CN117582535B - Liquid embolic agent and preparation method thereof - Google Patents
Liquid embolic agent and preparation method thereof Download PDFInfo
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- CN117582535B CN117582535B CN202410069746.1A CN202410069746A CN117582535B CN 117582535 B CN117582535 B CN 117582535B CN 202410069746 A CN202410069746 A CN 202410069746A CN 117582535 B CN117582535 B CN 117582535B
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- embolic agent
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- polyvinyl alcohol
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- 230000003073 embolic effect Effects 0.000 title claims abstract description 160
- 239000007788 liquid Substances 0.000 title claims abstract description 70
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 153
- 239000004372 Polyvinyl alcohol Substances 0.000 claims abstract description 74
- 229920002451 polyvinyl alcohol Polymers 0.000 claims abstract description 74
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims abstract description 40
- 239000011630 iodine Substances 0.000 claims abstract description 40
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 40
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- 239000003960 organic solvent Substances 0.000 claims abstract description 24
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 9
- 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 claims abstract description 7
- 238000001556 precipitation Methods 0.000 claims abstract description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- 238000010438 heat treatment Methods 0.000 claims description 24
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims description 22
- 238000004090 dissolution Methods 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 20
- 239000002244 precipitate Substances 0.000 claims description 18
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- 239000002253 acid Substances 0.000 claims description 15
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- 238000001035 drying Methods 0.000 claims description 12
- 239000000126 substance Substances 0.000 claims description 12
- 229960004679 doxorubicin Drugs 0.000 claims description 11
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- 238000001914 filtration Methods 0.000 claims description 10
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 10
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
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- 239000002246 antineoplastic agent Substances 0.000 claims description 8
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 7
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
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- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 claims description 4
- PTLCAOOLKNTSEU-UHFFFAOYSA-N COC(CC(C(C(CC(OC)OC)(C(N)=O)C(I)=C1N)I)(C1I)C(N)=O)OC Chemical compound COC(CC(C(C(CC(OC)OC)(C(N)=O)C(I)=C1N)I)(C1I)C(N)=O)OC PTLCAOOLKNTSEU-UHFFFAOYSA-N 0.000 claims description 4
- NKDKZBNRTDUKCR-UHFFFAOYSA-N COC(CNC(C(C=C(C=C1I)I)=C1I)=O)OC Chemical group COC(CNC(C(C=C(C=C1I)I)=C1I)=O)OC NKDKZBNRTDUKCR-UHFFFAOYSA-N 0.000 claims description 4
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 claims description 4
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 4
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 4
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- 229910002651 NO3 Inorganic materials 0.000 claims description 3
- 229910019142 PO4 Inorganic materials 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 3
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- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 6
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- 239000007787 solid Substances 0.000 description 4
- AQIRMRAKIFNYFZ-UHFFFAOYSA-N 2,4,6-triiodo-5-(prop-2-enoylamino)benzene-1,3-dicarboxylic acid Chemical compound OC(=O)C1=C(I)C(NC(=O)C=C)=C(I)C(C(O)=O)=C1I AQIRMRAKIFNYFZ-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
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- -1 phenoxyl alcohol Chemical compound 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
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- 230000035484 reaction time Effects 0.000 description 3
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 2
- 125000003158 alcohol group Chemical group 0.000 description 2
- 230000000973 chemotherapeutic effect Effects 0.000 description 2
- 239000000017 hydrogel Substances 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 125000006480 iodobenzyl group Chemical group 0.000 description 2
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 2
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- 230000007704 transition Effects 0.000 description 2
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- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- 208000005443 Circulating Neoplastic Cells Diseases 0.000 description 1
- 206010014513 Embolism arterial Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 206010045168 Tumour embolism Diseases 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
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- 125000005233 alkylalcohol group Chemical group 0.000 description 1
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
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- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- NTHXOOBQLCIOLC-UHFFFAOYSA-N iohexol Chemical compound OCC(O)CN(C(=O)C)C1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C1I NTHXOOBQLCIOLC-UHFFFAOYSA-N 0.000 description 1
- 229960001025 iohexol Drugs 0.000 description 1
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 1
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- YPJKMVATUPSWOH-UHFFFAOYSA-N nitrooxidanyl Chemical compound [O][N+]([O-])=O YPJKMVATUPSWOH-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses a liquid embolic agent and a preparation method thereof, and relates to the technical field of medical materials. The liquid embolic agent comprises a modified polyvinyl alcohol modified with iodine-containing molecules and negatively charged groups, and an organic solvent. Can be used as tumor therapy embolic agent and chemotherapy drug carrying embolic agent for TACE therapy. The liquid embolic agent provided by the invention has the effects of long-acting complete embolism, self development, a large amount of carried chemotherapy drugs, drug slow release, sufficient precipitation of solute and stable long-acting embolism, and has the advantages of simple use, short operation time, simple preparation method, safe raw materials and mild reaction conditions.
