Drug-loaded embolizing gel microspheres, method for preparing the same, and drug-loaded embolizing gel microspheres

Abstract

The application provides a drug-loaded embolization gel microsphere, a preparation method thereof and the drug-loaded embolization gel microsphere. The drug-loaded embolization gel microsphere is prepared from at least the following: an organic phase solution containing an emulsifier with a concentration of 0.05-2 g / mL; and an aqueous phase solution containing polyvinyl alcohol modification with a concentration of 0.01-2 g / mL, an olefin anionic monomer with a concentration of 0.01-1 g / mL, an enolic monomer with a concentration of 0.01-0.5 g / mL and an initiator with a mass of 3%-6% of the mass of the polyvinyl alcohol modification; wherein the modification degree of the polyvinyl alcohol modification is 10-25% calculated by the hydroxyl group. By setting the two-phase reaction system of the oil phase and the aqueous phase, the ternary copolymerization of the polyvinyl alcohol modification, the olefin anionic monomer and the enolic monomer is realized, and the combination of the uniformity of the particle size and the drug loading property is realized under the premise of effectively guaranteeing the high toughness and the moderate swelling degree.

Description

Technical Field

[0001] This application relates to the field of gel microsphere technology, and more particularly to a drug-loadable embolized gel microsphere, its preparation method, and the drug-loaded embolized gel microsphere. Background Technology

[0002] Malignant tumors (cancer) are among the most common causes of death. Treating cancer remains a major global challenge, especially for certain types such as liver cancer, where early symptoms are often subtle, and most patients are diagnosed at an advanced stage, making surgical resection difficult and resulting in relatively poor treatment outcomes and prognoses. Transarterial chemoembolization (TACE) is a minimally invasive technique that selectively injects embolic agents or anticancer drugs combined with microparticles to embolize the arteries supplying the tumor. It is a type of interventional vascular therapy. Its advantages are: firstly, embolizing the tumor's supplying arteries causes ischemia, hypoxia, and necrosis of the tumor tissue; secondly, increasing local drug concentration and prolonging the contact time between the drug and tumor tissue, resulting in significantly improved efficacy compared to simple perfusion chemotherapy and simple embolization. TACE is suitable for palliative and relatively radical treatment of liver cancer, kidney cancer, pancreatic cancer, lung cancer, and pelvic malignancies, as well as radical treatment of hepatic hemangiomas.

[0003] The effectiveness of TACE treatment largely depends on the performance and characteristics of the embolic agent. Traditional embolic agents are mostly liquid embolic agents, which have the problem of high fluidity. Newer solid embolic agents have problems such as insufficient compressibility, which can easily cause catheter blockage during the procedure, breakage of the embolic agent and leakage into other blood vessels; and low drug loading efficiency. Summary of the Invention

[0004] In view of this, the purpose of this application is to provide a drug-loadable embolization gel microsphere, its preparation method and the drug-loaded embolization gel microsphere.

[0005] For the purposes described above, this application provides drug-loadable embolic gel microspheres, prepared from at least the following substances:

[0006] Organic phase solution: including emulsifier with a concentration of 0.05-2 g / mL;

[0007] Aqueous solution: includes polyvinyl alcohol modifier at a concentration of 0.01-2 g / mL, olefin anionic monomer at a concentration of 0.01-1 g / mL, enol monomer at a concentration of 0.01-0.5 g / mL, and initiator at a mass of 3%-6% of the polyvinyl alcohol modifier.

[0008] In some embodiments, the polyvinyl alcohol modified product is prepared by modifying polyvinyl alcohol with a modifier, and the degree of modification of the polyvinyl alcohol modified product is 10-25% calculated in terms of hydroxyl groups; wherein the mass fraction of the polyvinyl alcohol is 5-15%, and the molar amount of the modifier is 3-10% of the molar amount of the polyvinyl alcohol; the modifier is an olefinic aldehyde monomer.

[0009] In some embodiments, the concentration of the polyvinyl alcohol modifier in the aqueous solution is 0.68-1.84 g / mL. The degree of modification of the polyvinyl alcohol modifier, calculated in terms of hydroxyl groups, can be 14-20%.

[0010] In some embodiments, the olefinic aldehyde monomer includes C=C and -CHO groups; the olefinic aldehyde monomer accounts for 4.5-7.2% of the molar amount of polyvinyl alcohol; and includes at least one of trans-2-hexen-1-ol diethyl acetal, trans-2-butenal diethyl acetal, α-pentylcinnamaldehyde dimethyl acetal, and cinnamaldehyde diethyl acetal.

[0011] In some embodiments, the concentration of the olefinic anionic monomer in the aqueous solution is 0.28-0.72 g / mL; including at least one of allyloxybenzenesulfonic acid, hydroxypropyl acrylate, and 2-hydroxy-3-allyloxy-1-propylsulfonic acid.

[0012] In some embodiments, the concentration of the enol monomer in the aqueous solution is 0.17-0.42 g / mL; including at least one of 3-buten-1-ol and 2-methylallylol.

[0013] In some embodiments, the initiator in the aqueous solution comprises 4.5-5% by mass of the polyvinyl alcohol modifier; including at least one of α-ketoglutaric acid, ammonium persulfate, and potassium persulfate.

[0014] In some embodiments, the concentration of the emulsifier in the organic phase solution is 1.0-1.61 g / mL, and the HBO value is 10-12; it includes at least one of sodium dodecyl sulfonate, sodium dodecylbenzene sulfonate, Tween, Span, whey protein, and monoglycerides of fatty acids.

[0015] In some embodiments, the solvent in the organic phase solution is an oil phase solvent, including at least one of liquid paraffin, n-hexane, mineral oil, and silicone oil.

[0016] In some embodiments, the drug-loadable embolic gel microspheres have a weight-average molecular weight of 50,000-300,000, a surface hydroxyl content of 50-80 mol / 100 mol PVA, a pore size of 0.1-1 μm, and a pore volume of 0.1-0.5 cm³. 3 / g, particle size 0.1-1000μm, can withstand compression deformation of 50-90%, compression recovery time of 5-30s, equilibrium swelling rate calculated based on the mass ratio of swelling water to dry pellets is between 60%-95%.

[0017] In some embodiments, the drug-loadable embolic gel microspheres have a weight-average molecular weight of 100,000-200,000, a surface hydroxyl content of 50-60 mol / 100 mol PVA, a pore size of 0.5-1 μm, and a pore volume of 0.3-0.5 cm³. 3 / g, particle size of 200-300μm, 350-450μm, 500-700μm or 800-1000μm, can withstand compression deformation of 50-90%, compression recovery time of 5-30s, equilibrium swelling rate calculated based on the mass ratio of swelling water to dry pellets is between 60% and 95%.

[0018] This application also provides a method for preparing drug-loadable embolized gel microspheres, including:

[0019] Provides polyvinyl alcohol modified products;

[0020] An organic phase solution is provided; said organic phase solution comprises an emulsifier at a concentration of 0.05-2 g / mL;

[0021] Provide an aqueous solution: the aqueous solution comprises a polyvinyl alcohol modifier at a concentration of 0.01-2 g / mL, an olefinic anionic monomer at a concentration of 0.01-1 g / mL, an enol monomer at a concentration of 0.01-0.5 g / mL, and an initiator at a mass of 3%-6% of the polyvinyl alcohol modifier;

[0022] The aqueous solution is added to the organic solution, and the mixture is stirred and reacted for a first time at a first temperature.

[0023] The product obtained from the reaction was frozen at a second temperature for a second time, thawed at a third temperature for a third time, and annealed at a fourth temperature for a fourth time to obtain the drug-loadable embolic gel microspheres.

[0024] In some embodiments, the first temperature is 40-60°C, the stirring speed is 300-600 rpm, and the first duration is 4-8 hours; and / or

[0025] The second temperature is -20 to -80°C, and the second duration is 6-12 hours; and / or

[0026] The third temperature is 20-30℃, and the third duration is 0.5-1h; and / or

[0027] The fourth temperature is 80-120℃, and the fourth duration is 2-4h.

