WO2021043004A1 - 聚[α-氰基丙烯酸酯]水解产物及其制备方法和应用 - Google Patents

聚[α-氰基丙烯酸酯]水解产物及其制备方法和应用 Download PDF

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WO2021043004A1
WO2021043004A1 PCT/CN2020/110386 CN2020110386W WO2021043004A1 WO 2021043004 A1 WO2021043004 A1 WO 2021043004A1 CN 2020110386 W CN2020110386 W CN 2020110386W WO 2021043004 A1 WO2021043004 A1 WO 2021043004A1
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poly
cyanoacrylate
drug
acid
microspheres
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French (fr)
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王俊平
郭寅
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Dalian Heyuan Medical Equipments Co Ltd
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Dalian Heyuan Medical Equipments Co Ltd
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Priority claimed from CN201910836249.9A external-priority patent/CN110527007B/zh
Priority claimed from CN201910836242.7A external-priority patent/CN110498877B/zh
Application filed by Dalian Heyuan Medical Equipments Co Ltd filed Critical Dalian Heyuan Medical Equipments Co Ltd
Priority to US17/640,480 priority Critical patent/US20220332862A1/en
Priority to JP2022515062A priority patent/JP7685989B2/ja
Priority to EP20861592.2A priority patent/EP4026859A4/en
Publication of WO2021043004A1 publication Critical patent/WO2021043004A1/zh
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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
    • C08F120/00—Homopolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride, ester, amide, imide or nitrile thereof
    • C08F120/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
    • C08F120/42—Nitriles
    • C08F120/50—Nitriles containing four or more carbon atoms
    • 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
    • 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
    • C08F122/00—Homopolymers of compounds having one or more unsaturated aliphatic radicals each having only one carbon-to-carbon double bond, and at least one being terminated by a carboxyl radical and containing at least one other carboxyl radical in the molecule; Salts, anhydrides, esters, amides, imides or nitriles thereof
    • 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
    • C08F122/00—Homopolymers of compounds having one or more unsaturated aliphatic radicals each having only one carbon-to-carbon double bond, and at least one being terminated by a carboxyl radical and containing at least one other carboxyl radical in the molecule; Salts, anhydrides, esters, amides, imides or nitriles thereof
    • C08F122/30—Nitriles
    • C08F122/32—Alpha-cyano-acrylic acid; Esters thereof
    • 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

Definitions

  • the present invention relates to the field of medicine and chemical industry, in particular to a poly[ ⁇ -cyanoacrylate] hydrolyzate and a preparation method and application thereof.
  • Intravascular embolism should be avoided, but if some blood vessels can be partially embolized selectively, good therapeutic effects can be received.
  • Vascular Occlusive Agents into the relevant arteries through inserted catheters to treat some diseases, especially for diseases that are difficult to control with surgery or drugs, such as tumors or gastric fundus.
  • Varicose veins This technique is medically called selective vascular embolization.
  • Transcatheter arterial embolization was first used in the 1970s to treat prostate hemorrhage after prostate biopsy or transurethral resection of the prostate and refractory hematuria derived from the prostate.
  • embolic agents When performing vascular embolization, embolic agents must be used. In addition to some natural embolic substances such as blood clots, balloons, metal balls, spring tubes, etc. can be used for mechanical blockage. Currently used embolic agents are divided into two categories: solid and liquid. Some natural embolic agents are also included in solid embolic agents.
  • Liposomes are mainly composed of cholesterol and phospholipids, and their structure is similar to cells, which can be used to carry drugs. There are two main problems with liposomes: first, how to load drugs, and secondly, how to prevent liposomes from being swallowed and destroyed by the reticuloendothelial system and how to release drugs in diseased tissues. Liposomes are low in toxicity, non-immunogenic, non-pyrogenic, and can be eliminated through normal metabolism, making them an ideal drug carrier.
  • nanoliposome drugs are mainly used to actively load drugs with the aid of ammonium ion gradient to prepare nanoliposome drugs, such as Doxil, which is a liquid nano-doxorubicin liposome.
  • Doxil which is a liquid nano-doxorubicin liposome.
  • the preparation process of this nanoliposome doxorubicin is complicated, the stability is poor, and it is difficult to actively release the drug at the tumor tissue site.
  • the present invention provides poly[ ⁇ -cyanoacrylate] hydrolyzate and a preparation method and application thereof.
  • the technical scheme of the present invention is as follows:
  • the present invention also claims the preparation method of the poly[ ⁇ -cyanoacrylate] hydrolysate: firstly prepare the ⁇ -cyanoacrylate polymer, and then hydrolyze the polymer to obtain poly[ ⁇ -cyanoacrylate] Hydrolyzate.
  • R is -CN, poly[2-cyanoacrylic acid], the chemical formula is:
  • the preparation method of poly[2-cyanoacrylic acid] is as follows: firstly prepare ⁇ -cyanoacrylate polymer, and then selectively hydrolyze the ester bond in the polymer under alkaline conditions. After purification, poly[2-cyanoacrylate] is obtained. Base acrylic].
  • the present invention claims to protect the application of the poly[ ⁇ -cyanoacrylate] hydrolysate by preparing poly[2-cyanoacrylic acid] into blank embolic microspheres.
  • the preparation method of the blank embolic microspheres is as follows: disperse poly[2-cyanoacrylic acid] in water to form negatively charged microspheres to obtain blank embolic microspheres.
  • the blank plug microspheres have a particle size ⁇ 1um and can be deformed.
  • the particle size of the blank embolic microspheres can be adjusted in the micron range to meet the requirements of embolization targets of different diameters.
  • the blank embolic microspheres have a deforming function to pass through the vascular stenosis on the embolic path. It can embolize blood vessels tightly and avoid ectopic embolism caused by shedding.
  • the present invention prepares poly[2-cyanoacrylic acid] into blank embolic microspheres, and then prepares them into drug-loaded embolic microspheres.
  • the preparation method of the drug-loaded embolic microspheres is as follows: the blank embolic microspheres are combined with a positively charged drug to obtain the drug-loaded embolic microspheres.
  • the drug-loaded embolic microspheres actively load (pH ⁇ 7.4) and release (pH ⁇ 6.5) drugs based on the principle of charge reversal.
  • the drug-loaded embolic microspheres can directly release the drug into the diseased tissue with high vascular permeability and low pH value, and the drug seldom flows through the whole body, thereby improving the local curative effect of the drug on the diseased tissue and reducing the drug Toxic and side effects on the whole body.
  • nonionic surfactant such as polyethylene glycol type nonionic surfactant or Tween surfactant or Span Surfactant or poloxamer, etc.
  • nonionic surfactant such as polyethylene glycol type nonionic surfactant or Tween surfactant or Span Surfactant or poloxamer, etc.
  • the degree of polymerization of poly[2-cyanoacrylic acid] can be controlled by the particle size of the ⁇ -cyanoacrylate emulsion. The smaller the particle size of the emulsion, the lower the degree of polymerization.
  • Poly[2-cyanoacrylic acid] with different molecular weight ranges can be separated and prepared by dialysis or gel chromatography.
  • the degree of polymerization of poly[2-cyanoacrylic acid] can be determined by the concentration of ⁇ -cyanoacrylate, and the lower the concentration, the lower the degree of polymerization.
  • Poly[2-cyanoacrylic acid] with different molecular weight ranges can be separated and prepared by dialysis or gel chromatography.
  • the degree of polymerization can be controlled, and the particle size of the blank embolic microspheres can be controlled accordingly.
  • Poly[2-cyanoacrylic acid] is rich in carboxyl groups. Under alkaline conditions, the carboxyl groups of blank embolic microspheres will be negatively charged, and repulsive forces are generated between the negative charges. Therefore, the blank embolic microspheres have elasticity and deformability.
  • Poly[2-cyanoacrylic acid] has a certain surface activity and is easily soluble in absolute ethanol. Disperse its ethanol solution in water to obtain blank embolic microspheres rich in carboxyl groups.
  • Poly[2-cyanoacrylic acid] has a certain surface activity and is easily soluble in absolute ethanol. Disperse its ethanol solution in water and modify part of the carboxyl groups of poly[2-cyanoacrylic acid] with active polyethylene glycol to obtain Carboxyl modified blank embolization microspheres.
