WO2021218637A1 - Microsphère d'embolie à auto-développement d'alginate de sodium modifié et son procédé de préparation et son application - Google Patents

Microsphère d'embolie à auto-développement d'alginate de sodium modifié et son procédé de préparation et son application Download PDF

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WO2021218637A1
WO2021218637A1 PCT/CN2021/087264 CN2021087264W WO2021218637A1 WO 2021218637 A1 WO2021218637 A1 WO 2021218637A1 CN 2021087264 W CN2021087264 W CN 2021087264W WO 2021218637 A1 WO2021218637 A1 WO 2021218637A1
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sodium alginate
modification
substitution rate
modified sodium
modified
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PCT/CN2021/087264
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Chinese (zh)
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冷鸿飞
徐小雨
谢辉
王华明
田圣涛
陶秀梅
陈鹏
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北京诺康达医药科技股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A61L24/0015—Medicaments; Biocides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/08—Polysaccharides
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
    • C08B37/0084—Guluromannuronans, e.g. alginic acid, i.e. D-mannuronic acid and D-guluronic acid units linked with alternating alpha- and beta-1,4-glycosidic bonds; Derivatives thereof, e.g. alginates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/04—Materials for stopping bleeding

Definitions

  • the invention relates to the technical field of biomedicine, in particular to a modified sodium alginate auto-imaging embolic microsphere, and a preparation method and application thereof.
  • TACE Transcatheter vascular embolization
  • the ideal embolic material should meet the following requirements: non-toxic, non-antigenic, has good biocompatibility, has no residue in the body, and can be completely degraded.
  • Sodium alginate is a polysaccharide sodium salt composed of a mixture of mannose and guolose extracted from natural plant brown algae, which meets the requirements of an ideal embolic material.
  • Chinese patent CN106620829A proposes a developing embolic material and a preparation method thereof. Sodium alginate is blended with tantalum powder and then cross-linked with calcium ions to prepare developing microspheres.
  • Chinese patent CN103432080A uses sodium alginate, nano silver and anti-tumor drugs to blend with calcium ion to prepare developing microspheres.
  • the developer is dispersed in a conventional stirring method, which is prone to disadvantages such as uneven dispersion and agglomeration of the developer.
  • the microspheres cannot be loaded with drugs or only through physical blending, and the long-term effective release of drugs cannot be controlled. It has a great influence on the efficacy of chemotherapy and embolization treatment of tumors.
  • the purpose of the present invention is to provide a modified sodium alginate embolization microsphere that can increase drug loading, shorten drug loading preparation time, have a long sustained release time, controllable degradation time, and has a visualization function.
  • a modified sodium alginate auto-imaging embolic microsphere comprising: modified sodium alginate and a developer;
  • the modified sodium alginate is sodium alginate that has undergone branching modification to introduce multiple hydroxyl groups, and then hydrophobically modified and sulfonated modified sodium alginate, and the branching substitution rate of the branching modification is 22- 81%; the hydrophobic substitution rate of the hydrophobic modification is 5-32%; the sulfonation substitution rate of the sulfonation modification is 57-266%.
  • the side chain groups of the sodium alginate are first modified by branching in a specific ratio, and a plurality of hydroxyl groups that can be used as sulfonation modification and hydrophobic modification sites are appropriately introduced (modification).
  • the sex site is on the hydroxyl group of the side chain of the sodium alginate structure), and then the hydroxyl group on the side chain is further subjected to a specific ratio of hydrophobic modification and sulfonation modification (the order of sulfonation modification and hydrophobic modification is not limited ), so as to introduce appropriately multiple hydrophobic groups and negatively charged sulfonic acid groups, so that when the negatively charged sulfonic acid groups and the positive and negative charges of the positively charged drugs are attracted to each other to achieve drug loading, both It can significantly increase the drug loading and drug loading rate of positively charged drugs, delay drug release time, reduce drug burst release, and improve the therapeutic effect of chemotherapy and embolization.
  • the branch substitution rate refers to the ratio of the number of moles of the grafted branching agent in the sodium alginate to the number of moles of the sodium alginate repeating unit (C 6 H 7 NaO 6 ) before being modified.
