CN110527007B - Poly (2-cyanoacrylate) and preparation method and application thereof - Google Patents

Poly (2-cyanoacrylate) and preparation method and application thereof Download PDF

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CN110527007B
CN110527007B CN201910836249.9A CN201910836249A CN110527007B CN 110527007 B CN110527007 B CN 110527007B CN 201910836249 A CN201910836249 A CN 201910836249A CN 110527007 B CN110527007 B CN 110527007B
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cyanoacrylate
poly
blank
medicine
microsphere
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CN110527007A (en
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王俊平
郭寅
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Dalian Heyuan Medical Devices Co ltd
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Dalian Heyuan Medical Devices Co ltd
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Priority to CN201910836249.9A priority Critical patent/CN110527007B/en
Priority to CN202210961226.2A priority patent/CN115093497A/en
Publication of CN110527007A publication Critical patent/CN110527007A/en
Priority to US17/640,480 priority patent/US20220332862A1/en
Priority to PCT/CN2020/110386 priority patent/WO2021043004A1/en
Priority to JP2022515062A priority patent/JP2022547140A/en
Priority to EP20861592.2A priority patent/EP4026859A4/en
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F8/00—Chemical modification by after-treatment
    • C08F8/12—Hydrolysis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/048—Macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • 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
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/418—Agents promoting blood coagulation, blood-clotting agents, embolising 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
    • A61L2300/60—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

Abstract

The invention relates to poly (2-cyanoacrylate) and a preparation method and application thereof, belonging to the field of pharmaceutical chemicals. Firstly, preparing alpha-cyanoacrylate polymer, and then selectively hydrolyzing ester bonds of the polymer under alkaline conditions to obtain the poly (2-cyanoacrylate). Poly (2-cyanoacrylate) is dispersed in water to form microsphere with negative charge, and the blank embolism microsphere with particle size capable of being regulated in micron level range and deformation function is used to pass through blood vessel in specific form to plug blood vessel tightly to avoid falling off and to avoid ectopic embolism is obtained. The novel medicine-carrying embolism microsphere is obtained by combining the blank embolism microsphere and the medicine with positive charges, the principle of charge reversal is adopted, the medicine with positive charges is actively loaded by using high molecular carboxyl, the medicine can be directly released at the local part of the pathological change tissue, and the medicine rarely flows throughout the body, so that the local curative effect of the medicine on the pathological change tissue is improved, and the toxic and side effects of the medicine on the whole body are reduced.

Description

Poly (2-cyanoacrylate) and preparation method and application thereof
Technical Field
The invention relates to the field of pharmaceutical chemicals, in particular to poly (2-cyanoacrylate) and a preparation method and application thereof.
Background
It is generally believed that intravascular embolization should be avoided, but some vessels receive good therapeutic results if they can be selectively partially embolized. In recent years, due to the development of medical technology, vascular embolization agents (Vascular occlusion agents) have been injected into the relevant artery through an inserted catheter to treat diseases, especially diseases that are difficult to control by surgery or drugs, such as tumors or varicose veins in the fundus of the stomach. This technique is medically known as selective vascular embolization. Transcatheter arterial embolization was first used in the 20 th century in the 70's to treat prostate bleeding following a needle biopsy of the prostate or transurethral resection of the prostate, as well as refractory hematuria of prostate origin. In the case of vascular embolization, embolization agents must be used, which may be mechanically occluded by balloons, metal balls, spring tubes, etc., in addition to some natural embolizing substances such as blood clots. The current embolic agents used are classified into solid and liquid types, and some natural embolic agents are also listed as solid embolic agents.
