阅读说明：本技术 一种生物可降解的血管支架材料的制备方法 (Preparation method of biodegradable vascular stent material ) 是由 不公告发明人 于 2020-04-23 设计创作，主要内容包括：本发明提供一种生物可降解的血管支架材料的制备方法,属于医用材料技术领域,包括利用葡萄糖酸、羟基乙酸聚合获得聚葡萄糖酸-羟基乙酸；利用乳酸聚合获得聚乳酸；利用聚葡萄糖酸-羟基乙酸与聚乳酸聚合得到聚(葡萄糖酸-羟基乙酸)-聚乳酸共聚物。本发明通过在聚乳酸中引入聚葡萄糖酸-羟基乙酸,提高了聚乳酸的亲水性,降低了聚乳酸的脆性,减弱了聚乳酸的自降解性,提高了聚乳酸的生物相容性。(The invention provides a preparation method of a biodegradable vascular stent material, belonging to the technical field of medical materials, and comprising the steps of polymerizing gluconic acid and glycolic acid to obtain polyglucosic acid-glycolic acid; polymerizing lactic acid to obtain polylactic acid; poly (gluconic acid-glycolic acid) -polylactic acid copolymer is obtained by polymerizing polygluconic acid-glycolic acid and polylactic acid. The invention improves the hydrophilicity of the polylactic acid, reduces the brittleness of the polylactic acid, weakens the self-degradability of the polylactic acid and improves the biocompatibility of the polylactic acid by introducing the polyglucosic acid-glycolic acid into the polylactic acid.)

1. A poly (gluconic acid-glycolic acid) -polylactic acid copolymer material having a structural formula of:

n is 160-1500, and m is 150-1500.

2. The copolymer material of claim 1, wherein the polyglucosate-hydroxyacetic acid has a weight average molecular weight of 40-375 kDa.

3. The copolymer material of claim 1, wherein the polylactic acid has a weight average molecular weight of 10-120 kDa.

4. The copolymeric material of claim 1 wherein said poly (gluconic acid-glycolic acid) -polylactic acid copolymer has a weight average molecular weight of 50-390 kDa.

5. Use of the poly (gluconic acid-glycolic acid) -polylactic acid copolymer material of claim 1 in the preparation of a medical material.

6. A preparation method of a biodegradable vascular stent material comprises the following steps:

a) polymerizing gluconic acid and glycolic acid to obtain polyglucosic acid-glycolic acid;

b) polymerizing lactic acid to obtain polylactic acid;

c) poly (gluconic acid-glycolic acid) -polylactic acid copolymer is obtained by polymerizing polygluconic acid-glycolic acid and polylactic acid.

7. The method for preparing biodegradable vascular stent material according to claim 6, wherein the method comprises the following steps: the conditions of the step a) are as follows: adding gluconic acid and glycolic acid into a solvent, adding a dehydrating agent, adding a catalyst, stirring and refluxing for reaction for 9-24h at the temperature of 100-160 ℃, cooling, slowly adding the cooled solution into a methanol solution, stirring and precipitating, and performing vacuum drying for 12-48 h at the temperature of 20-50 ℃ after suction filtration to obtain polyglutamic acid-glycolic acid; the solvent is dimethyl sulfoxide, the dehydrating agent is N, N-dicyclohexylcarbodiimide, and the catalyst is 4-dimethylaminopyridine.

8. The method for preparing biodegradable vascular stent material according to claim 6 or 7, wherein the method comprises the following steps: the addition ratio of the gluconic acid to the glycolic acid is 1: 0.5-3.

9. The method for preparing biodegradable vascular stent material according to claim 6, wherein the method comprises the following steps: the conditions of the step c) are as follows: adding polyglucosic acid-glycolic acid and polylactic acid into a solvent, adding a catalyst, adding a glue agent, adding an initiator, stirring and reacting for 6-18h at the temperature of 120-160 ℃, cooling, adding distilled water for precipitation, washing the precipitate for 2-3 times by using acetone, and then washing by using distilled water for 2-3 times to obtain a poly (gluconic acid-glycolic acid) -polylactic acid copolymer; the solvent is dimethyl sulfoxide, the dehydrating agent is N, N-dicyclohexylcarbodiimide, the catalyst is 4-dimethylaminopyridine, and the initiator is potassium ethoxide.

10. The method for preparing biodegradable vascular stent material according to claim 6 or 9, wherein the method comprises the following steps: the adding ratio of the polylactic acid to the polyglucosic acid-glycolic acid is 1: 0.1-1.