Description
Technical Field
The invention relates to the technical field of medical materials, in particular to a liquid embolic agent and a preparation method thereof.
Background
Interventional embolization has played an increasingly important role in clinical medicine in recent years, particularly in the treatment of tumors rich in blood vessels, such as liver cancer, and has become the first choice for the treatment of tumors that cannot be surgically resected. The existing tumor embolic agents are mainly iodized oil embolic agents and microsphere embolic agents. The iodized oil embolic agent is a more traditional tumor embolic agent, is in a liquid form, the accuracy in the conveying process is limited by the form, the thrombus is easy to generate, the iodized oil cannot be reserved in a target blood vessel for a long time, and can be gradually dissipated after a period of time, so that the long-term embolic effect cannot be achieved. The microsphere embolic agent is more novel than iodized oil, and can perform long-acting embolism on a target site, but can not completely plug a target site blood vessel due to shape limitation, and the embolic agent capable of adapting to the shape of the blood vessel is needed to realize complete embolism.
At present, the liquid embolic agent can be delivered in a liquid form and is precipitated as a solid after being delivered to a target site. However, most of the current liquid embolic agents have no covalently-linked X-ray developable groups, and are required to be mixed with additional contrast agents to achieve the development effect in the use process, and the existing liquid embolic agents are usually required to be mixed with tantalum powder or contrast agents, so that the mixing time is required to be longer than twenty minutes before the operation, and the operation time is prolonged. And none of the current liquid embolic agents can be loaded with drugs, which makes the existing liquid embolic agents unusable as tumor embolic agents. In addition, current liquid embolic agents are not capable of maximum effectiveness in embolizing, and can release large amounts of organic solvents, causing additional damage to the human blood vessels.
For example, chinese patent application CN 114984296A provides a thermally-induced hydrogel embolic agent with X-ray imaging capability. The invention uses amphiphilic polymers comprising hydrophilic block polyvinyl alcohol and hydrophobic block polyamino acid, mixed with contrast agent and water-based solvent to obtain thermally induced hydrogels for Transcatheter Arterial Embolism (TAE). The embolic agent is mixed with hydrophobic iodized oil at low temperature and, upon delivery into a target vessel, converts to a semi-solid gel upon stimulation by temperature. The embolic agent itself does not have visualization capabilities and still needs to be visualized with contrast agents, which increases the time and difficulty of pre-operative preparation. In addition, the thermal gel is converted from liquid to gel at a phase transition temperature, and the phase transition temperature of the embolic agent ranges from 4 ℃ to 37 ℃, so that the sol has high risk of being converted into gel in the catheter before reaching the blood vessel of the target site, blocking the catheter, and not completing the operation.
Chinese patent CN 101513542B provides a method for preparing a liquid embolic agent that can develop itself. Adding polyvinyl alcohol into pyrimidine, stirring, evaporating to remove the pyrimidine, dehumidifying the rest reactant in DMSO, adding an iodine-containing compound, dichloromethane and triethylamine after dissolving, precipitating and separating the obtained iodine-containing PVA in a mixture of butyl ether and acetone, washing and drying to obtain I-PVA. The iodine-containing PVA prepared by the method has a developing function, but the preparation method has the advantages of multiple steps, complex operation and high toxicity of the used solvent. The embolic agent prepared by the invention has no drug carrying function and can not be used as an embolic agent for chemoembolization by arterial catheter (TACE).
Chinese patent application CN 114773545A provides an embolic polymer solution and a method for preparing and using the same. The invention uses iodized phenol and halogenated alkyl alcohol to prepare iodized phenoxyl alcohol, the iodized phenoxyl alcohol reacts with cyclic ester and then reacts with acyl chloride to generate a first monomer, and the first monomer reacts with a micromolecular monomer to obtain the embolic polymer. The embolic agent is then delivered to physiological solution through a catheter and then precipitated, and the developing groups in the embolic agent are connected through covalent bonds, so that the embolic agent has a developing effect. However, the preparation method of the embolic agent is complex, the operation is difficult, and the embolic agent does not have drug carrying capacity and cannot be used for TACE embolism.
Chinese patent CN 102781974B provides an iodobenzyl ether-PVA as an injection embolic agent and a method for preparing the same. The invention uses polyvinyl alcohol to react with iodinated benzyl derivatives to obtain an embolic agent that precipitates to form an adhesive substance upon contact with body fluids, which itself can be developed under X-rays. The injection embolism composition provided by the invention comprises iodobenzyl ether-PVA and a solvent, wherein the solvent is selected from dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP) and tetraethylene glycol. The injection embolism composition is used for tumor embolism and the like. However, there is no interaction between the embolic composition and the drug, so the amount of drug loaded is very limited and the drug cannot be slowly released, and the ideal chemotherapeutic effect cannot be obtained when the embolic composition is used for TACE treatment.
