CN110498877A - Poly- (2- carboxy acrylic) and its preparation method and application - Google Patents
Poly- (2- carboxy acrylic) and its preparation method and application Download PDFInfo
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- CN110498877A CN110498877A CN201910836242.7A CN201910836242A CN110498877A CN 110498877 A CN110498877 A CN 110498877A CN 201910836242 A CN201910836242 A CN 201910836242A CN 110498877 A CN110498877 A CN 110498877A
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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
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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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
Abstract
The present invention relates to poly- (2- carboxy acrylics) and its preparation method and application, belong to field of medicine and chemical technology.Prepare a-cyanoacrylate polymer first, then under alkaline condition the ester bond of hydrating polymer and cyano to get arriving poly- (2- carboxy acrylic).The carboxyl of poly- (2- carboxy acrylic) is modified using reactive polyethylene glycol to get Organic Nano-Scale Pharmaceutical Carrier is arrived；Poly- (2- carboxy acrylic) can also be encapsulated in liposome to get to novel nano liposome, also belong to nano-medicament carrier.Organic Nano-Scale Pharmaceutical Carrier uses the principle of charge reversal, the drug of charge positive charge is actively loaded with high molecular carboxyl, conveying drug is targeted automatically by blood to the pathological tissues that vasopermeability is high, pH value is low, and directly release drug enters pathological tissues, drug seldom enters normal tissue, to improve drug to the curative effect of pathological tissues, mitigate the toxic side effect of drug normal tissue.
Description
Technical field
The present invention relates to field of medicine and chemical technology, and in particular to poly- (2- carboxy acrylic) and its preparation method and application.
Background technique
Nanotechnology is applied to field of medicine and chemical technology and is possible to significantly improve current some treatment methods.Nano medication carries
Body is a kind of drug delivery system that partial size is usually no more than 200nm, suitable for delivery anticancer drug and other is more toxic
Drug.Being mainly characterized by for nano-medicament carrier can Targeting distribution be higher to vasopermeability, the lower lesion group of pH value
Knit such as tumor tissues, it is thus possible to improve the curative effect of delivered drug, while reduce its side effect.With normal tissue phase
Than, tumor blood vessels endothelial cell gap is wider, poor structural integrity, and cause Nano medication passively to be accumulated to tumor tissues,
Seldom enter normal tissue, referred to as EPR effect simultaneously.The EPR effect of tumour is that current most of anti-tumor nano drugs play
The basis of effect.In addition, anti-with receptors ligand molecule, monoclonal with pathological tissues targeting in nano-carrier surface modification
Body etc., nano-medicament carrier will have the function of pathological tissues active targeting, preferably play on the basis of EPR effect anti-swollen
Tumor effect.
There are many nano-medicament carrier type, and wherein liposome is quite paid attention to.Liposome is mainly made of C/PL,
Structure is similar to cell, can be used for drug delivery.There are two the main problems of liposome: being how to load drug first, secondly
It is how to prevent liposome by reticuloendothelial system phagocytic and destruction and how in pathological tissues release drug.Liposome toxicity
Low, non-immunogenicity, without pyrogenicity, can be removed by eubolism, be a kind of more satisfactory pharmaceutical carrier.Mesh
Preceding nano liposome medicament, mainly actively loads drug by means of ammonium ion gradient, prepares nano liposome medicament, such as
Doxil is a kind of nanometer Evacet of liquid.But this nano liposomes adriamycin preparation process is complicated, stablizes
Property is poor, and is difficult to actively discharge drug at tumor tissues position.
Summary of the invention
In order to solve the problems existing in the prior art, the present invention provides a kind of preparation side of new material poly- (2- carboxy acrylic)
Method, and the preparation method and application of Organic Nano-Scale Pharmaceutical Carrier developed using poly- (2- carboxy acrylic).Of the invention
Technical solution is as follows:
The preparation method of poly- (2- carboxy acrylic), first prepares a-cyanoacrylate polymer, then under alkaline condition
The ester bond and cyano of hydrating polymer, dialysis remove impurity to get poly- (2- carboxy acrylic) is arrived.
Poly- (the 2- carboxy acrylic) being prepared according to the preparation method is claimed simultaneously in the present invention.
