CN113425886A - Vascular embolization agent and preparation method and application thereof - Google Patents
Vascular embolization agent and preparation method and application thereof Download PDFInfo
- Publication number
- CN113425886A CN113425886A CN202110734323.3A CN202110734323A CN113425886A CN 113425886 A CN113425886 A CN 113425886A CN 202110734323 A CN202110734323 A CN 202110734323A CN 113425886 A CN113425886 A CN 113425886A
- Authority
- CN
- China
- Prior art keywords
- drug
- bleomycin
- loaded microspheres
- vascular
- embolization agent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 230000010102 embolization Effects 0.000 title claims abstract description 47
- 230000002792 vascular Effects 0.000 title claims abstract description 44
- 238000002360 preparation method Methods 0.000 title abstract description 12
- 239000003814 drug Substances 0.000 claims abstract description 89
- 229940079593 drug Drugs 0.000 claims abstract description 86
- 239000004005 microsphere Substances 0.000 claims abstract description 83
- 108010006654 Bleomycin Proteins 0.000 claims abstract description 73
- 229960001561 bleomycin Drugs 0.000 claims abstract description 73
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 claims abstract description 73
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 47
- 238000011282 treatment Methods 0.000 claims abstract description 19
- 208000009443 Vascular Malformations Diseases 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 13
- 238000001179 sorption measurement Methods 0.000 claims abstract description 6
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 12
- 239000008103 glucose Substances 0.000 claims description 12
- 238000002156 mixing Methods 0.000 claims description 10
- 125000000129 anionic group Chemical group 0.000 claims description 7
- 125000000542 sulfonic acid group Chemical group 0.000 claims description 7
- 239000002245 particle Substances 0.000 claims description 5
- 125000002843 carboxylic acid group Chemical group 0.000 claims description 4
- 230000000295 complement effect Effects 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 230000003073 embolic effect Effects 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 14
- 208000005189 Embolism Diseases 0.000 abstract description 9
- 206010053648 Vascular occlusion Diseases 0.000 abstract description 5
- 208000021331 vascular occlusion disease Diseases 0.000 abstract description 5
- 230000009885 systemic effect Effects 0.000 abstract description 4
- 210000002381 plasma Anatomy 0.000 abstract description 3
- 231100000331 toxic Toxicity 0.000 abstract description 3
- 230000002588 toxic effect Effects 0.000 abstract description 3
- 230000009471 action Effects 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 36
- 241000283973 Oryctolagus cuniculus Species 0.000 description 16
- 210000004204 blood vessel Anatomy 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 210000001519 tissue Anatomy 0.000 description 9
- 229940040609 bleomycin injection Drugs 0.000 description 8
- 240000007711 Peperomia pellucida Species 0.000 description 7
- 210000001367 artery Anatomy 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 7
- 230000034994 death Effects 0.000 description 7
- 229940090044 injection Drugs 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 6
- 210000005069 ears Anatomy 0.000 description 6
- 239000004372 Polyvinyl alcohol Substances 0.000 description 5
- 208000007536 Thrombosis Diseases 0.000 description 5
- 208000025865 Ulcer Diseases 0.000 description 5
- 230000017531 blood circulation Effects 0.000 description 5
- 229920002451 polyvinyl alcohol Polymers 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 230000004083 survival effect Effects 0.000 description 5
- 208000034189 Sclerosis Diseases 0.000 description 4
- 150000001450 anions Chemical group 0.000 description 4
- 239000006228 supernatant Substances 0.000 description 4
- 208000014729 capillary malformation Diseases 0.000 description 3
- 238000012377 drug delivery Methods 0.000 description 3
- 230000003902 lesion Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 230000036269 ulceration Effects 0.000 description 3
- 206010028851 Necrosis Diseases 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 239000004952 Polyamide Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 201000011066 hemangioma Diseases 0.000 description 2
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 2
- 208000032300 lymphatic malformation Diseases 0.000 description 2
- 210000004088 microvessel Anatomy 0.000 description 2
- 230000017074 necrotic cell death Effects 0.000 description 2
- 229920000747 poly(lactic acid) Polymers 0.000 description 2
- 229920002647 polyamide Polymers 0.000 description 2
- 239000004626 polylactic acid Substances 0.000 description 2
- 231100000397 ulcer Toxicity 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 201000009371 venous hemangioma Diseases 0.000 description 2
- 206010002199 Anaphylactic shock Diseases 0.000 description 1
- 206010060964 Arterial haemorrhage Diseases 0.000 description 1
- 208000022211 Arteriovenous Malformations Diseases 0.000 description 1
- 206010008088 Cerebral artery embolism Diseases 0.000 description 1
- 208000032170 Congenital Abnormalities Diseases 0.000 description 1
- 208000027205 Congenital disease Diseases 0.000 description 1
- 206010061619 Deformity Diseases 0.000 description 1
- 208000010975 Dystrophic epidermolysis bullosa Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 208000032912 Local swelling Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010048654 Muscle fibrosis Diseases 0.000 description 1