[0028] In some embodiments, the method further includes immersing the drug-loadable embolic gel microspheres in a solution of the drug for 12-24 hours to obtain drug-loaded embolic gel microspheres.

[0029] This application also provides a drug-loaded embolic gel microsphere, comprising a drug-loaded embolic gel microsphere prepared by the method described in the preceding claim or the method described in the preceding claim, and a drug loaded on the drug-loaded embolic gel microsphere.

[0030] In some embodiments, the drug is a cationic drug, including at least one of doxorubicin, pirarubicin, and epirubicin; the drug loading in the drug-loaded embolic gel microspheres is 0.1-50 mg / mL based on the microsphere volume.

[0031] As can be seen from the above, the drug-loadable embolic gel microspheres provided in this application, through ternary copolymerization of modified polyvinyl alcohol, olefin anionic monomers, and enol monomers, enable the drug-loadable embolic gel microspheres to form more space for molecular chain regulation, possessing a high-strength and tough backbone, more drug-loading anionic groups, and a network structure that can comprehensively regulate compression resistance and balanced swelling, thereby achieving sustained drug release. By using a concentration of 0.01-2 g / mL for the polyvinyl alcohol modifier, 0.01-1 g / mL for the olefin anionic monomers, and 0.01-0.5 g / mL for the enol monomers, the resulting drug-loadable embolic gel microspheres can achieve both suitable swelling degree and drug loading capacity, while maintaining good compressive strength even under drug loading. Attached Figure Description

[0032] To more clearly illustrate the technical solutions in this application or related technologies, the drawings used in the description of the embodiments or related technologies will be briefly introduced below. Obviously, the drawings described below are only embodiments of this application. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0033] Figure 1 This is a schematic diagram of the preparation method of drug-loadable embolizable gel microspheres according to an embodiment of this application;

[0034] Figure 2 This is a schematic diagram of the drug-loadable embolization gel microspheres in this application when they are not loaded with drug;

[0035] Figure 3 This is a schematic diagram of a drug-loadable embolized gel microsphere loaded with pirarubicin, as described in an embodiment of this application. Detailed Implementation

[0036] To make the objectives, technical solutions, and advantages of this application clearer, the following detailed description is provided in conjunction with specific embodiments and the accompanying drawings.

[0037] It should be noted that, unless otherwise defined, the technical or scientific terms used in the embodiments of this application should have the ordinary meaning understood by those skilled in the art to which this application pertains. The terms "first," "second," and similar terms used in the embodiments of this application do not indicate any order, quantity, or importance, but are merely used to distinguish different components. Terms such as "comprising" or "including" mean that the element or object preceding the word encompasses the elements or objects listed following the word and their equivalents, without excluding other elements or objects.

[0038] Traditional embolic agents are liquid reagents composed of iodized oil and chemotherapy drugs. Due to their fluidity, they can easily reduce drug efficacy and cause systemic toxicity. Solid embolic agents, including gelatin sponges, polyvinyl alcohol particles, and microspheres, can be better fixed in blood vessels, have no toxic side effects, and offer improved therapeutic effects compared to traditional embolic agents. However, facing complex and diverse patient and surgical situations, current embolic agents still have many shortcomings, such as insufficient compressibility, which can easily cause catheter blockage during surgery, and the embolic agent breaking down and flowing into other blood vessels; poor morphology and particle size uniformity, leading to postoperative reflux; low drug loading efficiency; short sustained-release time; and the need to improve therapeutic efficacy. To further improve therapeutic effects, developing novel embolic agents with excellent performance that meet various clinical requirements remains an urgent problem to be solved.

[0039] Based on this, this application provides a high-strength, tough, drug-loadable embolic gel microsphere. The microsphere is prepared through copolymerization of modified polyvinyl alcohol and olefinic anionic monomers, and a synthetic process design. The resulting drug-loadable embolic gel microsphere exhibits high strength and toughness, excellent compression and resilience, effectively improving the embolization effect. Furthermore, it can load various cationic therapeutic drugs for sustained release. This addresses, to some extent, the problems of high fluidity, insufficient compressibility, and low drug loading efficiency in current embolic agents.

[0040] This application provides a drug-loadable embolizable gel microsphere, which is prepared from at least the following substances:

[0041] Organic phase solution: including emulsifier with a concentration of 0.05-2 g / mL;

[0042] Aqueous solution: includes polyvinyl alcohol modifier at a concentration of 0.01-2 g / mL, olefin anionic monomer at a concentration of 0.01-1 g / mL, enol monomer at a concentration of 0.01-0.5 g / mL, and initiator at a mass of 3%-6% of the polyvinyl alcohol modifier.

[0043] The drug-loadable embolic gel microspheres provided in this application are composed of an organic phase solution containing an emulsifier at a concentration of 0.05-2 g / mL and an aqueous phase solution containing a polyvinyl alcohol modifier at a concentration of 0.01-2 g / mL, an olefinic anionic monomer at a concentration of 0.01-1 g / mL, an enol monomer at a concentration of 0.01-0.5 g / mL, and an initiator at a mass of 3%-6% of the polyvinyl alcohol modifier. These drug-loadable embolic gel microspheres exhibit high strength and toughness, excellent compression and resilience, effectively enhancing the embolization effect, and can load various cationic therapeutic drugs to achieve sustained release.

[0044] The solvent for the organic phase solution can be an oil phase reagent. The oil phase reagent may include, but is not limited to, at least one of liquid paraffin, n-hexane, mineral oil, and silicone oil.

[0045] In some embodiments, the concentration of the emulsifier in the organic phase solution may be 1.0-1.61 g / mL, and the HBO value may be 10-12. The emulsifier may include at least one of sodium dodecyl sulfonate, sodium dodecylbenzene sulfonate, Tween, Span, whey protein, and monoglycerides of fatty acids.

[0046] In some embodiments, the concentration of the polyvinyl alcohol modifier in the aqueous solution can be 0.68-1.84 g / mL. The polyvinyl alcohol modifier can be prepared by modifying polyvinyl alcohol with a modifier. The degree of modification of the polyvinyl alcohol modifier, calculated in terms of hydroxyl groups, is 10-25%; wherein the mass fraction of the polyvinyl alcohol is 5-15%, and the modifier accounts for 3-10% of the molar amount of the polyvinyl alcohol; the modifier can be an olefinic aldehyde monomer.

[0047] In some embodiments, the degree of modification of the polyvinyl alcohol modifier, calculated in terms of hydroxyl groups, can be 14-20% to provide more reactive groups for ternary copolymerization. This improves the toughness of the skeleton of the final drug-loadable embolic gel microspheres and the abundance of functional groups in the network structure.

[0048] In some embodiments, the olefinic aldehyde monomer may include C=C and -CHO groups. The olefinic aldehyde monomer includes, but is not limited to, perillaldehyde, 3-phenylpropenal, p-dimethylaminopropenal, 5-methyl-2-(1-methylethyl)-2-hexenal, 2,6-dimethyl-5-heptenal, cinnamaldehyde diethyl acetal, methacrylaldehyde diacetyl acetal, acrylamide acetaldehyde dimethyl acetal, cis-3-hexen-1-acet-(1-ethoxy)acetaldehyde, 1,1-diethoxy-3,7-dimethyl-2,6-octadiene, trans-2-hexen-1-ol diethyl acetal, fumaraldehyde mono(dimethyl acetal), trans-2-butenal diethyl acetal, α-pentylcinnamaldehyde dimethyl acetal, etc.

[0049] In some embodiments, the olefinic aldehyde monomer accounts for 4.5-7.2% of the molar amount of polyvinyl alcohol; it may include at least one of trans-2-hexen-1-ol diethyl acetal, trans-2-butenal diethyl acetal, α-pentylcinnamaldehyde dimethyl acetal, and cinnamaldehyde diethyl acetal.