The application of poly- (the 2- carboxy acrylic) is claimed in the present invention, for poly- (2- carboxy acrylic) to be prepared into
For nano-medicament carrier.
It is further: the nano-medicament carrier the preparation method comprises the following steps: modifying poly- (2- carboxyl third with reactive polyethylene glycol
Olefin(e) acid) part carboxyl, the carboxyl not being modified be used to deliver the drug of charge positive charge to get to it is a kind of have actively load
(pH >=7.4) and the Organic Nano-Scale Pharmaceutical Carrier for discharging (pH≤6.5) charge positive charge pharmic function.
Further: the preparation method of the nano-medicament carrier is that poly- (2- carboxy acrylic) is encapsulated in lipid
Body has to get to a kind of by pH value gradient active loading (pH >=7.4) and release (pH≤6.5) charge positive charge pharmic function
Novel nano liposome, also belong to nano-medicament carrier.
Further: nano-medicament carrier is actively loaded with the principle of inversion charge and release drug.
Further: nano-medicament carrier targets conveying drug, nano-medicament carrier accumulation to vascular permeability by blood
Property high, pathological tissues that pH value is low, and directly release drug enters pathological tissues, and drug seldom enters normal tissue, is delivered
Drug to pathological tissues curative effect enhance, normal tissue toxic side effect mitigate.
Poly- (2- carboxy acrylic), chemical formula is claimed in the present invention simultaneously are as follows:-[CH-C- (COOH)2]n-。
More specific preferred preparation method and application are as follows:
The preparation of poly- 1. (2- carboxy acrylic)
(1) method one:
In the physiological saline of pH value 2.0-4.0 or 5% or more glucose solution or 5% or more dextran solution, use
Nonionic surfactant such as polyethylene glycol type nonionic surfactant or Tweens surfactant or spans surface are living
Property agent or poloxamer etc., prepare a-cyanoacrylate or the emulsion of its vegetable oil solution.Again by pH value adjust to 7.4 with
On, accelerate polymerization reaction to form a-cyanoacrylate polymer.The ester bond and cyano of hydrating polymer under alkaline condition again,
Vegetable oil will be saponified, and dialysis removes impurity to get poly- (2- carboxy acrylic) is arrived.
Non-ionic surfactant concentration is higher, and the dosage of a-cyanoacrylate is fewer, and micro emulsion volume is smaller.Poly- (2-
Carboxy acrylic) degree of polymerization size can be controlled by a-cyanoacrylate micro emulsion size, the smaller degree of polymerization of micro emulsion is smaller.
Poly- (the 2- carboxy acrylic) of different molecular weight ranges can be by dialysis or exclusion chromatography separation preparation.
(2) method two:
A-cyanoacrylate is dissolved in dehydrated alcohol or acetone or acetonitrile.In hard plastic disperser high speed dispersion condition
Under, the dehydrated alcohol or acetonitrile or acetone soln of a-cyanoacrylate, it is slowly dropped into acid water, magnetic stirrer over night.
High speed centrifugation collects a-cyanoacrylate polymeric precipitation object.The ester bond and cyano of hydrating polymer under alkaline condition again, thoroughly
Analysis removes impurity to get poly- (2- carboxy acrylic) is arrived.
The degree of polymerization size of poly- (2- carboxy acrylic) can determine that concentration is more oligomeric by the concentration of a-cyanoacrylate
It is right lower.
Poly- (the 2- carboxy acrylic) of different molecular weight ranges can be by dialysis or exclusion chromatography separation preparation.
2. the preparation of poly- (2- carboxy acrylic) nano-medicament carrier
(1) method one:
It is received with the part carboxyl that reactive polyethylene glycol modifies poly- (2- carboxy acrylic) to get to poly- (2- carboxy acrylic)
Rice pharmaceutical carrier.
The polyethylene glycol that polymer carboxyl combines can effectively prevent reticuloendothelial system to the skeleton material of nano-medicament carrier
Expect the rapid phagocytosis and destruction of poly- (2- carboxy acrylic), drug of the carboxyl not being modified actively to load charge positive charge.