- 208000028389 Nerve injury 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
- 208000005392 Spasm Diseases 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 210000002565 arteriole Anatomy 0.000 description 1
- 230000005744 arteriovenous malformation Effects 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000002612 cardiopulmonary effect Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010612 desalination reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000013020 embryo development Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 208000004298 epidermolysis bullosa dystrophica Diseases 0.000 description 1
- 239000010419 fine particle Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- 230000023597 hemostasis Effects 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 238000002991 immunohistochemical analysis Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 201000010849 intracranial embolism Diseases 0.000 description 1
- 230000002601 intratumoral effect Effects 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000013532 laser treatment Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 230000004089 microcirculation Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000008764 nerve damage Effects 0.000 description 1
- 238000011587 new zealand white rabbit Methods 0.000 description 1
- 210000001636 ophthalmic artery Anatomy 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 238000002428 photodynamic therapy Methods 0.000 description 1
- 210000001147 pulmonary artery Anatomy 0.000 description 1
- 208000005069 pulmonary fibrosis Diseases 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 231100000241 scar Toxicity 0.000 description 1
- 238000007632 sclerotherapy Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical group OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
- A61L24/0015—Medicaments; Biocides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/14—Peptides containing saccharide radicals; Derivatives thereof, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
-
- 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
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
- A61L2300/252—Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
-
- 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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
-
- 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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
- A61L2300/602—Type of release, e.g. controlled, sustained, slow
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/06—Flowable or injectable implant compositions
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Surgery (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Materials Engineering (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of medicines, and particularly relates to a vascular embolization agent, and a preparation method and application thereof. A vascular embolization agent at least comprises drug-loaded microspheres and bleomycin, wherein the drug-loaded microspheres load the bleomycin. The method has the advantages that the bleomycin is wrapped inside the drug-loaded microspheres through electrostatic adsorption to obtain the vascular embolization agent, and the vascular embolization agent has obvious slow release effect, can prolong the action time of the bleomycin, reduces the drug concentration in blood plasma, and reduces systemic toxic and side effects; and can realize the positioning embolism to cause the vascular occlusion, has good biocompatibility and degradability, and provides a new choice for the treatment of arteriovenous vascular malformation.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a vascular embolization agent, and a preparation method and application thereof.
Background
Vascular malformation (Vascular malformation) is a congenital disease caused by abnormal embryo development, including venous malformation, lymphatic malformation, capillary malformation and arteriovenous malformation, the incidence rate is about 1/100-200, and the Vascular malformation is the most dangerous and intractable type in the fields of hemangioma and Vascular malformation. Vascular malformations can progress, and focal enlargement can lead to disfigurement and functional, often complicated by ulceration. Once ulceration occurs, it is persistent and is followed by increasingly severe arterial bleeding. The local tissue is finally subjected to tissue ischemia due to the phenomenon of blood stealing, or necrosis of organs and limbs, and even death due to hemorrhage, infection, heart failure and the like.
On one hand, for capillary malformation, the wine stains are taken as the main treatment mode, the treatment mode comprises pulse dye laser treatment and domestic common photodynamic treatment through local illumination after photosensitive medicine injection, however, no matter which treatment mode is adopted, the limitation of the curative effect exists, most patients can only achieve the effects of improvement and desalination after receiving multiple treatments, and the complete treatment is difficult. In addition, for the patients with capillary malformation with large area, not only the treatment cost is hard to be loaded, but also the great pain such as burning and local swelling caused by the treatment, and the possible sequelae such as scar and burn, etc. are required to be born.