[0050] The olefinic anionic monomers are water-soluble monomers, including but not limited to acrylic acid, vinyl sulfonic acid, allyl sulfonic acid, maleic anhydride, styrene sulfonic acid, ethylene acetic acid, 2-acrylamido-2-methylpropanesulfonic acid, 2-acrylamido-2-methylpropionic acid, 2-hydroxy-3-allyloxy-1-propylsulfonic acid, allyloxybenzene sulfonic acid, isoprene sulfonate, hydroxypropyl acrylate, methacrylate sulfonate, cyclopentadiene sulfonic acid, etc.

[0051] In some embodiments, the concentration of the olefinic anionic monomer in the aqueous solution is 0.28-0.72 g / mL; it may include at least one selected from allyloxybenzenesulfonic acid, hydroxypropyl acrylate, and 2-hydroxy-3-allyloxy-1-propylsulfonic acid. Using these olefinic anionic monomers provides better anionic groups for good drug loading and a greater number of groups suitable for drug loading.

[0052] The enol monomers may be water-soluble monomers. In some embodiments, the concentration of the enol monomers may be 0.17-0.42 g / mL; they may include at least one of 3-buten-1-ol and 2-methylallylol. Such enol monomers can provide more hydroxyl groups for interaction, thereby adjusting the strength and drug loading.

[0053] In some embodiments, the initiator in the aqueous solution comprises 4.5-5% by mass of the polyvinyl alcohol modifier; including at least one of α-ketoglutaric acid, ammonium persulfate, and potassium persulfate.

[0054] In some embodiments, the drug-loadable embolic gel microspheres have a weight-average molecular weight of 50,000-300,000, a surface hydroxyl content of 50-80 mol / 100 mol PVA, a pore size of 0.1-1 μm, and a pore volume of 0.1-0.5 cm³. 3 / g, particle size 0.1-1000μm, can withstand compression deformation of 50-90%, compression recovery time of 5-30s, equilibrium swelling rate calculated based on the mass ratio of swelling water to dry pellets is between 60%-95%.

[0055] In some embodiments, the drug-loadable embolic gel microspheres have a weight-average molecular weight of 100,000-200,000, a surface hydroxyl content of 50-60 mol / 100 mol PVA, a pore size of 0.5-1 μm, and a pore volume of 0.3-0.5 cm³. 3 / g, particle size of 200-300μm, 350-450μm, 500-700μm or 800-1000μm, can withstand compression deformation of 50-90%, compression recovery time of 5-30s, equilibrium swelling rate calculated based on the mass ratio of swelling water to dry pellets is between 60% and 95%.

[0056] In some embodiments, drug-loadable embolic gel microspheres prepared in the same batch can be adjusted according to the formula to obtain microspheres with different narrow particle size distributions, and the particle size of the microspheres deviates from the average value by no more than 20%.

[0057] The drug-loadable embolic gel microspheres provided in this application, through the establishment of a two-phase reaction system consisting of an oil phase and an aqueous phase, achieve a combination of uniform particle size and drug-loadable properties while effectively ensuring high strength and toughness and moderate swelling degree. The use of a copolymer raw material comprising 0.01-2 g / mL polyvinyl alcohol modifier, 0.01-1 g / mL olefin anionic monomer, and 0.01-0.5 g / mL enol monomer in the aqueous solution effectively enhances the strength and overall performance of the polymer network in the resulting drug-loadable embolic gel microspheres and regulates the swelling degree of the microspheres. Furthermore, the olefin anionic monomer provides drug-loadable anions, facilitating subsequent loading of cationic drugs.

[0058] Based on the same inventive concept, corresponding to the drug-loadable embolic gel microspheres of any of the above embodiments, this application also provides a method for preparing drug-loadable embolic gel microspheres.

[0059] refer to Figure 1 The method for preparing the drug-loadable embolic gel microspheres includes:

[0060] S100 provides polyvinyl alcohol modified products;

[0061] S200 provides an organic phase solution; said organic phase solution includes an emulsifier at a concentration of 0.05-2 g / mL;

[0062] S300, providing an aqueous solution: the aqueous solution comprises a polyvinyl alcohol modifier at a concentration of 0.01-2 g / mL, an olefinic anionic monomer at a concentration of 0.01-1 g / mL, an enol monomer at a concentration of 0.01-0.5 g / mL, and an initiator at a mass of 3%-6% of the polyvinyl alcohol modifier; wherein the degree of modification of the polyvinyl alcohol modifier, calculated based on hydroxyl groups, is 10-25%;

[0063] S400, the aqueous phase solution is added to the organic phase solution, and the reaction is stirred at a first temperature for a first time;

[0064] S500, the product obtained from the reaction is frozen at a second temperature for a second time, thawed at a third temperature for a third time, and annealed at a fourth temperature for a fourth time to obtain the drug-loadable embolic gel microspheres.

[0065] In step S100, providing the polyvinyl alcohol modified material may include:

[0066] Provide a polyvinyl alcohol solution with a mass fraction of 5-15%;

[0067] A reaction system is obtained by adding a modifier to an aqueous solution of polyvinyl alcohol, wherein the molar amount of the modifier is 3-10% of the molar amount of polyvinyl alcohol. During the reaction, the pH value of the reaction system can be adjusted to 3-6 by adding an acid-base adjuster or the like. In some embodiments, the reaction can be carried out at 25°C under a nitrogen atmosphere with stirring for 18-36 hours. The nitrogen atmosphere helps prevent the oxidation of polyvinyl alcohol to generate byproducts.

[0068] In some embodiments, after the reaction is complete, the reaction product may be subjected to dialysis and freeze-drying to obtain a modified polyvinyl alcohol.

[0069] In some embodiments, the modifier may be an olefinic aldehyde monomer, including groups with structures such as C=C and -CHO. Olefinic aldehyde monomers include, but are not limited to, perillaldehyde, 3-phenylpropenal, p-dimethylaminopropenal, 5-methyl-2-(1-methylethyl)-2-hexenal, 2,6-dimethyl-5-heptenal, cinnamaldehyde diethyl acetal, methacrylaldehyde diacetyl acetal, acrylamide acetaldehyde dimethyl acetal, cis-3-hexen-1-acet-(1-ethoxy)acetaldehyde, 1,1-diethoxy-3,7-dimethyl-2,6-octadiene, trans-2-hexen-1-ol diethyl acetal, fumaraldehyde mono(dimethyl acetal), trans-2-butenal diethyl acetal, α-pentylcinnamaldehyde dimethyl acetal, etc.

[0070] In some embodiments, the olefinic aldehyde monomer accounts for 4.5-7.2% of the molar amount of polyvinyl alcohol; it may include at least one of trans-2-hexen-1-ol diethyl acetal, trans-2-butenal diethyl acetal, α-pentylcinnamaldehyde dimethyl acetal, and cinnamaldehyde diethyl acetal.

[0071] In step S200, providing the organic phase solution may include: dissolving an emulsifier in an organic phase reagent, stirring under N2 protection, and preparing an organic phase solution. The concentration of the emulsifier in the organic phase solution may be 0.05-2 g / mL.

[0072] In some embodiments, the solvent for the organic phase solution may be an oil phase reagent. The oil phase reagent may include, but is not limited to, at least one of liquid paraffin, n-hexane, mineral oil, and silicone oil.

[0073] In some embodiments, the concentration of the emulsifier may be 1.0-1.61 g / mL, and the HBO value may be 10-12. The emulsifier may include at least one of sodium dodecyl sulfonate, sodium dodecylbenzene sulfonate, Tween, Span, whey protein, and monoglycerides of fatty acids.