  • Polyethylene glycol combined with polymer carboxyl groups can effectively prevent the reticuloendothelial system from rapidly engulfing and destroying the framework material poly[2-cyanoacrylic acid] of blank embolic microspheres. Unmodified carboxyl groups are used to actively load positive charges. medicine.
  • the optimal ratio of carboxyl modification is related to the amount of drug carried and the type of drug.
  • the proportion of modified carboxyl groups will be higher.
  • the molecular weight of the drug is relatively small, the hydrophilicity
  • the ratio of modified carboxyl groups can be lower if the sex is stronger.
  • the proportion of modified carboxyl groups is also related to the individual differences in the application. It must be ensured that the reticuloendothelial system cannot quickly destroy the blank embolic microspheres. And the molecular weight of active polyethylene glycol should be specifically formulated according to clinical needs.
  • Poly[2-cyanoacrylic acid] blank embolization microspheres can adjust their particle size according to clinical needs, and have elasticity and deformability.
  • embolization treatment can pass through specific vascular stenosis and be close to the blood vessel wall. The effect is difficult to fall off and will not cause ectopic embolism.
  • the drug-loaded embolic microspheres can be loaded with one or more positively charged drugs for local embolization treatment with specific requirements. They can be directly released in diseased tissues with high vascular permeability and low pH. The drug enters the local diseased tissue, and the drug seldom flows through the whole body, thereby improving the local curative effect of the drug on the diseased tissue and reducing the toxic side effects of the drug on the whole body.
  • R is -COOH, poly[2-carboxyacrylic acid], the chemical formula is:
  • the preparation method of poly[2-carboxyacrylic acid] is as follows: first prepare ⁇ -cyanoacrylate polymer, then hydrolyze the ester bond and cyano group of the polymer under alkaline conditions, and dialysis to remove impurities to obtain poly[2-carboxyl group acrylic acid].
  • the present invention claims the application of the poly[ ⁇ -cyanoacrylate] hydrolysate, preparing poly[2-carboxyacrylic acid] into a nano-medicine carrier.
  • the preparation method of the nano-medicine carrier is: modifying part of the carboxyl groups of poly[2-carboxyacrylic acid] with active polyethylene glycol, and the unmodified carboxyl groups are used to transport positively charged drugs, that is, a drug with a positive charge is obtained.
  • the preparation method of the nano-medicine carrier is: encapsulating poly[2-carboxyacrylic acid] in liposomes to obtain an active loading (pH ⁇ 7.4) and release (pH ⁇ 6.5) with the aid of a pH gradient.
  • a new type of nano-liposome with the function of positively charged drugs is also a nano-drug carrier.
  • the nano drug carrier actively loads and releases drugs based on the principle of charge reversal.
  • the nano-medicine carrier delivers drugs through the blood.
  • the nano-medicine carrier accumulates in the diseased tissues with high vascular permeability and low pH, and directly releases the drug into the diseased tissue.
  • the drug rarely enters the normal tissue, and the carried drug
  • the curative effect on diseased tissues is enhanced, and the toxic and side effects on normal tissues are reduced.
  • nonionic surfactant such as polyethylene glycol type nonionic surfactant or Tween surfactant or Span Surfactant or poloxamer, etc.
  • nonionic surfactant such as polyethylene glycol type nonionic surfactant or Tween surfactant or Span Surfactant or poloxamer, etc.
  • the degree of polymerization of poly[2-carboxyacrylic acid] can be controlled by the size of ⁇ -cyanoacrylate microemulsion. The smaller the microemulsion, the lower the degree of polymerization.
  • Poly[2-carboxyacrylic acid] with different molecular weight ranges can be separated and prepared by dialysis or gel chromatography.
  • the degree of polymerization of poly[2-carboxyacrylic acid] can be determined by the concentration of ⁇ -cyanoacrylate, and the lower the concentration, the lower the degree of polymerization.
  • Poly[2-carboxyacrylic acid] with different molecular weight ranges can be separated and prepared by dialysis or gel chromatography.
  • Part of the carboxyl group of poly[2-carboxyacrylic acid] is modified with active polyethylene glycol to obtain poly[2-carboxyacrylic acid] nano-medicine carrier.
  • Polyethylene glycol combined with polymer carboxyl group can effectively prevent the reticuloendothelial system from rapidly engulfing and destroying the backbone material of nano-drug carrier poly[2-carboxyacrylic acid].
  • the unmodified carboxyl group is used to actively load positively charged drugs. .
  • the optimal ratio of carboxyl modification is related to the amount of drug carried and the type of drug.
  • the proportion of modified carboxyl groups will be higher.
  • the molecular weight of the drug is relatively small, the hydrophilicity
  • the ratio of modified carboxyl groups can be lower if the sex is relatively strong.
  • the proportion of modified carboxyl groups is also related to the individual differences in the application. It must be ensured that the reticuloendothelial system cannot quickly destroy the nanomedicine carrier.
  • the molecular weight of active polyethylene glycol should be specifically formulated according to clinical needs.
  • Phospholipids, cholesterol, PEG2000-DSPE, and poly[2-carboxyacrylic acid] were dissolved in absolute ethanol, and liposomes encapsulating poly[2-carboxyacrylic acid] were prepared by the film method, and the liposomes were removed by gel chromatography.
  • the poly[2-carboxyacrylic acid] on the outside can obtain nano liposomes encapsulating poly[2-carboxyacrylic acid], and then adjust the pH value of the external aqueous phase of the nano liposome to 7.4, and the pH value gradient inside and outside the liposome can reach Above 5.0, the nano-liposome with the function of actively loading positively charged drugs is obtained, which is also a nano-drug carrier.
  • each pH unit change will produce a 10-fold difference between the concentration of the molecular type and the ionic drug. If the pH gradient inside and outside the liposome is 3.0, theoretically it will cause the molecular type and ionic type of the drug. The difference of 1000 times the concentration. Because molecular drugs are easily combined with liposome bimolecular membranes, the process of transmembrane internal transfer of drug molecules is accelerated.
  • Poly[2-carboxyacrylic acid] combines with positively charged drugs to form a precipitate, which will further promote the entry of positively charged drugs into nano-liposomes and improve the ability of nano-liposomes to carry drugs.
  • Normal tissues have low vascular permeability and high pH (close to 7.4), whereas diseased tissues have high vascular permeability and low pH (close to 6.5), so the nano-medicine carrier will gradually accumulate in the diseased tissue after entering the blood circulation system , And release the carried drugs, thereby improving the efficacy of drugs on diseased tissues (except for prodrugs), and at the same time reducing the toxic and side effects of drugs on normal tissues.
  • the particle size of the new blank embolic microspheres is adjustable and has the ability to deform and pass through stenosis;
  • the new blank embolic microspheres can be used to prepare new drug-loaded embolic microspheres
  • the new drug-loaded embolic microspheres can improve the efficacy of the delivered drugs on the local diseased tissues
  • the new drug-loaded embolic microspheres can reduce the toxic and side effects of the carried drugs on the whole body;
  • N-acryloyl-aminoacetaldehyde-dimethyl acetal and butyl acetate must be used, which have high volatility and large residual amount, which is not conducive to The production environment has low security.
  • the invention only uses ⁇ -cyanoacrylate, vegetable oil, glucose, physiological saline, non-ionic surfactant, active polyethylene glycol, absolute ethanol, pure water, etc., has no toxic residue, no pollution, simple process, and production cost Low and high safety;
  • the number of molecules of anti-cancer drugs loaded per unit volume of DC-bead abroad is relatively small.
  • the drug-loaded embolic microspheres prepared by the present invention are calculated based on the chemical structure. In the molecular structure, about 50% of the carbon atoms carry a carboxyl negative charge, and about 20% of the carbon atoms in the DC-bead molecule carry a carboxyl negative charge.
  • the total amount of negative charges per unit mass of the drug-loaded embolic microspheres prepared by the present invention is significantly higher than that of DC-bead, and the drug-loading ability is significantly improved;
  • Foreign DC-bead is a more acidic sulfonic acid group, and its ability to selectively release drugs near tumor tissues is weak.