On the other hand, for venous malformation and lymphatic malformation, the international mainstream treatment mode is the treatment of intravascular sclerosis, localized lesions can not only improve functions but also realize more ideal appearance recovery through multiple treatments, but also can not avoid possible complications, such as tissue necrosis, nerve injury, muscle fibrosis, anaphylactic shock, pulmonary artery spasm and embolism, cardiopulmonary crisis, cerebral embolism and the like. For some huge lesions which involve the abdominal cavity and the pelvic cavity, endovascular sclerosis treatment is difficult to reach. For extremely large lesions, although the sclerosis treatment is feasible in theory, the sclerosis treatment is almost impossible to implement in actual operation; even if a locally effective sclerotherapy is achieved, secondary deformities and lengthy treatment periods can cause significant psychological and physiological trauma to the patient.
Bleomycin is originally a chemotherapeutic drug for malignant tumors and has low cytotoxicity. In recent years, a large number of documents report that bleomycin is used for treating oral and maxillofacial hemangioma and vascular malformation through intratumoral injection to obtain satisfactory curative effect, the main defects are short half-life period, and systemic toxic and side effects can be caused by using the bleomycin in a large dose in a short period, wherein pulmonary fibrosis is one of the most serious side effects. Currently, bleomycin is usually treated by bleomycin injection, but the retention time of bleomycin in a diseased blood vessel is short, so that the effective drug concentration is difficult to achieve and maintain.
Vascular malformation is a disease which is not solved at present, and interventional therapy gradually replaces traditional surgery to become a main treatment means at present.
Drug-loaded microspheres (DEBs) are of great interest in the field of interventional therapy due to their embolization effect on blood vessels and targeting of released drugs. A large number of researches prove that the drug-loaded microspheres can prolong the activity of the drug, improve the stability and carry out more accurate drug delivery, so that the release of the drug achieves more ideal effect to improve the curative effect. In tumor treatment, embolization chemotherapy of drug-loaded microspheres has been applied to treat tumors in the liver, kidney, gastrointestinal tract, breast, etc. The drug-loaded microspheres are not reported to be used for treating vascular malformation at present.
Disclosure of Invention
In view of the above problems in the prior art, it is an object of the present invention to provide a vascular embolization agent, and a preparation method and use thereof, for solving the problems in the prior art.
To achieve the above objects and other related objects, the present invention is achieved by the following technical solutions.
The invention aims to provide a vascular embolization agent, which at least comprises drug-loaded microspheres and bleomycin, wherein the drug-loaded microspheres load the bleomycin.
Preferably, the vascular embolization agent comprises:
2 mg/mL-8 mg/mL of bleomycin;
the drug-loaded microspheres complement the volume to 100%;
based on the total amount of the vascular embolization agent.
Preferably, the drug-loaded microspheres are drug-loaded microspheres containing anionic groups and used for loading bleomycin through electrostatic adsorption; the particle size of the drug-loaded microspheres is 50-500 μm.
More preferably, the particle size of the drug-loaded microsphere is 150-300 μm.
More preferably, the anionic groups are selected from one or both of sulphonic acid groups or carboxylic acid groups.
Further preferably, the anionic group is a sulfonic acid group.
The drug-loaded microsphere is a non-biodegradable microsphere with good biocompatibility and hydrophilicity. The drug-carrying microsphere skeleton can be the skeleton of the conventional drug-carrying microsphere in the prior art, for example, the skeleton takes polyvinyl alcohol, polyamide and polylactic acid as the main chain skeleton. The anion groups on the surface of the drug-loaded microsphere are mainly used for electrostatic adsorption of the bleomycin, so that the drug-loaded microsphere can be applied as long as the anion groups of the bleomycin drug property are not changed, such as sulfonic acid groups, carboxylic acid groups and the like. The existing drug-loaded microspheres with anionic groups loaded on the surfaces are all suitable for the invention, such as DC/LC-Beads drug-loaded microspheres, HepaSphere drug-loaded microspheres and CallSphere drug-loaded microspheres.
Still further preferably, the drug-loaded microspheres are polyvinyl alcohol drug-loaded microspheres containing sulfonic acid groups.
The polyvinyl alcohol microspheres containing sulfonic acid groups belong to the prior art and can be obtained by the preparation method in patents CN106729953B or/and CN 101810587B.
The second object of the present invention is to provide a method for preparing the vascular embolization agent, comprising the steps of: mixing the drug-loaded microspheres and bleomycin to obtain the vascular embolization agent.