Arterial embolization is also used to treat tumors, stop bleeding from tumors, and relieve pain from tumors. Tumor embolization therapy is an aspect of recent years of interventional radiology in which embolizing substances are injected into tumor vessels through catheters, causing the tumor vessels to become embolized, necrotizing, and reduced or obliterated in volume. Mainly suitable for patients who cannot tolerate the operation or have lost the operation chance without other suitable treatment methods. Has certain significance for treating intractable hemorrhage, pain and paracancer syndrome caused by tumor. Particularly, cancer tissue bleeding is caused by poor response of tumor blood vessels to vasoconstrictors and often blood coagulation disorder of cancer patients, so that blood clots cannot be formed at bleeding sites. Thus, infusion of vasopressin is often ineffective in stopping bleeding, and embolization can gain time for additional treatment. Arterial embolization therapy is currently used to treat tumors. Arterial Chemoembolization (TACE) is a procedure in which a chemotherapeutic drug is mixed with a contrast agent (iodine oil) and emulsified, and then the arterial perfusion of liver cancer is performed through a catheter, and then the arterial embolization of liver cancer is performed with an embolization agent such as gelatin sponge particles, which needs two steps and requires a long operation time with a thread for a doctor. In recent years, a novel TACE method has appeared, that is, drug-loaded microspheres (Drug-eluting microspheres, DEBs) with a slow release function are prepared from materials with good biocompatibility, and liver cancer artery delivery of drugs and embolic agents can be realized simultaneously under single image guidance, so that the operation steps are simplified, and the time for doctors to intervene in treatment on-line operation is shortened. In the DC-Bead molecular structure, a large number of sulfonic groups exist, so that the DC-Bead molecular structure can attract anticancer drugs with positive charges, is used for arterial vascular embolization of tumors, inhibits tumor growth, reduces tumor bleeding and relieves tumor pain. The DC-Bead has sulfonic acid group, has poor biocompatibility and is easy to cause allergy.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a preparation method of a new material poly (2-cyanoacrylate), a novel blank embolism microsphere developed by adopting poly (2-cyanoacrylate), a preparation method of a novel medicine-carrying embolism microsphere further developed by adopting the novel blank embolism microsphere and application. The technical scheme of the invention is as follows:
the preparation method of poly (2-cyanoacrylate) comprises the steps of firstly preparing alpha-cyanoacrylate polymer, then selectively hydrolyzing ester bonds in the polymer under alkaline conditions, and purifying to obtain the poly (2-cyanoacrylate).
The invention also relates to poly (2-cyanoacrylic acid) prepared by the method.
The invention claims the application of the poly (2-cyanoacrylate), which is to prepare the poly (2-cyanoacrylate) into blank embolism microsphere.
And further: the preparation method of the blank embolism microsphere comprises the following steps: dispersing poly (2-cyanoacrylate) in water to form microsphere with negative charge, and obtaining blank embolism microsphere.
And further: the particle size of the blank embolism microsphere can be adjusted within the micron-scale range to meet the requirement of embolization targets of blood vessels with different diameters, and the blank embolism microsphere has a deformation function as required so that the blood vessels can be tightly embolized through stenosis of the blood vessels on an embolization path, and ectopic embolization caused by shedding can be avoided.
The invention provides application of poly (2-cyanoacrylate), which is to prepare poly (2-cyanoacrylate) into blank embolism microspheres and then prepare the blank embolism microspheres into drug-loaded embolism microspheres.
And further: the preparation method of the drug-loaded embolism microsphere comprises the following steps: combining the blank embolism microsphere with the medicine with positive charge to obtain the medicine-carrying embolism microsphere.
Further: the drug-loaded embolism microsphere actively loads (pH is more than or equal to 7.4) and releases (pH is less than or equal to 6.5) drugs by the principle of charge reversal.
Further: the drug-loaded embolism microsphere can directly release the drug to enter the local part of the pathological tissue in the pathological tissue with high vascular permeability and low pH value, and the drug rarely flows throughout the body, thereby improving the curative effect of the drug on the local part of the pathological tissue and reducing the toxic and side effect of the drug on the whole body.
The invention also claims poly (2-cyanoacrylate), the chemical formula is:
-[-CH 2 -C(CN)(COOH)] n -。
more particularly preferred preparation and use are as follows:
1. preparation of poly (2-cyanoacrylic acid)
(1) The method comprises the following steps:
preparing the emulsion of the alpha-cyanoacrylate or the vegetable oil solution thereof by using a nonionic surfactant such as polyethylene glycol type nonionic surfactant, tween type surfactant, span type surfactant or poloxamer and the like in physiological saline with the pH value of 2.0-4.0 or glucose solution with the concentration of more than 5% or dextran solution with the concentration of more than 5%. Then the pH value is adjusted to be more than 7.4, and the polymerization reaction is accelerated to form the alpha-cyanoacrylate polymer. And selectively hydrolyzing ester bonds of the polymer under an alkaline condition, reserving cyano, saponifying the vegetable oil, and dialyzing to remove impurities to obtain the poly (2-cyanoacrylate).
