CN117323294B - Drug-loaded embolism microsphere and preparation method and application thereof - Google Patents
Drug-loaded embolism microsphere and preparation method and application thereof Download PDFInfo
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- CN117323294B CN117323294B CN202311244201.1A CN202311244201A CN117323294B CN 117323294 B CN117323294 B CN 117323294B CN 202311244201 A CN202311244201 A CN 202311244201A CN 117323294 B CN117323294 B CN 117323294B
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- 239000003814 drug Substances 0.000 title abstract description 81
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- 238000006243 chemical reaction Methods 0.000 claims description 32
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- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 6
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- 229920002845 Poly(methacrylic acid) Polymers 0.000 claims description 5
- NWGKJDSIEKMTRX-AAZCQSIUSA-N Sorbitan monooleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 claims description 4
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- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 3
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- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
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- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
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- 229910017604 nitric acid Inorganic materials 0.000 description 2
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- 235000002639 sodium chloride Nutrition 0.000 description 2
- 230000002459 sustained effect Effects 0.000 description 2
- 238000002834 transmittance Methods 0.000 description 2
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 1
- QKWWDTYDYOFRJL-UHFFFAOYSA-N 2,2-dimethoxyethanamine Chemical compound COC(CN)OC QKWWDTYDYOFRJL-UHFFFAOYSA-N 0.000 description 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- LFMCNJBSTUSMMC-UHFFFAOYSA-N 3-(dimethoxymethyl)aniline Chemical compound COC(OC)C1=CC=CC(N)=C1 LFMCNJBSTUSMMC-UHFFFAOYSA-N 0.000 description 1
- GFLPSABXBDCMCN-UHFFFAOYSA-N 4,4-diethoxybutan-1-amine Chemical compound CCOC(OCC)CCCN GFLPSABXBDCMCN-UHFFFAOYSA-N 0.000 description 1
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- 238000002835 absorbance Methods 0.000 description 1
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- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
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- 230000010109 chemoembolization Effects 0.000 description 1
- BFPSDSIWYFKGBC-UHFFFAOYSA-N chlorotrianisene Chemical compound C1=CC(OC)=CC=C1C(Cl)=C(C=1C=CC(OC)=CC=1)C1=CC=C(OC)C=C1 BFPSDSIWYFKGBC-UHFFFAOYSA-N 0.000 description 1
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- 239000000843 powder Substances 0.000 description 1
- 239000003761 preservation solution Substances 0.000 description 1
- 150000003141 primary amines Chemical group 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- 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
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/06—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Materials Engineering (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Materials For Medical Uses (AREA)
Abstract
The invention belongs to the technical field of biomedical materials, and provides a drug-loaded embolism microsphere, a preparation method and application thereof. In addition, the method has the advantages of few steps, simplicity, easiness in operation, low toxicity of the adopted raw material reagent and high biological safety. The embolic microsphere prepared by the invention can be further used for tumor vascular embolism and continuous administration, and realizes excellent tumor treatment effect.
Description
Technical Field
The invention relates to the technical field of biomedical materials, in particular to a drug-loaded embolism microsphere, a preparation method and application thereof.
Background
Liver cancer is called "king in cancer", and is called as a color change due to its high morbidity and mortality. Arterial Chemoembolization (TACE) is a widely used treatment for unresectable hepatocellular carcinoma (HCC), and is characterized by that after the chemotherapeutic drug and embolizing agent are mixed, they are injected, and passed through arterial puncture to embolize blood-supply artery of tumor, so that it can produce ischemic and anoxic necrosis of tumor tissue.
In the prior art, polymer microspheres are generally used as an embolic agent, and are mostly prepared by monomer polymerization. In the process, on one hand, free radical polymerization monomers (such as acrylic acid monomers, acrylic ester monomers and the like) are needed, but the monomers have poor stability, bad smell and possibly have the danger of inflammability and explosiveness; on the other hand, the polymerization reaction is difficult to control, and the byproducts are more; these have a number of adverse effects on production and use. For example, chinese patent CN103977458a discloses a polyhydroxy polymer embolic microsphere and a preparation process thereof, wherein a functionalized macromolecular hydrogel is prepared first, then an initiator is added, an anionic monomer is connected with a functional macromolecule through reversed-phase suspension polymerization, and the interior of the microsphere contains a functional group taking an organic acid radical as a negative charge carrier, but the invention connects the anionic monomer with the functional macromolecule through reversed-phase suspension polymerization, the reaction process is relatively complex, the byproducts are more, the reaction progress is difficult to control, and the compression deformation rate of the microsphere is only about 50%. As another example, chinese patent CN113975453a discloses a preparation method of hydrogel embolic microsphere, which uses acrylate monomer, vinyl alcohol carboxylic acid derivative monomer and cross-linking agent to crosslink, and synthesizes microsphere through normal phase suspension polymerization, but the method adopts acrylate monomer and vinyl alcohol carboxylic acid derivative monomer with poor chemical stability, which are easy to be affected by temperature, air and so on to go bad or self-polymerize, and are not easy to be stored and used, and these two monomers are easy to volatilize, bad taste, have certain toxicity and irritation, the acrylate monomer is inflammable and explosive, and harm to production personnel is large, and the difficulty of production is also increased; the normal phase suspension polymerization reaction process is more severe (the normal phase suspension polymerization reaction is fast, the heat is much, if the control is improper, the overpressure is easy to cause, the explosion is initiated, the safety is low, a cooling device, a pressure container and the like are needed to be equipped, the requirement on equipment is high), the reaction degree controllability is low (the parameters such as the particle size, the dispersity, the polymerization degree and the like of the product are difficult to effectively control and regulate, the quality of the synthesized product is easy to be unstable, even larger particle aggregates can be synthesized), the compression deformation rate of the prepared microsphere is only about 50%, and the drug loading rate is only about 90%.