Disclosure of Invention
The invention provides a liquid embolic agent and a preparation method thereof, aiming at solving at least one of the problems that the existing liquid embolic agent cannot be developed, the drug loading capacity is low, the slow release performance is poor, the solvent release capacity is large, and the toxicity is caused.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
A liquid embolic agent comprising a modified polyvinyl alcohol modified with iodine-containing molecules and negatively charged groups, and an organic solvent; the iodine-containing molecules and negatively charged groups are all substituted for hydroxyl groups on the polyvinyl alcohol main chain.
Preferably, in the liquid embolic agent, the mass concentration of the modified polyvinyl alcohol is 15-30%; further preferably, the mass concentration of the modified polyvinyl alcohol is 23%.
Preferably, the mass content of iodine in the modified polyvinyl alcohol is 40-50%, and the mass content of the negatively charged groups is 4% -7%.
Preferably, the organic solvent includes at least one of dimethyl sulfoxide and N-methyl pyrrolidone. Further preferably, the organic solvent is dimethyl sulfoxide.
Preferably, the negatively charged groups are derived from mineral acids. The negatively charged group is sulfonate, phosphate or nitrate. Further preferably, the negatively charged group is a sulfonate.
Preferably, the iodine-containing molecule is N- (2, 2-dimethoxyethyl) -2,3, 5-triiodobenzamide, 5-acrylamido-2, 4, 6-triiodobenzene-1, 3-dicarboxylic acid or 5-amino-1, 3-bis (2, 2-dimethoxyethyl) -2,4, 6-triiodoisophthalamide. Wherein, the N- (2, 2-dimethoxyethyl) -2,3, 5-triiodobenzamide can be prepared by a conventional method, such as a method in CN202111648826.5, and has a structure shown in the following formula (1):
formula (1);
The 5-acrylamido-2, 4, 6-triiodobenzene-1, 3-dicarboxylic acid can be prepared by conventional methods, such as the method in CN202111455520.8, and its structure is shown in formula (2) below:
Formula (2);
The 5-amino-1, 3-bis (2, 2-dimethoxyethyl) -2,4, 6-triiodoisophthalamide can be prepared by a conventional method, for example, by a method in CN202111648826.5, and has a structure represented by the following formula (3):
formula (3).
The invention also provides a preparation method of the liquid embolic agent, which comprises the following steps:
a. adding polyvinyl alcohol into water, heating and dissolving, adding acid serving as a source of negatively charged groups, heating and stirring for reacting for 1-3 hours, dripping reaction liquid into a precipitation solvent to obtain precipitate, filtering the precipitate, and drying in vacuum to obtain negatively charged group-modified PVA;
b. Heating and dissolving the PVA modified by the negatively charged group in an organic solvent A to obtain a solution I; dissolving the iodine-containing molecules in an organic solvent B to obtain a solution II; adding the solution I and the strong acid catalyst into the solution II, stirring for reaction, dripping the obtained reaction solution into pure water after the reaction is completed, separating out a solidified substance, filtering the solidified substance, and drying in vacuum to obtain the modified polyvinyl alcohol;
c. And adding the modified polyvinyl alcohol into the organic solvent for dissolution to obtain the liquid embolic agent.
Preferably, in step a, the weight average molecular weight of the polyvinyl alcohol is 55000-80000g/mol; further preferably, the weight average molecular weight of the polyvinyl alcohol is 60000-70000g/mol.
Preferably, in step a, the acid which is the source of the negatively charged groups is an inorganic acid, preferably concentrated sulfuric acid, phosphoric acid or nitric acid.
Preferably, in the step a, the temperature of the heating and dissolving is 70-90 ℃, and the temperature of the heating and stirring reaction is 30-40 ℃.
Preferably, in the step a, the precipitation solvent includes at least one of ethanol, n-hexane and dichloromethane.
Preferably, in step a, the mass ratio of polyvinyl alcohol, water and acid as source of negatively charged groups is 1: (3-5): (1.3-3). The mass of the acid as a source of negatively charged groups refers to the mass of the acid solution.
Preferably, in the step b, the temperature of the heating dissolution is 40-70 ℃, the temperature of the stirring reaction is 20-40 ℃, and the time of the stirring reaction is 0.5-2h.
Preferably, in step b, the organic solvent a is dimethyl sulfoxide.
Preferably, in the step B, the organic solvent B is dimethyl sulfoxide.
Preferably, in the step b, the strong acid catalyst comprises an organic strong acid or an inorganic strong acid, and specifically comprises at least one of concentrated hydrochloric acid, concentrated sulfuric acid and methane sulfonic acid.
Preferably, in the step B, the mass ratio of the PVA modified by the negatively charged group, the organic solvent a in the solution I, the iodine-containing molecule, the organic solvent B in the solution II, and the strong acid catalyst is 1: (3-5): (0.8-1): (18-22): (1.5-2.5). The mass of the strong acid catalyst refers to the mass of the strong acid solution.