  • the drug-loaded embolic microspheres prepared by the present invention carry weak acidity of the carboxyl group. Under different pH conditions, the drug release rate is different. The drug release rate is significantly accelerated near the tumor tissue with a low pH value, and the tumor has a strong tumor. The characteristics of selective release of drugs nearby;
  • the new nano-drug carrier can improve the efficacy of the carried drugs on diseased tissues
  • the new nano-medicine carrier can reduce the toxic and side effects of the carried drugs on normal tissues.
  • Figure 1 is a process diagram of traditional preparation of DC-Bead
  • Figure 2 shows blank embolic microspheres (50 times);
  • Figure 3 is a diagram showing the preparation and function of drug-loaded embolic microspheres
  • Figure 4 shows drug-loaded embolic microspheres loaded with doxorubicin (50 times);
  • Figure 5 shows the internal morphology of doxorubicin-loaded embolic microspheres after crushing
  • FIG. 8 Schematic diagram of the structure of poly[2-carboxyacrylic acid].
  • ⁇ -Isobutyl cyanoacrylate is dissolved in a 10% dextran solution of 0.25% polyethylene glycol 400 monooleate with a pH of 4.0 to form an ⁇ -isobutyl cyanoacrylate emulsion, and the pH is adjusted to 7.4.
  • EDC ⁇ HCL 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • NHS N-hydroxysuccinimide
  • the particle size and surface morphology of the new blank embolic microspheres were observed and measured with an optical microscope and a scanning electron microscope (as shown in Figure 2). Under different storage temperature conditions, the particle size changes of the new blank embolic microspheres during long-term storage were detected.
  • the new blank embolic microspheres can be used for the embolization treatment of arterial hemorrhage, such as traumatic pelvic and visceral hemorrhage, urinary system hemorrhage, gastrointestinal hemorrhage, severe nose and maxillofacial hemorrhage, massive hemoptysis, postoperative visceral hemorrhage. It can also be used for embolization treatment of venous bleeding, such as gastrointestinal varices.
  • An ultraviolet-visible spectrophotometer was used to determine the drug loading of the new drug-loaded embolic microspheres, the drug automatic loading speed and the drug release speed.
  • the tumor tissue block embedding method was adopted to establish a rabbit VX2 liver cancer model, and the effectiveness of using adriamycin-loaded embolization microspheres in the hepatic artery was evaluated (as shown in Figure 3).
  • an open hepatic artery cannula was used to inject doxorubicin-loaded embolization microspheres (as shown in Figure 4).
  • the concentration of doxorubicin in peripheral venous blood of experimental rabbits was determined by high performance liquid chromatography.
  • the new embolization drug-loaded microspheres can also be loaded with all positively charged drugs, which can be used for vascular embolization treatment with specific needs, which can improve the local efficacy of drugs on diseased tissues and reduce the toxic and side effects of drugs on the whole body (as shown in Figure 5) .
  • Preparation process Dissolve Tween-80 in physiological saline, adjust the pH value to 2.0 with 0.01N hydrochloric acid, and slowly drip ⁇ -butyl cyanoacrylate under the condition of high-speed dispersion of a rigid plastic rotor, for 9 minutes Finish internally, disperse in ice water with a hard plastic tissue disperser at high speed for 45 minutes, filter with 0.45 ⁇ m microporous membrane, adjust pH to 7.8 with 0.01N sodium hydroxide, store overnight, centrifuge at 8000rpm for 20 minutes at low temperature, 50% ethanol Wash 3 times, centrifuge at 8000Rpm for 20 minutes each time, save the precipitate, add 95% ethanol, hydrolyze with 0.1N sodium hydroxide to obtain a light yellow solution, remove the solvent by rotary evaporation, adjust the pH value to 7.4 with 0.1N hydrochloric acid, use
  • the dialysis bag with a molecular weight lower limit of 10,000 is subjected to pure water dialysis, the dialys
  • Preparation process Add polyethylene glycol 400 monooleate to 50% glucose, adjust the pH value to 2.0 with 0.01N hydrochloric acid, and slowly drip ⁇ -octyl cyanoacrylate under the condition of high-speed dispersion of the rigid plastic rotor , Completed within 9 minutes.
  • Preparation process Add Tween-80 and Span-20 to 20% glucose, adjust the pH to 2.0 with 0.01N hydrochloric acid, and add n-butyl cyanoacrylate to soybean oil to prepare a solution with good fluidity. Under the condition of high-speed dispersion of the plastic rotor, slowly drip the ⁇ -butyl cyanoacrylate soybean oil solution in 9 minutes, disperse in ice water with a hard plastic tissue disperser for 5 minutes, and filter with a 0.45 ⁇ m microporous filter membrane.
  • Adjust the pH value to 12 with 0.01N sodium hydroxide continue to disperse overnight, centrifuge at 8000rpm for 40 minutes, wash with pure water three times, centrifuge at 8000rpm for 20 minutes each time, save the precipitate, add an appropriate amount of 95% ethanol, and use 0.1N hydrogen Sodium oxide is hydrolyzed to obtain a light yellow solution.
  • the solvent is removed by rotary evaporation.
  • the pH value is adjusted to 7.4 with 0.1N hydrochloric acid.
  • the dialysis bag with a molecular weight lower limit of 10000 is used for pure water dialysis.
  • the dialysate is changed every 12 hours. [2-Carboxy acrylic acid].
  • Preparation process Add poloxamer to 5% dextran, adjust the pH value to 2.0 with 0.01N hydrochloric acid, and slowly drip ⁇ -cyanoacrylate isobutyl ester under the condition of high-speed dispersion of the rigid plastic rotor, within 9 minutes Finished within.
  • Preparation process Add n-butyl cyanoacrylate to absolute ethanol to form a transparent solution. Under the condition of high-speed dispersion of the hard plastic rotor, slowly drop the n-butyl cyanoacrylate in absolute ethanol solution.
  • Preparation process Add methyl ⁇ -cyanoacrylate into acetone to form a transparent solution. Under the condition of high-speed dispersion of the rigid plastic rotor, slowly drip the acetone solution of ⁇ -methyl cyanoacrylate into acetone, which is completed within 9 minutes.
  • the dialysis bag was subjected to pure water dialysis, the dialysate was changed every 12 hours, and then freeze-dried to obtain poly[2-carboxyacrylic acid].
  • Preparation process Add ethyl ⁇ -cyanoacrylate to acetonitrile to form a transparent solution. Under the condition of high-speed dispersion of the hard plastic rotor, slowly drip the ethyl ⁇ -cyanoacrylate acetonitrile solution, which is completed within 9 minutes.
  • the dialysis bag is subjected to pure water dialysis, the dialysate is changed every 12 hours, and then freeze-dried to obtain poly[2-carboxyacrylic acid].
  • Preparation process under magnetic stirring conditions, with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride [1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide, EDC ⁇ HCL ], 1-Hydroxybenzotriazole (N-Hydroxybenzotriazole, HOBT) as a catalyst, add 2g NH 2 -PEG to the nano-medicine carrier skeleton solution to modify the nano-medicine carrier skeleton, react overnight, put the above solution into the dialysis bag, Distilled water was dialyzed for 72 hours, and the water was changed every 12 hours to remove impurities with a molecular weight of less than 10,000 to obtain a nano-medicine carrier covered with PEG2000. Adjust the pH to 7.4 to obtain a nano-medicine carrier.
  • Preparation process Dissolve the above materials in 50mL of absolute ethanol, remove the absolute ethanol by rotary evaporation to obtain liposome membrane, add 50mL of water, filter with 200nm microporous membrane after hydration, adjust the pH to 7.4 with 0.001N sodium hydroxide
  • the gel chromatography removes the poly[2-carboxyacrylic acid] outside the liposome that is not encapsulated by the liposome, and after filtration, the nano-liposome that can actively load positively charged drugs is obtained, which is also a nano-drug carrier.
  • the new nano-medicine carrier has a spherical shape, uniform particle size and uniform distribution, and the Zeta potential can reach -52.5mV.
  • doxorubicin as an example, the mouse S180 sarcoma animal model and the C57BL6 tumor lung metastasis animal model proved that this nano-doxorubicin can significantly reduce the cardiotoxicity of doxorubicin, especially the heart failure caused by doxorubicin. At the same time, improve its anti-tumor effect (P ⁇ 0.01).
  • the rabbit liver cancer model was used to evaluate its efficacy. The results showed that compared with doxorubicin, its anti-cancer effect was significantly improved (P ⁇ 0.01).