Therefore, there is a need to develop a preparation method of embolic microspheres, which has the advantages of easy control of reaction process, few steps, few byproducts, simple operation, high compressibility of the embolic microspheres, high drug carrying speed, high drug carrying rate, long drug release time, and good sustained drug administration.
Disclosure of Invention
The present invention aims to solve at least one of the technical problems in the prior art described above. Therefore, the invention provides a drug-loaded embolism microsphere, and a preparation method and application thereof. The preparation method only relates to crosslinking reaction, but not polymerization reaction with lower controllable degree, the reaction process is mild and controllable, the operation is simpler, the embolic microsphere prepared by the preparation method has high compressible degree (the embolic microsphere can rebound to the original state after the compression deformation distance reaches 80% of the diameter of the embolic microsphere), high drug loading speed, high drug loading rate (the drug loading rate is not less than 90.63% within 5min and not less than 97.19 min and the drug loading rate is not less than 98.14% within 30 min), long drug release time (the drug release time of the drug loaded embolic microsphere can be about 30 days), and good sustained drug delivery and biocompatibility can be well realized.
The first aspect of the invention provides a method for preparing embolic microspheres.
Specifically, the preparation method of the embolic microsphere comprises the following steps:
(1) Firstly, dissolving an anionic polymer in water to obtain an anionic polymer solution;
(2) Adding a cross-linking agent into the anionic polymer solution, then adding an amide condensing agent and an alkaline substance to react, and neutralizing to obtain a cross-linked intermediate;
(3) Dissolving an oil-soluble dispersing agent in an organic solvent to obtain an oil phase; mixing the crosslinking intermediate, polyhydroxy polymer and catalyst to obtain a water phase; adding the water phase into the oil phase to perform a crosslinking reaction to obtain the embolic microsphere;
The cross-linking agent is an amino acetal compound.
The invention uses polyhydroxy polymer and anion polymer as raw materials, and selects amino acetal compound (amine compound with primary amine or protective group and acetal structure) as cross-linking agent, and prepares the embolism microsphere through cross-linking reaction. The amino acetal compound contains amino and acetal structure, so that the amino can be subjected to crosslinking reaction with the anionic groups in the anionic polymer, and the acetal structure can be subjected to crosslinking reaction with the hydroxyl groups in the polyhydroxy polymer, so that the polymer embolic microsphere is obtained. As the invention adopts two polymers as raw materials, the invention does not involve the use of monomers which have poor chemical stability, are easy to volatilize or are easy to be affected by temperature, air and the like to generate deterioration or self polymerization and possibly have flammable and explosive risks, compared with monomer compounds, the polymers are difficult to volatilize, have better chemical stability and biological safety and are easier to store and convenient to use, therefore, the method of the invention can not only reduce the damage to personnel and equipment, reduce the requirement on equipment, but also avoid the uncertainty brought by the polymerization process and reduce the generation of byproducts. In addition, the synthesis process of the invention only involves simple crosslinking reaction, the reaction process is mild and controllable, and the operation is simpler and more convenient.
Preferably, in step (1), the weight average molecular weight of the anionic polymer is 300000-1500000.
Further preferably, in step (1), the weight average molecular weight of the anionic polymer is 450000-1200000.
Preferably, in step (1), the anionic polymer is an organic acid group-containing anionic polymer or a salt thereof.
Further preferably, in step (1), the anionic polymer comprises at least one of polyacrylic acid, polymethacrylic acid, and polysaccharide polymer containing acid groups. The above anionic polymers (especially polyacrylic acid) are all good biological materials.
Preferably, the acid group-containing polysaccharide polymer comprises hyaluronic acid and/or carboxymethyl cellulose.
Preferably, in step (3), hydroxyl groups are attached to adjacent carbons of the polyhydroxy polymer or only one carbon atom not containing hydroxyl groups is separated between every two carbons to which hydroxyl groups are attached.
