阅读说明：本技术 聚（2-氰基丙烯酸）及其制备方法和应用 (Poly- (2- alpha-cyanoacrylate) and its preparation method and application ) 是由 王俊平 郭寅 于 2019-09-05 设计创作，主要内容包括：本发明涉及聚(2-氰基丙烯酸)及其制备方法和应用,属于医药化工领域。首先制备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的酯键,即得到聚(2-氰基丙烯酸)。将聚(2-氰基丙烯酸)分散于水中形成带有负电荷的微球,即得到新型空白栓塞微球,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。将空白栓塞微球与荷正电荷的药物相结合,即得到新型载药栓塞微球,其采用电荷反转的原理,用高分子的羧基主动装载荷正电荷的药物,能在病变组织局部直接释放药物,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。(The present invention relates to poly- (2- alpha-cyanoacrylates) 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 selective hydrolysis polymer to get arrive poly- (2- alpha-cyanoacrylate).It is dispersed in water poly- (2- alpha-cyanoacrylate) to form the microballoon with negative electrical charge, obtain the white embolism microball of novel air, its partial size can adjustment in range in the micron-scale, and have the function of by deformation with by the blood vessel of specific modality, can close vascular embolization avoid falling off and cause dystopy embolism.Blank embolism microball is combined with the drug of charge positive charge, obtain novel load medicine embolism microball, it uses the principle of charge reversal, the drug of charge positive charge is actively loaded with high molecular carboxyl, drug can be directly discharged in pathological tissues part, drug seldom carries out whole body flowing, to improve drug to the curative effect of pathological tissues part, mitigates drug to the toxic side effect of whole body.)

The preparation method of poly- 1. (2- alpha-cyanoacrylate), it is characterised in that: first prepare a-cyanoacrylate polymer, then in alkali Property under the conditions of ester bond in selective hydrolysis polymer, after purification to get arriving poly- (2- alpha-cyanoacrylate).

Poly- (2- alpha-cyanoacrylate) that 2. preparation method as described in claim 1 is prepared.

The application of poly- (2- alpha-cyanoacrylate) 3. as claimed in claim 2, it is characterised in that: make poly- (2- alpha-cyanoacrylate) For at blank embolism microball.

The application of poly- (2- alpha-cyanoacrylate) 4. as claimed in claim 3, it is characterised in that: the blank embolism microball The preparation method comprises the following steps: poly- (2- alpha-cyanoacrylate) is dispersed in water to form the microballoon with negative electrical charge to get micro- to blank embolism Ball.

The application of poly- (2- alpha-cyanoacrylate) 5. as claimed in claim 4, it is characterised in that: the partial size of blank embolism microball >= 1um, and can deform.

The application of poly- (2- alpha-cyanoacrylate) 6. as claimed in claim 3, it is characterised in that: blank embolism microball to be prepared into Carry medicine embolism microball.

The application of poly- (2- alpha-cyanoacrylate) 7. as claimed in claim 6, it is characterised in that: the load medicine embolism microball The preparation method comprises the following steps: combining blank embolism microball with the drug of charge positive charge to get load medicine embolism microball is arrived.

The application of poly- (2- alpha-cyanoacrylate) 8. as claimed in claim 7, it is characterised in that: carry medicine embolism microball to invert electricity The principle of lotus actively loads and release drug.

The application of poly- (2- alpha-cyanoacrylate) 9. as claimed in claim 7, it is characterised in that: it is logical in blood vessel to carry medicine embolism microball The pathological tissues that permeability is high, pH value is low can directly discharge drug and enter pathological tissues part.

Poly- 10. (2- alpha-cyanoacrylate), chemical formula are as follows:-[- CH₂-C(CN)(COOH)]_n-。

Technical field

The present invention relates to field of medicine and chemical technology, and in particular to poly- (2- alpha-cyanoacrylate) and its preparation method and application.