  • the new nano-medicine carrier is loaded with doxorubicin
  • a kind of nano-doxorubicin covered with polyethylene glycol is formed.
  • it After entering the body, it can circulate in the blood for a long time, and it is difficult to enter normal tissues with extremely low vascular permeability. Passively accumulates in tumor tissues with high vascular permeability, so it can improve the anti-tumor effect of doxorubicin and reduce the toxic reaction of doxorubicin.
  • the new nano-drug carrier After intravenous infusion into the blood, the new nano-drug carrier will accumulate in tumor tissues, infection sites or inflammatory sites with high vascular permeability, thereby improving the efficacy of anti-cancer drugs, antibacterial drugs or anti-tumor drugs, while reducing their adverse reactions .
  • the results of in vivo distribution studies show that the new nano-lipid drug carrier significantly reduces the distribution of doxorubicin to the heart and other normal tissues and organs, and the distribution of tumors or infectious and inflammatory lesions is significantly improved. The results are shown in Figure 6-8.

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Abstract

一种聚[α-氰基丙烯酸酯]水解产物及其制备方法和应用，属于医药化工领域。主要技术方案为：聚[α-氰基丙烯酸酯]水解产物，化学式为：式（I），R＝-CN或-COOH。聚[2-氰基丙烯酸]分散于水中形成带有负电荷的微球，即得到空白栓塞微球，其粒径能在微米级范围内调整，且具有由变形功能以通过特定形态的血管，可以紧密栓塞血管避免脱落造成异位栓塞；聚[2-羧基丙烯酸]可用于制备新型纳米药物载体，可以提高所运载药物对病变组织的疗效，减轻所运载药物对正常组织的毒副作用。

Description

聚[α-氰基丙烯酸酯]水解产物及其制备方法和应用 技术领域
本发明涉及医药化工领域，具体涉及聚[α-氰基丙烯酸酯]水解产物及其制备方法和应用。
背景技术
一般认为血管内栓塞应当避免，但某些血管如果能选择性地使之部分栓塞，却能收到良好的治疗效果。近年来，由于医疗技术的发展，人们已可以通过插入的导管向有关动脉注入血管栓塞剂(Vascular Occlusive Agent)来治疗一些疾病，尤其对于一些难以用手术或药物控制的疾病，例如肿瘤或者胃底静脉曲张。这种技术在医疗上称为选择性血管栓塞术。经导管动脉栓塞术在20世纪70年代首先被用于治疗前列腺穿刺活检或经尿道前列腺切除术后的前列腺出血以及前列腺来源的顽固性血尿。在进行血管栓塞术时，必须使用栓塞剂，除使用一些天然的栓塞物质如血凝块外，可用气囊、金属小球、弹簧管等进行机械性堵塞。目前使用的栓塞剂分为固体和液体二大类，一些天然的栓塞剂也列入固体类栓塞剂。
纳米药物载体种类很多，其中脂质体颇受重视。脂质体主要由胆固醇与磷脂组成，结构类似于细胞，可用于运载药物。脂质体的主要问题有两个：首先是如何装载药物，其次是如何防止脂质体被网状内皮系统吞噬和破坏及如何在病变组织释放药物。脂质体毒性低、无免疫原性、无致热原性，能够通过正常代谢而被清除，是一种比较理想的药物载体。目前的纳米脂质体药物，主要是借助于铵离子梯度主动装载药物，制备纳米脂质体药物，例如Doxil，是一种液体的纳米阿霉素脂质体。但是，这种纳米脂质体阿霉素制备工艺复杂，稳定性差，而且在肿瘤组织部位难以主动释放药物。
发明内容
针对现有技术存在的问题，本发明提供聚[α-氰基丙烯酸酯]水解产物及其制备方法和应用。本发明的技术方案如下：
聚[α-氰基丙烯酸酯]水解产物，化学式为：
Figure PCTCN2020110386-appb-000001
R＝-CN或-COOH。
本发明同时请求保护所述聚[α-氰基丙烯酸酯]水解产物的制备方法为：先制备α-氰基丙烯酸酯聚合物，再水解聚合物，即得到聚[α-氰基丙烯酸酯]水解产物。
R为-CN，聚[2-氰基丙烯酸]，化学式为：
Figure PCTCN2020110386-appb-000002
聚[2-氰基丙烯酸]的制备方法为：先制备α-氰基丙烯酸酯聚合物，再在碱性条件下选择性水解聚合物中的酯键，纯化后，即得到聚[2-氰基丙烯酸]。
本发明请求保护所述聚[α-氰基丙烯酸酯]水解产物的应用，将聚[2-氰基丙烯酸]制备成为空白栓塞微球。
进一步的，所述空白栓塞微球的制备方法为：将聚[2-氰基丙烯酸]分散于水中形成带有负电荷的微球，即得到空白栓塞微球。
进一步的，所述的空白栓塞微球的粒径≥1um，且可以变形。
进一步的，空白栓塞微球的粒径能在微米级范围内调整，以适应不同管径血管栓塞靶点的要求，同时根据需要空白栓塞微球具有变形功能，以通过栓塞路径上的血管狭窄，可紧密栓塞血管，能避免脱落造成的异位栓塞。
本发明将聚[2-氰基丙烯酸]制备成为的空白栓塞微球，再制备成为载药栓塞微球。
进一步的，所述载药栓塞微球的制备方法为：将空白栓塞微球与荷正电荷的药物相结合，即得到载药栓塞微球。
进一步的，载药栓塞微球以反转电荷的原理主动装载(pH≥7.4)和释放(pH≤6.5)药物。
进一步的，载药栓塞微球在血管通透性高、pH值低的病变组织，能直接释放药物进入病变组织局部，药物很少进行全身流动，从而提高药物对病变组织局部的疗效，减轻药物对全身的毒副作用。
更具体优选的制备方法和应用如下：
1.聚[2-氰基丙烯酸]的制备
(1)方法一：
在pH值2.0-4.0的生理盐水或5％以上葡萄糖溶液或5％以上右旋糖酐溶液中，用非离子表面活性剂如聚乙二醇型非离子表面活性剂或吐温类表面活性剂或司盘类表面活性剂或泊洛沙姆等，制备α-氰基丙烯酸酯或其植物油溶液的乳剂。再将pH值调节到7.4以上，加速聚合反应形成α-氰基丙烯酸酯聚合物。再在碱性条件下选择性水解聚合物的酯键并保留氰基，植物油将会皂化，透析除去杂质，即得到聚[2-氰基丙烯酸]。