The higher the nonionic surfactant content, the less the amount of alpha-cyanoacrylate used, and the smaller the emulsion particle size. The polymerization degree of the poly (2-cyanoacrylate) can be controlled by the particle size of the alpha-cyanoacrylate emulsion, and the polymerization degree is smaller when the particle size of the emulsion is smaller.
Poly (2-cyanoacrylic acid) of different molecular weight ranges can be isolated by dialysis or gel chromatography.
(2) The second method comprises the following steps:
the alpha-cyanoacrylate is dissolved in absolute ethyl alcohol or acetone or acetonitrile. Under the condition of high-speed dispersion by a hard plastic disperser, the anhydrous alcohol, acetonitrile or acetone solution of alpha-cyanoacrylate is slowly dropped into acidic water, and then the mixture is magnetically stirred overnight. The alpha-cyanoacrylate polymer precipitate was collected by high speed centrifugation. And selectively hydrolyzing ester bonds of the polymer under alkaline conditions, reserving cyano groups, and dialyzing to remove impurities to obtain the poly (2-cyanoacrylate).
The degree of polymerization of poly (2-cyanoacrylate) may be determined by the concentration of the alpha-cyanoacrylate, which is lower the degree of polymerization.
Poly (2-cyanoacrylic acid) of different molecular weight ranges can be isolated by dialysis or gel chromatography.
2. Preparation of poly (2-cyanoacrylate) blank embolism microsphere
The particle size of the blank embolism microsphere can be controlled by controlling the polymerization degree of the poly (alpha-cyanoacrylate) by controlling the polymerization time or the concentration of the alpha-cyanoacrylate.
The poly (2-cyanoacrylate) is rich in carboxyl, the carboxyl of the blank embolism microsphere can carry negative charges under alkaline conditions, and repulsive force is generated between the negative charges, so that the blank embolism microsphere has elasticity and deformability.
(1) The method comprises the following steps:
poly (2-cyanoacrylate) has certain surface activity and is easy to dissolve in absolute ethyl alcohol, and the ethyl alcohol solution is dispersed in water to obtain blank embolism microsphere rich in carboxyl.
(2) The second method comprises the following steps:
the poly (2-cyanoacrylate) has certain surface activity and is easy to dissolve in absolute ethyl alcohol, the ethyl alcohol solution is dispersed in water, and part of carboxyl of the poly (2-cyanoacrylate) is modified by active polyethylene glycol, so that the blank embolism microsphere modified by carboxyl is obtained.
The polyethylene glycol combined by the polymer carboxyl can effectively prevent the rapid phagocytosis and destruction of the skeleton material poly (2-cyanoacrylate) of the hollow embolism microsphere by a reticuloendothelial system, and the unmodified carboxyl is used for actively loading the medicine with positive charge.
The optimal proportion of carboxyl modification is related to the amount of the carried medicine and the type of the medicine, when the molecular weight of the medicine is larger and the hydrophilicity is poorer, the proportion of the modified carboxyl is a little higher, when the molecular weight of the medicine is smaller and the hydrophilicity is stronger, the proportion of the modified carboxyl is a little lower, in addition, the proportion of the modified carboxyl is also related to the individual difference of application, the reticular endothelial system can not be ensured to rapidly destroy the blank embolism microsphere, and in short, the specific proportion of carboxyl modification and the molecular weight of the active polyethylene glycol are specifically established according to the clinical requirements.
3. Application of poly (2-cyanoacrylate) blank embolism microsphere
The poly (2-cyanoacrylate) blank embolism microsphere can adjust the particle size according to clinical needs, has elasticity and deformability, and can pass through specific angiostenosis when the particle size is larger than or equal to 8um, and is hard to fall off under the tight action with the vessel wall, so that ectopic embolism cannot be generated.
4. Preparation of poly (2-cyanoacrylate) drug-loaded embolism microsphere
Combining the poly (2-cyanoacrylate) blank embolism microsphere with various medicines with positive charges to obtain various medicine-carrying embolism microspheres.