Preferably, in step c, the organic solvent includes one of dimethyl sulfoxide and N-methyl pyrrolidone.
The invention also provides application of the liquid embolic agent in serving as an embolic agent for tumor treatment.
The invention also provides application of the liquid embolic agent in carrying the embolic agent as a chemotherapeutic drug for TACE treatment.
Preferably, the chemotherapeutic agent is a positively charged agent.
Preferably, the chemotherapeutic agent comprises at least one of doxorubicin, epirubicin, and ib Li Tikang.
The invention has the following beneficial effects:
the invention can provide a liquid embolic agent and a preparation method thereof, the liquid embolic agent is conveyed in a liquid form, and rapidly precipitates and solidifies to embolize the blood vessel of the target part after reaching the blood vessel of the target part, so that long-acting complete embolization can be realized;
the liquid embolic agent is connected with the developing molecule through a covalent bond, has an X-ray developing function, does not need to be mixed with a contrast agent, greatly reduces the operation time of the operation, and ensures that the operation is more convenient and quicker;
the liquid embolic agent can rapidly load a plurality of chemotherapeutic drugs in large quantity, is convenient and quick to load, does not need long-time operation, and greatly reduces operation time;
the liquid embolic agent slowly and stably releases the drug at the target site, has no burst release, and has long-acting chemotherapy effect;
Through the adjustment of molecular weight, concentration, iodine content, charged molecular content and the like, the liquid embolic agent can use less volume to embolize a designated cavity, thereby reducing the release of an organic solvent and reducing the adverse effect on blood vessels of a human body;
In addition, the embolic agent can also provide a similar elastic modulus to the vessel wall, ensuring longer-lasting and stable embolization.
The embolic agent is simple and convenient to use, greatly reduces the operation time before operation, has few preparation steps, is simple to operate, uses safe raw materials, and has mild reaction conditions.
Drawings
FIG. 1 is a diagram of a solidified material precipitated in injection water of the liquid embolic agent prepared in example 1;
FIG. 2 is a schematic diagram of a pipeline embolism by using the liquid embolic agent prepared in example 1;
FIG. 3 is a diagram of an aneurysm embolism model prepared using the liquid embolic agent obtained in example 1;
Fig. 4 is a view showing the development of the model of an aneurysm embolism in example 1 under X-rays.
Detailed Description
The following describes in further detail the embodiments of the present invention with reference to the drawings and examples. The following examples are illustrative of the invention and are not intended to limit the scope of the invention.
In the following examples, the concentration of concentrated sulfuric acid used was 98%, the concentration of concentrated hydrochloric acid was 37%, the concentration of nitric acid was 69%, and the concentration of phosphoric acid was 85%, all by mass, unless otherwise specified.
Example 1
A method for preparing a liquid embolic agent, comprising the steps of:
a. Adding 3g of polyvinyl alcohol (weight average molecular weight of 80000 g/mol) into 9g of water, heating to 70 ℃ for dissolution, adding 3mL of concentrated sulfuric acid (density of 1.83g/mL, mass of 5.49 g), heating to 40 ℃ for stirring reaction, dripping the reaction liquid into ethanol after reaction for 1h to obtain a precipitate, filtering the precipitate and drying in vacuum for 24h to obtain sulfonate group modified polyvinyl alcohol (ePVA);
b. adding 3g of polyvinyl alcohol modified by sulfonate groups into 15g of dimethyl sulfoxide, heating to 70 ℃ for dissolution to obtain a solution I; 3g of N- (2, 2-dimethoxyethyl) -2,3, 5-triiodobenzamide was dissolved in 60mL of dimethyl sulfoxide to obtain solution II; adding the solution I and 6.3mL of concentrated hydrochloric acid into the solution II, heating to 20 ℃, stirring and reacting for 2 hours, then dripping the obtained reaction solution into pure water, separating out a solidified substance, filtering the solidified substance, and drying in vacuum for 24 hours to obtain modified polyvinyl alcohol, namely iodine-containing ePVA;
c. 3g of modified polyvinyl alcohol was dissolved in 10g of dimethyl sulfoxide to obtain a 23% strength liquid embolic agent.
Iodine content test and negatively charged group content test are carried out on the modified polyvinyl alcohol in the liquid embolic agent. The test results showed that the iodine content was 40% and the sulfonate content was 7%.
The solid precipitated from the injection of the liquid embolic agent is shown in figure 1.
The prepared liquid embolic agent is subjected to pipeline embolism simulation, and the simulation result is shown in figure 2, so that a complete embolism effect can be achieved.
And preparing an aneurysm embolism model by using the prepared liquid embolic agent, wherein the embolism result is shown in figure 3. The aneurysm embolism model is developed under X-ray, and the development result is shown in fig. 4, so that the aneurysm embolism model has a good development effect and does not need the addition of a developer.