非离子表面活性剂含量越高，α-氰基丙烯酸酯的用量越少，乳剂粒径越小。聚[2-氰基丙烯酸]的聚合度大小可由α-氰基丙烯酸酯乳剂粒径大小来控制，乳剂粒径越小聚合度越小。
不同分子量范围的聚[2-氰基丙烯酸]可由透析法或凝胶色谱法分离制备。
(2)方法二：
将α-氰基丙烯酸酯溶于无水乙醇或丙酮或乙腈中。在硬塑分散器高速分散条件下，把α-氰基丙烯酸酯的无水乙醇或乙腈或丙酮溶液，缓慢滴入酸性水中，磁力搅拌过夜。高速离心收集α-氰基丙烯酸酯聚合沉淀物。再在碱性条件下选择性水解聚合物的酯键并保留氰基，透析除去杂质，即得到聚[2-氰基丙烯酸]。
聚[2-氰基丙烯酸]的聚合度大小可由α-氰基丙烯酸酯的浓度决定，其浓度越低聚合度越低。
不同分子量范围的聚[2-氰基丙烯酸]可由透析法或凝胶色谱法分离制备。
2.聚[2-氰基丙烯酸]空白栓塞微球的制备
通过控制聚[α-氰基丙烯酸酯]的聚合时间或α-氰基丙烯酸酯浓度，控制其聚合度，可由此控制空白栓塞微球的粒径大小。
聚[2-氰基丙烯酸]富含羧基，空白栓塞微球在碱性条件下，其羧基会带有负 电荷，负电荷之间产生排斥力，因此空白栓塞微球具有弹性和变形能力。
(1)方法一：
聚[2-氰基丙烯酸]有一定表面活性作用且易溶于无水乙醇，将其乙醇溶液分散于水中，即得到富含羧基的空白栓塞微球。
(2)方法二：
聚[2-氰基丙烯酸]有一定表面活性作用且易溶于无水乙醇，将其乙醇溶液分散于水中，并用活性聚乙二醇修饰聚[2-氰基丙烯酸]的部分羧基，即得到羧基修饰的空白栓塞微球。
聚合物羧基结合的聚乙二醇可有效防止网状内皮系统对空白栓塞微球的骨架材料聚[2-氰基丙烯酸]的迅速吞噬和破坏，未被修饰的羧基用以主动装载荷正电荷的药物。
羧基修饰的最佳比例与所运载的药物量和药物种类有关，当药物的分子量比较大，亲水性比较差，则被修饰的羧基比例就要高一点，当药物的分子量比较小，亲水性比较强，则被修饰的羧基比例就可以低一点，此外被修饰羧基的比例还与应用的个体差异有关，必须确保网状内皮系统不能迅速的破坏空白栓塞微球，总之具体的羧基修饰比例和活性聚乙二醇的分子量，要根据临床需求具体制定。
3.聚[2-氰基丙烯酸]空白栓塞微球的应用
聚[2-氰基丙烯酸]空白栓塞微球可根据临床需要调整其粒径大小，且具有弹性和变形能力，粒径≥8um时，行栓塞治疗可通过特定的血管狭窄，并与血管壁紧密作用难以脱落，不会产生异位栓塞。
4.聚[2-氰基丙烯酸]载药栓塞微球的制备
将聚[2-氰基丙烯酸]空白栓塞微球与荷正电荷的各种药物相结合，即得到各种载药栓塞微球。
5.聚[2-氰基丙烯酸]载药栓塞微球的应用
根据临床需要，载药栓塞微球能装载不同的一种或多种荷正电荷药物，进行有特定要求的局部栓塞治疗，其在血管通透性高、pH值低的病变组织，能直接释放药物进入病变组织局部，药物很少进行全身流动，从而提高药物对病变组织局部的疗效，减轻药物对全身的毒副作用。
R为-COOH，聚[2-羧基丙烯酸]，化学式为：
Figure PCTCN2020110386-appb-000003
聚[2-羧基丙烯酸]的制备方法为：先制备α-氰基丙烯酸酯聚合物，再在碱性条件下水解聚合物的酯键和氰基，透析除去杂质，即得到聚[2-羧基丙烯酸]。
本发明请求保护所述聚[α-氰基丙烯酸酯]水解产物的应用，将聚[2-羧基丙烯酸]制备成为纳米药物载体。
进一步的，所述纳米药物载体的制备方法为：用活性聚乙二醇修饰聚[2-羧基丙烯酸]的部分羧基，未被修饰的羧基用于运载荷正电荷的药物，即得到一种具有借助pH值梯度主动装载(pH≥7.4)和释放(pH≤6.5)荷正电荷药物功能的新型纳米药物载体。
进一步的，所述纳米药物载体的制备方法为：将聚[2-羧基丙烯酸]包封于脂 质体，即得到一种具有借助pH值梯度主动装载(pH≥7.4)和释放(pH≤6.5)荷正电荷药物功能的新型纳米脂质体，也属于纳米药物载体。
进一步的，纳米药物载体以反转电荷的原理主动装载和释放药物。
进一步的，纳米药物载体通过血液靶向输送药物，纳米药物载体蓄积到血管通透性高、pH值低的病变组织，并直接释放药物进入病变组织，药物很少进入正常组织，所运载的药物对病变组织疗效增强，对正常组织毒副作用减轻。
更具体优选的制备方法和应用如下：
1.聚[2-羧基丙烯酸]的制备
(3)方法一：
在pH值2.0-4.0的生理盐水或5％以上葡萄糖溶液或5％以上右旋糖酐溶液中，用非离子表面活性剂如聚乙二醇型非离子表面活性剂或吐温类表面活性剂或司盘类表面活性剂或泊洛沙姆等，制备α-氰基丙烯酸酯或其植物油溶液的乳剂。再将pH值调节到7.4以上，加速聚合反应形成α-氰基丙烯酸酯聚合物。再在碱性条件下水解聚合物的酯键和氰基，植物油将会皂化，透析除去杂质，即得到聚[2-羧基丙烯酸]。
非离子表面活性剂含量越高，α-氰基丙烯酸酯的用量越少，微乳体积越小。聚[2-羧基丙烯酸]的聚合度大小可由α-氰基丙烯酸酯微乳大小来控制，微乳越小聚合度越小。
不同分子量范围的聚[2-羧基丙烯酸]可由透析法或凝胶色谱法分离制备。
(4)方法二：
将α-氰基丙烯酸酯溶于无水乙醇或丙酮或乙腈中。在硬塑分散器高速分散条件下，把α-氰基丙烯酸酯的无水乙醇或乙腈或丙酮溶液，缓慢滴入酸性水中，磁力搅拌过夜。高速离心收集α-氰基丙烯酸酯聚合沉淀物。再在碱性条件下水解聚合物的酯键和氰基，透析除去杂质，即得到聚[2-羧基丙烯酸]。
聚[2-羧基丙烯酸]的聚合度大小可由α-氰基丙烯酸酯的浓度决定，其浓度越低聚合度越低。
不同分子量范围的聚[2-羧基丙烯酸]可由透析法或凝胶色谱法分离制备。
2.聚[2-羧基丙烯酸)纳米药物载体的制备
(1)方法一：
用活性聚乙二醇修饰聚[2-羧基丙烯酸]的部分羧基，即得到聚[2-羧基丙烯酸]纳米药物载体。
聚合物羧基结合的聚乙二醇可有效防止网状内皮系统对纳米药物载体的骨架材料聚[2-羧基丙烯酸]的迅速吞噬和破坏，未被修饰的羧基用以主动装载荷正电荷的药物。
羧基修饰的最佳比例与所运载的药物量和药物种类有关，当药物的分子量比较大，亲水性比较差，则被修饰的羧基比例就要高一点，当药物的分子量比较小，亲水性比较强，则被修饰的羧基比例就可以低一点，此外被修饰羧基的比例还与应用的个体差异有关，必须确保网状内皮系统不能迅速的破坏纳米药物载体，总 之具体的羧基修饰比例和活性聚乙二醇的分子量，要根据临床需求具体制定。
(2)方法二：
将磷脂、胆固醇、PEG2000-DSPE、聚[2-羧基丙烯酸]溶于无水乙醇，用薄膜法制备内部包封聚[2-羧基丙烯酸]的脂质体，采用凝胶色谱法除去脂质体外面的聚[2-羧基丙烯酸]，即得到包封聚[2-羧基丙烯酸]的纳米脂质体，再调节纳米脂质体外水相的pH值至7.4，脂质体内外pH值梯度可达5.0以上，即得到具有主动装载荷正电荷药物功能的纳米脂质体，也属于纳米药物载体。
根据Henderson-Hasselbalch理论,每个pH值单位的变化会产生分子型与离子型药物浓度10倍之差，如果脂质体内外pH值梯度为3.0时,理论上就会造成药物分子型与离子型浓度的1000倍之差。由于分子型药物易与脂质体双分子膜结合,从而加快了药物分子的跨膜内转过程。
聚[2-羧基丙烯酸]与荷正电荷药物结合形成沉淀，会进一步促进荷正电荷药物进入纳米脂质体，提高纳米脂质体运载药物的能力。
3.聚[2-羧基丙烯酸]纳米药物载体的应用
采用聚[2-羧基丙烯酸]制备的纳米药物载体，以反转电荷的原理，在碱性条件下如pH＝7.4,借助于羧基主动装载荷正电荷的药物，反之在酸性条件下如pH＝6.5，会自发释放所运载的荷正电荷药物。