Background technique

It is generally acknowledged that Endovascular Embolization should avoid, if but certain blood vessels can selectively be allowed to part embolism, but can Receive good therapeutic effect.In recent years, due to the development of medical technology, people can be moved by the conduit of insertion to related Arteries and veins injects vascular occlusive agent (Vascular Occlusive Agent) to treat some diseases, is difficult to use hand particularly with some Art or the disease of drug control, such as tumour or varices of fundus of stomach.This technology is medically being known as selective blood vessel bolt Fill in art.Transcatheter arterial em-bolization was primarily used for treating aspiration biopsy of prostatic gland or per urethra prostate in the 1970s The intractable blood urine of hemorrhage of prostate and prostate source after resection.When carrying out Vascular embolization, it is necessary to use bolt Suppository can carry out mechanicalness with air bag, prill, bourdon tube etc. in addition to using some natural embolization materials such as blood clot Blocking.Suppository used at present is divided into two major class of solid and liquid, and some natural suppositories are also included in solid kind suppository.

Arterial embolization is also used for treatment tumour, tumour hemostasis, tumour analgesic.Tumor embolism treatment is to intervene in recent years Property radiology development one aspect, i.e., by conduit by embolization material inject tumor vessel in, make tumor vessel embolism, tumour Ischemic necrosis, volume-diminished or disappearance.It is mainly adapted to not be resistant to perform the operation or lost operative chance and without other conjunctions Suitable treatment method person.There is definite meaning for intractable bleeding, pain and paraneoplastic syndrome caused by treatment tumour.It is special It is not cancerous tissue bleeding, since tumor vessel is poor to vasoconstrictor response, and because cancerous swelling patient often has blood coagulation disorders, Bu Neng Blutpunkte forms blood clot.Therefore stopped blooding Chang Wuxiao with infusion pitressin, and Embolization can gain time, to carry out other treatment. Currently used is that tumour is treated in arterial embolization chemotherapy ruling by law.Chemoembolization art (Transarterial Chemoembolization, TACE) it is that it is dynamic to carry out liver cancer through conduit after chemotherapeutics and contrast agent (lipiodol) mixing and emulsifying Arteries and veins perfusion needs two steps to complete then with suppository such as gelfoam particle Embolization for Hepatic Carcinoma artery, when doctor carries out band line operation Between it is longer.In recent years, there is a kind of novel TACE method, i.e., there is sustained release using the preferable material preparation of biocompatibility The drug bearing microsphere (Drug-loaded microspheres) of function, or be medicament slow-release microsphere (Drug-eluting Beads, DEB), drug can be achieved at the same time under single image guiding and the liver cancer artery of suppository delivers, simplify operation Step shortens the time that doctor's interventional therapy is operated with line.In DC-Bead molecular structure, there are a large amount of sulfonic groups, can inhale Leader tape has the anticancer drug of charge positive charge, for the arteries embolism of tumour, inhibits tumour growth, reduces tumour bleeding, subtract The pain of light tumour.There is sulfonic group in DC-Bead, biocompatibility is bad, and easily causes allergy.

Summary of the invention

In view of the problems of the existing technology, the present invention provides a kind of preparation side of new material poly- (2- alpha-cyanoacrylate) Method, and the novel blank embolism microball developed using poly- (2- alpha-cyanoacrylate), and using novel blank embolism microball into The preparation method and application for the novel load medicine embolism microball that one step is developed.Technical scheme is as follows:

The preparation method of poly- (2- alpha-cyanoacrylate), first prepares a-cyanoacrylate polymer, then under alkaline condition Ester bond in selective hydrolysis polymer, after purification to get arrive poly- (2- alpha-cyanoacrylate).

Poly- (the 2- alpha-cyanoacrylate) being prepared according to the preparation method is claimed simultaneously in the present invention.

The application of poly- (the 2- alpha-cyanoacrylate) is claimed in the present invention, for poly- (2- alpha-cyanoacrylate) to be prepared into For blank embolism microball.