Preferably, the bleomycin is dissolved in an isotonic regulator to form a bleomycin solution, and then the bleomycin solution is mixed with the drug-loaded microspheres to obtain the vascular embolization agent.
More preferably, the bleomycin solution and the drug-loaded microspheres are stirred once every 3-6 min to realize that the drug-loaded microspheres load the bleomycin, and the stirring is carried out for 1-5 times.
Preferably, the isotonicity adjusting agent is selected from an aqueous glucose solution.
More preferably, the concentration of the glucose aqueous solution is 3 to 7 wt%.
Further preferably, the concentration of the aqueous glucose solution is 5 wt%.
Preferably, the concentration of the bleomycin solution is 5-15 mg/mL.
More preferably, the concentration of the bleomycin solution is 5-10 mg/mL.
The invention also aims to provide the application of the vascular embolization agent in preparing a medicament for vascular malformation interventional therapy.
The invention has the beneficial effects that:
1) the vascular embolization agent can realize slow release of bleomycin in tissues after arterial puncture injection, reduce blood flow speed by plugging local arterioles, prolong the action time of bleomycin, reduce the concentration of drugs in blood plasma, reduce systemic toxic and side effects, realize positioning embolization and cause vascular occlusion.
2) In the application, after the rabbit ear artery model is used and the vascular embolization agent is injected into an arterial blood vessel for 2 weeks, the vascular occlusion and blood flow interruption of the administration part are found through visual observation and HE staining under a conventional microscope, but the conventional bleomycin injection does not have obvious change, which indicates that the vascular embolization agent can effectively treat the vascular malformation.
3) The preparation method of the vascular embolization agent provided by the application has the advantages of simple process, stable result and reproducibility, and can realize industrial mass production.
Drawings
FIG. 1 shows a schematic representation of rabbit ear embolism model of application example 1 of the present application.
Fig. 2 shows a graph of mean microvascular density in application example 1 of the present application.
FIG. 3 shows a schematic representation of rabbit ear embolism model in comparative example 1 of the present application.
Detailed Description
The following description of the embodiments of the present invention is provided for illustrative purposes, and other advantages and effects of the present invention will become apparent to those skilled in the art from the present disclosure.
Before the present embodiments are further described, it is to be understood that the scope of the invention is not limited to the particular embodiments described below; it is also to be understood that the terminology used in the examples is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention. Test methods in which specific conditions are not specified in the following examples are generally carried out under conventional conditions or under conditions recommended by the respective manufacturers.
When numerical ranges are given in the examples, it is understood that both endpoints of each of the numerical ranges and any value therebetween can be selected unless the invention otherwise indicated. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In addition to the specific methods, devices, and materials used in the examples, any methods, devices, and materials similar or equivalent to those described in the examples may be used in the practice of the invention in addition to the specific methods, devices, and materials used in the examples, in keeping with the knowledge of one skilled in the art and with the description of the invention.
In the application, the drug-loaded microspheres are drug-loaded microspheres containing anionic groups and are used for loading bleomycin through electrostatic adsorption. The drug-carrying microsphere skeleton can be the skeleton of the conventional drug-carrying microsphere in the prior art, for example, the skeleton takes polyvinyl alcohol, polyamide and polylactic acid as the main chain skeleton. The anion groups on the surface of the drug-loaded microsphere are mainly used for electrostatic adsorption of the bleomycin, so that the drug-loaded microsphere can be applied as long as the anion groups of the bleomycin drug property are not changed, such as sulfonic acid groups, carboxylic acid groups and the like. Preferably, the drug-loaded microspheres are polyvinyl alcohol microspheres containing sulfonic acid groups so as to realize complete loading with bleomycin. In order to facilitate the test, in the embodiment of the application, the drug-loaded microspheres are purchased from Callispheres' drug-loaded embolization microspheres of Gnity & Li biomedical science and technology, Suzhou, and the particle size is 150-300 μm. The drug-loaded microspheres are blue gel-like fine particles with uniform particle size, and are preserved in penicillin bottles by 0.9% sodium chloride solution, and each bottle is filled with not less than 0.9g of drug-loaded microspheres.