  • the hydrophobic substitution rate refers to the ratio of the number of moles of grafted hydrophobic monomers in the sodium alginate after branching modification to the number of moles of the sodium alginate repeating unit before the modification
  • the sulfonation substitution rate refers to the number of moles of the branched modified sodium alginate.
  • the invention is microspherical.
  • the particle size of the microspheres is 100-1000 ⁇ m, so as to facilitate selective embolization of the inner diameter of blood vessels in different parts.
  • the branch substitution rate of the branch modification is 45%-50%
  • the hydrophobic substitution rate of the hydrophobic modification is 18-25%
  • the sulfonation substitution rate of the sulfonation modification is 82- 121%, in order to further improve the drug loading efficiency, and the sustained release effect is better.
  • the ratio of the branching substitution rate, the hydrophobic substitution rate to the sulfonation substitution rate is 1:(0.4-0.5):(2.5-2.7), so as to obtain a better drug-loading efficiency and relaxation. Interpretation effect.
  • the branched modified branch modifier is one or more of glycerol, pentaerythritol, and diglycerol, preferably pentaerythritol;
  • the hydrophobically modified hydrophobic modifier is one or more of oleic acid, octylamine, dodecylamine, and hexadecylamine, preferably oleic acid;
  • the sulfonated modified sulfonating agent is one or more of sulfite derivatives, chlorosulfonic acid, and concentrated sulfuric acid, preferably sulfite derivatives.
  • the sulfite derivative has the following chemical formula:
  • the sulfite derivative is prepared from sodium bisulfite and sodium nitrite.
  • the sulfite derivative is prepared from sodium bisulfite and sodium nitrite.
  • Synthesis, Characterization, and Anticoagulant Activity of Carboxymethyl Starch Sulfates Lihong Fan, Yugui Gong, Mi Cao, Song Gao, Yi Sun, Lingyun Chen, Hua Zheng, Weiguo Xie, J. APPL. POLYM. 2013 DOI: 10.1002/APP.38088).
  • the branching modifier is pentaerythritol
  • the branch substitution rate is 45%-50%
  • the hydrophobic modifier is oleic acid
  • the hydrophobic substitution rate is 18-25%
  • the sulfonating agent is sub Sulfate derivatives
  • the sulfonation substitution rate is 82-121%; more preferably, the ratio of the branching substitution rate, the hydrophobic substitution rate to the sulfonation substitution rate is 1:(0.4-0.5):( 2.5-2.7).
  • the viscosity of the sodium alginate is 55-619mpa ⁇ s, preferably 280-400mpa ⁇ s, so as to ensure the degradation cycle and facilitate the production of small particle size microspheres.
  • the branching modification, hydrophobic modification and sulfonation modification in the present invention can be carried out by the conventional method of modifying sodium alginate in this field.
  • branching modification includes the following steps: adding sodium alginate to the acetone solution of halogenated hydrocarbons, and adjusting the pH of the solution to 8-12, 30-55 React at °C for 3 ⁇ 6h, add branched modified monomer (branched modifier), the molar ratio of branched modified monomer to unmodified sodium alginate repeat unit is (0.3-1): 1. Stir and react at 80-100°C for 8-24 hours, add excess acetone solution, filter with suction, collect the precipitate, wash and dry to obtain branched modified sodium alginate.
  • the skilled person can select specific reaction conditions for each step according to the common knowledge in the field and the reaction method described in the present invention to achieve the expected branching substitution rate, hydrophobic substitution rate and sulfonation substitution rate.
  • the content of the developer in the embolic microspheres is 8-30 wt%, so as to ensure the development effect without affecting the fluidity of the modified sodium alginate solution of the present invention during preparation; preferably, the The imaging agent is an X-ray imaging agent or an MRI imaging agent.
  • the X-ray developer is iohexol, iotroram, ioverol, diatrizoate meglumine, triiodobenzoic acid or other iodine-based developers, or barium sulfate, nano silver, tantalum powder, etc.
  • the MRI developer is Fe 3 O 4 and so on.
  • the embolic microspheres can also be loaded with positively charged drugs, preferably the drugs are anti-tumor drugs; more preferably doxorubicin hydrochloride, irinotecan, topotecan, epirubicin One or more of, epirubicin, bleomycin, cisplatin, carboplatin, oxaliplatin, lobaplatin, fluorouracil, and mitomycin.