The optimal proportion of carboxyl modified is related with the medication amount and medicament categories that are delivered, when the molecular weight of drug compares
Greatly, hydrophily is poor, then the carboxyl ratio being modified will it is high a bit, when the molecular weight of drug is smaller, hydrophily compares
By force, then the carboxyl ratio being modified can be lower, and the ratio for being furthermore modified carboxyl is also related with the individual difference of application,
It must assure that reticuloendothelial system cannot rapidly destroy nano-medicament carrier, in a word specific carboxyl modified ratio and activity poly
The molecular weight of ethylene glycol will specifically be formulated according to clinical demand.
(2) method two:
Phosphatide, cholesterol, PEG2000-DSPE, poly- (2- carboxy acrylic) are dissolved in dehydrated alcohol, prepared with membrane process
The liposome of encapsulated inside poly- (2- carboxy acrylic) removes poly- (the 2- carboxyl propylene outside liposome using exclusion chromatography
Acid) to get to encapsulating the nano liposomes of poly- (2- carboxy acrylic), then adjust the pH value of nano liposomes outer aqueous phase to 7.4,
PH value gradient is arrived up to 5.0 or more with the nano liposomes for actively loading charge positive charge pharmic function inside and outside liposome,
Also belong to nano-medicament carrier.
According to Henderson-Hasselbalch theory, the variation of each pH value unit can generate molecule-type and ionic
The difference that 10 times of drug concentration theoretically will result in drug molecule type and ion if pH value gradient is 3.0 inside and outside liposome
1000 times of difference of type concentration.Since molecule-type medicine is easily in conjunction with liposome bimolecular film, to accelerate drug molecule
Journey is turned in cross-film.
Poly- (2- carboxy acrylic) forms precipitating in conjunction with charge positive charge drug, can further promote charge positive charge drug into
Enter nano liposomes, improves the ability of nano liposomes drug delivery.3. poly- (2- carboxy acrylic) nano-medicament carrier is answered
With
The nano-medicament carrier prepared using poly- (2- carboxy acrylic), with the principle of inversion charge, under alkaline condition
Such as pH=7.4, the drug of charge positive charge is actively loaded by means of carboxyl, otherwise spontaneous can be released such as pH=6.5 in acid condition
Put delivered charge positive charge drug.
Normal tissue vascular permeability is low, and pH value is higher (close to 7.4), otherwise pathological tissues vasopermeability is high, pH value
Lower (close to 6.5), thus nano-medicament carrier enter blood circulation system after can gradually accumulate pathological tissues, and discharge institute
The drug of delivery to improve drug to the curative effect (except pro-drug) of pathological tissues, while mitigating drug normal tissue
Toxic side effect.
Beneficial effects of the present invention are as follows:
(1) a kind of preparation method of new material rich carboxylic poly- (2- carboxy acrylic) is provided；
(2) poly- (2- carboxy acrylic) can be used for preparing Organic Nano-Scale Pharmaceutical Carrier；
(3) institute's drug delivery can be improved to the curative effect of pathological tissues in Organic Nano-Scale Pharmaceutical Carrier；
(4) Organic Nano-Scale Pharmaceutical Carrier can mitigate the toxic side effect of institute's drug delivery normal tissue.
Detailed description of the invention
The electromicroscopic photograph of poly- (2- carboxy acrylic) the nanometer adriamycin of Fig. 1.
The electromicroscopic photograph of poly- (2- carboxy acrylic) the nanometer Evacet of Fig. 2.
The structural schematic diagram of Fig. 3 poly- (2- carboxy acrylic).
Specific embodiment
The present invention will be further explained with reference to the examples below, if the raw materials used in the present invention and setting without specified otherwise
Standby is common raw material and equipment.