Example 2
A method for preparing a liquid embolic agent, comprising the steps of:
a. Adding 3g of polyvinyl alcohol (with the weight-average molecular weight of 55000 g/mol) into 10g of water, heating to 80 ℃ for dissolution, adding 6mL of nitric acid (with the density of 1.41g/mL and the mass of 8.46 g), heating to 30 ℃ for stirring reaction, dripping the reaction liquid into n-hexane after 3 hours of reaction to obtain a precipitate, filtering the precipitate and drying the precipitate in vacuum for 24 hours to obtain nitrate radical modified polyvinyl alcohol (ePVA);
b. Adding 3g of polyvinyl alcohol modified by nitrate groups into 10g of dimethyl sulfoxide, heating to 40 ℃ for dissolution to obtain a solution I; 2.74g of 5-amino-1, 3-bis (2, 2-dimethoxyethyl) -2,4, 6-triiodo-isophthalamide was dissolved in 55mL of dimethyl sulfoxide to obtain solution II; adding solution I and 4.24mL of methanesulfonic acid (99 wt%) into solution II, heating to 30 ℃ and stirring for reaction for 1.5h, then dripping the obtained reaction solution into pure water to precipitate a solidified substance, filtering the solidified substance and drying in vacuum for 24h to obtain modified polyvinyl alcohol, namely iodine-containing ePVA;
c. 2g of modified polyvinyl alcohol was dissolved in 10g of N-methylpyrrolidone to give a liquid embolic agent having a concentration of 16.7%.
Iodine content test and negatively charged group content test are carried out on the modified polyvinyl alcohol in the liquid embolic agent. The test results showed an iodine content of 43% and a nitrate content of 7%.
Example 3
A method for preparing a liquid embolic agent, comprising the steps of:
a. Adding 3g of polyvinyl alcohol (weight average molecular weight 68000 g/mol) into 15g of water, heating to 90 ℃ for dissolution, adding 2.4mL of phosphoric acid (density 1.685g/mL, mass 4.04 g), heating to 35 ℃ for stirring reaction, dropwise adding the reaction solution into dichloromethane after 2h of reaction, obtaining a precipitate, filtering the precipitate and drying in vacuum for 24h to obtain polyvinyl alcohol modified by phosphate groups (ePVA);
b. Adding 3g of polyvinyl alcohol modified by phosphate groups into 9g of dimethyl sulfoxide, heating to 55 ℃ for dissolution to obtain a solution I; 2.4g of 5-acrylamido-2, 4, 6-triiodobenzene-1, 3-dicarboxylic acid was dissolved in 49mL of dimethyl sulfoxide to give solution II; adding the solution I and 2.5mL of concentrated sulfuric acid into the solution II, heating to 40 ℃, stirring and reacting for 0.5h, then dripping the obtained reaction solution into pure water, separating out a solidified substance, filtering the solidified substance and drying in vacuum for 24h to obtain modified polyvinyl alcohol, namely iodine-containing ePVA;
c. 4g of modified polyvinyl alcohol was dissolved in 10g of N-methylpyrrolidone to give a liquid embolic agent having a concentration of 28.6%.
Iodine content test and negatively charged group content test are carried out on the modified polyvinyl alcohol in the liquid embolic agent. The test result showed that the iodine content was 49% and the phosphate content was 4%.
Comparative example 1
As compared with example 1, a polyvinyl alcohol having a weight average molecular weight of 30000g/mol was used, and the other conditions were not changed. In the obtained product, the iodine content of the modified polyvinyl alcohol is 38%, and the sulfonate content is 4%.
Comparative example 2
In comparison with example 1, polyvinyl alcohol having a weight average molecular weight of 130000g/mol was used, and the other conditions were not changed. In the obtained product, the content of modified polyvinyl alcohol iodine is 32%, and the content of sulfonate is 2%.
Comparative example 3
In comparison with example 1, the reaction time in step a was 5 hours, and the other conditions were unchanged. In the obtained product, the content of modified polyvinyl alcohol iodine is 2 percent, and the content of sulfonate is 18 percent.
Comparative example 4
In step c, as compared with example 1, ePVA g of iodine-containing solution was dissolved in 10g of dimethyl sulfoxide to obtain a liquid embolic agent. In the liquid embolic agent, the iodine content in the modified polyvinyl alcohol is 40 percent, and the sulfonate content is 7 percent.
Comparative example 5
Compared with example 1, the reaction of the step a is not carried out, other conditions are not changed, and the obtained product has the modified polyvinyl alcohol iodine content of 59% and does not contain sulfonate.
The weight average molecular weight of the polyvinyl alcohol affects the water solubility and viscosity of the solution, thereby affecting the curing time and delivery properties of the embolic agent. The larger the weight average molecular weight of the polyvinyl alcohol, the lower the water solubility, the greater the solution viscosity and the faster the curing time of the embolic agent. Too high a viscosity and too fast a curing time may result in poor delivery properties and failure to deliver the embolic agent to the targeted site vessel. Too small viscosity and too slow curing time can cause ectopic embolism or incapacity of embolism of the embolic agent, and the safety is affected.