Preferably, in step (3), the polyhydroxy polymer has a degree of polymerization of 1000 to 2000, and/or the polyhydroxy polymer has an alcoholysis degree of 70% to 99%.
Further preferably, in step (3), the degree of polymerization of the polyhydroxypolymer is 1400 to 1700, and/or the degree of alcoholysis of the polyhydroxypolymer is 88 to 99%.
Preferably, in the step (3), the polyhydroxy polymer is polyvinyl alcohol and/or polysaccharide macromolecular compound. The above polyhydroxyl polymers, especially polyvinyl alcohol, are biological materials with good biocompatibility.
Preferably, the polysaccharide macromolecular compound comprises gelatin and/or cellulose.
Preferably, the polyhydroxy polymer is polyvinyl alcohol and the anionic polymer is polyacrylic acid. Polyvinyl alcohol-based polyhydroxy polymers can provide good backbone action, while polyacrylic acid-based anionic polymers have good hydrophilicity and drug-carrying properties.
Further preferably, the amino acetal compound comprises at least one of amino acetaldehyde diethyl acetal, amino acetaldehyde dimethyl acetal, 4-amino butyraldehyde diethyl acetal, 5-diethoxy-1-pentylamine, and 3- (dimethoxymethyl) aniline.
Preferably, in the step (2), the temperature of the reaction is 30-60 ℃, and the time of the reaction is 1-10h.
Preferably, in the step (2), the amide condensing agent is a water-soluble carbodiimide condensing agent and/or a quaternary ammonium salt condensing agent.
Further preferably, in the step (2), the amide condensing agent is at least one of N-succinimidyl (NHS), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI), diisopropylcarbodiimide (DIC), dicyclohexylcarbodiimide (DCC), 4- (4, 6-dimethoxytriazin-2-yl) -4-methylmorpholine hydrochloride.
Preferably, in the step (2), the alkaline substance is a water-soluble organic base and/or an inorganic base.
Further preferably, in the step (2), the basic substance is at least one of triethylamine, 1, 8-diaza-4, 5-dihydroxy-9, 10-anthraquinone diene, 4-dimethylaminopyridine, sodium hydroxide, and potassium hydroxide.
Preferably, in the step (2), the neutralization is performed by adding at least one of hydrochloric acid, sulfuric acid and nitric acid. The neutralization function is as follows: (1) Suitable conditions are created for the subsequent reaction, and (2) the stability of the intermediate product is improved, so that the intermediate product is convenient to store.
Preferably, the embolic microsphere comprises the following raw material components in parts by weight:
Preferably, in step (3), the catalyst is an acidic substance.
Preferably, the acidic substance comprises at least one of hydrochloric acid, sulfuric acid, nitric acid, and methanesulfonic acid.
Preferably, in the step (3), the oil-soluble dispersant includes at least one of span 80, span 20 and tween 20.
Preferably, in step (3), the organic solvent includes at least one of liquid paraffin, petroleum ether, and corn oil.
Preferably, in the step (3), the temperature of the crosslinking reaction is 40-70 ℃, and the time of the crosslinking reaction is 5-10h.
Further preferably, in the step (3), the temperature of the crosslinking reaction is 50-60 ℃, and the time of the crosslinking reaction is 6-8 hours.
Preferably, in the step (3), after the crosslinking reaction, the embolic microspheres are soaked and stored in a salt solution after washing and sieving to obtain wet embolic microspheres (wet spheres), or after the crosslinking reaction, the embolic microspheres are dried to obtain powdery dry embolic microspheres (dry spheres). The wet ball or the dry ball can be prepared by the method, can be stored and used in a dry state or a wet state, and can meet the requirements of different use scenes and doctors; the dry ball is stored in solid powder, the storage time is long, the drug adsorption capacity is strong, the drug carrying variety is wide, and the vascular fit is good; the wet ball has good elasticity, strong conveying performance of the catheter and convenient use (the wet ball is more convenient than the dry ball because the dry ball can be obtained through more complicated drying steps).
Preferably, the saline solution comprises physiological saline and/or Phosphate (PBS) buffer.
Preferably, the drying is freeze-drying.
Preferably, before the drying, the microspheres are soaked with a short-chain alcohol or an aqueous solution containing an electrolyte, and then subjected to a program gradient prefreezing.
Preferably, the short chain alcohol comprises at least one of methanol, ethanol, propanol.
Preferably, the electrolyte-containing aqueous solution includes at least one of an acid solution, an alkali solution, and a salt solution.
Preferably, the acid solution is at least one of hydrochloric acid, sulfuric acid, acetic acid and phosphoric acid.
Preferably, the alkali solution is at least one of sodium hydroxide, potassium hydroxide and ammonium hydroxide solution
Preferably, the salt solution is at least one of sodium chloride, sodium acetate, sodium carbonate and sodium bicarbonate.