The preparation of embodiment 1--- poly- (2- carboxy acrylic)
(1) it is formulated: α-cyanoacrylaten-butyl 0.9mL
Tween-80 3.0mL
Physiological saline (pH value 2.0) 50mL
Preparation process: Tween-80 is dissolved in physiological saline, with 0.01N hydrochloric acid tune pH value to 2.0, in hard plastic rotor
Under the conditions of high speed dispersion, α-cyanoacrylaten-butyl is slowly dropped into, is completed within 9 minutes, with hard plastic tissue in ice water
It disperser high speed dispersion 45 minutes, was saved with 0.45 μm of filtering with microporous membrane with 0.01N sodium hydroxide tune pH value to 7.8
At night, 8000rpm low-temperature centrifugation 20 minutes, 50% ethanol washing 3 times, each 8000Rpm was centrifuged 20 minutes, is left and taken sediment, is added
Enter 95% ethyl alcohol, with 0.1N sodium hydroxide hydrolysis, obtains pale yellow solution, rotary evaporation removes solvent, with 0.1N hydrochloric acid tune pH value
To 7.4, dialysed with the bag filter row pure water of lower molecular weight limits 10000, change within every 12 hours a dialyzate, freeze-drying to get
To poly- (2- carboxy acrylic).
(2) it is formulated: alpha-cyanoacrylate monooctyl ester 0.9mL
Polyethylene glycol 400 monoleate 6.0mL
50% glucose (pH value 2.0) 50mL
Preparation process: polyethylene glycol 400 monoleate is added in 50% glucose, and 0.01N hydrochloric acid tune pH value is extremely
2.0, under the conditions of the high speed dispersion of hard plastic rotor, alpha-cyanoacrylate monooctyl ester is slowly dropped into, is completed within 9 minutes.In ice
Dispersed 5 minutes in water with hard plastic tissue dispersion device, with 0.45 μm of filtering with microporous membrane, extremely with 0.01N sodium hydroxide tune pH value
7.8, continue dispersion overnight, 8000rpm low-temperature centrifugation 40 minutes, three times, each 8000rpm was centrifuged 20 minutes pure water, was stayed
95% appropriate amount of ethanol is added in taking precipitate, with 0.1N sodium hydroxide hydrolysis, obtains pale yellow solution, and rotary evaporation removes solvent, uses
0.1N hydrochloric acid tune pH value is dialysed with the bag filter row pure water of lower molecular weight limits 10000, changes a dialyzate within every 12 hours to 7.4,
It is freeze-dried to get poly- (2- carboxy acrylic) is arrived.
Preparation process: Tween-80 and Arlacel-20 are added in 20% glucose, 0.01N hydrochloric acid tune pH value to 2.0, α-cyanogen
Base n-butyl acrylate is added in soya-bean oil, is prepared into the solution of good fluidity, under the conditions of the high speed dispersion of hard plastic rotor,
α-cyanoacrylaten-butyl soybean oil solution is slowly dropped into, and is completed within 9 minutes, is dispersed in ice water with hard plastic tissue dispersion device
5 minutes, continue dispersion overnight, 8000rpm low temperature with 0.01N sodium hydroxide tune pH value to 12 with 0.45 μm of filtering with microporous membrane
Centrifugation 40 minutes, three times, each 8000rpm is centrifuged 20 minutes pure water, leaves and takes sediment, 95% appropriate amount of ethanol is added, use
0.1N sodium hydroxide hydrolysis, obtains pale yellow solution, and rotary evaporation removes solvent and uses molecular weight with 0.1N hydrochloric acid tune pH value to 7.4
The bag filter row pure water of lower limit 10000 is dialysed, and a dialyzate is changed within every 12 hours, is freeze-dried to get poly- (2- carboxyl propylene is arrived
Acid).
(4) it is formulated: isobutyl alpha-cyanoacrylate 0.9mL
Poloxamer 6.0mL
5% dextran (pH value 2.0) 50mL
Preparation process: poloxamer is added in 5% dextran, 0.01N hydrochloric acid tune pH value to 2.0, is turned in hard plastic
Under the conditions of the high speed dispersion of son, isobutyl alpha-cyanoacrylate is slowly dropped into, is completed within 9 minutes.Hard plastic is used in ice water
Tissue dispersion device disperses 5 minutes, continues to disperse with 0.01N sodium hydroxide tune pH value to 7.8 with 0.45 μm of filtering with microporous membrane
Overnight, 8000rpm low-temperature centrifugation 40 minutes, three times, each 8000rpm was centrifuged 20 minutes pure water, is left and taken sediment, is added
95% appropriate amount of ethanol obtains pale yellow solution, rotary evaporation removes solvent, with 0.1N hydrochloric acid tune pH with 0.1N sodium hydroxide hydrolysis
Value is dialysed with the bag filter row pure water of lower molecular weight limits 10000 to 7.4, changes within every 12 hours a dialyzate, be freeze-dried, i.e.,
Obtain poly- (2- carboxy acrylic).