  • drugs are anti-tumor drugs; more preferably doxorubicin hydrochloride, irinotecan, topotecan, epirubicin
  • epirubicin One or more of, epirubicin, bleomycin, cisplatin, carboplatin, oxaliplatin, lobaplatin, fluorouracil, and mitomycin.
  • the drug is water-soluble, and the hydrophobicity of the embolic microspheres can prolong the sustained release time of the drug.
  • the present invention also provides a method for preparing the above-mentioned embolic microspheres, which uses a mixed solution of the modified sodium alginate aqueous solution and the developer as a raw material liquid, and is prepared by an electrostatic droplet method.
  • the mass fraction of the aqueous solution of modified sodium alginate is 1% to 15%.
  • the mixing method of the aqueous solution of modified sodium alginate and the developer is: 200-300r/min after stirring for 30-50min, ultrasonic dispersion for 20-30min, and finally 800-1000r/min for high-speed dispersion for 30- 50min; preferably, after stirring at 300r/min for 40min, ultrasonic dispersion for 30min, and finally high-speed shearing at 900r/min for 35min to facilitate uniform dispersion of the developer.
  • the crosslinking agent used in the crosslinking of the modified sodium alginate is selected from one or more of calcium chloride, magnesium chloride, barium chloride, and copper chloride, preferably calcium chloride. Conducive to safety after embolization.
  • the preparation method of the porous microspherical embolic microspheres of the present invention is:
  • the imaging agent in the microspheres prepared by the method of the present invention is uniformly dispersed without aggregation, and can achieve precise imaging effects during and after vascular embolization.
  • the present invention also provides an application of the embolization microspheres or methods described above in the preparation of products for vascular embolization or hemostasis.
  • the present invention significantly increases the drug loading amount and drug loading rate of the embolic microspheres, can prolong the drug slow release time, reduce the drug burst release, relatively reduce the drug side effects and prolong the drug onset time, Effectively improve the effect of chemotherapy and embolization treatment.
  • the modification of the side chain of sodium alginate by the present invention does not affect the degradation performance and biocompatibility of the sodium alginate main chain structure.
  • Fig. 1 is the microscopic observation results of the dispersion liquid of each embodiment of the experimental example 2 of the present invention and the comparative example.
  • modified sodium alginate auto-imaging embolic microspheres were prepared and further loaded with drugs according to the following method:
  • Branch modification add sodium alginate with a viscosity of 619mpa ⁇ s to the acetone solution of dibromoethane, adjust the pH of the solution to 10, pre-react at 55°C for 3h, add pentaerythritol, pentaerythritol and sodium alginate The molar ratio of the repeating unit is 0.3:1, and the reaction is stirred at 80°C for 24 hours, an excess of acetone solution is added, and the precipitate is collected by suction filtration, washed and dried to obtain branched modified sodium alginate.
  • Hydrophobic modification add oleic acid and branched modified sodium alginate to N, N-dimethylformamide, add dicyclohexylcarbodiimide and 4-dimethylaminopyridine under stirring conditions , React at room temperature for 24h to obtain hydrophobically modified sodium alginate.
  • the molar ratio of oleic acid to the above-mentioned sodium alginate repeating unit is 0.3:1.
  • the sulfonating agent is a sodium bisulfite derivative, and its chemical formula is:
  • steps 2 and 3 are not limited.
  • the modified sodium alginate obtained by the above three-step modification is configured into a 1% aqueous solution of modified sodium alginate, and the modified sodium alginate is fully dissolved in the water by stirring.
  • tantalum powder to the modified sodium alginate aqueous solution so that the content of the tantalum powder is 8wt%, and after stirring at 200r/min for 30min, ultrasonically disperse for 20min, and finally 800r/min high-speed shearing for 30min until the tantalum powder is evenly dispersed. Mixture.
  • the solidified modified sodium alginate auto-imaging plug microspheres were stored in a maintenance solution (a calcium chloride solution with a concentration of 3%) at a ratio of 1 g/5 ml.