[0074] In step S300, the concentration of the polyvinyl alcohol modifier in the aqueous solution can be 0.68-1.84 g / mL. The concentration of the olefinic anionic monomer is 0.28-0.72 g / mL. The concentration of the enol monomer is 0.17-0.42 g / mL. Using this concentration combination in the aqueous solution facilitates better copolymerization of the three substances, effectively improving the strength and overall performance of the polymer network in the obtained drug-loadable embolic gel microspheres, and adjusting the swelling degree of the drug-loadable embolic gel microspheres.

[0075] In some embodiments, the olefinic anionic monomer may include at least one selected from allyloxybenzenesulfonic acid, hydroxypropyl acrylate, and 2-hydroxy-3-allyloxy-1-propylsulfonic acid. Choosing these olefinic anionic monomers provides a better anionic group for loading drugs.

[0076] In some embodiments, the enol monomer may include at least one of 3-buten-1-ol and 2-methylallylol. These enol monomers enable drug-loadable embolic gel microspheres to possess good strength.

[0077] In some embodiments, the initiator in the aqueous solution comprises 4.5-5% by mass of the polyvinyl alcohol modifier; including at least one of α-ketoglutaric acid, ammonium persulfate, and potassium persulfate.

[0078] In step S400, the first temperature can be 40-60℃, the stirring speed can be 300-600 rpm, and the first time duration can be 4-8 hours. After the reaction is completed, the product obtained can be filtered, and the precipitate obtained by filtration can be washed several times with deionized water to initially obtain drug-loadable embolic gel microspheres.

[0079] In step S500, the second temperature can be -20 to -80°C, and the second duration can be 6-12 hours. The third temperature can be 20-30°C, and the third duration can be 0.5-1 hour. The fourth temperature can be 80-120°C, and the fourth duration can be 2-4 hours. This freeze-thaw (i.e., freeze-thaw)-annealing process enables hydrogen bonding between the unmodified hydroxyl groups in polyvinyl alcohol and the hydroxyl groups in enol monomers, further enhancing the mechanical properties of the resulting drug-loadable embolic gel microspheres.

[0080] In some embodiments, the process may further include immersing the drug-loadable embolic gel microspheres in a drug solution for 12-24 hours to obtain drug-loaded embolic gel microspheres. This immersion time in the drug solution allows for drug loading within the microspheres, forming porous polyvinyl alcohol drug-loadable embolic gel microspheres, thus preparing the drug-loaded embolic gel microspheres.

[0081] In some embodiments, the drug is an anthracycline (cationic) drug, including at least one of doxorubicin, pirarubicin, and epirubicin; the drug loading in the drug-loaded embolic gel microspheres is 0-50 mg / mL, calculated by microsphere volume. Specifically, the drug loading is determined by the concentration of the drug in the solution and the immersion time. The embolic gel microspheres before pirarubicin loading can be as follows... Figure 2 As shown, the embolization gel microspheres loaded with pirarubicin can be as follows: Figure 3 As shown.

[0082] In some embodiments, the drug-loaded embolized gel microspheres may be combined with different dyes to form different colors, including but not limited to brilliant blue, lemon yellow, amaranth, indigo, curcumin, reactive blue, reactive yellow, etc.

[0083] This application also provides a drug-loadable embolic gel microsphere prepared by the method described in the preceding claim or the method described in the preceding claim, and a drug loaded on the drug-loadable embolic gel microsphere.

[0084] In some embodiments, the drug is a cationic drug, including at least one of doxorubicin, pirarubicin, and epirubicin; the drug loading in the drug-loaded embolic gel microspheres is 0.1-50 mg / mL based on the microsphere volume.

[0085] In some embodiments, the drug-loaded embolic gel microspheres further include a dye to give the drug-loaded embolic gel microspheres a color. Dyes include, but are not limited to, brilliant blue, tartrazine, amaranth, indigo, curcumin, reactive blue, and reactive yellow.

[0086] The drug-loaded embolic gel microspheres can be used for vascular intervention via microcatheters, with microcatheter sizes including but not limited to 1.8F, 2.0F, 2.2F, 2.5F, or 2.7F. These drug-loaded embolic gel microspheres can be used for transarterial chemoembolization (TACE) treatment of malignant tumors, such as lung cancer and liver cancer, by injecting the microspheres into the tumor's blood vessels through a microcatheter to form an embolism. The drug-loaded embolic gel microspheres achieve therapeutic effects on malignant tumors through drug release.

[0087] The resulting drug-loaded embolic gel microspheres exhibit high strength and toughness, excellent compression and resilience, effectively enhancing the embolization effect. They can also load various cationic therapeutic drugs for sustained release. When the drug loading is above 30 mg / mL, the compressive deformation rate can reach over 70%, and complete morphological recovery is achieved.

[0088] The technical solution of the present invention will be further described below with reference to specific embodiments.

[0089] Unless otherwise specified, the experimental methods described in the following examples are conventional methods.

[0090] Unless otherwise specified, all experimental materials used in the following examples were purchased from conventional biochemical reagent stores.

[0091] Example 1

[0092] 1.1 Test Methods:

[0093] Preparation of modified polyvinyl alcohol: A certain amount of polyvinyl alcohol was weighed and dissolved in hot water at 95°C to prepare a solution with a mass fraction of 12.5%. 5% (molar amount) of acrolein diacetal was added to the polyvinyl alcohol solution. The pH of the system was adjusted to 5.5. The mixture was stirred and reacted under a nitrogen atmosphere at 25°C for 32 hours. After the reaction was completed, the modified polyvinyl alcohol was obtained by dialysis and freeze-drying. The weight-average molecular weight of the polyvinyl alcohol was 145,000.

[0094] Synthesis of drug-loadable embolic gel microspheres: Sodium dodecyl sulfonate was dissolved in liquid paraffin at a concentration of 1.2 g / mL and stirred under N2 protection to prepare an organic phase solution. A certain amount of polyvinyl alcohol modifier, allyloxybenzenesulfonic acid, 3-buten-1-ol, and ammonium persulfate initiator were dissolved in deionized water to prepare an aqueous phase solution. The concentration of polyvinyl alcohol modifier was 0.68 g / mL, the concentration of allyloxybenzenesulfonic acid was 0.34 g / mL, the concentration of 3-buten-1-ol was 0.24 g / mL, and the amount of ammonium persulfate was 5% of the mass of polyvinyl alcohol modifier. The aqueous phase solution was added to the organic phase solution, and the mixture was stirred at 450 rpm at 50 °C for 6 h. The product was filtered and washed several times with deionized water to obtain drug-loadable embolic gel microspheres.

[0095] Post-processing of drug-loadable embolization gel microspheres: The drug-loadable embolization gel microspheres were frozen at -40℃ for 8 hours, then thawed at 25℃ for 0.6 hours, and finally annealed at 100℃ for 3 hours to obtain the final microsphere product.

[0096] Drug-loadable embolizing gel microspheres were loaded with the drug pirarubicin to obtain drug-loadable embolizing gel microspheres: The prepared drug-loadable embolizing gel microspheres were placed in a sufficient amount of 10 mg / ml pirarubicin aqueous solution and soaked for 24 h.

[0097] 1.2 Detection Method:

[0098] The degree of modification of the polyvinyl alcohol modified by group titration was tested. The average pore size and particle size of the drug-loadable embolic gel microspheres were obtained by microscopic observation after lyophilization, and the pore volume was measured by mercury removal method.

[0099] The compressibility of drug-loaded embolized gel microspheres was tested using a universal testing machine in compression mode. The compression recovery time was obtained by microscopic observation of the rebound after compression. The equilibrium swelling rate was determined by the mass ratio of swollen water to dry spheres.

[0100] The concentration difference of the drug solution before and after absorption was determined by the ultraviolet spectroscopy characteristic peak method, and the drug loading concentration of the drug-loaded embolized gel microspheres was obtained.

[0101] 1.3 Experimental Results:

[0102] The degree of modification of the polyvinyl alcohol modifier is calculated as 18.2% based on the substitution ratio of hydroxyl groups.