Technical Field

The invention belongs to the technical field of medical materials, and particularly relates to a preparation method of a biodegradable vascular stent material.

Background

The death rate of cardiovascular diseases is higher than that of tumors and other diseases, accounts for more than 40 percent of the death rate of resident diseases, and the morbidity and the death rate of the cardiovascular diseases are in a continuously rising trend, so the cardiovascular diseases are listed as important public health problems in China. Drug therapy and surgical treatment are the traditional methods for treating cardiovascular and cerebrovascular diseases. The drug therapy is to treat cardiovascular and cerebrovascular diseases by reducing blood viscosity through drugs so as to improve blood fluidity, but the drug therapy has long period and slow effect and has poor treatment effect on severe patients; the operation treatment mainly refers to coronary bypass surgery, the method brings great trauma to patients, the postoperative recovery period is long, the price is high, the operation difficulty is high, and partial patients cannot bear the operation due to poor constitution. 20 years ago, the U.S. Food and Drug Administration (FDA) approved artificial endovascular stents for aortic aneurysms, and this rapid development of intraluminal interventional therapy changed the surgical approach to vascular surgery. The intravascular stent aims at restoring the normal flow of blood vessels, an inner stent is arranged at a vascular lesion position to support the blood vessels and reduce the elastic retraction and the remodeling of the blood vessels, and the mechanical property of the intravascular stent plays a decisive role in the treatment effect in the process of treating vascular stenosis diseases.

The vascular stent is used as a foreign body, can cause the long-term inflammatory reaction of the vascular wall, leads to the long-term thrombosis after the stent operation and the restenosis in the stent, and after the treatment is finished, the vascular support is not needed any more, and the degradable material draws attention of people. Polylactic acid can be hydrolyzed into lactic acid in vivo, participates in human metabolism, has no physiological rejection reaction, and finally has the degradation products of carbon dioxide and water, has good biocompatibility and mechanical property, and is a mainstream material in the current degradable stent. However, polylactic acid is applied to medical treatment and suffers from the following problems: (1) polylactic acid has a large amount of ester bonds and weak hydrophilicity, and when the polylactic acid is used as a tissue engineering material and a carrier material of hydrophilic drugs such as protein and polypeptide, the compatibility of the polylactic acid with cells and drugs is seriously influenced; (2) the degradation of polylactic acid is caused by hydrolysis of ester bonds on a high molecular chain, a large amount of carboxylic acid is generated by the breakage of the ester bonds, the problems of inflammation, local serious water accumulation and the like caused by excessive local acidity of an organism are caused by the large accumulation of the carboxylic acid, and meanwhile, the degradation rate is difficult to control because the large amount of the carboxylic acid can generate an autocatalytic degradation effect; (3) polylactic acid is a linear copolymer, and has too wide relative molecular weight distribution, low heat distortion temperature, poor impact resistance and high brittleness, so that the required strength is difficult to achieve.

Disclosure of Invention

The invention aims to provide a raw poly (gluconic acid-glycolic acid) -polylactic acid copolymer which has good hydrophilicity, weakened self-degradation and better flexibility.

The technical scheme adopted by the invention for realizing the purpose is as follows:

an object of the present invention is to provide a poly (gluconic acid-glycolic acid) -polylactic acid copolymer material having a structural formula of the following formula (1):

n is 160-1500, and m is 150-1500.

In the poly (gluconic acid-glycolic acid) -polylactic acid copolymer, the introduction of the polygluconic acid-glycolic acid can reduce the crystallinity of the polylactic acid, the gluconic acid contains unreacted hydroxyl, the hydroxyl has hydrophilicity, and the copolymer contains a large number of gluconic acid fragments, so that the hydrophilicity is improved; the long chain of gluconic acid is introduced into the polylactic acid, so that the flexibility of the poly (gluconic acid-glycolic acid) -polylactic acid copolymer is improved, and the brittleness is weakened; in addition, the terminal carboxyl of the copolymer is an important reason for causing ester bond degradation of the copolymer, the ester bond number in the copolymer is reduced by introducing polyglutamic acid-glycolic acid, the collision probability of acid radicals and the ester bond is also reduced, and the hydroxyl and the terminal carboxyl in the gluconic acid can form intermolecular hydrogen bonds to weaken the reactivity of the carboxyl. In a word, the poly (gluconic acid-glycolic acid) -polylactic acid copolymer has good hydrophilicity, weakened self-degradation and better flexibility.

Preferably, the polyglucosic acid-glycolic acid has a weight average molecular weight of 40-375 kDa.