  • Example 2-7 modified sodium alginate auto-imaging embolic microspheres were prepared according to the method of Example 1 and further loaded with drugs. The only difference lies in the preparation of raw materials and dosage, reaction conditions, developer mixing method and preparation electric field force. The voltages are not exactly the same. In addition, in Examples 6-7, the order of steps 2 and 3 are interchanged.
  • Example 2-7 the differences between Examples 2-7 and Example 1 in the sodium alginate raw material in step 1, the concentration of the modified sodium alginate aqueous solution in step 4, the content of the developer, and the drug-carrying drug are shown in Table 1. See Table 2 for the difference between the amount of raw materials and reaction conditions during chemical modification and Example 1, and see Table 3 for the difference between the amount of raw materials and reaction conditions during hydrophobic modification and Example 1. In sulfonation modification The difference between the amount of raw materials and the reaction conditions in Example 1 is shown in Table 4, the difference between the developer mixing mode and Example 1 is shown in Table 5. 1 is the same, and examples 4-7 are 11kv.
  • Example Developer mixing method 2 Stir at 200r/min for 50min, ultrasonically disperse for 20min, and finally shear at 800r/min for 30min 3 After stirring at 200r/min for 50min, ultrasonic dispersion for 30min, and finally 800r/min high-speed shearing for 30min 4 After stirring at 260r/min for 50min, ultrasonic dispersion for 25min, and finally 1000r/min high-speed shearing for 50min 5 After stirring at 300r/min for 40min, ultrasonic dispersion for 30min, finally 900r/min high-speed shearing for 35min 6 After stirring at 230r/min for 35min, ultrasonic dispersing for 25min, and finally high-speed shearing at 900r/min for 35min 7 After stirring at 230r/min for 50min, ultrasonic dispersion for 25min, and finally 1000r/min high-speed shearing for 50min
  • modified sodium alginate auto-imaging embolic microspheres were prepared and further loaded with drugs according to the following method:
  • Branch modification add sodium alginate with a viscosity of 110mpa ⁇ s to the acetone solution of dibromoethane, adjust the pH of the solution to 11, pre-react at 30°C for 4h, add glycerin, glycerin and sodium alginate The molar ratio of the repeating unit is 0.35:1, and the reaction is stirred at 100°C for 8 hours, an excess of acetone solution is added, and the precipitate is collected by suction filtration, washed and dried to obtain branched modified sodium alginate.
  • steps 2 and 3 are not limited.
  • the modified sodium alginate obtained by the above-mentioned three-step modification is configured into a modified sodium alginate aqueous solution with a mass fraction of 5%, and the modified sodium alginate is fully dissolved in the water by stirring.
  • Example 6 Through the electrostatic droplet generating device of Example 1, the above-mentioned mixed liquid was injected into a barium chloride aqueous solution with a mass concentration of 5% for cross-linking and curing for 24 hours to obtain modified sodium alginate auto-imaging embolic microspheres.
  • the specific preparation method is the same as in Example 1, except that the electric field force and voltage are 7.5 kv.
  • Drug loading The drug loading method of this example is the same as that of Example 1, except that the drug is epirubicin.
  • modified sodium alginate auto-imaging embolic microspheres were prepared and further loaded with drugs according to the following method:
  • Branching modification This embodiment adopts the same branching modification method as that of Example 8, except that the viscosity of sodium alginate is 90mpa ⁇ s, and dipolyglycerol is used instead of glycerin, dipolyglycerol and alginic acid
  • the molar ratio of sodium repeating unit is 0.6:1, and the reaction time is 12h.
  • Hydrophobic modification This embodiment uses the same hydrophobic modification method as that of Example 8, except that: dodecylamine is used instead of octylamine, and the molar ratio of dodecylamine to the above-mentioned sodium alginate repeating unit is 0.4:1.
  • steps 2 and 3 are not limited.
  • the modified sodium alginate obtained by the above three-step modification is configured into a modified sodium alginate aqueous solution with a mass fraction of 2%, and the modified sodium alginate is fully dissolved in the water by stirring.
  • ferroferric oxide added to the modified sodium alginate aqueous solution to make the content of ferroferric oxide 15wt%. After stirring at 240r/min for 38min, ultrasonically disperse for 30min, and finally high-speed shearing at 1000r/min for 55min to four The ferroferric oxide is evenly dispersed to obtain a mixed solution.