Preferably, the program gradient prefreezing is: cooling to-20-0deg.C from 25-30deg.C, maintaining for 1-2h, cooling to-80- -40deg.C, and maintaining for 1-2h.
In a second aspect the invention provides an embolic microsphere.
An embolic microsphere prepared by the preparation method, wherein the particle size of the embolic microsphere is 100-1200 mu m.
Preferably, the embolic microsphere has a molecular structure represented by the following formula (I) or formula (II):
in a third aspect the invention provides a drug-loaded embolic microsphere.
The drug-loaded embolic microsphere comprises embolic microspheres and drugs, wherein the embolic microspheres are prepared by the preparation method, and the particle size of the embolic microspheres is 100-1200 mu m.
Preferably, the drug is a chemotherapeutic drug.
Further preferably, the drug is Doxorubicin (DOX).
The fourth aspect of the invention provides a method for preparing the drug-loaded embolic microsphere.
A preparation method of drug-loaded embolism microsphere comprises the following steps:
soaking the embolism microsphere in a solution containing a drug, and taking out to obtain the drug-loaded embolism microsphere.
In a fifth aspect, the invention provides the use of a drug-loaded embolic microsphere.
An application of embolic microspheres in preparing embolic agent for treating cancer is provided.
An application of embolic microspheres in preparing embolic agent for treating hepatocellular carcinoma is provided.
Compared with the prior art, the invention has the following beneficial effects:
According to the invention, the amino acetal compound cross-linking agent is adopted to cross-link the anionic polymer and the polyhydroxy polymer into balls, and the use of monomers is not involved, so that the complex and difficult-to-control polymerization reaction is not involved, the reaction process is simple, the reaction condition is mild and controllable, the prepared embolic microsphere has good elasticity, high compressibility (the compression deformation distance can rebound to the original state after reaching 80% of the diameter of the embolic microsphere), high drug loading speed, high drug loading rate (the drug loading rate is not lower than 90.63% in 5min, the drug loading rate is not lower than 97.19% in 15min, the drug loading rate is not lower than 98.14% in 30 min), and long drug release duration (the drug release time of the drug loaded embolic microsphere can be up to about 30 days) and good biocompatibility. In addition, the method has the advantages of few steps, simplicity, easiness in operation, low toxicity of the adopted raw material reagent and high biological safety. The drug-loaded embolism microsphere prepared by the invention can be further used for tumor vascular embolism and continuous drug administration, and realizes excellent tumor treatment effect.
Drawings
FIG. 1 is a morphology image (scanning electron microscope image) of embolic microspheres of example 1;
FIG. 2 is an infrared spectrum of embolic microspheres of example 1;
FIG. 3 is a graph showing the release of drug from the drug-loaded embolic microspheres of example 1 and comparative example 1.
Detailed Description
In order to make the technical solutions of the present invention more apparent to those skilled in the art, the following examples will be presented. It should be noted that the following examples do not limit the scope of the invention.
The starting materials, reagents or apparatus used in the following examples are all available from conventional commercial sources or may be obtained by methods known in the art unless otherwise specified.
Example 1
A preparation method of embolic microspheres comprises the following steps:
(1) 10g of polyacrylic acid (weight average molecular weight: 450000) was dissolved in 90g of distilled water to obtain a polyacrylic acid solution.
(2) Then 0.1g of aminoacetaldehyde diethanol crosslinker was added to the polyacrylic acid solution and stirred at room temperature to form a homogeneous solution. To the above solution, 1g of EDCI and 0.2g of NHS were added, and 0.5mL of triethylamine was added, and the mixture was stirred at room temperature in a dark place to effect an amide condensation reaction for 10 hours. After the completion of the reaction, hydrochloric acid was added for neutralization, and then dialysis with a purified aqueous solution and freeze-drying were performed to obtain a crosslinked intermediate (solid).
(3) 1L of liquid paraffin was added to a 2L three-necked flask, followed by 10g of span 80, and the mixture was stirred to obtain an oil phase. 5g of the crosslinked intermediate and 5g of polyvinyl alcohol (polymerization degree 1700, alcoholysis degree 88%) were dissolved in 20g of distilled water, and 5mL of concentrated hydrochloric acid was added thereto and stirred for 30 minutes to obtain a water phase. The aqueous phase was slowly added dropwise to the oil phase with stirring at 300 rpm. After the dripping is completed, stirring and dispersing for 20min, then heating to 60 ℃, and carrying out crosslinking reaction for 6h to obtain the embolic microsphere.
(4) And washing the obtained embolic microspheres after the reaction for 5 times by ethanol and water respectively, and screening the embolic microspheres to the ranges of 100-300 mu m, 300-500 mu m, 500-800 mu m and 800-1200 mu m according to the particle size by using a screen. Soaking the embolic microspheres in physiological saline to obtain wet spheres, wherein the volume ratio of the embolic microspheres to the physiological saline is 2:8.