Preferably, the polylactic acid has a weight average molecular weight of 10 to 120 kDa.

Preferably, the poly (gluconic acid-glycolic acid) -polylactic acid copolymer has a weight average molecular weight of 50 to 390 kDa.

The invention also aims to provide application of the poly (gluconic acid-glycolic acid) -polylactic acid copolymer material in preparing medical materials. Preferably, the medical material is a biodegradable vascular stent material.

Another object of the present invention is to provide a method for preparing a biodegradable vascular stent material, which improves the problems of weak hydrophilicity, high self-degradation and high brittleness of polylactic acid by copolymerizing polylactic acid and polyglycolic acid, and the method specifically comprises: polymerizing gluconic acid and glycolic acid to obtain polyglucosic acid-glycolic acid; polymerizing lactic acid to obtain polylactic acid; poly (gluconic acid-glycolic acid) -polylactic acid copolymer is obtained by polymerizing polygluconic acid-glycolic acid and polylactic acid. The invention improves the hydrophilicity of the polylactic acid, reduces the brittleness of the polylactic acid and weakens the self-degradability of the polylactic acid by introducing the polyglucosic acid-glycolic acid into the polylactic acid.

For the purposes of the present invention, the conditions for the preparation of polyglucosic acid-glycolic acid are: adding gluconic acid and glycolic acid into a solvent, adding a dehydrating agent, adding a catalyst, stirring and refluxing for reaction for 9-24h at the temperature of 100-160 ℃, cooling, slowly adding the cooled solution into a methanol solution, stirring and precipitating, and performing vacuum drying for 12-48 h at the temperature of 20-50 ℃ after suction filtration to obtain polyglutamic acid-glycolic acid; the solvent is dimethyl sulfoxide, the dehydrating agent is N, N-dicyclohexylcarbodiimide, and the catalyst is 4-dimethylaminopyridine. The gluconic acid has carboxyl and hydroxyl, the glycolic acid has hydroxyl and carboxyl, the gluconic acid and the hydroxyl and the carboxyl in the glycolic acid can be comprehensively reacted to form ester bonds, the ester comprehensive reaction is an endothermic reaction, the high temperature provides energy for condensation, the catalyst 4-dimethylaminopyridine reduces the reaction activation energy of the gluconic acid and the glycolic acid, water molecules generated in the comprehensive reaction are removed by reflux, and the reaction is moved to the polymerization direction to generate the polygluconic acid-glycolic acid.

Preferably, the ratio of the gluconic acid to the glycolic acid added is 1: 0.5-3.

In the present invention, the conditions for preparing the polylactic acid are as follows: weighing lactic acid, adding into a flask, raising the temperature to 150 ℃ at 100-80 kPa for dehydration for 30-150min, adding a catalyst under the protection of nitrogen, raising the temperature to 180 ℃ at 1-5kPa, and reacting for 6-15 h. After the reaction is finished, adding acetone to dissolve the product, pouring the product into a large amount of deionized water to separate out polylactic acid, washing for 3-5 times, and vacuum-drying for 24-48h at 30-50 ℃; the catalyst is stannous chloride. The lactic acid molecule contains hydroxyl and carboxyl, the hydroxyl and the carboxyl are subjected to comprehensive reaction to generate a lactic acid dimer, unreacted hydroxyl and carboxyl still exist on the lactic acid dimer, the comprehensive melon can be continuously carried out, the lactic acid polycondensation reaction is an endothermic reaction, the lactic acid is dehydrated at high temperature to generate an oligomer, the catalyst stannous chloride reduces the reaction activation energy, the reaction rate is improved, and the lactic acid molecule gradually reacts and polymerizes to generate the long-chain polylactic acid. During the polycondensation of lactic acid, micromolecular water with a lower boiling point is generated, the polymerization reaction is a reversible reaction, and water generated by the polycondensation is removed through decompression, so that the reaction is transferred to the direction of generating the polylactic acid, and the polylactic acid is finally obtained. By controlling the time of the lactic acid polymerization reaction, polylactic acid with small molecular weight can be obtained.

