CN113354823B - Block polymer for full-degradable vascular stent and preparation method thereof - Google Patents

Abstract

The invention discloses a block polymer for a fully degradable vascular stent and a preparation method thereof, and the block polymer comprises the following steps: step 1: the hydroxyl end group in the polylactic acid reacts with carbonyldiimidazole in a solvent to obtain the polylactic acid with the end group of carbonylimidazole; and 2, step: reacting the polylactic acid with the end group of carbonyl imidazole and the polymer with the end group of hydroxyl, which are obtained in the step 1, in a solvent to obtain a block polymer with a linking site of carbonate; the invention provides a method for quickly and efficiently constructing a block polymer through the special reactivity of carbonyl diimidazole, and can realize the efficient coupling of two polymers with hydroxyl functional end groups under mild conditions, thereby forming a block copolymer with a definite molecular structure; the block polymer has a definite structure, and various performances such as degradation, toughness and the like of a target polymer are more effectively improved through fine adjustment of various polymer blocks.

Description

A block polymer for fully degradable vascular stent and its preparation method

technical field

The invention relates to the field of medical materials and medical devices, in particular to a block polymer used for fully degradable vascular stents and a preparation method.

Background technique

At present, vascular stent implantation has become one of the most effective means for the treatment of coronary heart disease. Traditional stent products are non-degradable metal-based drug-coated stents. The non-degradable materials do not match the chemical composition, physical structure and mechanical properties of the surrounding tissue, which can easily lead to late thrombosis and complications caused by permanent stent retention. Fully degradable polymer stents can theoretically avoid a series of adverse events caused by permanent retention of metal stents because they can be gradually degraded to complete absorption. Therefore, the development of fully degradable vascular stents based on polymer materials has become an inevitable trend in the development of vascular stents.

Polylactic acid materials not only have relatively high mechanical strength, but also can be gradually metabolized into small lactic acid molecules in the body and further decomposed into carbon dioxide and water, which has good biocompatibility. However, conventional polylactic acid materials also have some disadvantages, such as the high brittleness of the material itself, which leads to the risk of fracture of the stent after implantation. The polylactic acid molecular chain is relatively rigid and has almost no long chain branches, resulting in low melt strength, which causes many difficulties in the melt extrusion processing of the scaffold.

Contents of the invention

Aiming at the problems existing in the prior art, the present invention provides a block polymer for fully degradable vascular stent with dual adjustable degradation performance and mechanical performance and a preparation method.

The technical scheme adopted in the present invention is:

A method for preparing a block polymer for fully degradable vascular stents, comprising the following steps:

Step 1: the hydroxyl end group in polylactic acid reacts with carbonyldiimidazole in a solvent to obtain polylactic acid whose end group is carbonylimidazole;

Step 2: react the polylactic acid whose terminal group is carbonylimidazole obtained in step 1 with the polymer whose terminal group is hydroxyl in a solvent to obtain a block polymer whose linkage site is carbonate.

Further, the molar ratio of hydroxyl end groups in polylactic acid to carbonyldiimidazole in step 1 is 1:1˜1:5.

Further, the reaction temperature in the step 1 is from room temperature to 100°C, and the reaction time is from 5h to 24h.

Further, the polymer whose terminal group is a hydroxyl group is one of polycaprolactone, polytrimethylene carbonate, and polydioxanone.

Further, in the step 2, the molar ratio of the polylactic acid whose end group is carbonylimidazole to the polymer whose end group is hydroxyl is 1:1˜10:1.

Further, the reaction temperature in the step 2 is room temperature to 150°C, and the reaction time is 5h to 48h.

Further, the solvent is one or a mixture of two or more of chloroform, dichloromethane, tetrahydrofuran, hexafluoroisopropanol, and acetone in any proportion.

Further, the step 1 and step 2 are purified after the reaction is completed, and the purification process is as follows:

Pour the reaction solution into anhydrous ether or anhydrous methanol, suction filter to obtain the target polymer, and then further purify the target polymer;

The purification process is as follows:

Dissolve the target polymer in a solvent, precipitate in excess anhydrous methanol or anhydrous ether, filter with suction, and dry in vacuum; repeat the purification process N times.