5. Application of poly (2-cyanoacrylate) drug-loaded embolism microsphere
According to clinical requirements, the drug-loaded embolism microsphere can be loaded with one or more different positively charged drugs to perform local embolism treatment with specific requirements, the drug-loaded embolism microsphere can directly release the drug to enter the local part of a diseased tissue in the diseased tissue with high vascular permeability and low pH value, and the drug rarely flows throughout the body, so that the local curative effect of the drug on the diseased tissue is improved, and the toxic and side effects of the drug on the whole body are reduced.
The invention has the following beneficial effects:
(1) Provides a preparation method of a new material of carboxyl-rich poly (2-cyanoacrylate);
(2) The poly (2-cyanoacrylate) can be used for preparing novel blank embolism microspheres;
(3) The novel blank embolism microsphere has adjustable particle size and the capability of deforming to pass through stenosis;
(4) The novel blank embolism microsphere can be used for preparing a novel medicine-carrying embolism microsphere;
(5) The novel drug-loaded embolism microsphere can improve the curative effect of the carried drug on the local lesion tissues;
(6) The novel drug-loaded embolism microsphere can reduce the toxic and side effects of the carried drug on the whole body;
(7) In the prior art of foreign DC-beads (as shown in figure 1), N-acryloyl-aminoacetaldehyde-dimethyl acetal and butyl acetate must be used, so that the volatility is high, the residual quantity is large, the production environment is not facilitated, and the safety is low. The invention only uses alpha-cyanoacrylate, vegetable oil, glucose, normal saline, nonionic surfactant, active polyethylene glycol, absolute ethyl alcohol, pure water and the like, has no toxic residue, no pollution, simple process, low production cost and higher safety;
(8) The number of molecules of the anti-cancer drugs loaded in the unit volume of the foreign DC-bead is small. According to the chemical structure calculation, the medicine-carrying embolism microsphere prepared by the invention has a molecular structure, wherein about 50% of carbon atoms carry a carboxyl negative charge, and about 20% of carbon atoms carry a carboxyl negative charge in a DC-bead molecule. The total negative charge per unit mass of the medicine-carrying embolism microsphere prepared by the invention is obviously higher than that of DC-bead, and the medicine-carrying capacity is obviously improved;
(9) Foreign DC-bead is a sulfonic acid group with strong acidity, and the ability of selectively releasing drugs near tumor tissues is weak. The drug-loaded embolization microsphere prepared by the invention has weak acidity of carboxyl carried by the microsphere, different drug release speeds under different pH values, remarkably accelerated drug release speed near tumor tissues with low pH values, and strong characteristic of selectively releasing drugs near tumors.
Drawings
FIG. 1 is a diagram of a conventional process for preparing DC-Bead;
FIG. 2 is a blank embolic microsphere (50 fold);
FIG. 3 is a diagram of the preparation and action of drug-loaded embolic microspheres;
FIG. 4 shows loaded (50-fold) tampon microspheres with doxorubicin;
fig. 5 shows the internal form of the crushed drug-loaded embolization microspheres loaded with adriamycin.
Detailed Description
The present invention will be further illustrated and explained with reference to specific examples, wherein the raw materials and equipment used in the present invention are all common raw materials and equipment unless otherwise specified.
EXAMPLE 1 preparation of Poly (2-cyanoacrylic acid)
(1) The formula is as follows: alpha-Cyanoacrylic acid n-butyl ester
Normal saline, sesame oil, tween-80, span-20 and absolute ethyl alcohol
The n-butyl alpha-cyanoacrylate was dissolved in refined pyrogen-free sesame oil to form 10mL of a 30% oil solution of n-butyl alpha-cyanoacrylate, which was dispersed in a 0.25% solution of Tween-80 and span-20 in physiological saline at pH 4.0. And adjusting the pH value to 7.8 to initiate n-butyl α -cyanoacrylate polymerization, centrifuging and separating the precipitate after 12 hours, washing the precipitate with absolute ethyl alcohol and centrifuging for 5 times, dispersing the precipitate in 50mL of absolute ethyl alcohol, adding sodium hydroxide, selectively hydrolyzing ester bonds and retaining cyano groups, evaporating under reduced pressure to remove the absolute ethyl alcohol, mixing with 100mL of distilled water, centrifuging at 8000rpm for 20 minutes, discarding the supernatant, washing with shaking water, centrifuging again, and repeating for 5 times to obtain the poly (2-cyanoacrylate).