[0103] The surface hydroxyl content of the drug-loadable embolizing gel microspheres is 58 mol / 100 mol PVA.

[0104] The drug-loadable embolic gel microspheres have an average pore size of 0.7 μm and a pore volume of 0.45 cm³. 3 / g.

[0105] The particle size of the drug-loadable embolic gel microspheres is between 350-450 μm.

[0106] The properties of the prepared drug-loaded embolized gel microspheres are as follows: the drug-loaded embolized gel microspheres can withstand 85% compression deformation, the compression recovery time is 21s, and the equilibrium swelling rate is 87% calculated based on the mass ratio of swelling water to dry microspheres.

[0107] The drug-loaded embolizing gel microspheres contain a drug concentration of 37.5 mg / mL. These microspheres can be used for vascular intervention and embolization via a 2.2F microcatheter.

[0108] Example 2

[0109] 1.1 Test Methods:

[0110] Preparation of modified polyvinyl alcohol: A certain amount of polyvinyl alcohol was weighed and dissolved in hot water at 95°C to prepare a 10% (w / w) solution. 6.5% (w / w) of trans-2-hexen-1-ol diethyl acetal was added, and the pH of the system was adjusted to 6. The mixture was stirred and reacted under a nitrogen atmosphere at 25°C for 30 hours. After the reaction was completed, the modified polyvinyl alcohol was obtained by dialysis and freeze-drying. The weight-average molecular weight of the polyvinyl alcohol was 180,000.

[0111] Synthesis of drug-loadable embolic gel microspheres: Span 80 was weighed and dissolved in n-hexane to a concentration of 1.0 g / mL. The solution was stirred under N2 protection to prepare an organic phase solution. A certain amount of polyvinyl alcohol modifier, hydroxypropyl acrylate, 2-methylallyl alcohol, and ammonium persulfate initiator were dissolved in deionized water to prepare an aqueous phase solution. The concentrations of the polyvinyl alcohol modifier and hydroxypropyl acrylate were 0.28 g / mL, the 2-methylallyl alcohol was 0.42 g / mL, and the amount of ammonium persulfate was 4% of the weight of the polyvinyl alcohol modifier. The aqueous phase solution was added to the organic phase solution, and the mixture was stirred at 380 rpm at 50 °C for 6 h. The product was filtered and washed several times with deionized water to obtain drug-loadable embolic gel microspheres.

[0112] Post-processing of drug-loadable embolization gel microspheres: The drug-loadable embolization gel microspheres were frozen at -50℃ for 6 hours, then thawed at 30℃ for 0.5 hours, and finally annealed at 110℃ for 2.5 hours to obtain the final microsphere product.

[0113] Drug-loadable embolizing gel microspheres were loaded with the drug pirarubicin to obtain drug-loadable embolizing gel microspheres: The prepared drug-loadable embolizing gel microspheres were placed in a sufficient amount of 10 mg / ml pirarubicin aqueous solution and soaked for 24 h.

[0114] 1.2 Detection Method:

[0115] The degree of modification of the polyvinyl alcohol modified by group titration was tested. The average pore size and particle size of the drug-loadable embolic gel microspheres were obtained by microscopic observation after lyophilization, and the pore volume was measured by mercury removal method.

[0116] The compressibility of drug-loaded embolized gel microspheres was tested using a universal testing machine in compression mode. The compression recovery time was obtained by microscopic observation of the rebound after compression. The equilibrium swelling rate was determined by the mass ratio of swollen water to dry spheres.

[0117] The concentration difference of the drug solution before and after absorption was determined by the ultraviolet spectroscopy characteristic peak method, and the drug loading concentration of the drug-loaded embolized gel microspheres was obtained.

[0118] 1.3 Experimental Results:

[0119] The degree of modification of the polyvinyl alcohol modifier, calculated based on the hydroxyl group substitution ratio, is 16.8%.

[0120] The surface hydroxyl content of the drug-loadable embolizing gel microspheres is 52 mol / 100 mol PVA.

[0121] The drug-loadable embolic gel microspheres have an average pore size of 0.8 μm and a pore volume of 0.42 cm³. 3 / g.

[0122] The particle size of the drug-loadable embolic gel microspheres is between 200-300 μm.

[0123] The properties of the prepared drug-loaded embolic gel microspheres are as follows:

[0124] The drug-loaded embolized gel microspheres can withstand 88% compression deformation, have a compression recovery time of 16s, and have an equilibrium swelling rate of 72% calculated based on the mass ratio of swollen water to dry microspheres.

[0125] The drug-loaded embolic gel microspheres contain a drug concentration of 32.8 mg / mL. These drug-loaded embolic gel microspheres can be used for vascular intervention and embolization via a 2.0F microcatheter.

[0126] Example 3

[0127] 1.1 Test Methods:

[0128] Preparation of modified polyvinyl alcohol: A certain amount of polyvinyl alcohol was weighed and dissolved in hot water at 95°C to prepare a 13.5% (w / w) solution. 4.5% (w / w) of dimethylaminopropenal (dimethylaminopropenal) was added, and the pH of the system was adjusted to 4. The mixture was stirred and reacted under a nitrogen atmosphere at 25°C for 30 hours. After the reaction was completed, the modified polyvinyl alcohol was obtained by dialysis and freeze-drying. The weight-average molecular weight of the polyvinyl alcohol was 126,000.

[0129] Synthesis of drug-loadable embolic gel microspheres: Span 80 was weighed and dissolved in n-hexane to a concentration of 1.5 g / mL. The solution was stirred under N2 protection to prepare an organic phase solution. A certain amount of polyvinyl alcohol modifier, 2-hydroxy-3-allyloxy-1-propanesulfonic acid, 2-methylallyl alcohol, and potassium persulfate initiator were dissolved in deionized water to prepare an aqueous phase solution. The concentration of polyvinyl alcohol modifier was 1.42 g / mL, the concentration of allyloxybenzenesulfonic acid was 0.63 g / mL, the concentration of 3-buten-1-ol was 0.17 g / mL, and the amount of potassium persulfate was 4.5% of the mass of polyvinyl alcohol modifier. The aqueous phase solution was added to the organic phase solution, and the mixture was stirred at 450 rpm at 55 °C for 5 h. The product was filtered and washed several times with deionized water to obtain drug-loadable embolic gel microspheres.

[0130] Post-processing of drug-loadable embolization gel microspheres: The drug-loadable embolization gel microspheres were frozen at -40℃ for 8 hours, then thawed at 25℃ for 1 hour, and finally annealed at 120℃ for 3 hours to obtain the final microsphere product.

[0131] Drug-loadable embolizing gel microspheres were loaded with the drug pirarubicin to obtain drug-loadable embolizing gel microspheres: The prepared drug-loadable embolizing gel microspheres were placed in a sufficient amount of 15 mg / ml pirarubicin aqueous solution and soaked for 24 h.

[0132] 1.2 Detection Method:

[0133] The degree of modification of the polyvinyl alcohol modified by group titration was tested. The average pore size and particle size of the drug-loadable embolic gel microspheres were obtained by microscopic observation after lyophilization, and the pore volume was measured by mercury removal method.

[0134] The compressibility of drug-loaded embolic gel microspheres was tested using a universal testing machine in compression mode. The compression recovery time was obtained by microscopic observation of the rebound after compression. The equilibrium swelling rate was determined by the mass ratio of swollen water to dry spheres.

[0135] The concentration difference of the drug solution before and after absorption was measured by the ultraviolet spectroscopy characteristic peak method to obtain the drug loading concentration of the drug-loadable embolized gel microspheres.

[0136] 1.3 Experimental Results:

[0137] The degree of modification of the polyvinyl alcohol modifier, calculated based on the hydroxyl group substitution ratio, is 14.3%.

[0138] The surface hydroxyl content of the drug-loadable embolizing gel microspheres is 62 mol / 100 mol PVA.