Further, in the step 1, the mass concentration of polylactic acid in the solvent is 0.2 g/mL-5 g/mL; the mass concentration of the polymer whose end group is a hydroxyl group in the solvent is 0.1 g/mL-10 g/mL.

A block polymer used for fully degrading vascular stents, the polymer whose terminal group is a hydroxyl group is one of polycaprolactone, polytrimethylene carbonate, and polydioxanone; the obtained block The segment polymer corresponds to one of polylactic acid-polycaprolactone PLA-PCL, polylactic acid-polytrimethylene carbonate PLA-PTMC, and polylactic acid-polydioxanone PLA-PDO;

The structure is as follows:

Among them, the molecular weight of polylactic acid is 50,000 to 300,000, the molecular weight of polycaprolactone is 1,000 to 50,000, the molecular weight of polytrimethylene carbonate is 1,000 to 50,000, and the molecular weight of polydioxanone is 1,000 to 50,000. 50000.

The beneficial effects of the present invention are:

(1) The block polymer used for fully degradable vascular stent obtained by the present invention has double adjustable performance of degradation performance and mechanical performance;

(2) The present invention provides a fast and efficient method for building block polymers through the special reactivity of carbonyldiimidazole, which can realize efficient coupling of two polymers with hydroxyl functional end groups under mild conditions, thereby Formation of block copolymers with well-defined molecular structures;

(3) The block polymer used in the fully degradable vascular stent obtained in the present invention has a clear structure, and through the fine adjustment of each polymer block, various properties such as degradation and toughness of the target polymer can be more effectively improved.

Description of drawings

Fig. 1 is a synthetic route diagram of the target block polymer of the present invention.

Fig. 2 is the structure of the target block polymer obtained in the present invention.

Detailed ways

The present invention will be further described below in conjunction with the accompanying drawings and specific embodiments.

A method for preparing a block polymer for fully degradable vascular stents, comprising the following steps:

Step 1: The hydroxyl end group in the polylactic acid and carbonyldiimidazole (CDI) react in a solvent to obtain polylactic acid (PLA-CDI) whose end group is carbonylimidazole; the mole of the hydroxyl end group in the polylactic acid and carbonyldiimidazole The ratio is 1:1～1:5. The reaction temperature is from room temperature to 100°C, and the reaction time is from 5h to 24h. The mass concentration of polylactic acid in the solvent is 0.2g/mL-5g/mL. The reaction solvent is one or a mixture of two or more of chloroform, dichloromethane, tetrahydrofuran, hexafluoroisopropanol and acetone in any proportion.

After the reaction is completed, the purification process is as follows:

Pour the reaction solution into anhydrous ether or anhydrous methanol, suction filter to obtain the target polymer, and then further purify the target polymer;

The purification process is as follows:

Dissolve the target polymer in a solvent (chloroform), precipitate in excess anhydrous methanol or anhydrous ether, filter with suction, and dry in vacuum; repeat the purification process N times. The optimal ratio of chloroform to ether or methanol is 1:5. In order to effectively remove the residual impurities in the product, the target product is subjected to the above dissolution and precipitation process for three times.

Step 2: react the polylactic acid whose terminal group is carbonylimidazole obtained in step 1 with the polymer whose terminal group is hydroxyl in a solvent to obtain a block polymer whose linkage site is carbonate. The polymer whose end group is a hydroxyl group is one of polycaprolactone, polytrimethylene carbonate, and polydioxanone; the obtained block polymers are respectively polylactic acid-polycaprolactone (PLA-PCL ), polylactic acid-polytrimethylene carbonate (PLA-PTMC) and polylactic acid-polydioxanone (PLA-PDO). The molar ratio of the polylactic acid whose end group is carbonylimidazole to the polymer whose end group is hydroxyl is 1:1-10:1. The reaction temperature is from room temperature to 150°C, and the reaction time is from 5h to 48h. The mass concentration of the polymer whose end group is a hydroxyl group in the solvent is 0.1 g/mL-10 g/mL. The solvent is one of chloroform, dichloromethane, tetrahydrofuran, hexafluoroisopropanol, and acetone, or a mixture of two or more of them in arbitrary proportions.