It is further: the blank embolism microball the preparation method comprises the following steps: poly- (2- alpha-cyanoacrylate) is dispersed in water The microballoon with negative electrical charge is formed to get blank embolism microball is arrived.

It is further: the partial size of blank embolism microball can adjustment in range in the micron-scale, to adapt to different tube diameters blood vessel bolt The requirement of target spot is filled in, while blank embolism microball has the function of deformation as needed, to pass through the hemadostewnosis on embolism path, Can close vascular embolization, be avoided that dystopy embolism caused by falling off.

The application of poly- (the 2- alpha-cyanoacrylate) is claimed in the present invention, for poly- (2- alpha-cyanoacrylate) to be prepared into For blank embolism microball, then be prepared into carry medicine embolism microball.

It is further: the described load medicine embolism microball the preparation method comprises the following steps: by the medicine of blank embolism microball and charge positive charge Object combines to arrive load medicine embolism microball.

It is further: to carry medicine embolism microball with the principle of inversion charge and actively load (pH >=7.4) and release (pH≤6.5) Drug.

It is further: carry medicine embolism microball in the pathological tissues that vasopermeability is high, pH value is low, can directly discharge drug into Enter pathological tissues part, drug seldom carries out whole body flowing, to improve drug to the curative effect of pathological tissues part, mitigates drug To the toxic side effect of whole body.

Poly- (2- alpha-cyanoacrylate), chemical formula is claimed in the present invention simultaneously are as follows:

-[-CH₂-C(CN)(COOH)]_n-。

More specific preferred preparation method and application are as follows:

The preparation of poly- 1. (2- alpha-cyanoacrylate)

(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 of selective hydrolysis polymer under alkaline condition again And retaining cyano, vegetable oil will be saponified, and dialysis removes impurity to get poly- (2- alpha-cyanoacrylate) is arrived.

Non-ionic surfactant concentration is higher, and the dosage of a-cyanoacrylate is fewer, and emulsion partial size is smaller.Poly- (2- Alpha-cyanoacrylate) degree of polymerization size can be controlled by a-cyanoacrylate emulsion particle size, the smaller polymerization of emulsion partial size It spends smaller.

Poly- (the 2- alpha-cyanoacrylate) 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 of selective hydrolysis polymer and guarantor under alkaline condition again Cyano is stayed, dialysis removes impurity to get poly- (2- alpha-cyanoacrylate) is arrived.

The degree of polymerization size of poly- (2- alpha-cyanoacrylate) can determine that concentration is more oligomeric by the concentration of a-cyanoacrylate It is right lower.

Poly- (the 2- alpha-cyanoacrylate) of different molecular weight ranges can be by dialysis or exclusion chromatography separation preparation.

2. the preparation of poly- (2- alpha-cyanoacrylate) blank embolism microball

By controlling the polymerization time or a-cyanoacrylate concentration of poly- (a-cyanoacrylate), its polymerization is controlled Thus degree, can control the particle size of blank embolism microball.

Poly- (2- alpha-cyanoacrylate) is rich in carboxyl, and under alkaline condition, carboxyl can have negative electrical charge to blank embolism microball, Repulsive force is generated between negative electrical charge, therefore blank embolism microball has elasticity and deformability.

(1) method one:

Poly- (2- alpha-cyanoacrylate) has certain surface active function and is soluble in dehydrated alcohol, disperses its ethanol solution in To get to rich carboxylic blank embolism microball in water.

(2) method two:

Poly- (2- alpha-cyanoacrylate) has certain surface active function and is soluble in dehydrated alcohol, disperses its ethanol solution in In water, and the part carboxyl of poly- (2- alpha-cyanoacrylate) is modified to get the blank embolism of carboxyl modified is arrived with reactive polyethylene glycol Microballoon.