The PBS solution prepared above has a molecular structure shown in the following formula (I):
Example 2
A preparation method of embolic microspheres comprises the following steps:
(1) 15g of polymethacrylic acid (weight average molecular weight: 1200000) was dissolved in 85g of distilled water to obtain a polymethacrylic acid solution.
(2) Then 0.15g of aminoacetaldehyde diethanol crosslinker was added to the polymethacrylic acid solution and stirred at room temperature to form a homogeneous solution. To the above solution, 1.2g EDCI and 0.3g NHS were added, and the mixture was stirred at room temperature in the dark to effect an amide condensation reaction for 15 hours. After the reaction is completed, the product is dialyzed and freeze-dried to obtain a cross-linked intermediate (solid).
(3) 2L liquid paraffin is added into a 3L three-necked flask, then 15g span 80 and 10g Tween 20 are added, and the mixture is mixed and stirred to obtain an oil phase. 10g of the crosslinked intermediate and 12g of polyvinyl alcohol (polymerization degree: 1400, alcoholysis degree: 99%) were dissolved in 30g of distilled water, and 10mL of concentrated hydrochloric acid was added thereto and stirred for 30 minutes to obtain a water phase. The aqueous phase was slowly added dropwise to the oil phase with stirring at 350 rpm. After the dripping is completed, stirring and dispersing for 30min, then heating to 50 ℃, and carrying out crosslinking reaction for 8h to obtain the embolic microsphere.
(4) And washing the obtained embolic microspheres after the reaction with ethanol and water for 5 times, and screening the embolic microspheres to the ranges of 100-300 mu m, 300-500 mu m, 500-800 mu m and 800-1200 mu m by using a screen. Soaking the embolic microspheres in PBS solution to obtain wet spheres, wherein the volume ratio of the embolic microspheres to the PBS solution is 2:7.
The PBS solution prepared above has a molecular structure shown in the following formula (II):
Example 3
A preparation method of embolic microspheres is different from that of the embodiment 1 in that in the step (4), the screened microspheres are taken, added with methanol for soaking for 30min (the volume ratio of the microspheres to the methanol is 1:10), filtered out, added with pure water (the volume ratio of the microspheres to the pure water is 1:2), then the sample is placed in 0 ℃ for prefreezing for 1h, then transferred to-60 ℃ for prefreezing for 1h, finally the sample is freeze-dried in a freeze dryer, and the freeze-drying conditions are set at-75 ℃ for 20pa and 8h, so as to obtain dry microspheres.
Example 4
A preparation method of embolic microspheres is different from that of the embodiment 1 in that in the step (4), screened microspheres are taken, sodium hydroxide solution with the concentration of 0.05M is added for soaking for 20min (the volume ratio of the microspheres to the sodium hydroxide solution is 1:50), pure water (the volume ratio of the microspheres to the pure water is 1:1) is used for washing 5 times after filtration, then a sample is placed into a temperature of minus 20 ℃ for prefreezing for 1h, then the sample is transferred into a temperature of minus 80 ℃ for prefreezing for 1h, finally the sample is subjected to freeze-drying in a freeze dryer, and freeze-drying conditions are set to be minus 80 ℃ for 50pa and 6h, so that dry microspheres are prepared.
Example 5
A preparation method of embolic microspheres is different from that of the embodiment 1 in that in the step (4), the sieved microspheres are taken, physiological saline is added for soaking for 60min (the volume ratio of the microspheres to the physiological saline is 1:100), ethanol is added for soaking for 60min (the volume ratio of the microspheres to the ethanol is 1:15) after filtering, and pure water is added after filtering (the volume ratio of the microspheres to the pure water is 1:4). And then placing the sample into a-10 ℃ for pre-freezing for 1h, transferring into a-70 ℃ for pre-freezing for 1h, and finally freeze-drying the sample in a freeze dryer, wherein the freeze-drying conditions are set to be-80 ℃ for 10pa and 7h, so as to obtain the dry balls.
Example 6
A preparation method of embolic microspheres is different from that of the embodiment 2 in that in the step (4), the sieved microspheres are soaked in methanol with the volume ratio of 1:10 for 30min, pure water with the volume ratio of 1:2 is added after the methanol is filtered out, then the sample is placed in 0 ℃ for prefreezing for 1h, then the sample is transferred to-60 ℃ for prefreezing for 1h, finally the sample is freeze-dried in a freeze dryer, and the freeze-drying conditions are set at-75 ℃ for 20pa and 8h, so that dry microspheres are prepared.