Both sulfonate and developing groups react with hydroxyl groups on the polyvinyl alcohol backbone, the reaction time in step a determining the number of negatively charged groups attached to the polyvinyl alcohol backbone, which further affects the number of attached developing groups in step b. Step a has excessively long reaction time, too many negatively charged groups are connected on the polyvinyl alcohol main chain, and too few developing molecules are connected in step b, so that the embolic agent has excessively high water solubility and cannot be precipitated in a blood environment.
The concentration of the embolic agent affects the curing time and viscosity of the embolic agent, the greater the concentration, the shorter the curing time and the greater the viscosity. But above a certain concentration iodine ePVA will not dissolve.
The X-ray developability of the embolic agent is provided by iodine-containing molecules, the higher the iodine-containing molecule content of the embolic agent, the greater the developability under X-rays.
The charged molecules covalently connected on the main chain of the embolic agent polyvinyl alcohol and the charged chemotherapeutic drugs generate electrostatic force, so that more drugs can be adsorbed. Theoretically, the higher the charge level of the embolic agent, the more drug can be loaded.
The precipitation performance of the embolic agent is affected by the combined action of a plurality of factors such as the weight average molecular weight of the polyvinyl alcohol, the content of negatively charged groups and iodine-containing molecules, the concentration of the embolic agent and the like. Under the synergistic effect of all factors, the embolic agent can ensure that solutes in the embolic agent can be completely separated out to form embolic agent precipitates, thereby reducing the total volume of the embolic agent used, reducing the release of organic solvents and improving the safety of products.
Test example 1
Curing time and catheter transport performance test:
and (3) dripping the prepared embolic agent sample into purified water to form granular precipitate, and dripping the granular precipitate at a constant speed for 10s. And (3) counting after the dripping is finished, and respectively fishing out part of particles at 30s,60s,90s,120s and 150s, so that the size and shape of the particles fished out at each time point are uniform, no adhesion or deformity exists, and the particles are arranged on two layers of cleaning cloth and are used for drying the surface water. Respectively taking precipitated particles at different time points, turning two layers of clean cloth on the particles, pressing for 10s by using a 1.5N weight, observing whether viscous liquid seeps out or is adhered to the clean cloth, and if the viscous liquid seeps out and is not adhered to the clean cloth, recording the time point as curing time.
The embolic agent was aspirated with a 2.5mL syringe, the air was removed, and the device was connected to a saline-flushed catheter having an inner diameter of 0.021 inches, and the other end of the catheter was placed in saline. The pushing syringe slowly and uniformly injects the embolic agent, and the injection speed is 1mL/min. It is observed whether the catheter is blocked.
TABLE 1 curing time of embolic agent obtained in examples and comparative examples
As can be seen from the data in Table 1, the use of a polyvinyl alcohol having a smaller weight average molecular weight results in an increase in the curing time of the embolic agent, and the use of a polyvinyl alcohol having a larger weight average molecular weight results in a decrease in the curing time of the embolic agent, which may be inconvenient to transport during operation.
The polyvinyl alcohol in comparative example 3 has mainly sulfonate groups attached thereto, and iodine-containing molecules are substantially absent, so that the obtained embolic agent has excellent hydrophilicity, does not precipitate in aqueous solution, and cannot be used as a liquid embolic agent. In contrast, comparative example 5 did not undergo the step a reaction, and all of the polyvinyl alcohol was iodine-containing molecules, which resulted in an embolic agent curing time that was too fast, and the catheter was easily blocked during delivery.
Test example 2
Embolic agent viscosity test: 5mL of embolic agent was added to a Ubbelometer and tested at 37℃according to ASTM D445, measuring the time from the first timing mark to the second timing mark to the nearest 0.1 seconds. Two flow time measurements were made and averaged. The viscosity of the embolic agent is calculated.
TABLE 2 viscosity of embolic agents obtained in examples and comparative examples
From the data in Table 2, it can be seen that the greater the weight average molecular weight of the polyvinyl alcohol, the greater the dynamic viscosity of the embolic agent, and the smaller the molecular weight of the polyvinyl alcohol, the lower the dynamic viscosity of the embolic agent. Meanwhile, the concentration of the embolic agent has a larger influence on the dynamic viscosity, and the larger the embolic agent concentration is, the larger the viscosity is.
The embolic agent with the viscosity of 80-150 mPa.s can achieve the best embolic effect when the tumor blood vessel is embolized.
Test example 3
Maximum drug loading test: 80mg of doxorubicin powder was dissolved in 1ml of 30% embolic agent solution, and the doxorubicin-dissolved embolic agent was added dropwise to Phosphate Buffered Saline (PBS). 5.76g sodium dodecyl sulfate, 2000mL purified water, 2.72mL orthophosphoric acid, 2000mL acetonitrile and 240mL methanol were mixed well as a leaching solution. Adding the solidified embolic agent into the leaching solution for leaching for 24 hours to obtain the test solution. And (3) taking another part of leaching solution, dissolving 80mg of doxorubicin as a standard solution, and respectively testing the test solution and the standard solution by using a high performance liquid chromatograph to obtain the quantity of the embolic agent precipitated doxorubicin, namely the maximum drug loading quantity.