In the embodiment of the application, the preparation method of the vascular embolization agent comprises the following steps: dissolving bleomycin in an isotonic regulator, injecting the mixture into an injector 1, and connecting the injector 1 with an injector 2 filled with drug-loaded microspheres by adopting a three-way valve; and pulling the injector 2 while pushing the injector 1 to mix the bleomycin solution and the drug-loaded microspheres to prepare the vascular embolization agent.
In the examples of the present application, an aqueous glucose solution was used as the isotonic adjusting agent.
In the embodiment of the application, the drug-loaded microsphere is marked as M, the bleomycin is marked as B, and the vascular embolization agent is marked as MB.
Example 1
In this example, the preparation of the vascular embolization agent includes the following steps:
1) mixing 15mg of bleomycin and 3mL of 5% glucose aqueous solution to prepare 5mg/mL of bleomycin solution, extracting 2mL of bleomycin solution and injecting the bleomycin solution into the injector 1; meanwhile, another syringe 2 is used for extracting 10mL of sodium chloride solution of the drug-loaded microspheres, and after standing, 2.5mL of the drug-loaded microspheres are obtained by discarding supernatant.
2) The three-way valve is used for communicating the injector 2 filled with the drug-loaded microspheres with the injector 1 filled with the bleomycin solution, pushing the injector 1 filled with the bleomycin solution and drawing the injector 2 filled with the drug-loaded microspheres; mixing the drug-loaded microspheres and the bleomycin solution into a syringe, covering a cap, standing, shaking up every 5min, and loading for 15min in total.
In this embodiment, the mass-to-volume ratio of bleomycin to the drug-loaded microspheres in the vascular embolization agent is 4 mg: 1mL, marked MB.
Example 2
In this example, the preparation of the vascular embolization agent includes the following steps:
1) mixing 15mg of bleomycin and 3mL of 5% glucose aqueous solution to prepare 5mg/mL of bleomycin solution, extracting 5mL, and injecting into the injector 1; meanwhile, another injector 2 is used for extracting 10mL of sodium chloride solution of the drug-loaded microspheres, and 5mL of the drug-loaded microspheres are obtained by standing and then discarding supernatant.
2) The three-way valve is used for communicating the injector 2 filled with the drug-loaded microspheres with the injector 1 filled with the bleomycin solution, pushing the injector 1 filled with the bleomycin solution and drawing the injector 2 filled with the drug-loaded microspheres; mixing the drug-loaded microspheres and the bleomycin solution into a syringe, covering a cap, standing, shaking up every 5min, and loading for 15min in total.
In this embodiment, the mass-to-volume ratio of bleomycin to the drug-loaded microspheres in the vascular embolization agent is 5 mg: 1mL, labeled MB-2.
Example 3
In this example, the preparation of the vascular embolization agent includes the following steps:
1) mixing 15mg of bleomycin and 3mL of 5% glucose aqueous solution to prepare 5mg/mL of bleomycin solution, extracting 2mL of bleomycin solution and injecting the bleomycin solution into the injector 1; meanwhile, another syringe 2 is used for extracting 10mL of sodium chloride solution of the drug-loaded microspheres, and 5mL of the drug-loaded microspheres are obtained by standing and then discarding supernatant.
2) The three-way valve is used for communicating the injector 2 filled with the drug-loaded microspheres with the injector 1 filled with the bleomycin solution, pushing the injector 1 filled with the bleomycin solution and drawing the injector 2 filled with the drug-loaded microspheres; mixing the drug-loaded microspheres and the bleomycin solution into a syringe, covering a cap, standing, shaking up every 5min, and loading for 15min in total.
In this embodiment, the mass-to-volume ratio of bleomycin to the drug-loaded microspheres in the vascular embolization agent is 2 mg: 1mL, labeled MB-3.
Example 4
In this example, the preparation of the vascular embolization agent includes the following steps:
1) mixing 15mg of bleomycin and 3mL of 5% glucose aqueous solution to prepare 5mg/mL of bleomycin solution, extracting 3mL, and injecting into the injector 1; meanwhile, another syringe 2 is used for extracting 10mL of sodium chloride solution of the drug-loaded microspheres, and 5mL of the drug-loaded microspheres are obtained by standing and then discarding supernatant.
2) The three-way valve is used for communicating the injector 2 filled with the drug-loaded microspheres with the injector 1 filled with the bleomycin solution, pushing the injector 1 filled with the bleomycin solution and drawing the injector 2 filled with the drug-loaded microspheres; mixing the drug-loaded microspheres and the bleomycin solution into a syringe, covering a cap, standing, shaking up every 5min, and loading for 15min in total.