[0139] The drug-loadable embolic gel microspheres have an average pore size of 0.7 μm and a pore volume of 0.46 cm³. 3 / g.

[0140] The particle size of the drug-loadable embolic gel microspheres is between 500-600 μm.

[0141] The properties of the prepared drug-loaded embolic gel microspheres are as follows:

[0142] The drug-loaded embolized gel microspheres can withstand 72% compression deformation, have a compression recovery time of 18s, and have an equilibrium swelling rate of 92% calculated based on the mass ratio of swollen water to dry microspheres.

[0143] The drug-loaded embolic gel microspheres contain a drug concentration of 31.3 mg / mL. These drug-loaded embolic gel microspheres can be used for vascular intervention and embolization via a 2.5F microcatheter.

[0144] Example 4

[0145] 1.1 Test Methods:

[0146] Preparation of modified polyvinyl alcohol: A certain amount of polyvinyl alcohol was weighed and dissolved in hot water at 95°C to prepare a solution with a mass fraction of 8.5%. 7.2% (molar amount) of cinnamaldehyde diethyl acetal was added to adjust the pH of the system to 5. The mixture was stirred and reacted under a nitrogen atmosphere at 25°C for 30 hours. After the reaction was completed, the modified polyvinyl alcohol was obtained by dialysis and freeze-drying. The weight-average molecular weight of the polyvinyl alcohol was 212,000.

[0147] Synthesis of drug-loadable embolic gel microspheres: Sodium dodecylbenzenesulfonate was dissolved in methoxysilicone oil at a concentration of 1.61 g / mL and stirred under N2 protection to prepare an organic phase solution. A certain amount of polyvinyl alcohol modifier, allyloxybenzenesulfonic acid, 2-methylallyl alcohol, and potassium persulfate initiator were dissolved in deionized water to prepare an aqueous phase solution. The concentration of polyvinyl alcohol modifier was 1.84 g / mL, the concentration of allyloxybenzenesulfonic acid was 0.72 g / mL, the concentration of 3-buten-1-ol was 0.39 g / mL, and the amount of potassium persulfate was 5% of the mass of polyvinyl alcohol modifier. The aqueous phase solution was added to the organic phase solution, and the mixture was stirred at 520 rpm at 60 °C for 4.5 h. The product was filtered and washed several times with deionized water to obtain drug-loadable embolic gel microspheres.

[0148] Post-processing of drug-loadable embolization gel microspheres: The drug-loadable embolization gel microspheres were frozen at -60℃ for 6 hours, then thawed at 25℃ for 1 hour, and finally annealed at 110℃ for 4 hours to obtain the final microsphere product.

[0149] Drug-loadable embolizing gel microspheres were loaded with the drug pirarubicin to obtain drug-loadable embolizing gel microspheres: The prepared drug-loadable embolizing gel microspheres were placed in a sufficient amount of 15 mg / ml pirarubicin aqueous solution and soaked for 24 h.

[0150] 1.2 Detection Method:

[0151] The degree of modification of the polyvinyl alcohol modified by group titration was tested. The average pore size and particle size of the drug-loadable embolic gel microspheres were obtained by microscopic observation after lyophilization, and the pore volume was measured by mercury removal method.

[0152] The compressibility of drug-loaded embolized gel microspheres was tested using a universal testing machine in compression mode. The compression recovery time was obtained by microscopic observation of the rebound after compression. The equilibrium swelling rate was determined by the mass ratio of swollen water to dry spheres.

[0153] The concentration difference of the drug solution before and after absorption was determined by the ultraviolet spectroscopy characteristic peak method, and the drug loading concentration of the drug-loaded embolized gel microspheres was obtained.

[0154] 1.3 Experimental Results:

[0155] The degree of modification of the polyvinyl alcohol modifier, calculated based on the hydroxyl group substitution ratio, is 19.8%.

[0156] The surface hydroxyl content of the drug-loadable embolizing gel microspheres is 64 mol / 100 mol PVA.

[0157] The drug-loadable embolic gel microspheres have an average pore size of 0.45 μm and a pore volume of 0.32 cm³. 3 / g.

[0158] The particle size of the drug-loadable embolic gel microspheres is between 150-300 μm.

[0159] The properties of the prepared drug-loaded embolic gel microspheres are as follows:

[0160] The drug-loaded embolized gel microspheres can withstand 81% compression deformation, have a compression recovery time of 22s, and have an equilibrium swelling rate of 65% calculated based on the mass ratio of swollen water to dry microspheres.

[0161] The drug-loaded embolic gel microspheres contain a pirarubicin concentration of 30.4 mg / mL. These drug-loaded embolic gel microspheres can be used for vascular intervention and embolization via a 2.0F microcatheter.

[0162] The results obtained from the above embodiments are listed below:

[0163] Table 1

[0164]

[0165]

[0166] Results Analysis: The above experimental results show that the drug-loaded embolization gel microspheres prepared in Examples 1 to 4 of this application can withstand a compression deformation rate of more than 70% under the premise that the drug loading concentration is greater than 30 mg / mL. In this way, the microspheres can be smoothly delivered to the lesion blood vessel through the catheter without rupture, and achieve stable embolization and drug release through morphological recovery, thereby achieving the technical effect of improving the drug loading efficiency of embolization microspheres.

[0167] Comparative Example 1

[0168] The only difference from Example 2 is that 2-methylallyl alcohol in Example 2 was replaced with acrylamide. Experimental results:

[0169] The drug-loadable embolic gel microspheres have an average pore size of 0.64 μm and a pore volume of 0.33 cm³. 3 / g.

[0170] The particle size of the drug-loadable embolic gel microspheres is between 120 and 350 μm.

[0171] The properties of the prepared drug-loaded embolic gel microspheres are as follows:

[0172] The drug-loaded embolized gel microspheres can withstand 74% compression deformation, with a compression recovery time of 24 seconds. After being compressed to 70%, they can only recover to 92% of their original height. The equilibrium swelling rate is 97% calculated based on the mass ratio of swollen water to dry microspheres.

[0173] The drug-loaded embolizing gel microspheres contain a pirarubicin concentration of 28.2 mg / mL. These drug-loaded embolizing gel microspheres can be used for vascular intervention and embolization via a 2.0F microcatheter; however, the microspheres are prone to irreversible deformation after passing through the catheter.

[0174] Comparative Example 2

[0175] The only difference from Example 2 is that the hydroxypropyl acrylate in Example 2 was replaced with acrylic acid. Experimental results:

[0176] The drug-loadable embolic gel microspheres have an average pore size of 0.94 μm and a pore volume of 0.56 cm³. 3 / g.

[0177] The particle size of the drug-loadable embolic gel microspheres is between 200-400 μm.

[0178] The properties of the prepared drug-loaded embolic gel microspheres are as follows:

[0179] The drug-loaded embolized gel microspheres can withstand 52% compression deformation, have a compression recovery time of 12s, and have an equilibrium swelling rate of 124% calculated based on the mass ratio of swollen water to dry microspheres. The microspheres are prone to rupture after being compressed to 45%.

[0180] The drug-loaded embolizing gel microspheres contain a drug concentration of 31.4 mg / mL. These drug-loaded embolizing gel microspheres can be used for vascular intervention and embolization via a 2.5F microcatheter; however, the microspheres have poor compressibility and are prone to rupture.

[0181] Comparative Example 3

[0182] The only difference from Example 2 is that the modification method of the polyvinyl alcohol modified product in Example 2 is improved, and the molar number of the modifier is adjusted to make its degree of modification 8.4%.

[0183] Experimental results:

[0184] The degree of modification of the polyvinyl alcohol modifier is calculated as 8.4% based on the hydroxyl group substitution ratio.

[0185] The surface hydroxyl content of the drug-loadable embolizing gel microspheres is 58 mol / 100 mol PVA.