The experiment was repeated with 80mg doxorubicin powder replaced by 80mg epirubicin powder or 200mg ib Li Tikang powder, respectively.
TABLE 3 maximum doxorubicin drug loading of embolic agents obtained in examples and comparative examples
Table 4 maximum epirubicin loading of embolic agents obtained for examples and comparative examples
Table 5 maximum irinotecan loading of embolic agents obtained in examples and comparative examples
Comparative example 3 failed to precipitate in PBS and failed to perform drug loading tests.
From the data in Table 3, it can be seen that comparative example 5 does not have an interaction force with doxorubicin and cannot carry more drug because it does not contain a negatively charged group.
Test example 4
Embolic drug release test: taking 1mL of the embolism agent loaded with doxorubicin, adding 1000mLPBS into a dissolution instrument cup, installing a dissolution instrument rotating basket on a dissolution rod, immersing the dissolution instrument rotating basket into PBS, dripping the embolism agent into the rotating basket to precipitate the embolism agent, setting the rotating speed of the dissolution instrument to be 100rpm, starting the instrument and starting timing. At the prescribed time point, about 2mL of release medium was pipetted into a clean 10mL penicillin bottle and after the test was completed poured back into the dissolution cup in which the sample was located. The dissolution apparatus was stopped at the time point of medium replacement by rotating and taking out the dissolution cup, discarding the old medium in the cup, rinsing the dissolution cup with purified water and reinstalling the dissolution cup, then taking 1000mL of PBS to the dissolution cup with a measuring cylinder as a new release medium, and restarting the dissolution apparatus. The concentration of doxorubicin in the dissolved sample was measured at 480nm using an ultraviolet spectrophotometer, and the sampling time point and results were clearly recorded. The test results are shown in Table 6.
TABLE 6 drug Release of embolic Agents from examples and comparative examples
Comparative example 3 failed to precipitate in PBS and failed to perform the release test.
From the data in Table 6, it can be seen that comparative example 5, which does not contain negatively charged groups, does not have interaction force with doxorubicin, cannot be sustained release, and does not achieve good chemotherapeutic effect when used in vivo, as release is substantially completed in one day. Examples 1-3 had no burst effect at the early stage and eventually released more than 90% of the drug loading, which is superior to the release effect of the comparative example.
Test example 5
Simulated embolism performance test: the embolic agent of the present invention was used with commercially available embolic microspheres (CALLISPHERE) to embolize a vascular model connected to a water pump at a water flow rate of 150mL/s, and the volume of water flowing through the occluded vessel was measured within 1 minute after embolization.
TABLE 7 post-embolic Water flow volume of embolic Agents from examples and comparative examples
From the data in Table 7, it can be seen that the embolic effect of the liquid embolic agent used in the present invention on the vascular model is significantly better than that of embolic microspheres.
Test example 6
Mechanical property test: and (3) dripping the embolic agent into purified water, placing the obtained precipitated solid under a texture analyzer probe, setting a compression mode, compressing and deforming by 50%, keeping for 10 seconds, and recording the elastic modulus of a sample.
TABLE 8 elastic modulus of embolic Agents obtained in examples and comparative examples
Comparative example 3 was unable to precipitate and was unable to perform the elastic modulus test.
The elastic modulus of the arterial vessel was about 0.26MPa, and as can be seen from the data in table 8, the elastic modulus of the example of the present invention was substantially the same as that of the vessel at the embolization site, which ensured the optimal embolization effect.
Test example 7
X-ray development performance test: and taking the embolic agent for CT test, and recording CT value.
TABLE 9 CT values of embolic Agents obtained in examples and comparative examples
As can be seen from the data in Table 9, the example embolic agent developed substantially in agreement with the contrast agent (iohexol), and comparative example 3 was substantially incapable of developing under X-rays due to the substantial absence of iodine-containing molecules.
Test example 8
Plug usage test: an aneurysm model of 1cm in diameter was embolized with embolic agent, and the volume of embolic agent used to effect embolization was recorded.
Table 10 amounts of embolization achieved for aneurysms for different examples and comparative examples
As is clear from the data in Table 10, when an aneurysm having a diameter of 1cm and a volume of 0.785cm 3 was occluded, 2.6mL of the embolic agent was used in example 1 (30%), 3.9mL of the embolic agent was used in example 2 (20%), and 1.8mL of the embolic agent was used in example 3 (20%), and all of the modified polyvinyl alcohol in the examples was converted into a precipitate by calculation. In comparative examples 1 and 2 (30%), however, the polyvinyl alcohol could not be completely precipitated, and more than 4mL of embolic agent was used to complete the embolization of the aneurysm. Comparative example 3 failed to precipitate and failed to conduct the test. Comparative example 4 (10%) the concentration of polyvinyl alcohol was too low and a large amount of embolic agent was used to embolize the aneurysm. In comparative example 5 (30%), a certain loss is generated during the delivery process due to the too high iodine content, so that 4mL of embolic agent is needed to realize the embolization of the aneurysm.