After the reaction is completed, the purification process is as follows:

Pour the reaction solution into anhydrous ether or anhydrous methanol, suction filter to obtain the target polymer, and then further purify the target polymer;

The purification process is as follows:

Dissolve the target polymer in a solvent (chloroform), precipitate in excess anhydrous methanol or anhydrous ether, filter with suction, and dry in vacuum; repeat the purification process N times. The optimal ratio of chloroform to ether or methanol is 1:5. In order to effectively remove the residual impurities in the product, the target product is subjected to the above dissolution and precipitation process for three times.

The reaction process is shown in Figure 1,

A block polymer used for fully degrading vascular stents, the polymer whose terminal group is a hydroxyl group is one of polycaprolactone, polytrimethylene carbonate, and polydioxanone; the obtained block The segment polymer corresponds to one of polylactic acid-polycaprolactone PLA-PCL, polylactic acid-polytrimethylene carbonate PLA-PTMC, and polylactic acid-polydioxanone PLA-PDO;

The structure is as follows:

Among them, the molecular weight of polylactic acid is 50,000 to 300,000, the molecular weight of polycaprolactone is 1,000 to 50,000, the molecular weight of polytrimethylene carbonate is 1,000 to 50,000, and the molecular weight of polydioxanone is 1,000 to 50,000. 50000.

Example 1

A block polymer for fully degradable vascular stents was prepared according to the following steps:

Step 1: React polylactic acid (Mw=50000) with carbonyldiimidazole in a chloroform solution at room temperature for 24 hours to obtain a polylactic acid material whose end group is carbonylimidazole. The mass concentration of polylactic acid was 1 g/mL.

Wherein, the molar ratio of polylactic acid hydroxyl group to carbonyldiimidazole is 1:1, after the solvent is concentrated, it is poured into anhydrous methanol, and the polylactic acid material whose target end group is carbonylimidazole is obtained by suction filtration.

Step 2: React carbonyl imidazole polylactic acid and polycaprolactone (Mw=1000) in chloroform solution for 48 hours at 50°C to obtain a polylactic acid-polycaprolactone block polymer whose linking site is carbonate . Wherein the mass concentration of the polylactic acid of carbonylimidazole is 3g/mL. The molar ratio of polylactic acid to polycaprolactone is 1:1. After the solvent is concentrated, it is poured into anhydrous ether, and the target block polymer material is obtained by suction filtration.

Compared with the conventional polylactic acid material with the same molecular weight, the block polymer material obtained in this example has a processing temperature lowered by 10°C and a toughness increased by 20%. The results of the simulated body fluid degradation experiment at 37°C show that the degradation rate is increased by 25%. .

Example 2

A block polymer for fully degradable vascular stents was prepared according to the following steps:

Step 1: React polylactic acid (Mw=80000) with carbonyldiimidazole in a chloroform solution for 24 hours at room temperature to obtain a polylactic acid material whose end group is carbonylimidazole. The mass concentration of polylactic acid is 0.5g/mL.

Wherein, the molar ratio of polylactic acid hydroxyl group to carbonyldiimidazole is 1:3, after the solvent is concentrated, it is poured into anhydrous methanol, and the polylactic acid material whose target terminal group is carbonylimidazole is obtained by suction filtration.

Step 2: React carbonyl imidazole polylactic acid and polycaprolactone (Mw=2000) in chloroform solution for 48 hours at 80°C to obtain a polylactic acid-polycaprolactone block polymer whose linking site is carbonate . Wherein the mass concentration of the polylactic acid of carbonylimidazole is 1 g/mL. The molar ratio of polylactic acid to polycaprolactone is 1:1. After the solvent is concentrated, it is poured into anhydrous ether, and the target block polymer material is obtained by suction filtration.