Example 7
A preparation method of embolic microspheres is different from that of the embodiment 2 in that in the step (4), screened microspheres are taken, sodium hydroxide solution with the volume ratio of 1:50 and the concentration of 0.05M is added for soaking for 20min, pure water is used for washing 5 times after filtration (the volume ratio of the microspheres to the pure water is 1:1), then a sample is placed into a temperature of minus 20 ℃ for prefreezing for 1h, then the sample is transferred into a temperature of minus 80 ℃ for prefreezing for 1h, finally the sample is freeze-dried in a freeze dryer, and freeze-drying conditions are set to be minus 80 ℃ for 50pa and 6h, so that dry microspheres are prepared.
Example 8
A preparation method of embolic microspheres is different from that of example 2 in that in step (4), the sieved microspheres are taken, physiological saline (the volume ratio of the microspheres to the physiological saline is 1:100) is added for soaking for 60min, ethanol (the volume ratio of the microspheres to the ethanol is 1:15) is added for soaking for 60min after filtration, and pure water (the volume ratio of the microspheres to the pure water is 1:4) is added for filtration. And then placing the sample into a-10 ℃ for pre-freezing for 1h, transferring into a-70 ℃ for pre-freezing for 1h, and finally freeze-drying the sample in a freeze dryer, wherein the freeze-drying conditions are set to be-80 ℃ for 10pa and 7h, so as to obtain the dry balls.
Comparative example 1
This comparative example provides a commercially available embolic microsphere product HEPASPHERE (model: V325HS, gauge: 25mg, size: 50-100 μm).
Product effect test
1. Embolic microsphere morphology
As shown in FIG. 1, the SEM image of the embolic microsphere prepared in example 1 shows that the embolic microsphere prepared in accordance with the present invention has a smooth spherical shape with a particle size ranging from about 100 μm to about 300. Mu.m.
As shown in FIG. 2, the infrared spectrum of the embolic microsphere prepared in example 1 shows that, in FIG. 2, 3000-3600cm -1 is carboxyl and hydroxyl O-H stretching vibration, 1600-1700cm -1 is carboxyl and amide C=O stretching vibration, 1462cm -1 is methylene C-H bending vibration, 1409cm -1 is hydroxyl O-H bending vibration, and 1100cm -1 is ether bond C-O stretching vibration. The above results indicate that the polymer obtained in example 1 of the present invention has a molecular structure represented by formula (I). In fig. 2, TRANSMITTANCE is transmittance, and Wavenumber is wave number.
2. Microsphere compression performance test
And adding the dry spheres prepared in the examples 3 and 6 and the embolic microspheres prepared in the comparative example into normal saline for swelling and reconstruction, and then respectively spreading the swelled and reconstructed embolic microspheres, the wet spheres prepared in the examples 1-2 and the embolic microspheres prepared in the comparative example 1 in a sample tray of a deformation tester for testing. The deformation tester probe was lowered at 0.1mm/s until the compression set distance reached 20%, 50% and 80% of the diameter of the embolic microsphere. After the applied pressure is removed, the embolic microspheres can rebound to the original state and pass without breakage, and do not pass if rebound to the original state or breakage occurs. The results are shown in Table 1.
TABLE 1 compression Performance test results of embolic microspheres
Test sample | Compression of 20% | Compression of 50% | Compression of 80% | Morphology after testing |
Example 1 Wet bulb | By passing through | By passing through | By passing through | Smooth spherical shape |
EXAMPLE 3 Dry sphere reconstruction | By passing through | By passing through | By passing through | Smooth spherical shape |
EXAMPLE 2 Wet bulb | By passing through | By passing through | By passing through | Smooth spherical shape |
EXAMPLE 6 Dry sphere reconstruction | By passing through | By passing through | By passing through | Smooth spherical shape |
Comparative example 1 | By passing through | By passing through | Not pass through | Smooth spherical shape |
As shown in the table above, the shape of the embolic microsphere prepared by the invention is still smooth and spherical after the compression performance test, and the embolic microsphere can still rebound after the compression deformation distance reaches 80% of the diameter of the embolic microsphere. The commercial product of comparative example 1 had a smooth spherical shape after the compression performance test, but could not rebound to the original shape when the compression set distance reached 80% of the diameter of the embolic microsphere, and had a low degree of compressibility due to breakage.
The results show that the embolic microsphere prepared by the invention has high compressibility no matter whether wet ball or dry ball is rebuilt. Compared with the commercial product of the comparative example 1, the embolic microsphere prepared by the invention has better compression performance and is not easy to be damaged by extrusion.
3. Drug loading performance test
Wet ball drug loading: the wet spheres (particle size 100-300 μm) of examples 1 and 2 were taken, the preservation solution was removed, and then 1mL of the wet spheres was taken with a measuring cylinder, and 8mL of doxorubicin solution having a concentration of 5mg/mL was added. The drug loading rate was calculated according to formula (I) by measuring the drug concentration in the solution at 483nm wavelength with an ultraviolet spectrophotometer at intervals (5 min, 15min, 30 min) to monitor the absorption load of the microspheres to the drug.
