prepared by epoxy ring-opening cross-linking polymerization of a polyhydroxy long-chain polymer and a cross-linking agent with a terminal epoxy propylene group.

2. The polyhydroxy long-chain polymer embolic microspheres according to claim 1, characterized in that: The cross-linking agent includes a glycidyl ether compound having an end group of propylene oxide; Optionally, the glycidyl ether compound includes polyethylene glycol diglycidyl ether, glycerol triglycidyl ether, glycerol diglycidyl ether, polypropylene glycol diglycidyl ether, 1,4-butanediol diglycidyl ether, resorcinol diglycidyl ether, bisphenol A diglycidyl ether, 1,6-hexanediol diglycidyl ether, neopentyl glycol diglycidyl ether, PEG 500 - one or more of diglycidyl ether and pentaerythritol glycidyl ether.

3. The polyhydroxy long-chain polymer embolic microspheres according to claim 1, characterized in that: The polyhydroxy long-chain polymer includes one or more of polyvinyl alcohol, starch, gelatin, ethylene vinyl alcohol copolymer, hyaluronic acid, chitosan, sodium alginate, dextran, polyquaternium-10, polyglycerol, cellulose, hydroxymethyl cellulose and hydroxyethyl cellulose.

4. The polyhydroxy long-chain polymer embolic microspheres according to any one of claims 1 to 3, characterized in that: The embolic microspheres further include sulfonic acid groups, which are obtained by bonding a compound containing a sulfonic acid group to a hydroxyl group on the polyhydroxy long-chain polymer; Optionally, the compound containing a sulfonic acid group includes one or more of 1,4-butane sultone, 1,3-propane sultone, and sodium 2-chloroethyl sulfonate.

5. A method for preparing polyhydroxy long-chain polymer embolic microspheres according to any one of claims 1 to 4, characterized in that: include: S1. adding the alkaline catalyst and the polyhydroxy long-chain polymer to water to form an alkaline aqueous solution, and then adding a crosslinking agent, stirring the reaction to obtain an aqueous solution; S2. Under stirring, the aqueous solution is added to the oil phase solution containing a dispersant to obtain an oil-in-water reverse suspension polymerization system; S3. Keep stirring, heat, purify and collect the water-in-oil reverse suspension polymerization system to obtain the polyhydroxy long-chain polymer embolic microspheres.

6. The preparation method according to claim 5, characterized in that: In step S1, under stirring conditions, the alkaline catalyst is first added to water to prepare the alkaline aqueous solution, the polyhydroxy long-chain polymer is dissolved in the alkaline aqueous solution, and then the cross-linking agent is added and mixed uniformly to obtain the aqueous phase solution; Optionally, the mass percentage of the polyhydroxy long-chain polymer in the aqueous solution is 1-10%; Optionally, the cross-linking agent accounts for 5 to 30% of the mass percentage of the polyhydroxy long-chain polymer.

7. The preparation method according to claim 5, characterized in that: In step S1, before adding the cross-linking agent, adding a modifier to the alkaline aqueous solution, wherein the modifier includes a compound containing a sulfonic acid group; Optionally, the feed mass ratio of the modifier to the polyhydroxy long-chain polymer is (1-5):1; Optionally, the compound containing a sulfonic acid group includes one or more of 1,4-butane sultone, 1,3-propane sultone, and sodium 2-chloroethyl sulfonate.

8. The preparation method according to claim 5, characterized in that: The alkaline catalyst includes KOH and / or NaOH solution. Optionally, the mass concentration of the alkaline catalyst is 5-25%.

9. The preparation method according to claim 5, characterized in that: In step S3, the reverse phase suspension polymerization system is heated to 30-90° C. at a stirring rate of 100-500 r / min for a heating reaction for 5-36 hours.

10. The preparation method according to claim 9, characterized in that: In step S2, the mass percentage of the dispersant in the oil phase solution is 0.5-5%; Optionally, the dispersant includes Tween series compounds and / or Span series compounds; Optionally, the dispersant includes Tween 20 and Span 80, and the mass ratio of the Tween 20 to the Span 80 is 1:(1-5).

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