Compared with the conventional polylactic acid material of the same molecular weight, the block polymer material obtained in this example has a processing temperature lowered by 12°C and a toughness increased by 23%. The results of the simulated body fluid degradation experiment at 37°C show that the degradation rate is increased by 30%. .

Example 3

A block polymer for fully degradable vascular stents was prepared according to the following steps:

Step 1: React polylactic acid (Mw=100000) with carbonyldiimidazole in chloroform solution for 48 hours at room temperature to obtain a polylactic acid material whose end group is carbonylimidazole. The mass concentration of polylactic acid is 0.1 g/mL.

Wherein, the molar ratio of polylactic acid hydroxyl group to carbonyldiimidazole is 1:2, after the solvent is concentrated, it is poured into anhydrous methanol, and the polylactic acid material whose target terminal group is carbonylimidazole is obtained by suction filtration.

Step 2: React carbonyl imidazole polylactic acid and polycaprolactone (Mw=1000) in chloroform solution for 48 hours at 80°C to obtain a polylactic acid-polycaprolactone block polymer whose linking site is carbonate . Wherein the mass concentration of the polylactic acid of carbonylimidazole is 1 g/mL. The molar ratio of polylactic acid to polycaprolactone is 1:1. After the solvent is concentrated, it is poured into anhydrous ether, and the target block polymer material is obtained by suction filtration.

Compared with the conventional polylactic acid material of the same molecular weight, the block polymer material obtained in this example has a processing temperature lowered by 12°C and a toughness increased by 23%. The results of the simulated body fluid degradation experiment at 37°C show that the degradation rate is increased by 25%. .

Example 4

A block polymer for fully degradable vascular stents was prepared according to the following steps:

Step 1: React polylactic acid (Mw=80000) with carbonyldiimidazole in a chloroform solution for 24 hours at room temperature to obtain a polylactic acid material whose end group is carbonylimidazole. The mass concentration of polylactic acid is 0.5g/mL.

Wherein, the molar ratio of polylactic acid hydroxyl group to carbonyldiimidazole is 1:3, after the solvent is concentrated, it is poured into anhydrous methanol, and the polylactic acid material whose target terminal group is carbonylimidazole is obtained by suction filtration.

Step 2: React carbonyl imidazole polylactic acid and polytrimethylene carbonate (Mw=4000) in chloroform solution for 48 hours at room temperature to obtain polylactic acid-polycaprolactone block polymerization with carbonate linkage site thing. Wherein the mass concentration of the polylactic acid of carbonylimidazole is 1 g/mL. The molar ratio of polylactic acid to polycaprolactone is 1:1. After the solvent is concentrated, it is poured into anhydrous ether, and the target block polymer material is obtained by suction filtration.

Compared with the conventional polylactic acid material with the same molecular weight, the block polymer material obtained in this example has a processing temperature lowered by 15°C and a toughness increased by 25%. The results of the simulated body fluid degradation experiment at 37°C show that the degradation rate is increased by 36%. .

Example 5

A block polymer for fully degradable vascular stents was prepared according to the following steps:

Step 1: React polylactic acid (Mw=80000) with carbonyldiimidazole in a chloroform solution for 24 hours at room temperature to obtain a polylactic acid material whose end group is carbonylimidazole. The mass concentration of polylactic acid is 0.5g/mL.

Wherein, the molar ratio of polylactic acid hydroxyl group to carbonyldiimidazole is 1:3, after the solvent is concentrated, it is poured into anhydrous methanol, and the polylactic acid material whose target terminal group is carbonylimidazole is obtained by suction filtration.

Step 2: React carbonyl imidazole polylactic acid and polydioxanone (Mw=4000) in chloroform solution for 48 hours at 40°C to obtain a polylactic acid-polycaprolactone block whose linkage site is carbonate polymer. Wherein the mass concentration of the polylactic acid of carbonylimidazole is 13g/mL. The molar ratio of polylactic acid to polycaprolactone is 1:1. After the solvent is concentrated, it is poured into anhydrous ether, and the target block polymer material is obtained by suction filtration.