正常组织血管通透性低，pH值较高(接近7.4)，反之病变组织血管通透性高，pH值较低(接近6.5)，因此纳米药物载体进入血液循环系统后会逐渐蓄积到病变组织，并释放所运载的药物，从而提高药物对病变组织的疗效(前体药物除外)，同时减轻药物对正常组织的毒副作用。
本发明的有益效果如下：
(1)提供了一种新材料富含羧基的聚[2-氰基丙烯酸]的制备方法；
(2)聚[2-氰基丙烯酸]可用于制备新型空白栓塞微球；
(3)新型空白栓塞微球粒径大小可调，且具有变形通过狭窄的能力；
(4)新型空白栓塞微球可用于制备新型载药栓塞微球；
(5)新型载药栓塞微球可提高所运载药物对病变组织局部的疗效；
(6)新型载药栓塞微球可以减轻所运载药物对全身的毒副作用；
(7)国外DC-bead现有技术中(如图1所示)，必须使用N-丙烯酰-氨基乙醛-二甲基缩醛、醋酸丁酯，挥发性高，残留量大，不利于生产环境，安全性较低。本发明仅使用α-氰基丙烯酸酯、植物油、葡萄糖、生理盐水、非离子表面活性剂、活性聚乙二醇、无水乙醇、纯水等，无毒性残留，无污染，工艺简单，生产成本低，安全性较高；
(8)国外DC-bead的单位体积所装载抗癌药物的分子数较少。本发明制备的载药栓塞微球，根据化学结构推算，其分子结构中，大约50％的碳原子携带一个羧基负电荷，而DC-bead分子中大约20％碳原子携带一个羧基负电荷。本发明制备的载药栓塞微球的单位质量负电荷总量显著高于DC-bead，装载药物的能力显著提高；
(9)国外DC-bead是酸性较强的磺酸基团，在肿瘤组织附近选择性释放药物的能力弱。本发明制备的载药栓塞微球所携带的羧基酸性较弱，在不同pH值条件下，释放药物速度不一样，在pH值低的肿瘤组织附近，释放药物速度显著加快，具有较强的肿瘤附近选择性释放药物的特点；
(10)提供了一种新材料富含羧基的聚[2-羧基丙烯酸]的制备方法；
(11)聚[2-羧基丙烯酸]可用于制备新型纳米药物载体；
(12)新型纳米药物载体可以提高所运载药物对病变组织的疗效；
(13)新型纳米药物载体可以减轻所运载药物对正常组织的毒副作用。
附图说明
图1为传统制备DC-Bead的工艺图；
图2为空白栓塞微球(50倍)；
图3为载药栓塞微球制备及发挥作用图；
图4为装载阿霉素的载药栓塞微球(50倍)；
图5为装载阿霉素的载药栓塞微球粉碎后的内部形态；
图6聚[2-羧基丙烯酸]纳米阿霉素的电镜照片；
图7聚[2-羧基丙烯酸]纳米阿霉素脂质体的电镜照片；
图8聚[2-羧基丙烯酸]的结构示意图。
具体实施方式
下面结合具体实施例对本发明做进一步的说明和解释，若无特殊说明，本发明所用原料及设备均为常用原料和设备。
实施例1---聚[2-氰基丙烯酸]的制备
(1)配方：α-氰基丙烯酸正丁酯
生理盐水、芝麻油、吐温-80、司盘-20、无水乙醇
将α-氰基丙烯酸正丁酯溶于精制无热原的芝麻油中，形成30％的α-氰基丙烯酸正丁酯的油溶液10mL，分散于pH值4.0的0.25％的吐温-80和司盘-20的生理盐水溶液中。再调节pH值至7.8引发α-氰基丙烯酸正丁酯聚合反应，12小时后离心分离沉淀物，用无水乙醇洗涤沉淀物并离心反复5次，将沉淀物分散于50ml无水乙醇中，加入氢氧化钠，选择性水解酯键并保留氰基，减压蒸发除去无水乙醇，再与100mL蒸馏水混合，8000rpm离心20分钟，弃去上清液，震摇水洗，再离心，反复5次，即得到聚[2-氰基丙烯酸]。
(2)配方：α-氰基丙烯酸辛酯
50％葡萄糖溶液、泊洛沙姆、无水乙醇
将α-氰基丙烯酸辛酯溶于pH值4.0的0.25％泊洛沙姆的50％葡萄糖溶液中，形成α-氰基丙烯酸辛酯乳剂，pH值调至7.4，在搅拌条件下，室温下聚合12小时，离心分离沉淀物，将沉淀物分散于50ml无水乙醇中，加入氢氧化钠，选择性水解酯键并保留氰基，减压蒸发除去无水乙醇，再与100mL蒸馏水混合，8000rpm离心20分钟，弃去上清液，震摇水洗，再离心，反复5次，即得到聚[2-氰基丙烯酸]。
(3)配方：α-氰基丙烯酸异丁酯
10％右旋糖酐溶液、聚乙二醇400单油酸酯、无水乙醇
将α-氰基丙烯酸异丁酯溶于pH值4.0的0.25％聚乙二醇400单油酸酯的10％右旋糖酐溶液中，形成α-氰基丙烯酸异丁酯乳剂，pH值调至7.4，在搅拌条件下，室温下聚合12小时，离心分离沉淀物，再将沉淀物分散于50ml无水乙醇中，加入氢氧化钠，选择性水解酯键并保留氰基，减压蒸发除去无水乙醇，再与100mL蒸馏水混合，8000rpm离心20分钟，弃去上清液，震摇水洗，再离心，反复5次，即得到聚[2-氰基丙烯酸]。
(4)配方：α-氰基丙烯酸正丁酯
无水乙醇
将α-氰基丙烯酸正丁酯溶于无水乙醇制成50％乙醇溶液，聚合1周，再加氢氧化钠选择性水解酯键并保留氰基，减压蒸发除去无水乙醇，再与100mL蒸馏水混合，8000rpm离心20分钟，弃去上清液，震摇水洗，再离心，反复5次，即得到聚[2-氰基丙烯酸]。
(5)配方：α-氰基丙烯酸甲酯
丙酮、无水乙醇
将α-氰基丙烯酸甲酯溶于无水乙醇制成50％丙酮溶液，聚合2周，再减压除去丙酮，分散于无水乙醇中，再加氢氧化钠选择性水解酯键并保留氰基，减压蒸发除去无水乙醇，与100mL蒸馏水混合，8000rpm离心20分钟，弃去上清液，震摇水洗，再离心，反复5次，即得到聚[2-氰基丙烯酸]。
(6)配方：α-氰基丙烯酸乙酯
乙腈、无水乙醇
将α-氰基丙烯酸乙酯溶于乙腈制成50％乙腈溶液，聚合2周，再减压除去乙腈，分散于无水乙醇中，再加氢氧化钠选择性水解酯键并保留氰基，减压蒸发除去无水乙醇，与100mL蒸馏水混合，8000rpm离心20分钟，弃去上清液，震摇水洗，再离心，反复5次，即得到聚[2-氰基丙烯酸]。
实施例2---聚[2-氰基丙烯酸]空白栓塞微球的制备
(1)配方：聚[2-氰基丙烯酸]
无水乙醇、水
取0.5g聚[2-氰基丙烯酸]制成5mL无水乙醇溶液。置旋转蒸发器中，挥发乙醇至器壁上形成薄膜，与50mL蒸馏水混合，水合12小时，8000rpm离心20分钟，弃去上清液，震摇水洗，再离心，反复5次，即得到空白栓塞微球。
(2)配方：聚[2-氰基丙烯酸]
氨基聚乙二醇2000、水
用氨基聚乙二醇2000修饰羧基，活性聚乙二醇修饰的催化剂：
EDC·HCL：1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐；
NHS：N-羟基丁二酰亚胺。聚乙二醇修饰之后，8000rpm离心20分钟，弃去上清液，震摇水洗，再离心，反复5次，即得到聚乙二醇修饰的空白栓塞微球。
实施例3---聚[2-氰基丙烯酸]载药栓塞微球的制备
(1)配方：空白栓塞微球
阿霉素
取空白栓塞微球1mL，与等体积pH值7.4的2mg/mL阿霉素1/15M等渗磷酸盐缓冲液混合，震摇15分钟，倾去剩余阿霉素溶液，再用pH值7.4的1/15M等渗磷酸盐缓冲液冲洗，即得到可供肿瘤动脉血管栓塞的阿霉素载药栓塞微球。
(2)配方：空白栓塞微球
庆大霉素
取空白栓塞微球1mL，与等体积pH值7.4的10mg/mL庆大霉素1/15M等渗磷酸盐缓冲液，震摇5分钟，倾去剩余庆大霉素溶液，再用pH值7.4的1/15M等渗磷酸盐缓冲液冲洗，即得到有抗炎治疗需求的庆大霉素载药栓塞微球。
聚[2-氰基丙烯酸]栓塞微球的功效
1.新型空白栓塞微球