(5) it is formulated: α-cyanoacrylaten-butyl 0.9mL
Dehydrated alcohol 5.0mL
Water (pH value 2.0) 50mL
Preparation process: α-cyanoacrylaten-butyl is added to absolute ethanol, and clear solution is formed, in hard plastic rotor
Under the conditions of high speed dispersion, α-cyanoacrylaten-butyl ethanol solution is slowly dropped into, is completed within 9 minutes, in ice water
Middle hard plastic tissue dispersion device disperses 15 minutes, with 0.45 μm of filtering with microporous membrane, extremely with 0.01N sodium hydroxide tune filtrate pH value
7.8, continue dispersion overnight, 8000rpm low-temperature centrifugation 15 minutes, three times, each 8000rpm was centrifuged 15 minutes pure water, was stayed
95% appropriate amount of ethanol is added in taking precipitate, with 0.1N sodium hydroxide hydrolysis, obtains pale yellow solution, and rotary evaporation removes solvent, uses
0.1N hydrochloric acid tune pH value is dialysed with the bag filter row pure water of lower molecular weight limits 10000, changes a dialyzate within every 12 hours to 7.4,
It is freeze-dried to get poly- (2- carboxy acrylic) is arrived.
(6) it is formulated: Mecrilate 0.9mL
Acetone 5.0mL
Water (pH value 2.0) 50mL
Preparation process: by Mecrilate adding into acetone, forming clear solution, in the high speed point of hard plastic rotor
Under the conditions of dissipating, Mecrilate acetone soln is slowly dropped into, is completed within 9 minutes, with hard plastic tissue in ice water
Disperser disperses 15 minutes, continues to disperse with 0.01N sodium hydroxide tune filtrate pH value to 7.8 with 0.45 μm of filtering with microporous membrane
Overnight, 8000rpm low-temperature centrifugation 15 minutes, three times, each 8000rpm was centrifuged 15 minutes pure water, is left and taken sediment, is added
95% appropriate amount of ethanol obtains pale yellow solution, rotary evaporation removes solvent, with 0.1N hydrochloric acid tune pH with 0.1N sodium hydroxide hydrolysis
Value is dialysed with the bag filter row pure water of lower molecular weight limits 10000 to 7.4, changes within every 12 hours a dialyzate, be freeze-dried, i.e.,
Obtain poly- (2- carboxy acrylic).
(7) it is formulated: α-cyanoacrylate 0.9mL
Acetonitrile 5.0mL
Water (pH value 2.0) 50mL
Preparation process: α-cyanoacrylate is added in acetonitrile, forms clear solution, in the high speed point of hard plastic rotor
Under the conditions of dissipating, α-cyanoacrylate acetonitrile solution is slowly dropped into, is completed within 9 minutes, with hard plastic tissue in ice water
Disperser disperses 15 minutes, continues to disperse with 0.01N sodium hydroxide tune filtrate pH value to 7.8 with 0.45 μm of filtering with microporous membrane
Overnight, 8000rpm low-temperature centrifugation 15 minutes, three times, each 8000rpm was centrifuged 15 minutes pure water, is left and taken sediment, is added
95% appropriate amount of ethanol obtains pale yellow solution, rotary evaporation removes solvent, with 0.1N hydrochloric acid tune pH with 0.1N sodium hydroxide hydrolysis
Value is dialysed with the bag filter row pure water of lower molecular weight limits 10000 to 7.4, changes within every 12 hours a dialyzate, be freeze-dried, i.e.,
Obtain poly- (2- carboxy acrylic).
The preparation of poly- (2- carboxy acrylic) nano-medicament carrier of embodiment 2---
(1) it is formulated: poly- (2- carboxy acrylic) 590mg
2000 2000mg of amino-polyethyleneglycols
Preparation process: under the conditions of magnetic agitation, with 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride
[1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide, EDCHCL], N- maloyl
Imines (N-Hydroxy succinimide, NHS) is catalyst, and 2g NH is added into nano-medicament carrier skeleton solution2-
PEG modifies nano-medicament carrier skeleton, and above-mentioned solution overnight, is put into bag filter by reaction, with distilled water dialysis 72h, every 12h
A water is changed, impurity of the molecular weight less than 10000 is removed to get the nano-medicament carrier for covering PEG2000 to surface, adjusts pH value
To 7.4 to get nano-medicament carrier.