In this embodiment, the mass-to-volume ratio of bleomycin to the drug-loaded microspheres in the vascular embolization agent is 3 mg: 1mL, labeled MB-3.
Application example 1
In this example, the vascular embolization agent MB prepared in example 1 was injected by rabbit arteriopuncture to observe thrombosis, and the method included the following steps:
20 New Zealand white rabbits weighing 2.5-3.0 kg were randomly divided into an experimental group and a blank group, each group consisting of 10 rabbits, 0.5mL of MB prepared in example 1 was injected into the center of the ear of each rabbit in the experimental group by arterial puncture, and 0.5mL of bleomycin injection was injected into the center of the ear of each rabbit in the blank group by arterial puncture. After administration, rabbit ear tissues are respectively taken at 24h, 48h, 7d and 14d, and the vascular occlusion and tissue destruction conditions of each rabbit ear are observed through HE staining; by immunohistochemical analysis, pathological sections of rabbit ears were observed under an optical microscope, the number of microvessels contained in each unit field of view observed under a height microscope (x 20) was counted, five fields of view were randomly extracted, and the average value was calculated to obtain the mean microvessel density at different periods.
The operation of the arteriopuncture injection is as follows: after rabbit ears are disinfected, a longitudinal incision is made at the central vein of the root part of the back side of the rabbit ears, the rabbit ears are separated layer by layer, a accompanying blood vessel with the diameter of about 1mm can be separated beside the central vein, namely, the central artery of the rabbit ears, OT needles are used for puncture drug delivery after the blood vessel is dissociated, and isotonic glucose solution is injected after the drug delivery to ensure that the drugs completely enter the blood vessel. Hemostasis was pressed after injection was completed, followed by suturing.
Fig. 1 is a diagram of a rabbit ear embolism model of application example 1. Compared with the comparative example 2, the rabbit after the vascular embolization agent is injected by arterial puncture has the advantages that the vascular occlusion and the blood flow interruption at the administration position are more obvious, and the blood flow from the far end to the ear tip gradually tends to be normal, so that the vascular embolization agent can effectively embolize a target blood vessel, thereby achieving the treatment effect on the vascular malformation.
Fig. 2 is a graph of mean microvascular density at 24h, 48h, 7d, 14d after administration in application example 1. As can be seen from fig. 2, the MB group and the M group have no obvious difference within 24h after administration, but the average blood vessel density value of the rabbits in the MB group becomes smaller and smaller along with the development of time, which indicates that the blocked blood vessels are more and more, and the blood vessel embolization agent MB can effectively embolize the target blood vessels.
Comparative example 1
In this comparative example 1, the case of thrombus formation was observed by auricular artery puncture using bleomycin injection, which comprises the following steps;
the effective doses of the bleomycin injection are respectively 1.5mg, 2.0mg, 2.5mg, 3.0mg and 3.5mg through arterial puncture in 10 auricular arteries on both sides of 5 rabbits, the concentration of the bleomycin injection is 5mg/mL, and the solvent is glucose aqueous solution. And (5) observing the thrombosis condition.
The results of the experiments are shown in table 1 below and fig. 3.
TABLE 1
| Bleomycin dose (mg) (left/right) | Results |
| 1.5/1.5 | Survival |
| 2.0/2.0 | Surviving topical ulcer |
| 2.5/2.5 | Survival |
| 3.0/3.0 | Survival |
| 3.5/3.5 | Survival |
As can be seen from Table 1 above, bleomycin did not cause death of the animals after otic arterial puncture injection, but resulted in local tissue ulceration.
FIG. 3 is a schematic representation of rabbit ear embolism model of comparative example 1. As can be seen from FIG. 3, after the bleomycin is injected by ear arteriopuncture, the phenomenon of vascular embolism in rabbit ears is not obvious, because the bleomycin injection does not stay near the target blood vessel after the arteriopuncture, plasma enters the blood circulation, and when the bleomycin injection is serious, the tissue is damaged to cause local ulcer of the tissue part.
Comparative example 2
In the comparative example 2, the thrombus formation condition is observed by only using the drug-loaded microsphere through arterial puncture, and the method comprises the following steps;
0.45mL, 0.60mL, 0.75mL and 0.9mL of drug-loaded microspheres were injected into 8 auricular arteries on both sides of 4 rabbits by arterial puncture, and the thrombosis was observed.