用光学显微镜，扫描电子显微镜对新型空白栓塞微球的粒径大小，表面形态特征进行观察与测定(如图2所示)。在不同贮存温度条件下，检测新型空白栓塞微球长期贮存过程中的粒径变化。新型空白栓塞微球可用于动脉性出血的栓塞治疗，如外伤性盆腔和内脏出血，泌尿系统出血，消化道出血，严重鼻和颌面部出血、大咯血、术后内脏出血。也可用于静脉性出血的栓塞治疗，如消化道静脉曲张。
2.新型载药栓塞微球
用紫外-可见分光光度计测定新型载药栓塞微球的载药量，药物自动装载速度及药物释放速度。采取肿瘤组织块包埋法，建立兔VX2肝癌模型，评价了肝动脉使用阿霉素载药栓塞微球的有效性(如图3所示)。在瘤块包埋种植两周后，采取开腹式肝动脉插管注射阿霉素载药栓塞微球(如图4所示)。用高效液相色谱法测定实验兔外周静脉血阿霉素浓度。采用疫荧光染色技术，观察瘤体内阿霉素的分布和肿瘤微血管密度。结果表明这种新型载药栓塞微球大小可以有效栓塞肿瘤动脉血管，抗肿瘤疗效显著，肿瘤血管密度显著降低。动物实验表明此种新型载药栓塞微球还能用于肾癌、肾上腺癌、盆腔内各种富含血管的肿瘤、颌面部恶性肿瘤、四肢、脊柱骨盆恶性肿瘤的治疗。新型栓塞载药微球也可装载荷正电荷的一切药物，用于有特定需求的血管栓塞治疗，可以提高药物对病变组织局部的疗效，减轻药物对全身的毒副作用(如图5所示)。
实施例4---聚[2-羧基丙烯酸]的制备
(1)配方：α-氰基丙烯酸正丁酯     0.9mL
吐温-80                 3.0mL
生理盐水(pH值2.0)      50mL
制备工艺：将吐温-80溶入生理盐水中，用0.01N盐酸调pH值至2.0，在硬塑转子的高速分散条件下，把α-氰基丙烯酸正丁酯缓慢滴入，9分钟之内完成，在冰水中用硬塑组织分散器高速分散45分钟，用0.45μm微孔滤膜过滤，用 0.01N氢氧化钠调pH值至7.8，保存过夜，8000rpm低温离心20分钟，50％乙醇洗涤3次，每次8000Rpm离心20分钟，留取沉淀物，加入95％乙醇，用0.1N氢氧化钠水解，得浅黄色溶液，旋转蒸发除去溶媒，用0.1N盐酸调pH值至7.4，用分子量下限10000的透析袋行纯水透析，每12小时换一次透析液，冷冻干燥，即得到聚[2-羧基丙烯酸]。
(2)配方：α-氰基丙烯酸辛酯         0.9mL
聚乙二醇400单油酸酯      6.0mL
50％葡萄糖(pH值2.0)       50mL
制备工艺：将聚乙二醇400单油酸酯加入到50％葡萄糖中，0.01N盐酸调pH值至2.0，在硬塑转子的高速分散条件下，把α-氰基丙烯酸辛酯缓慢滴入，9分钟之内完成。在冰水中用硬塑组织分散器分散5分钟，用0.45μm微孔滤膜过滤，用0.01N氢氧化钠调pH值至7.8，继续分散过夜，8000rpm低温离心40分钟，纯水洗涤三次，每次8000rpm离心20分钟，留取沉淀物，加入95％乙醇适量，用0.1N氢氧化钠水解，得浅黄色溶液，旋转蒸发除去溶媒，用0.1N盐酸调pH值至7.4，用分子量下限10000的透析袋行纯水透析，每12小时换一次透析液，冷冻干燥，即得到聚[2-羧基丙烯酸]。
Figure PCTCN2020110386-appb-000004
制备工艺：将吐温-80和司盘-20加入20％葡萄糖中，0.01N盐酸调pH值至2.0，α-氰基丙烯酸正丁酯加入豆油中，制备成流动性良好的溶液，在硬塑转子的高速分散条件下，把α-氰基丙烯酸正丁酯豆油溶液缓慢滴入，9分钟之内完成，在冰水中用硬塑组织分散器分散5分钟，用0.45μm微孔滤膜过滤，用0.01N氢氧化钠调pH值至12，继续分散过夜，8000rpm低温离心40分钟，纯水洗涤三次，每次8000rpm离心20分钟，留取沉淀物，加入95％乙醇适量，用0.1N氢氧化钠水解，得浅黄色溶液，旋转蒸发除去溶媒，用0.1N盐酸调pH值至7.4，用分子量下限10000的透析袋行纯水透析，每12小时换一次透析液，冷冻干燥，即得到聚[2-羧基丙烯酸]。
(4)配方：α-氰基丙烯酸异丁酯       0.9mL
泊洛沙姆                  6.0mL
5％右旋糖酐(pH值2.0)      50mL
制备工艺：将泊洛沙姆加入到5％右旋糖酐中，0.01N盐酸调pH值至2.0，在硬塑转子的高速分散条件下，把α-氰基丙烯酸异丁酯缓慢滴入，9分钟之内完成。在冰水中用硬塑组织分散器分散5分钟，用0.45μm微孔滤膜过滤，用0.01N氢氧化钠调pH值至7.8，继续分散过夜，8000rpm低温离心40分钟，纯水洗涤三次，每次8000rpm离心20分钟，留取沉淀物，加入95％乙醇适量，用 0.1N氢氧化钠水解，得浅黄色溶液，旋转蒸发除去溶媒，用0.1N盐酸调pH值至7.4，用分子量下限10000的透析袋行纯水透析，每12小时换一次透析液，冷冻干燥，即得到聚[2-羧基丙烯酸]。
(5)配方：α-氰基丙烯酸正丁酯     0.9mL
无水乙醇                5.0mL
水(pH值2.0)            50mL
制备工艺：将α-氰基丙烯酸正丁酯加入无水乙醇中，形成透明溶液，在硬塑转子的高速分散条件下，把α-氰基丙烯酸正丁酯无水乙醇溶液缓慢滴入，9分钟之内完成，在冰水中用硬塑组织分散器分散15分钟，用0.45μm微孔滤膜过滤，用0.01N氢氧化钠调滤液pH值至7.8，继续分散过夜，8000rpm低温离心15分钟，纯水洗涤三次，每次8000rpm离心15分钟，留取沉淀物，加入95％乙醇适量，用0.1N氢氧化钠水解，得浅黄色溶液，旋转蒸发除去溶媒，用0.1N盐酸调pH值至7.4，用分子量下限10000的透析袋行纯水透析，每12小时换一次透析液，冷冻干燥，即得到聚[2-羧基丙烯酸]。
(6)配方：α-氰基丙烯酸甲酯       0.9mL
丙酮                    5.0mL
水(pH值2.0)            50mL
制备工艺：将α-氰基丙烯酸甲酯加入丙酮中，形成透明溶液，在硬塑转子的高速分散条件下，把α-氰基丙烯酸甲酯丙酮溶液缓慢滴入，9分钟之内完成，在冰水中用硬塑组织分散器分散15分钟，用0.45μm微孔滤膜过滤，用0.01N氢氧化钠调滤液pH值至7.8，继续分散过夜，8000rpm低温离心15分钟，纯水洗涤三次，每次8000rpm离心15分钟，留取沉淀物，加入95％乙醇适量，用0.1N氢氧化钠水解，得浅黄色溶液，旋转蒸发除去溶媒，用0.1N盐酸调pH值至7.4，用分子量下限10000的透析袋行纯水透析，每12小时换一次透析液，冷冻干燥，即得到聚[2-羧基丙烯酸]。
(7)配方：α-氰基丙烯酸乙酯       0.9mL
乙腈                    5.0mL
水(pH值2.0)            50mL
制备工艺：将α-氰基丙烯酸乙酯加入乙腈中，形成透明溶液，在硬塑转子的高速分散条件下，把α-氰基丙烯酸乙酯乙腈溶液缓慢滴入，9分钟之内完成，在冰水中用硬塑组织分散器分散15分钟，用0.45μm微孔滤膜过滤，用0.01N氢氧化钠调滤液pH值至7.8，继续分散过夜，8000rpm低温离心15分钟，纯水洗涤三次，每次8000rpm离心15分钟，留取沉淀物，加入95％乙醇适量，用0.1N氢氧化钠水解，得浅黄色溶液，旋转蒸发除去溶媒，用0.1N盐酸调pH值至7.4，用分子量下限10000的透析袋行纯水透析，每12小时换一次透析液，冷冻干燥，即得到聚[2-羧基丙烯酸]。
实施例5---聚[2-羧基丙烯酸]纳米药物载体的制备