[0186] The drug-loadable embolic gel microspheres have an average pore size of 0.75 μm and a pore volume of 0.40 cm³. 3 / g.

[0187] The particle size of the drug-loadable embolic gel microspheres is between 150-300 μm.

[0188] The properties of the prepared drug-loaded embolic gel microspheres are as follows:

[0189] The drug-loaded embolized gel microspheres can withstand 68% compression deformation, have a compression recovery time of 15s, and have an equilibrium swelling rate of 84% calculated based on the mass ratio of swollen water to dry microspheres.

[0190] The drug-loaded embolic gel microspheres contain a pirarubicin concentration of 26.4 mg / mL. These drug-loaded embolic gel microspheres can be used for vascular intervention and embolization via a 2.0F microcatheter.

[0191] A decrease in the degree of polyvinyl alcohol modification will affect the drug loading capacity of the microspheres.

[0192] Comparative Example 4

[0193] The only difference from Example 2 is that the freeze-thaw process in Example 2 is omitted.

[0194] Experimental results:

[0195] The drug-loadable embolic gel microspheres have an average pore size of 0.64 μm and a pore volume of 0.31 cm³. 3 / g.

[0196] The particle size of the drug-loadable embolic gel microspheres is between 200-300 μm.

[0197] The properties of the prepared drug-loaded embolic gel microspheres are as follows:

[0198] The drug-loaded embolized gel microspheres can withstand 44% compression deformation, have a compression recovery time of 15s, and have an equilibrium swelling rate of 76% calculated based on the mass ratio of swollen water to dry microspheres.

[0199] The drug-loaded embolic gel microspheres contain a pirarubicin concentration of 26.3 mg / mL. These drug-loaded embolic gel microspheres can be used for vascular intervention and embolization via a 2.0F microcatheter.

[0200] Comparative Example 5

[0201] The only difference from Example 2 is that the annealing process in Example 2 is omitted.

[0202] Experimental results:

[0203] The drug-loadable embolic gel microspheres have an average pore size of 0.72 μm and a pore volume of 0.43 cm³.3 / g.

[0204] The particle size of the drug-loadable embolic gel microspheres is between 200-350 μm.

[0205] The properties of the prepared drug-loaded embolic gel microspheres are as follows:

[0206] The drug-loaded embolized gel microspheres can withstand 53% compression deformation, have a compression recovery time of 21s, and have an equilibrium swelling rate of 74% calculated based on the mass ratio of swollen water to dry microspheres.

[0207] The drug-loaded embolic gel microspheres contain a pirarubicin concentration of 29.7 mg / mL. These drug-loaded embolic gel microspheres can be used for vascular intervention and embolization via a 2.0F microcatheter.

[0208] Comparative Example 6

[0209] The only difference from Example 2 is that the concentration of the polyvinyl alcohol modifier is replaced with 0.64 g / mL, the concentration of hydroxypropyl acrylate is replaced with 0.76 g / mL, and the concentration of 2-methylallyl alcohol is replaced with 0.53 g / mL.

[0210] Experimental results:

[0211] The drug-loadable embolic gel microspheres have an average pore size of 0.87 μm and a pore volume of 0.45 cm³. 3 / g.

[0212] The particle size of the drug-loadable embolic gel microspheres is between 150-400 μm.

[0213] The properties of the prepared drug-loaded embolic gel microspheres are as follows:

[0214] The drug-loaded embolized gel microspheres can withstand 27% compression deformation, have a compression recovery time of 12s, and have an equilibrium swelling rate of 146% calculated based on the mass ratio of swollen water to dry microspheres.

[0215] The drug-loaded embolic gel microspheres contain a pirarubicin concentration of 17.2 mg / mL. These drug-loaded embolic gel microspheres cannot be embolized via catheters and are very fragile.

[0216] Comparative Example 7

[0217] The only difference from Example 2 is that the concentration of the polyvinyl alcohol modifier is replaced with 1.92 g / mL, the concentration of hydroxypropyl acrylate is replaced with 0.24 g / mL, and the concentration of 2-methylallyl alcohol is replaced with 0.15 g / mL.

[0218] Experimental results:

[0219] The drug-loadable embolic gel microspheres have an average pore size of 0.47 μm and a pore volume of 0.25 cm³. 3 / g.

[0220] The particle size of the drug-loadable embolic gel microspheres is between 100-200 μm.

[0221] The properties of the prepared drug-loaded embolic gel microspheres are as follows:

[0222] The drug-loaded embolized gel microspheres can withstand 75% compression deformation, have a compression recovery time of 18s, and have an equilibrium swelling rate of 55% calculated based on the mass ratio of swelling water to dry microspheres.

[0223] The drug-loaded embolizing gel microspheres contain a pirarubicin concentration of 12.2 mg / mL. These microspheres can be used for vascular intervention and embolization via a 2.0F microcatheter, but the drug loading is very low.

[0224] Comparative Example 8

[0225] The only difference from Example 2 is that the concentration of hydroxypropyl acrylate in Example 2 is replaced with 0.08 g / mL.

[0226] Experimental results:

[0227] The drug-loadable embolic gel microspheres have an average pore size of 0.52 μm and a pore volume of 0.32 cm³. 3 / g.

[0228] The particle size of the drug-loadable embolic gel microspheres is between 100-200 μm.

[0229] The properties of the prepared drug-loaded embolic gel microspheres are as follows:

[0230] The drug-loaded embolized gel microspheres can withstand 67% compression deformation, have a compression recovery time of 20s, and have an equilibrium swelling rate of 52% calculated based on the mass ratio of swollen water to dry microspheres.

[0231] The drug-loaded embolization gel microspheres contain a pirarubicin concentration of 14.7 mg / mL. These microspheres can be used for vascular intervention and embolization via a 2.0F microcatheter; however, the drug loading is relatively low, and the microsphere formation is affected, resulting in poor sphericity.

[0232] The experimental results obtained from the above comparative examples are listed below:

[0233] Table 2-1

[0234]

[0235]

[0236] Table 2-2

[0237]

[0238] Comparing the various embodiments with Comparative Example 1, it can be seen that when the enol monomer 2-methylallyl alcohol in this application is replaced with acrylamide, the drug-loaded embolic gel microspheres prepared have a drug loading concentration of less than 30 mg / mL and poor compressibility, failing to reach blood vessels smoothly. Comparing the various embodiments with Comparative Example 2, it can be seen that when the olefin anionic monomer hydroxypropyl acrylate in this application is replaced with acrylic acid, the drug-loaded embolic gel microspheres prepared can withstand less than 70% compressibility, are prone to rupture, and fail to reach blood vessels smoothly. Comparing the various embodiments with Comparative Example 3, it can be seen that when the degree of modification of the polyvinyl alcohol modifier is less than the set range of 10-25% in this application, the drug loading concentration of the prepared drug-loaded embolic gel microspheres is less than 30 mg / mL and can withstand less than 70% compressibility, failing to effectively load the drug. Comparing the embodiments with Comparative Example 4, it can be seen that omitting the freeze-thaw process in this application weakens the hydrogen bonding interactions between the unmodified hydroxyl groups and enol hydroxyl groups in the polyvinyl alcohol within the system, reducing the toughness of the drug-loaded embolic gel microspheres and making them prone to breakage during compression in the catheter. Simultaneously, it also weakens the enlarged pore size and pore penetration effects caused by ice crystal formation and melting, thereby reducing the drug loading capacity. Comparing the embodiments with Comparative Example 5, it can be seen that omitting the annealing process in this application reduces the molecular chain rearrangement and interaction optimization caused by water evaporation, thereby reducing the compressibility deformation of the drug-loaded embolic gel microspheres.