Compared with the conventional polylactic acid material with the same molecular weight, the block polymer material obtained in this example has a processing temperature lowered by 25°C and a toughness increased by 30%. The results of the simulated body fluid degradation experiment at 37°C show that the degradation rate is increased by 45%. .

The block polymer obtained in the present invention has excellent degradation performance and mechanical performance, can effectively improve the comprehensive performance of the fully degradable vascular stent, and further improve the quality of life of patients. The existing polylactic acid-polytrimethylene carbonate, polylactic acid-polycaprolactone, and polylactic acid-polydioxanone are all random copolymers. However, the preparation method of the present invention provides a fast and efficient construction of a block copolymer with a definite structure through the special reactivity of carbonyldiimidazole. The method of the invention can realize high-efficiency coupling of two polymers with hydroxyl functional end groups under mild conditions, and form a block copolymer with a definite molecular structure. Since the target block copolymer has a clear structure, the degradation, toughness and other properties of the target polymer can be more effectively improved through the fine adjustment of each polymer block.

Claims (6)

1. A method for preparing a block polymer for fully degradable vascular stent, characterized in that, comprising the following steps: Step 1: The hydroxyl end group in the polylactic acid and carbonyldiimidazole react in a solvent to obtain polylactic acid whose end group is carbonylimidazole; the mol ratio of the hydroxyl end group in the polylactic acid to carbonyldiimidazole is 1:1～1: 5; Step 2: react the polylactic acid whose terminal group is carbonylimidazole obtained in step 1 and the polymer whose terminal group is hydroxyl in a solvent to obtain a block polymer whose linking site is carbonate; the polylactic acid whose terminal group is carbonylimidazole The molar ratio to the polymer whose end group is hydroxyl is 1:1～10:1; the polymer whose end group is hydroxyl is one of polycaprolactone, polytrimethylene carbonate, and polydioxanone The obtained block polymer corresponds to one of polylactic acid-polycaprolactone PLA-PCL, polylactic acid-polytrimethylene carbonate PLA-PTMC, polylactic acid-polydioxanone PLA-PDO; The structure is as follows:

Among them, the molecular weight of polylactic acid is 50,000 to 300,000, the molecular weight of polycaprolactone is 1,000 to 50,000, the molecular weight of polytrimethylene carbonate is 1,000 to 50,000, and the molecular weight of polydioxanone is 1,000 to 50,000. 50000. 2. A method for preparing a block polymer for fully degradable vascular stent according to claim 1, characterized in that the reaction temperature in the step 1 is from room temperature to 100°C, and the reaction time is from 5h to 24h. 3 . The method for preparing a block polymer for fully degradable vascular stent according to claim 1 , wherein the reaction temperature in step 2 is room temperature to 150° C., and the reaction time is 5 h to 48 h. 4 . 4. a kind of block polymer preparation method that is used for fully degrading vascular stent according to claim 1 is characterized in that, described solvent is in chloroform, methylene dichloride, tetrahydrofuran, hexafluoroisopropanol, acetone A mixture of one or two or more in any proportion. 5. A kind of block polymer preparation method for fully degradable vascular stent according to claim 1, is characterized in that, after described step 1 and step 2 react, carry out purification, purification process is as follows: Pour the reaction solution into anhydrous ether or anhydrous methanol, suction filter to obtain the target polymer, and then further purify the target polymer; The purification process is as follows: Dissolve the target polymer in a solvent, precipitate in excess anhydrous methanol or anhydrous ether, filter with suction, and dry in vacuum; repeat the purification process N times. 6. A method for preparing a block polymer for fully degradable vascular stent according to claim 1, wherein the mass concentration of polylactic acid in the solvent in the step 1 is 0.2g/mL～5g/mL mL; the mass concentration of the polymer whose terminal group is hydroxyl in the solvent is 0.1g/mL～10g/mL.

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