The results of the experiments are shown in table 2 below.
TABLE 2
| Microsphere dose (mL) (left/right) | Results |
| 0.45/0.45 | Survival |
| 0.60/0.60 | Embolism of ophthalmic artery |
| 0.75/0.75 | Death was caused by death |
| 0.9/0.9 | Death was caused by death |
From the above table 2, after the drug-loaded microspheres which are not loaded with bleomycin are subjected to auricular artery puncture injection, the drug-loaded microspheres enter systemic circulation, mild patients cause artery embolism of rabbit eyes, and severe patients cause systemic microcirculation disturbance of rabbits to cause death.
The foregoing embodiments are merely illustrative of the principles and utilities of the present invention and are not intended to limit the invention. Any person skilled in the art can modify or change the above-mentioned embodiments without departing from the spirit and scope of the present invention. Accordingly, it is intended that all equivalent modifications or changes which can be made by those skilled in the art without departing from the spirit and technical spirit of the present invention be covered by the claims of the present invention.
Claims (10)
1. The vascular embolization agent is characterized by at least comprising drug-loaded microspheres and bleomycin, wherein the drug-loaded microspheres load the bleomycin.
2. The vascular embolization agent of claim 1, wherein the vascular embolization agent comprises:
2 mg/mL-8 mg/mL of bleomycin;
the drug-loaded microspheres complement the volume to 100%;
based on the total amount of the vascular embolization agent.
3. The vascular embolic agent of claim 1, wherein the drug-loaded microspheres are drug-loaded microspheres comprising anionic groups for loading bleomycin by electrostatic adsorption; the particle size of the drug-loaded microspheres is 50-500 μm.
4. The vascular embolization agent of claim 3, wherein the anionic groups are selected from one or both of sulfonic acid groups or carboxylic acid groups.
5. A method for preparing a vascular embolization agent according to any one of claims 1 to 4, comprising the steps of: mixing the drug-loaded microspheres and bleomycin to obtain the vascular embolization agent.
6. The process of claim 5 wherein bleomycin is dissolved in an isotonic adjusting agent to form a bleomycin solution which is then mixed with said drug loaded microspheres to obtain said vascular embolization agent.
7. The method of claim 6, wherein the isotonic adjusting agent is selected from the group consisting of an aqueous glucose solution.
8. The method according to claim 7, wherein the concentration of the aqueous glucose solution is 3 to 7 wt%.
9. The method according to claim 6, wherein the concentration of the bleomycin in the bleomycin solution is 5 to 15 mg/mL.
10. Use of a vascular embolization agent according to any one of claims 1 to 4 for the manufacture of a medicament for the interventional treatment of vascular malformations.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110734323.3A CN113425886A (en) | 2021-06-30 | 2021-06-30 | Vascular embolization agent and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110734323.3A CN113425886A (en) | 2021-06-30 | 2021-06-30 | Vascular embolization agent and preparation method and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN113425886A true CN113425886A (en) | 2021-09-24 |
Family
ID=77758089
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110734323.3A Pending CN113425886A (en) | 2021-06-30 | 2021-06-30 | Vascular embolization agent and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113425886A (en) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101670095A (en) * | 2009-04-13 | 2010-03-17 | 北京大学 | Pharmaceutical composition for treating embolism and preparation method thereof |
| WO2010124654A1 (en) * | 2009-04-30 | 2010-11-04 | 北京圣医耀科技发展有限责任公司 | Vascular embolus of sodium alginate microspheres comprising drug for resisting hemangioma, preparation method, and use thereof |
| CN102250277A (en) * | 2011-05-17 | 2011-11-23 | 郑隆泗 | Macromolecular polymer capable of carrying medicine and used for embolism |
| WO2015149559A1 (en) * | 2014-04-03 | 2015-10-08 | 广州一代医药科技有限公司 | Pharmaceutical composition for anti-vascular diseases and anti-tumor and use thereof |