(2) The formula is as follows: octyl alpha-cyanoacrylate
50% glucose solution, poloxamer, and anhydrous ethanol
Dissolving alpha-octyl cyanoacrylate in a 0.25 percent poloxamer 50 percent glucose solution with the pH value of 4.0 to form an alpha-octyl cyanoacrylate emulsion, adjusting the pH value to 7.4, polymerizing for 12 hours at room temperature under the stirring condition, centrifugally separating precipitates, dispersing the precipitates in 50mL of absolute ethyl alcohol, adding sodium hydroxide, selectively hydrolyzing ester bonds and retaining cyano groups, decompressing and evaporating to remove the absolute ethyl alcohol, mixing with 100mL of distilled water, centrifuging for 20 minutes at 8000rpm, discarding supernate, washing with shaking water, centrifuging again, and repeating for 5 times to obtain the poly (2-cyanoacrylate).
(3) The formula is as follows: isobutyl alpha-cyanoacrylate
10% dextran solution, polyethylene glycol 400 monooleate, and absolute ethyl alcohol
Dissolving alpha-isobutyl cyanoacrylate in 10% dextran solution of 0.25% polyglycol 400 monooleate in pH 4.0 to form alpha-isobutyl cyanoacrylate emulsion, regulating pH to 7.4, polymerizing at room temperature for 12 hr while stirring, centrifuging to separate precipitate, dispersing the precipitate in 50mL anhydrous alcohol, adding sodium hydroxide to hydrolyze ester bond selectively while retaining cyano group, vacuum evaporating to eliminate anhydrous alcohol, mixing with 100mL distilled water, centrifuging at 8000rpm for 20 min, discarding supernatant, washing with shaking water, centrifuging again, and repeating for 5 times to obtain poly (2-cyanoacrylate).
(4) The formula is as follows: alpha-Cyanoacrylic acid n-butyl ester
Anhydrous ethanol
Dissolving alpha-n-butyl cyanoacrylate in absolute ethyl alcohol to prepare a 50% ethanol solution, polymerizing for 1 week, adding sodium hydroxide to selectively hydrolyze ester bonds and retain cyano groups, evaporating under reduced pressure to remove absolute ethyl alcohol, mixing with 100mL of distilled water, centrifuging at 8000rpm for 20 minutes, discarding supernatant, washing with shaking water, centrifuging again, and repeating for 5 times to obtain poly (2-cyanoacrylate).
(5) The formula is as follows: alpha-cyanoacrylic acid methyl ester
Acetone, absolute ethyl alcohol
Dissolving alpha-methyl cyanoacrylate in absolute ethyl alcohol to prepare 50% acetone solution, polymerizing for 2 weeks, removing acetone under reduced pressure, dispersing in absolute ethyl alcohol, adding sodium hydroxide to selectively hydrolyze ester bonds and retain cyano groups, evaporating under reduced pressure to remove absolute ethyl alcohol, mixing with 100mL of distilled water, centrifuging at 8000rpm for 20 minutes, discarding supernatant, washing with shaking water, centrifuging again, and repeating for 5 times to obtain poly (2-cyanoacrylate).
(6) The formula is as follows: alpha-Cyanoacrylic acid ethyl ester
Acetonitrile, absolute ethyl alcohol
Dissolving alpha-ethyl cyanoacrylate in acetonitrile to prepare 50% acetonitrile solution, polymerizing for 2 weeks, removing acetonitrile under reduced pressure, dispersing in absolute ethyl alcohol, adding sodium hydroxide to selectively hydrolyze ester bonds and retain cyano groups, evaporating under reduced pressure to remove absolute ethyl alcohol, mixing with 100mL of distilled water, centrifuging at 8000rpm for 20 minutes, discarding supernatant, washing with shaking water, centrifuging again, and repeating for 5 times to obtain poly (2-cyanoacrylate).
EXAMPLE 2 preparation of Poly (2-Cyanoacrylic acid) blank embolic microspheres
(1) The formula is as follows: poly (2-cyanoacrylic acid)
Absolute ethyl alcohol and water
0.5g of poly (2-cyanoacrylate) was taken to prepare 5mL of an anhydrous ethanol solution. Placing the mixture in a rotary evaporator, volatilizing ethanol until the wall of the evaporator forms a film, mixing the film with 50mL of distilled water, hydrating for 12 hours, centrifuging for 20 minutes at 8000rpm, removing supernatant, washing with shaking water, centrifuging again, and repeating for 5 times to obtain the blank embolism microsphere.