(2) it is formulated: poly- (2- carboxy acrylic) 590mg
Polyethylene glycol-hydrazides 2000mg
Preparation process: under the conditions of magnetic agitation, with 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride
[1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide, EDCHCL], 1- hydroxy benzo three
Azoles (N-Hydroxybenzotriazole, HOBT) is catalyst, and 2g NH is added into nano-medicament carrier skeleton solution2-
PEG modifies nano-medicament carrier skeleton, and above-mentioned solution overnight, is put into bag filter by reaction, with distilled water dialysis 72h, every 12h
A water is changed, impurity of the molecular weight less than 10000 is removed to get the nano-medicament carrier for covering PEG2000 to surface, adjusts pH value
To 7.4 to get nano-medicament carrier.
Preparation process: above-mentioned material is dissolved in 50mL dehydrated alcohol, rotary evaporation removes dehydrated alcohol, obtains liposome
50mL water, 200nm filtering with microporous membrane after hydration, with 0.001N sodium hydroxide tune pH value to 7.4, exclusion chromatography is added in film
Remove outside liposome not by liposomal encapsulated poly- (2- carboxy acrylic), to get to can actively load lotus after filtering
The nano liposomes and nano-medicament carrier of positive charge drug.
The effect of poly- (2- carboxy acrylic) nano-medicament carrier
Under a scanning electron microscope, form is spherical, uniform particle diameter, is evenly distributed for Organic Nano-Scale Pharmaceutical Carrier, Zeta electricity
Position is reachable -52.5mV.It is dynamic by the neoplasm lung metastasis of small white mouse S180 sarcoma animal model, C57BL6 by taking adriamycin as an example
Object model proves that the cardiac toxic of adriamycin can be significantly reduced in this nanometer adriamycin, and especially significant decrease adriamycin is led
The incidence of heart failure is caused, while improving its antitumor action (P < 0.01).Using rabbit liver cancer model, its drug effect is evaluated, as a result
Show compared with adriamycin, antitumaous effect significantly improves (P < 0.01).After Organic Nano-Scale Pharmaceutical Carrier loads adriamycin,
The nanometer adriamycin for forming a kind of surface covering polyethylene glycol can recycle for a long time in blood into after body, it is difficult into
Enter the extremely low normal tissue of vasopermeability, but can passively accumulate the high tumor tissues of vasopermeability, therefore can mention
The antitumor action of high adriamycin, and mitigate the toxic reaction of adriamycin.This product is added in adriamycin dried frozen aquatic products and is shaked, is i.e. shape
At nanometer adriamycin drug, the other medicines of charge positive charge can also be delivered.Intravenous drip enters after blood, novel nano medicine
Object carrier can accumulate the high tumor tissues of vasopermeability, infection site or inflammation part, to improve anticancer drug, resist
The drug effect of bacterium drug or anti-tumor drug, while mitigating its adverse reaction.Distribution result of study shows novel nano lipid in vivo
Pharmaceutical carrier significantly reduces distribution of the adriamycin to the normal tissues organ such as heart, tumour or infectious point with inflammation foci
Cloth significantly improves.
Above-described embodiment is only intended to citing and explanation of the invention, and is not intended to limit the invention to described
In scope of embodiments.Furthermore it will be appreciated by persons skilled in the art that the present invention is not limited to the above embodiment, according to this hair
Bright introduction can also make more kinds of variants and modifications, these variants and modifications all fall within present invention model claimed
In enclosing.
Claims (8)
- The preparation method of poly- 1. (2- carboxy acrylic), it is characterised in that: first prepare a-cyanoacrylate polymer, then in alkali Property under the conditions of hydrating polymer ester bond and cyano, dialysis remove impurity to get arrive poly- (2- carboxy acrylic).
- Poly- (2- carboxy acrylic) that 2. preparation method as described in claim 1 is prepared.