Claims (11)
1. A liquid embolic agent characterized by: comprises modified polyvinyl alcohol modified by iodine-containing molecules and negatively charged groups, and an organic solvent; the iodine-containing molecules and negatively charged groups are all obtained by substituting hydroxyl groups on a polyvinyl alcohol main chain; the weight average molecular weight of the polyvinyl alcohol is 55000-80000g/mol; the mass percentage of iodine in the modified polyvinyl alcohol is 40-50%, the negatively charged groups are derived from inorganic acid, and the mass percentage of the negatively charged groups is 4% -7%; in the liquid embolic agent, the mass concentration of the modified polyvinyl alcohol is 15-30%.
2. The liquid embolic agent of claim 1, wherein: the organic solvent comprises at least one of dimethyl sulfoxide and N-methyl pyrrolidone.
3. The liquid embolic agent of claim 1, wherein: the negatively charged group is sulfonate, phosphate or nitrate.
4. The liquid embolic agent of claim 1, wherein: the iodine-containing molecule is N- (2, 2-dimethoxyethyl) -2,3, 5-triiodobenzamide, 5-acrylamide-2, 4, 6-triiodobenzene-1, 3-dicarboxylic acid or 5-amino-1, 3-bis (2, 2-dimethoxyethyl) -2,4, 6-triiodoisophthalamide.
5. A method of preparing a liquid embolic agent according to any of claims 1-4, wherein: the method comprises the following steps:
a. adding polyvinyl alcohol into water, heating and dissolving, adding acid serving as a source of negatively charged groups, heating and stirring for reacting for 1-3 hours, dripping reaction liquid into a precipitation solvent to obtain precipitate, filtering the precipitate, and drying in vacuum to obtain negatively charged group-modified PVA;
b. Heating and dissolving the PVA modified by the negatively charged group in an organic solvent A to obtain a solution I; dissolving iodine-containing molecules in an organic solvent B to obtain a solution II; adding the solution I and the strong acid catalyst into the solution II, and stirring for reaction; after the reaction is completed, dripping the obtained reaction solution into pure water to separate out a solidified substance, filtering the solidified substance, and drying the solidified substance in vacuum to obtain the modified polyvinyl alcohol;
c. And adding the modified polyvinyl alcohol into the organic solvent for dissolution to obtain the liquid embolic agent.
6. The method for preparing the liquid embolic agent according to claim 5, wherein: in the step a, the temperature of heating and dissolving is 70-90 ℃, and the temperature of heating and stirring reaction is 30-40 ℃;
and/or in step a, the precipitation solvent comprises at least one of ethanol, n-hexane and dichloromethane;
and/or in step a, the mass ratio of polyvinyl alcohol, water and acid as source of negatively charged groups is 1: (3-5): (1.3-3);
And/or in the step b, the temperature of heating and dissolving is 40-70 ℃, the temperature of stirring reaction is 20-40 ℃, and the time of stirring reaction is 0.5-2h;
and/or in the step b, the organic solvent A is dimethyl sulfoxide;
And/or in the step B, the organic solvent B is dimethyl sulfoxide;
and/or in step b, the strong acid catalyst comprises an organic strong acid or an inorganic strong acid;
And/or in step B, the mass ratio of the PVA modified with the negatively charged group, the organic solvent a, the iodine-containing molecule, the organic solvent B, and the strong acid catalyst is 1: (3-5): (0.8-1): (18-22): (1.5-2.5).
7. The method for preparing the liquid embolic agent according to claim 5, wherein: the acid as a source of negatively charged groups is concentrated sulfuric acid, phosphoric acid or nitric acid.
8. The method for preparing the liquid embolic agent according to claim 5, wherein: the strong acid catalyst is concentrated hydrochloric acid, concentrated sulfuric acid or methane sulfonic acid.
9. Use of a liquid embolic agent according to any one of claims 1-4 or a liquid embolic agent prepared by the method of preparation of a liquid embolic agent according to any one of claims 5-8 as a tumor treating embolic agent.
10. Use of a liquid embolic agent according to any one of claims 1-4 or a liquid embolic agent prepared by the method of preparation of a liquid embolic agent according to any one of claims 5-8 as a chemotherapeutic agent for TACE treatment carrying embolic agent.
11. Use of a liquid embolic agent according to claim 10 for carrying embolic agent as a chemotherapeutic agent for TACE treatment, wherein: the chemotherapeutic agent includes at least one of doxorubicin, epirubicin, and ib Li Tikang.
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