(2) The formula is as follows: poly (2-cyanoacrylic acid)
Amino polyethylene glycol 2000 and water
Carboxyl modified by amino polyethylene glycol 2000, active polyethylene glycol modified catalyst: EDC. HCL:1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride;
NHS: n-hydroxysuccinimide. And after polyethylene glycol modification, centrifuging at 8000rpm for 20 minutes, discarding supernatant, washing with shaking water, centrifuging again, and repeating for 5 times to obtain blank embolism microsphere modified by polyethylene glycol.
EXAMPLE 3 preparation of Poly (2-Cyanoacrylic acid) drug-loaded embolic microspheres
(1) The formula is as follows: blank embolic microspheres
Adriamycin
Mixing 1mL of blank embolism microsphere with 2mg/mL of adriamycin 1/15M isotonic phosphate buffer solution with the same volume and pH value of 7.4, shaking for 15 minutes, dumping out the residual adriamycin solution, and washing with 1/15M isotonic phosphate buffer solution with pH value of 7.4 to obtain the adriamycin medicine-carrying embolism microsphere for tumor arterial vessel embolism.
(2) The formula is as follows: blank embolic microspheres
Gentamicin
And (3) taking 1mL of blank embolism microsphere and 10mg/mL of gentamicin 1/15M isotonic phosphate buffer solution with the same volume and pH value of 7.4, shaking for 5 minutes, dumping out the residual gentamicin solution, and washing with 1/15M isotonic phosphate buffer solution with the pH value of 7.4 to obtain the gentamicin medicine-carrying embolism microsphere with the requirement of anti-inflammatory treatment.
Effect of Poly (2-Cyanoacrylic acid) embolic microspheres
1. Novel blank embolism microsphere
The particle size and surface morphology of the novel blank embolism microsphere are observed and measured by an optical microscope and a scanning electron microscope (as shown in figure 2). Under the condition of different storage temperatures, the particle size change of the novel blank embolism microsphere in the long-term storage process is detected. The novel blank embolism microsphere can be used for embolism treatment of arterial hemorrhage, such as traumatic pelvic cavity and visceral hemorrhage, urinary system hemorrhage, alimentary tract hemorrhage, severe nasal and maxillofacial hemorrhage, hemoptysis, and postoperative visceral hemorrhage. It can also be used for the treatment of venous hemorrhage such as digestive tract varicosis.
2. Novel medicine-carrying embolism microsphere
The drug loading, the automatic drug loading speed and the drug release speed of the novel drug-loaded embolism microsphere are measured by an ultraviolet-visible spectrophotometer. A tumor tissue block embedding method is adopted to establish a rabbit VX2 liver cancer model, and the effectiveness of using the adriamycin drug-loaded embolism microspheres in hepatic artery is evaluated (as shown in figure 3). Two weeks after tumor block embedding implantation, an open hepatic artery cannula was used to inject doxorubicin drug-loaded embolizing microspheres (as shown in fig. 4). The doxorubicin concentration in the peripheral venous blood of the experimental rabbits was determined by high performance liquid chromatography. And (3) observing the distribution of the adriamycin in the tumor and the density of tumor capillaries by adopting a fluorescent staining technology. The result shows that the novel medicine-carrying embolism microsphere can effectively embolize tumor arterial blood vessels, has obvious anti-tumor curative effect and obviously reduces the density of the tumor blood vessels. Animal experiments show that the novel drug-loaded embolism microsphere can also be used for treating various tumors rich in blood vessels in kidney cancer, adrenal cancer and pelvic cavity, malignant tumors of maxillofacial region, and malignant tumors of four limbs and spinal pelvis. The novel embolism drug-loaded microsphere can also be loaded with all drugs with positive charges, is used for vascular embolism treatment with specific requirements, can improve the local curative effect of the drugs on pathological tissues, and reduces the toxic and side effects of the drugs on the whole body (as shown in figure 5).
The foregoing examples are provided for illustration and description of the invention and are not intended to limit the invention to the described examples. Furthermore, it will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, and that many variations and modifications may be made in accordance with the teachings of the present invention, which variations and modifications are within the scope of the present invention as claimed.