In the present invention, the above-mentioned poly (gluconic acid-glycolic acid) -polylactic acid copolymer is prepared under the following conditions: adding polyglucosic acid-glycolic acid and polylactic acid into a solvent, adding a catalyst, adding a glue agent, adding an initiator, stirring and reacting for 6-18h at the temperature of 120-160 ℃, cooling, adding distilled water for precipitation, washing the precipitate for 2-3 times by using acetone, and then washing by using distilled water for 2-3 times to obtain a poly (gluconic acid-glycolic acid) -polylactic acid copolymer; the solvent is dimethyl sulfoxide, the dehydrating agent is N, N-dicyclohexylcarbodiimide, the catalyst is 4-dimethylaminopyridine, and the initiator is potassium ethoxide. The potassium ethoxide is used as an initiator, glycolic acid-polyglutamic acid-glycolic acid copolymer containing alcohol end groups is formed after polymerization, and the copolymer is used as a macroinitiator and is copolymerized with polylactic acid to form poly (gluconic acid-glycolic acid) -polylactic acid copolymer. The introduction of polygluconic acid-glycolic acid can reduce the crystallinity of polylactic acid, the gluconic acid contains unreacted hydroxyl which has hydrophilicity, and the copolymer contains a large number of gluconic acid fragments, so that the hydrophilicity is improved; after the polygluconic acid-glycolic acid and the polylactic acid are copolymerized, a gluconic acid long chain is introduced into the polylactic acid, so that the flexibility of the poly (gluconic acid-glycolic acid) -polylactic acid copolymer is improved, and the brittleness is weakened; the terminal carboxyl of the copolymer is an important reason for causing ester bond degradation of the copolymer, the ester bond number in the copolymer is reduced by introducing polyglutamic acid-glycolic acid, the collision probability of acid radicals and the ester bond is also reduced, and the hydroxyl in the gluconic acid and the terminal carboxyl can form intermolecular hydrogen bonds to weaken the reactivity of the carboxyl.

Preferably, the ratio of the polylactic acid to the polyglucosic acid-glycolic acid is 1: 0.1-1.

The invention has the beneficial effects that: 1) the poly (gluconic acid-glycolic acid) -polylactic acid copolymer has good hydrophilicity, weakened self-degradation and better flexibility; 2) the preparation method of the invention obtains the poly (gluconic acid-glycolic acid) -polylactic acid copolymer by copolymerizing the polylactic acid with the polygluconic acid-glycolic acid, introduces the polygluconic acid-glycolic acid into the polylactic acid, improves the hydrophilicity of the polylactic acid, reduces the brittleness of the polylactic acid, weakens the self-degradability of the polylactic acid, and has the advantages of non-toxic and harmless raw materials, less steps and simple operation flow.

The invention adopts the technical scheme to provide the preparation method of the biodegradable vascular stent material, which makes up the defects of the prior art, and has reasonable design and convenient operation.

Drawings

FIG. 1 is a schematic water absorption of the resulting material of the present invention;

FIG. 2 is a graph showing the weight loss of the resulting material of the present invention;

fig. 3 is a schematic diagram of the biocompatibility of the obtained material of the present invention.

Detailed Description

Exemplary embodiments that embody features and advantages of the invention are described in detail below. It is to be understood that the invention is capable of other and different embodiments and its several details are capable of modification without departing from the scope of the invention, and that the description is intended to be illustrative in nature and not to be construed as limiting the invention.

The invention provides polyglutamic acid-glycolic acid prepared from gluconic acid and glycolic acid, wherein the addition ratio of the gluconic acid to the glycolic acid is 1: 0.5-2, e.g. 1: 0.8, 1: 1. 1: 1.3, 1: 1.5, 1: 1.8, the adding proportion can be 1: 0.8-1.8.

The molecular weight of the polyglucosic acid-glycolic acid obtained in one embodiment of the invention is 40-375kDa, and can be 55, 90, 130, 235 and 350 kDa.

In one embodiment of the invention, polylactic acid is obtained with a molecular weight of 10-120kDa, such as 20, 50, 80, 100, 110 kDa.

In one embodiment of the present invention, the poly (gluconic acid-glycolic acid) -polylactic acid copolymer has a molecular weight of 50-390kDa, such as 70, 90, 130, 180, 230, 280, 350, 380 kDa.

In an embodiment of the invention, the adding ratio of the polylactic acid to the polyglucosic acid-glycolic acid is 1: 0.1-1, e.g. 1: 0.2, 1: 0.5, 1: 0.7, 1: 0.9, the addition ratio can be 1: 0.2-0.9.

In one embodiment of the present invention, gelatin treatment is provided in an amount of 1-10 wt%, such as 2, 3, 5, 7, 9 wt%, etc., and gelatin may be used in an amount of 2-9 wt%.

The following will further illustrate a method for preparing a biodegradable vascular stent material according to an embodiment of the present invention with reference to specific examples.