[0239] Comparing the examples with Comparative Example 6, it can be seen that when the concentration of the polyvinyl alcohol modifier is below 0.68 g / mL, the concentration of hydroxypropyl acrylate is above 0.72 g / mL, and the concentration of 2-methylallyl alcohol is above 0.42 g / mL, the drug-loaded embolic gel microspheres prepared have a drug loading concentration of less than 30 mg / mL, and can withstand less than 70% compression deformation, making them easily breakable and unusable. Comparing the examples with Comparative Example 7, it can be seen that when the concentration of the polyvinyl alcohol modifier is higher than 1.84 g / mL, the concentration of hydroxypropyl acrylate is lower than 0.28 g / mL, and the concentration of 2-methylallyl alcohol is lower than 0.17 g / mL, the drug-loaded embolic gel microspheres prepared have a drug loading concentration of less than 30 mg / mL, indicating a low drug loading. Comparing the examples with Comparative Example 8, it can be seen that when the concentration of hydroxypropyl acrylate is lower than 0.28 mg / mL, the drug loading concentration of the prepared drug-loaded embolic gel microspheres is lower than 30 mg / mL, and the compressive deformation can withstand less than 70%, affecting the microsphere formability and resulting in poor sphericity.

[0240] Therefore, when the concentrations of the components in the ternary copolymer exceed the ranges of 0.68-1.84 g / mL for polyvinyl alcohol modifiers, 0.28-0.72 g / mL for olefin anionic monomers, and 0.17-0.42 g / mL for enol monomers, the compressive strength, compressive deformation tolerance, and compression recovery properties of the drug-loaded embolic gel microspheres will decrease, making them prone to breakage. Simultaneously, the decrease in the concentration of olefin anionic monomers will lead to a significant reduction in drug loading capacity. Omitting the freeze-thaw annealing process described in this application will result in a decrease in the compressive deformation tolerance and pore size of the drug-loaded embolic gel microspheres, thereby reducing drug loading capacity to some extent.

[0241] Those skilled in the art should understand that the discussion of any of the above embodiments is merely exemplary and is not intended to imply that the scope of this disclosure (including the claims) is limited to these examples; within the framework of this disclosure, the technical features of the above embodiments or different embodiments can also be combined, the steps can be implemented in any order, and there are many other variations of different aspects of the embodiments of this disclosure as described above, which are not provided in detail for the sake of brevity.

[0242] Although this disclosure has been described in conjunction with specific embodiments thereof, many substitutions, modifications and variations of these embodiments will be apparent to those skilled in the art from the foregoing description.

[0243] This disclosure is intended to cover all such substitutions, modifications, and variations that fall within the broad scope of the appended claims. Therefore, any omissions, modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of this disclosure should be included within the scope of protection of this disclosure.

Claims

1. Drug-loadable embolic gel microspheres, characterized in that, Prepared from at least the following substances: Organic phase solution: including emulsifier with a concentration of 0.05-2 g / mL; Aqueous solution: including polyvinyl alcohol modifier at a concentration of 0.01-2 g / mL, olefin anionic monomer at a concentration of 0.01-1 g / mL, enol monomer at a concentration of 0.01-0.5 g / mL, and initiator at a mass of 3%-6% of the polyvinyl alcohol modifier; The modified polyvinyl alcohol is prepared by modifying polyvinyl alcohol with a modifier, and the degree of modification of the modified polyvinyl alcohol is 10-25% calculated based on hydroxyl groups; wherein, the mass fraction of the polyvinyl alcohol is 5-15%, and the molar number of the modifier is 3-10% of the molar number of the polyvinyl alcohol; the modifier is an olefinic aldehyde monomer.

2. The drug-loadable embolizing gel microspheres according to claim 1, wherein, In the aqueous solution, the concentration of the polyvinyl alcohol modifier is 0.68-1.84 g / mL.

3. The drug-loadable embolizing gel microspheres according to claim 2, wherein, The olefinic aldehyde monomer comprises C=C and -CHO groups; the olefinic aldehyde monomer accounts for 4.5-7.2% of the molar amount of polyvinyl alcohol; and includes at least one of trans-2-hexen-1-ol diethyl acetal, trans-2-butenal diethyl acetal, α-pentylcinnamaldehyde dimethyl acetal, and cinnamaldehyde diethyl acetal; and / or The degree of modification of the polyvinyl alcohol modifier is 14-20% calculated based on hydroxyl groups.

4. The drug-loadable embolizing gel microspheres according to claim 1, wherein, In the aqueous solution, the concentration of the olefinic anionic monomer is 0.28-0.72 g / mL; including at least one of allyloxybenzenesulfonic acid, hydroxypropyl acrylate, and 2-hydroxy-3-allyloxy-1-propylsulfonic acid; and / or The concentration of the enol monomer is 0.17-0.42 g / mL; including at least one of 3-buten-1-ol and 2-methylallylol.

5. The drug-laden embolizing gel microspheres according to claim 1, wherein, In the aqueous solution, the initiator comprises 4.5-5% of the mass of the polyvinyl alcohol modified substance; and includes at least one of α-ketoglutaric acid, ammonium persulfate, and potassium persulfate; and / or In the organic phase solution, the concentration of the emulsifier is 1.0-1.61 g / mL, and the HBO value is 10-12; It includes at least one of sodium dodecyl sulfonate, sodium dodecylbenzene sulfonate, Tween, Span, whey protein, and monoglyceride fatty acid glycerides.

6. The drug-laden embolizing gel microspheres according to claim 1, wherein, The drug-loaded embolization gel microspheres have a weight average molecular weight of 500-300,000, a surface hydroxyl content of 50-80 mol / 100 mol PVA, a pore size of 0.1-1 μm, and a pore volume of 0.1-0.5 cm 3 The drug-loaded embolization gel microspheres have a weight average molecular weight of 500-300,000, a surface hydroxyl content of 50-80 mol / 100 mol PVA, a pore size of 0.1-1 μm, and a pore volume of 0.1-0.5 cm 7. A method of preparing drug-loaded embolizing gel microspheres, characterized by, include: Provides polyvinyl alcohol modified products; Provide organic phase solution; The organic phase solution includes an emulsifier with a concentration of 0.05-2 g / mL; An aqueous solution is provided, comprising: a polyvinyl alcohol modifier at a concentration of 0.01-2 g / mL; an olefinic anionic monomer at a concentration of 0.01-1 g / mL; an enol monomer at a concentration of 0.01-0.5 g / mL; and an initiator at a mass of 3%-6% of the polyvinyl alcohol modifier. The polyvinyl alcohol modifier is prepared by modifying polyvinyl alcohol with a modifier, and the degree of modification of the polyvinyl alcohol modifier is 10-25% calculated based on hydroxyl groups. The polyvinyl alcohol has a mass fraction of 5-15%, and the molar amount of the modifier is 3-10% of the molar amount of polyvinyl alcohol. The modifier is an olefinic aldehyde monomer. The aqueous solution is added to the organic solution, and the mixture is stirred and reacted for a first time at a first temperature. The product obtained from the reaction was frozen at a second temperature for a second time, thawed at a third temperature for a third time, and annealed at a fourth temperature for a fourth time to obtain the drug-loadable embolic gel microspheres. The first temperature is 40-60℃, the stirring speed is 300-600 rpm, and the first duration is 4-8 hours; and / or The second temperature is -20 to -80°C, and the second duration is 6-12 hours; and / or The third temperature is 20-30℃, and the third duration is 0.5-1h; and / or The fourth temperature is 80-120℃, and the fourth duration is 2-4h.

8. Drug-loaded embolizing gel microspheres, characterized by, The drug-loadable embolic gel microspheres prepared by the method of any one of claims 1-6 or the method of preparing drug-loadable embolic gel microspheres according to claim 7, and the drug loaded on the drug-loadable embolic gel microspheres.

9. The drug laden embolizing gel microspheres according to claim 8, wherein, The drug is a cationic drug, including at least one of doxorubicin, pirarubicin, and epirubicin; the drug loading in the drug-loaded embolic gel microspheres is 0.1-50 mg / mL based on the microsphere volume.

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