| CN107899064A (en) * | 2017-10-27 | 2018-04-13 | 华威（深圳）医疗器械有限责任公司 | A kind of medicine-carried and the preparation method and its usage for having the liquid embolizing agent of developability concurrently |
| CN109021169A (en) * | 2018-08-31 | 2018-12-18 | 深圳市比德泰克生物医药科技有限公司 | A kind of sodium alginate polymer, novel alga acid natremia pipe embolism chemical therapeutic composition and its preparation method and application |
-
2021
- 2021-06-30 CN CN202110734323.3A patent/CN113425886A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101670095A (en) * | 2009-04-13 | 2010-03-17 | 北京大学 | Pharmaceutical composition for treating embolism and preparation method thereof |
| WO2010124654A1 (en) * | 2009-04-30 | 2010-11-04 | 北京圣医耀科技发展有限责任公司 | Vascular embolus of sodium alginate microspheres comprising drug for resisting hemangioma, preparation method, and use thereof |
| CN102250277A (en) * | 2011-05-17 | 2011-11-23 | 郑隆泗 | Macromolecular polymer capable of carrying medicine and used for embolism |
| WO2015149559A1 (en) * | 2014-04-03 | 2015-10-08 | 广州一代医药科技有限公司 | Pharmaceutical composition for anti-vascular diseases and anti-tumor and use thereof |
| CN107899064A (en) * | 2017-10-27 | 2018-04-13 | 华威（深圳）医疗器械有限责任公司 | A kind of medicine-carried and the preparation method and its usage for having the liquid embolizing agent of developability concurrently |
| CN109021169A (en) * | 2018-08-31 | 2018-12-18 | 深圳市比德泰克生物医药科技有限公司 | A kind of sodium alginate polymer, novel alga acid natremia pipe embolism chemical therapeutic composition and its preparation method and application |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2019204145B2 (en) | Dodecafluoropentane emulsion as a stroke and ischemia therapy | |
| US7670592B2 (en) | Polyvinyl alcohol microspheres, injectable solutions and therapeutic uses of the same | |
| Rong et al. | Alginate-calcium microsphere loaded with thrombin: a new composite biomaterial for hemostatic embolization | |
| US5614204A (en) | Angiographic vascular occlusion agents and a method for hemostatic occlusion | |
| US20020009415A1 (en) | Microspheres for use in the treatment of cancer | |
| US20080050436A1 (en) | Methods and compounds for obliteration of vessels | |
| US20110129526A1 (en) | Compositions and methods for treating vascular disease | |
| MXPA01011919A (en) | Use of biodegradable microspheres that release an anticancer agent for treating gliobastoma. | |
| US10179188B1 (en) | Resorbable embolization spheres | |
| KR101875843B1 (en) | Diffusion enhancing compounds and their use alone or with thrombolytics | |
| CN101536987A (en) | Sodium alginate microballoon vein suppository containing hemangioma-resisting medicant, preparation method and application thereof | |
| Kunliang et al. | A biodegradable multifunctional porous microsphere composed of carrageenan for promoting imageable trans-arterial chemoembolization | |
| CN113143955A (en) | Modified lauromacrogol foam hardening agent, preparation method and application | |
| CN113425886A (en) | Vascular embolization agent and preparation method and application thereof | |
| CN107550879A (en) | A kind of preparation method of gelfoam drug bearing microsphere | |
| CN108992431B (en) | Doxorubicin embolism microsphere and preparation method thereof | |
| CN107648598B (en) | A kind of pharmaceutical composition for treating acute ischemic cerebral apoplexy | |
| CN104324032B (en) | Antituberculotics three compound recipe microsphere vascular targeting thromboembolism slow releasing agent and its production and use | |
| WO2015196984A1 (en) | Use of polylactic acid microsphere for hemorrhagic diseases | |
| CN103083341B (en) | Use of anthracycline antibiotics in preparation of medicines for treating age-related macular degeneration | |
| Gan et al. | Outcome in acute stroke with different intra-arterial infusion rate of urokinase on thrombolysis | |
| CN103169718B (en) | Application of anthracene nucleus antibiotic and its pharmaceutical salt for treating neovascular glaucoma | |
| Zhang et al. | Recombinant Plasminogen Activator Modified Nanoparticles for Targeting Thrombolysis in Branch Retinal Vein Occlusion | |
| Gu et al. | Experimental renal embolization: preliminary results with polyacrylonitrile-based multiblock copolymers | |
| Horák et al. | Targeted chemoembolization of tumors with poly (2‐hydroxyethyl methacrylate) particles |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20210924 |