The polyethylene glycol that polymer carboxyl combines can effectively prevent reticuloendothelial system to the skeleton material of blank embolism microball Expect the rapid phagocytosis and destruction of poly- (2- alpha-cyanoacrylate), 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 blank embolism microball, in a word specific carboxyl modified ratio and activity poly The molecular weight of ethylene glycol will specifically be formulated according to clinical demand.

3. the application of poly- (2- alpha-cyanoacrylate) blank embolism microball

Poly- (2- alpha-cyanoacrylate) blank embolism microball can need to adjust according to clinic its particle size, and have elasticity and Deformability, when partial size >=8um, row embolotherapy can be by specific hemadostewnosis, and closely acts on vascular wall and be difficult to take off It falls, dystopy embolism will not be generated.

The preparation of poly- 4. (2- alpha-cyanoacrylate) load medicine embolism microball

Poly- (2- alpha-cyanoacrylate) blank embolism microball is combined with the various drugs of charge positive charge to get various loads are arrived Medicine embolism microball.

The application of poly- 5. (2- alpha-cyanoacrylate) load medicine embolism microball

According to clinical needs, different one or more charge positive charge drugs can be loaded by carrying medicine embolism microball, carry out spy The localized plug of provisioning request is treated, and in the pathological tissues that vasopermeability is high, pH value is low, can directly be discharged drug and be entered lesion Tissue local, drug seldom carry out whole body flowing, to improve drug to the curative effect of pathological tissues part, mitigate drug to whole body 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- alpha-cyanoacrylate) is provided；

(2) poly- (2- alpha-cyanoacrylate) can be used for preparing novel blank embolism microball；

(3) novel blank embolism microball particle size is adjustable, and there is deformation to pass through narrow ability；

(4) novel blank embolism microball can be used for preparing novel load medicine embolism microball；

(5) institute's drug delivery can be improved to the curative effect of pathological tissues part in novel load medicine embolism microball；

(6) novel load medicine embolism microball can mitigate institute's drug delivery to the toxic side effect of whole body；

(7) foreign countries DC-bead is in the prior art (as shown in Figure 1), it is necessary to use N- acryloyl-aminoacetaldehyde-dimethyl Acetal, butyl acetate, volatility is high, and residual quantity is big, is unfavorable for production environment, and safety is lower.Alpha-cyano is used only in the present invention Acrylate, vegetable oil, glucose, physiological saline, nonionic surfactant, reactive polyethylene glycol, dehydrated alcohol, pure water Deng non-toxic residual is pollution-free, simple process, and production cost is low, and safety is higher；

(8) molecular number of the loaded anticancer drug of unit volume of foreign countries DC-bead is less.Load stype prepared by the present invention Microballoon is filled in, is calculated according to chemical structure, in molecular structure, about 50% carbon atom one carboxyl negative electrical charge of carrying, and DC- About 20% carbon atom carries a carboxyl negative electrical charge in bead molecule.The unit mass prepared by the present invention for carrying medicine embolism microball Negative electrical charge total amount is significantly higher than DC-bead, and the ability for loading drug significantly improves；

(9) foreign countries DC-bead is acid stronger sulfonic acid group, in the ability of tumor tissues property release drug selected around It is weak.Carboxyl acidity entrained by load medicine embolism microball prepared by the present invention is weaker, under different ph values, discharges drug speed Different, near the low tumor tissues of pH value, release drug speed is dramatically speeded up, and there is stronger tumor vicinity selectively to release The characteristics of putting drug.

Detailed description of the invention

Fig. 1 is the artwork that tradition prepares DC-Bead；

Fig. 2 is blank embolism microball (50 times)；

Fig. 3 is to carry the preparation of medicine embolism microball and the figure that plays a role；

Fig. 4 is the load medicine embolism microball (50 times) for loading adriamycin；

Fig. 5 is the smashed external morphology of load medicine embolism microball for loading adriamycin.

Specific embodiment

The present invention is described further combined with specific embodiments below and explains, if without specified otherwise, institute of the present invention It is common raw material and equipment with raw material and equipment.