Dry-ball drug loading: 25mg of dry spheres (particle size interval 100-300 μm in pure water) in examples 3 and 6 were taken, and 16mL of doxorubicin solution having a concentration of 2.5mg/mL was added, respectively. The drug loading rate was calculated according to formula (I) by measuring the drug concentration in the solution at 483nm wavelength with an ultraviolet spectrophotometer at intervals (5 min, 15min, 30 min) to monitor the absorption load of the microspheres to the drug.
Drug loading= (total drug input weight-weight of drug remaining in solution)/total drug input weight×100% formula (i).
The results are shown in Table 2 below.
TABLE 2 drug loading test results for embolic microspheres
Test sample | Carrying medicine for 5min | Carrying medicine for 15min | Carrying medicine for 30min | Morphology after drug loading |
Example 1 Wet bulb | 91.25% | 97.19% | 98.66% | Smooth spherical shape |
EXAMPLE 3 Dry ball | 93.46% | 98.87% | 99.28% | Smooth spherical shape |
EXAMPLE 2 Wet bulb | 90.63% | 97.26% | 98.14% | Smooth spherical shape |
EXAMPLE 6 Dry ball | 92.52% | 98.53% | 99.19% | Smooth spherical shape |
Comparative example 1 Dry bulb | 49.80% | 86.50% | 94.30% | Smooth spherical shape |
As shown in the table above, the drug loading rate of the embolic microsphere prepared by the invention is not lower than 90.63% (even up to 93.46%) in 5min, not lower than 97.19% (even up to 98.87%) in 15min, and not lower than 98.14% (even up to 99.28%) in 30 min. The commercial product of comparative example 1 has a drug loading rate of only 49.80% within 5min, and therefore, two steps of drug loading (namely, adding 8mL of doxorubicin solution with concentration of 2.5mg/mL initially after 10min of drug loading and adding 8mL of doxorubicin solution with concentration of 2.5mg/mL initially) are needed to achieve a drug loading rate of 94.30% after 30min of drug loading, and the drug loading rate is still lower than that of the embolic microsphere of the invention.
The results show that the embolic microsphere prepared by the invention has high drug carrying speed and high drug carrying rate, and the microsphere can still keep a smooth sphere after drug carrying.
4. Drug release performance test of drug-loaded embolic microspheres
(1) The embolic microspheres of example 1 and comparative example 1 were added to 20mg/mL doxorubicin solution, respectively, and shaken slightly inverted several times; and standing for 2 hours, taking the supernatant to test absorbance, and calculating the initial drug loading rate of the drug loading embolism microsphere.
(2) Then the drug-carrying embolism microsphere is injected into a filter bag, and the residual liquid medicine is filtered; and then the drug-loaded embolism microsphere is put into a filter bag and then placed into a beaker, a magnetic stirring rotor is added, and 200mL of 0.9% NaCl physiological saline is added.
(3) Placing the beaker filled with the drug-loaded embolic microspheres and physiological saline in a water bath stirring light-shielding environment at 37 ℃, respectively at 5min, 10min, 15min, 20min, 30min, 45min, 60min, 90min and 120min, taking 3mL of release liquid by a pipetting gun, detecting the drug concentration in the solution by an ultraviolet spectrophotometer, and recording test data; 3mL of physiological saline was simultaneously added to the beaker. After 120min, one test sample was taken daily and the above detection steps were repeated.
The test result of the drug release performance is shown in figure 3, and the graph shows that the drug release time of the drug-loaded embolism microsphere prepared by the invention can be up to about 30 days (d), and the drug release is durable. Whereas the drug release time of the drug-loaded embolic microsphere of comparative example 1 was only about 10 days, it was disadvantageous to achieve long-term drug delivery treatment.
Claims (2)
1. The preparation method of the embolic microsphere is characterized by comprising the following steps:
(1) Firstly, dissolving an anionic polymer in water to obtain an anionic polymer solution;
(2) Adding a cross-linking agent into the anionic polymer solution, then adding an amide condensing agent and an alkaline substance to react, and neutralizing to obtain a cross-linked intermediate;
(3) Dissolving an oil-soluble dispersing agent in an organic solvent to obtain an oil phase; mixing the crosslinking intermediate, polyhydroxy polymer and catalyst to obtain a water phase; adding the water phase into the oil phase to perform a crosslinking reaction to obtain the embolic microsphere;
The cross-linking agent is an amino acetal compound;
in the step (3), the polyhydroxy polymer is polyvinyl alcohol;
In the step (3), the catalyst is an acidic substance;
In the step (1), the anionic polymer is polyacrylic acid or polymethacrylic acid;
In the step (2), the amide condensing agent is at least one of N-succinimidyl, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, diisopropylcarbodiimide, dicyclohexylcarbodiimide, 4- (4, 6-dimethoxy triazine-2-yl) -4-methylmorpholine hydrochloride;
in the step (2), the cross-linking agent is aminoacetaldehyde diethyl acetal;
In the step (3), after the crosslinking reaction, washing and screening, soaking and preserving the embolic microspheres with a salt solution to obtain wet embolic microspheres, or after the crosslinking reaction, drying to obtain powdery dry embolic microspheres.