- The application of poly- (2- carboxy acrylic) 3. as claimed in claim 2, it is characterised in that: make poly- (2- carboxy acrylic) It is standby to become nano-medicament carrier.
- The application of poly- (2- carboxy acrylic) 4. as claimed in claim 3, it is characterised in that: the nano-medicament carrier The preparation method comprises the following steps: modifying the carboxyl of poly- (2- carboxy acrylic) with reactive polyethylene glycol to get nano-medicament carrier is arrived.
- The application of poly- (2- carboxy acrylic) 5. as claimed in claim 3, it is characterised in that: the nano-medicament carrier The preparation method comprises the following steps: poly- (2- carboxy acrylic) is encapsulated in liposome to get nano-medicament carrier is arrived.
- The application of poly- (2- carboxy acrylic) 6. as described in claim 4 or 5, it is characterised in that: nano-medicament carrier is with anti- The principle for turning charge actively loads and release drug.
- The application of poly- (2- carboxy acrylic) 7. as described in claim 4 or 5, it is characterised in that: nano-medicament carrier passes through Blood targeting conveying drug, the pathological tissues that nano-medicament carrier accumulation is high to vasopermeability, pH value is low, and directly discharge medicine Object enters pathological tissues.
- Poly- 8. (2- carboxy acrylic), chemical formula are as follows:-[CH-C- (COOH)2]n-。
Priority Applications (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910836242.7A CN110498877B (en) | 2019-09-05 | 2019-09-05 | Poly (2-carboxy acrylic acid) and preparation method and application thereof |
| CN202210966640.2A CN115353578A (en) | 2019-09-05 | 2019-09-05 | Poly (2-carboxy acrylic acid) and application thereof in nano-drugs |
| US17/640,480 US20220332862A1 (en) | 2019-09-05 | 2020-08-21 | Poly[alpha-cyanoacrylate] hydrolyzate and preparation method and application thereof |
| EP20861592.2A EP4026859A4 (en) | 2019-09-05 | 2020-08-21 | Poly[alpha-cyanoacrylate] hydrolyzate and preparation method and applicaiton thereof |
| PCT/CN2020/110386 WO2021043004A1 (en) | 2019-09-05 | 2020-08-21 | Poly[alpha-cyanoacrylate] hydrolyzate and preparation method and applicaiton thereof |
| JP2022515062A JP2022547140A (en) | 2019-09-05 | 2020-08-21 | Hydrolysis product of poly[α-cyanoacrylate], its preparation and use |
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| WO2021043004A1 (en) * | 2019-09-05 | 2021-03-11 | 大连合元医疗器械有限公司 | Poly[alpha-cyanoacrylate] hydrolyzate and preparation method and applicaiton thereof |
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|---|---|---|---|---|
| US4013703A (en) * | 1974-10-04 | 1977-03-22 | Johnson & Johnson | Cyanoacrylic acid adducts |
| CN1424919A (en) * | 2000-03-15 | 2003-06-18 | 舍林股份公司 | Microcapsules comprising functionalised polyalkylcyanoacrylates |
| CN103031122A (en) * | 2011-09-29 | 2013-04-10 | 上海上诺精细化学有限公司 | Encapsulation gel breaker and preparation method of encapsulation gel breaker |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3975422A (en) * | 1972-11-21 | 1976-08-17 | Johnson & Johnson | Preparation of bis (2-cyanoacrylate)monomers |
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- 2019-09-05 CN CN202210966640.2A patent/CN115353578A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4013703A (en) * | 1974-10-04 | 1977-03-22 | Johnson & Johnson | Cyanoacrylic acid adducts |
| CN1424919A (en) * | 2000-03-15 | 2003-06-18 | 舍林股份公司 | Microcapsules comprising functionalised polyalkylcyanoacrylates |
| CN103031122A (en) * | 2011-09-29 | 2013-04-10 | 上海上诺精细化学有限公司 | Encapsulation gel breaker and preparation method of encapsulation gel breaker |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021043004A1 (en) * | 2019-09-05 | 2021-03-11 | 大连合元医疗器械有限公司 | Poly[alpha-cyanoacrylate] hydrolyzate and preparation method and applicaiton thereof |
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| CN115353578A (en) | 2022-11-18 |
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