Claims (10)

1. A method for preparing poly (2-cyanoacrylate), characterized in that: preparing an emulsion of alpha-cyanoacrylate or a vegetable oil solution thereof by using a nonionic surfactant polyethylene glycol type nonionic surfactant or a Tween surfactant or a span surfactant or poloxamer in physiological saline with a pH value of 2.0-4.0 or a glucose solution with a concentration of more than 5% or a dextran solution with a concentration of more than 5%; then adjusting the pH value to be more than 7.4, and accelerating the polymerization reaction to form an alpha-cyanoacrylate polymer; dispersing in anhydrous ethanol, adding sodium hydroxide to selectively hydrolyze ester bond of polymer under alkaline condition and retain cyano group, saponifying vegetable oil, and dialyzing to remove impurities to obtain poly (2-cyanoacrylate).
2. A method for preparing poly (2-cyanoacrylate), characterized in that: dissolving alpha-cyanoacrylate in absolute ethyl alcohol or acetone or acetonitrile; slowly dripping anhydrous ethanol, acetonitrile or acetone solution of alpha-cyanoacrylate into acidic water under the condition of high-speed dispersion of a hard plastic disperser, and magnetically stirring overnight; centrifuging at high speed to collect the alpha-cyanoacrylate polymer precipitate; dispersing the poly (2-cyanoacrylate) in absolute ethyl alcohol, adding sodium hydroxide to selectively hydrolyze ester bonds of polymers under an alkaline condition and retain cyano groups, and dialyzing to remove impurities to obtain the poly (2-cyanoacrylate).
3. Poly (2-cyanoacrylic acid) prepared by the method of claim 1 or 2.
4. Use of poly (2-cyanoacrylic acid) prepared by the process of claim 1 or 2, wherein: the poly (2-cyanoacrylate) is prepared into blank embolization microspheres.
5. Use of poly (2-cyanoacrylate) according to claim 4, characterized in that: the preparation method of the blank embolism microsphere comprises the following steps: dispersing poly (2-cyanoacrylate) in water to prepare microsphere with negative charge, and obtaining blank embolism microsphere.
6. Use of poly (2-cyanoacrylate) according to claim 5, wherein: the blank embolism microsphere has the grain diameter more than or equal to 1 mu m and can deform.
7. Use of poly (2-cyanoacrylate) according to claim 4, characterized in that: preparing the blank embolism microsphere into a drug-loaded embolism microsphere.
8. Use of poly (2-cyanoacrylate) according to claim 7, wherein: the preparation method of the drug-loaded embolism microsphere comprises the following steps: combining the blank embolism microsphere with the medicine with positive charge to obtain the medicine-carrying embolism microsphere.
9. Use of poly (2-cyanoacrylate) according to claim 7, characterized in that: the drug loaded embolic microspheres actively load and release the drug by the principle of charge reversal.
10. Use of poly (2-cyanoacrylate) according to claim 7, characterized in that: the drug-loaded embolism microsphere can directly release drugs into the local part of the pathological tissue when the pathological tissue has high vascular permeability and low pH value.
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Family Cites Families (11)

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US3975422A (en) * 1972-11-21 1976-08-17 Johnson & Johnson Preparation of bis (2-cyanoacrylate)monomers
US4013703A (en) * 1974-10-04 1977-03-22 Johnson & Johnson Cyanoacrylic acid adducts
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US20070259047A1 (en) * 2004-02-26 2007-11-08 Yasuaki Ogawa Protein Sustained-Release Microparticle Preparation for Injection and Process for Producing the Same
CN101011608A (en) * 2007-01-12 2007-08-08 李艳芳 Developing polylactic acid microsphere blood vessel suppository containing antitumor agent
CN101671270B (en) * 2008-09-11 2013-07-31 杭州澳赛诺化工有限公司 Method for synthesizing cyanoacetylene derivatives
CN103087149B (en) * 2011-11-02 2015-11-25 中国人民解放军军事医学科学院毒物药物研究所 Containing the cyanoacrylate acid derivative and its production and use of peptide fragment
CN103030575B (en) * 2013-01-04 2014-10-01 中国农业大学 Double-cyano acidamide compound, and synthetic method and application of compound

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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