2. The method for preparing embolic microspheres according to claim 1, wherein in step (3), the oil-soluble dispersant is at least one of span 80, span 20, tween 20.
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Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105517580A (en) * | 2013-03-15 | 2016-04-20 | 马修·R·德勒埃 | Imageable embolic microsphere |
WO2017133419A1 (en) * | 2016-02-03 | 2017-08-10 | 三捷生物科技(北京)有限公司 | Drug-loaded microsphere and preparation method and use thereof |
DE102018222807A1 (en) * | 2017-12-22 | 2019-06-27 | Shandong Rientech Medical Technology Co., Ltd. | Degradable embolic microspheres with high drug loading capacity and process for their preparation |
CN110201215A (en) * | 2019-06-11 | 2019-09-06 | 科睿驰(深圳)医疗科技发展有限公司 | A kind of gradient crosslinked high resiliency embolism microball and its preparation process |
CN111569144A (en) * | 2020-05-22 | 2020-08-25 | 科睿驰(深圳)医疗科技发展有限公司 | Medicine-carrying embolism microsphere with developing function and preparation method thereof |
CN115779134A (en) * | 2022-11-17 | 2023-03-14 | 科睿驰(深圳)医疗科技发展有限公司 | Embolism microsphere and preparation method thereof |
WO2023035384A1 (en) * | 2021-09-10 | 2023-03-16 | 苏州浩微生物医疗科技有限公司 | Hydrogel embolization microsphere and preparation method therefor |
CN116270488A (en) * | 2023-03-22 | 2023-06-23 | 四川大川合颐生物科技有限公司 | Porous polyacrylic acid drug-loaded embolism microsphere and preparation method thereof |
WO2023124736A1 (en) * | 2021-12-30 | 2023-07-06 | 上海汇禾医疗科技有限公司 | X-ray developable molecule, x-ray developable embolic microsphere and preparation method therefor |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105816920B (en) * | 2016-03-29 | 2018-10-23 | 江南大学 | A kind of preparation method of modified sodium alginate embolism microball |
CN108114310B (en) * | 2017-12-22 | 2022-11-25 | 张海军 | Degradable drug-loaded microsphere and preparation method thereof |
CN114099442B (en) * | 2020-08-25 | 2024-01-30 | 复旦大学 | Multifunctional microsphere preparation for tumor chemoradiotherapy embolism treatment and image and preparation method thereof |
-
2023
- 2023-09-25 CN CN202311244201.1A patent/CN117323294B/en active Active
Patent Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105517580A (en) * | 2013-03-15 | 2016-04-20 | 马修·R·德勒埃 | Imageable embolic microsphere |
WO2017133419A1 (en) * | 2016-02-03 | 2017-08-10 | 三捷生物科技(北京)有限公司 | Drug-loaded microsphere and preparation method and use thereof |
DE102018222807A1 (en) * | 2017-12-22 | 2019-06-27 | Shandong Rientech Medical Technology Co., Ltd. | Degradable embolic microspheres with high drug loading capacity and process for their preparation |
CN110201215A (en) * | 2019-06-11 | 2019-09-06 | 科睿驰(深圳)医疗科技发展有限公司 | A kind of gradient crosslinked high resiliency embolism microball and its preparation process |
CN111569144A (en) * | 2020-05-22 | 2020-08-25 | 科睿驰(深圳)医疗科技发展有限公司 | Medicine-carrying embolism microsphere with developing function and preparation method thereof |
WO2023035384A1 (en) * | 2021-09-10 | 2023-03-16 | 苏州浩微生物医疗科技有限公司 | Hydrogel embolization microsphere and preparation method therefor |
WO2023124736A1 (en) * | 2021-12-30 | 2023-07-06 | 上海汇禾医疗科技有限公司 | X-ray developable molecule, x-ray developable embolic microsphere and preparation method therefor |
CN115779134A (en) * | 2022-11-17 | 2023-03-14 | 科睿驰(深圳)医疗科技发展有限公司 | Embolism microsphere and preparation method thereof |
CN116270488A (en) * | 2023-03-22 | 2023-06-23 | 四川大川合颐生物科技有限公司 | Porous polyacrylic acid drug-loaded embolism microsphere and preparation method thereof |
Non-Patent Citations (1)
Title |
---|
Advances in Degradable Embolic Microspheres: A State of the Art Review;Jensen Doucet等;《J Funct Biomater.》;20180126;第9卷(第1期);14 * |
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