  • Example 6 Through the electrostatic droplet generating device of Example 1, the above-mentioned mixed liquid was injected into a copper chloride aqueous solution with a mass concentration of 12% for cross-linking and curing for 24 hours to obtain modified sodium alginate auto-developing embolic microspheres.
  • the specific preparation method is the same as in Example 1, except that the electric field force and voltage are 30kv.
  • modified sodium alginate embolic microspheres were prepared according to the method of Example 5, except that the sulfonation modification was not performed.
  • modified sodium alginate embolic microspheres were prepared according to the method of comparative example 1, except that the hydrophobic modification was not carried out.
  • modified sodium alginate embolization microspheres were prepared according to the method of Example 5. The only difference is that glucose is used as the branching monomer, and the substitution rate of each step is unchanged.
  • modified sodium alginate embolic microspheres were prepared according to the method of Example 5. The only difference is: in the hydrophobic modification step: the molar ratio of oleic acid to the above-mentioned sodium alginate repeating unit is 0.8:1; the hydrophobic substitution rate is 60% , The replacement rate of the remaining two steps remains unchanged.
  • modified sodium alginate embolization microspheres were prepared according to the method of Example 5. The only difference is: in the sulfonation modification step: the molar ratio of the sulfonating agent and the sodium alginate repeating unit is 0.4:1, and the sulfonation The chemical substitution rate is 32%.
  • modified sodium alginate was prepared according to the formula of Example 5.
  • the specific method of adding developer in step 5 is: adding tantalum powder to the modified sodium alginate aqueous solution obtained in step 4 so that the content of tantalum powder is 15wt%, and mixed at 1000r/min for 100min.
  • the particle size test method is: the microscope method specified in Appendix B of YY/T 1574-2017;
  • This experimental example further tests the developer dispersion effect of the products of Examples 1-9 and Comparative Examples 1-6.
  • the specific method is to take 0.5ml of the dispersion liquid (ie the mixed liquid obtained in step 5) after the developer is dispersed. On a glass slide, cover with a cover glass and observe under a microscope with a 20-fold objective lens. The observation result is shown in Figure 1. It can be seen from Figure 1 that the conventional dispersion method (Comparative Example 6) has a significantly lower dispersion effect than the method used in the present invention.
  • the invention provides a modified sodium alginate auto-imaging embolic microsphere, and a preparation method and application thereof.
  • the modified sodium alginate auto-imaging embolic microspheres of the present invention include: modified sodium alginate and a developer; the modified sodium alginate is modified by branching to introduce multiple hydroxyl groups, and then hydrophobically modified And sulfonated modified sodium alginate, the branching substitution rate of the branch modification is 22-81%; the hydrophobic substitution rate of the hydrophobic modification is 5-32%; the sulfonated modified sulfonate The chemical substitution rate is 57-266%.
  • the embolic microspheres of the present invention can not only significantly increase the drug loading and drug loading rate of negatively charged drugs, but also delay drug release time and reduce drug burst release, and have good economic value and application prospects .

Abstract

Microsphère d'embolie à auto-développement d'alginate de sodium modifié et son procédé de préparation et son application. La microsphère d'embolie à auto-développement d'alginate de sodium modifié comprend de l'alginate de sodium modifié et un agent de développement. Le procédé de préparation de l'alginate de sodium modifié consiste : à exécuter une modification de ramification pour introduire une pluralité de groupes hydroxyle et ensuite à exécuter une modification hydrophobe et une modification de sulfonation, le taux de substitution de ramification étant de 22 à 81 %, le taux de substitution hydrophobe étant de 5 à 32 %, et le taux de substitution de sulfonation étant de 57 à 266 %. Lorsque la microsphère d'embolie à auto-développement d'alginate de sodium est utilisée comme support de médicament, la capacité de charge de médicament et le taux de charge de médicament d'un médicament négativement chargé peuvent être remarquablement améliorés, le temps de libération de médicament peut être retardé, et la libération rapide du médicament est réduite.
PCT/CN2021/087264 2020-04-28 2021-04-14 Microsphère d'embolie à auto-développement d'alginate de sodium modifié et son procédé de préparation et son application WO2021218637A1 (fr)

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