(1)配方：聚[2-羧基丙烯酸]    590mg
氨基聚乙二醇2000      2000mg
制备工艺：在磁力搅拌条件下，以1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐[1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide，EDC·HCL]、N-羟基丁二酰亚胺(N-Hydroxy succinimide，NHS)为催化剂，向纳米药物载体骨架溶液中加入2g NH 2-PEG，修饰纳米药物载体骨架，反应过夜，将上述溶液放入透析袋，用蒸馏水透析72h,每12h换一次水，去除分子量小于10000的杂质，即得到表面覆盖PEG2000的纳米药物载体，调pH值至7.4，即得纳米药物载体。
(2)配方：聚[2-羧基丙烯酸]    590mg
聚乙二醇-酰肼       2000mg
制备工艺：在磁力搅拌条件下，以1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐[1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide，EDC·HCL]、1-羟基苯并三唑(N-Hydroxybenzotriazole，HOBT)为催化剂，向纳米药物载体骨架溶液中加入2g NH 2-PEG，修饰纳米药物载体骨架，反应过夜，将上述溶液放入透析袋，用蒸馏水透析72h,每12h换一次水，去除分子量小于10000的杂质，即得到表面覆盖PEG2000的纳米药物载体，调pH值至7.4，即得纳米药物载体。
Figure PCTCN2020110386-appb-000005
制备工艺：将上述材料溶于50mL无水乙醇，旋转蒸发除去无水乙醇，得到脂质体膜，加入50mL水，水合后200nm微孔滤膜过滤，用0.001N氢氧化钠调pH值到7.4，凝胶色谱法除去脂质体外面的未被脂质体包封的聚[2-羧基丙烯酸]，过滤后，即得到能够主动装载荷正电荷药物的纳米脂质体，也是纳米药物载体。
聚[2-羧基丙烯酸]纳米药物载体的功效
新型纳米药物载体在扫描电子显微镜下，形态球状、粒径均一、分布均匀，Zeta电位为可达-52.5mV。以阿霉素为例，通过小白鼠S180肉瘤动物模型、C57BL6的肿瘤肺转移动物模型证明，这种纳米阿霉素可以显著降低阿霉素的心脏毒性，特别是显著降低阿霉素导致心衰的发生率，同时提高其抗肿瘤作用(P<0.01)。采用家兔肝癌模型，评价其药效，结果表明，与阿霉素相比，其抗癌作用显著提高(P<0.01)。新型纳米药物载体装载阿霉素之后，形成一种表面覆盖聚乙二醇的纳米阿霉素，进入机体之后，可以在血液中长期循环，难以进入血管通透性极低的正常组织，但是会被动蓄积到血管通透性高的肿瘤组织，因此可以提高阿霉素的抗肿瘤作用，而减轻阿霉素的毒性反应。将本品加入阿霉素冻干品中震摇，即形成纳米阿霉素药物，也可以运载荷正电荷的其它药物。静脉滴注进入血液之后，新型纳米药物载体会蓄积到血管通透性高的肿瘤组织、感染部位或者炎症部位，从而提高抗癌药物、抗菌药物或抗肿瘤药物的药效，同时减轻其不良反应。体内分布研究结果表明，新型纳米脂质药物载体显著减轻了阿霉素向心脏等正常 组织器官的分布，肿瘤或感染性和炎症病灶的分布显著提高。结果见图6-8。
上述实施例只是用于对本发明的举例和说明，而非意在将本发明限制于所描述的实施例范围内。此外本领域技术人员可以理解的是，本发明不局限于上述实施例，根据本发明的教导还可以做出更多种的变型和修改，这些变型和修改均落在本发明所要求保护的范围内。

Claims (19)

  1. 聚[α-氰基丙烯酸酯]水解产物，其特征在于，化学式为：
    Figure PCTCN2020110386-appb-100001
    R＝-CN或-COOH。
  2. 如权利要求1所述聚[α-氰基丙烯酸酯]水解产物的制备方法，其特征在于，先制备α-氰基丙烯酸酯聚合物，再水解聚合物，即得到聚[α-氰基丙烯酸酯]水解产物。
  3. 如权利要求1所述聚[α-氰基丙烯酸酯]水解产物，其特征在于，为聚[2-氰基丙烯酸]，化学式为：
    Figure PCTCN2020110386-appb-100002
  4. 如权利要求3所述聚[α-氰基丙烯酸酯]水解产物，其特征在于，所述的聚[2-氰基丙烯酸]制备方法为：先制备α-氰基丙烯酸酯聚合物，再在碱性条件下选择性水解聚合物中的酯键，纯化后，即得到聚[2-氰基丙烯酸]。
  5. 如权利要求1所述聚[α-氰基丙烯酸酯]水解产物的应用，其特征在于，将聚[2-氰基丙烯酸]制备成空白栓塞微球。
  6. 如权利要求5所述应用，其特征在于，所述的空白栓塞微球的制备方法为：将聚[2-氰基丙烯酸]分散于水中形成带有负电荷的微球，即得到空白栓塞微球。
  7. 如权利要求5所述应用，其特征在于，所述的空白栓塞微球的粒径≥1um，且可以变形。
  8. 如权利要求5所述应用，其特征在于，空白栓塞微球的粒径能在微米级范围内调整，以适应不同管径血管栓塞靶点的要求，同时根据需要空白栓塞微球具有变形功能，以通过栓塞路径上的血管狭窄，可紧密栓塞血管，能避免脱落造成的异位栓塞。
  9. 如权利要求5所述应用，其特征在于，将所述的空白栓塞微球制备成载药栓塞微球。
  10. 如权利要求9所述应用，其特征在于，所述的载药栓塞微球的制备方法为：将空白栓塞微球与荷正电荷的药物相结合，即得到载药栓塞微球。
  11. 如权利要求9所述应用，其特征在于，所述的载药栓塞微球以反转电荷的原理主动装载和释放药物。
  12. 如权利要求9所述应用，其特征在于，所述的载药栓塞微球在血管通透性高、 pH值低的病变组织，能直接释放药物进入病变组织局部。
  13. 如权利要求1所述聚[α-氰基丙烯酸酯]水解产物，其特征在于，为聚[2-羧基丙烯酸]，化学式为：
    Figure PCTCN2020110386-appb-100003
  14. 如权利要求13所述聚[α-氰基丙烯酸酯]水解产物，其特征在于，所述的聚[2-羧基丙烯酸]制备方法为：先制备α-氰基丙烯酸酯聚合物，再在碱性条件下水解聚合物的酯键和氰基，透析除去杂质，即得到聚[2-羧基丙烯酸]。
  15. 如权利要求13所述聚[α-氰基丙烯酸酯]水解产物的应用，其特征在于，将聚[2-羧基丙烯酸]制备成为纳米药物载体。
  16. 如权利要求15所述应用，其特征在于，所述的纳米药物载体的制备方法为：用活性聚乙二醇修饰聚[2-羧基丙烯酸]的羧基，即得到纳米药物载体。
  17. 如权利要求15所述应用，其特征在于，所述的纳米药物载体的制备方法为：将聚[2-羧基丙烯酸]包封于脂质体，即得到纳米药物载体。
  18. 如权利要求15所述应用，其特征在于，所述的纳米药物载体以反转电荷的原理主动装载和释放药物。
  19. 如权利要求15所述应用，其特征在于，所述的纳米药物载体通过血液靶向输送药物，纳米药物载体蓄积到血管通透性高、pH值低的病变组织，并直接释放药物进入病变组织。
PCT/CN2020/110386 2019-09-05 2020-08-21 聚[α-氰基丙烯酸酯]水解产物及其制备方法和应用 Ceased WO2021043004A1 (zh)

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