CN115521430A

CN115521430A - Organic metal catalyst, preparation method and application of degradable biological material

Info

Publication number: CN115521430A
Application number: CN202111122492.8A
Authority: CN
Inventors: 周珍石; 王世杰
Original assignee: Suzhou Ruijinuo Medical Technology Co ltd
Current assignee: Suzhou Ruijinuo Medical Technology Co ltd
Priority date: 2021-09-24
Filing date: 2021-09-24
Publication date: 2022-12-27
Anticipated expiration: 2041-09-24
Also published as: CN115521430B

Abstract

The invention discloses an organic metal catalyst, a preparation method of a degradable biological material and application of the degradable biological material. The preparation method comprises the following steps: s1, synthesizing a product a by using polyether polyol, an organic metal catalyst and diisocyanate as raw materials; s2, synthesizing a product b by taking polyester polyol and the product a as raw materials; s3, cleaning and filtering the product b to obtain the degradable biological material; the application is the application of the degradable biological material in the preparation of implantable and non-implantable medical devices; the organic metal catalyst is at least one of organic bismuth, organic zinc and organic zirconium. According to the invention, by improving the preparation method and using the organic metal catalysts of specific types and proportions, the heavy metal tin is not introduced into the prepared degradable biological material, the mechanical property is not lower than that of the material prepared by adopting the tin organic metal catalysts, the biological safety is high, and the method is more suitable for the medical field.

Description

Organic metal catalyst, preparation method and application of degradable biological material

Technical Field

The invention belongs to the field of materials, and particularly relates to an organic metal catalyst, and a preparation method and application of a degradable biological material prepared by using the catalyst.

Background

The degradable biomaterial generally contains hydrolysable groups such as ester, anhydride, carbonic anhydride, amide or urethane bonds on the main chain, and in a living environment, the groups can be degraded through simple chemical reaction or enzyme catalysis, and the degradation products are small molecular substances such as water, carbon dioxide and the like, so that the groups can be metabolized, absorbed or discharged by organisms, and are harmless to human bodies. And the material has the advantages of good biocompatibility and affinity, adjustable physicochemical properties and the like, and can be used for repairing and reconstructing damaged organism tissues and organs and a drug carrier material.

Degradable biomaterials such as Polyhydroxyalkanoates (PHAs), which have good biocompatibility, have been applied to biomedical devices such as drug carriers, surgical sutures, implant materials, bone clamps, etc.; degradable biological materials such as Polycaprolactone (PCL) have the advantages of good biocompatibility, good film forming property, high chemical stability, no toxicity and harmlessness of degradation products and the like, and become the most widely applied synthetic degradable biological materials at present, but when the degradable biological materials are synthesized, toxic heavy metal tin catalysts are often introduced, one part of the materials cannot meet the national supervision requirement, and the other part of the materials meets the current national supervision requirement (the residual quantity of tin is not more than 200 mu g/g), but still contains a certain amount of toxic heavy metal residues, so that certain biological safety hidden dangers can be brought to human bodies, and the degradable biological materials are not suitable for being applied in the medical field.

The organic metal catalyst is one of the aids for preparing the degradable biological material, wherein the organic tin catalyst is the most widely used traditional catalyst in the synthesis process of the degradable material, and has been proved by the documents [ research progress of toxic effect of organic tin compounds on organisms, the environment of Sichuan, 36 vol.2 of 2017, zhulingjiao and the like ], the organic tin compound belongs to a neurotoxic substance, wherein toxicity can influence energy metabolism of a nervous system and clearance of oxygen free radicals to cause serious diseases, such as a series of symptoms of headache, dizziness, amnesia and the like caused by systemic nerve damage.

In recent years, catalysts such as organic bismuth, zinc, zirconium, nickel, neodymium, cerium and the like are applied to the synthesis of degradable biological materials. Wherein, the organic bismuth has the green safety characteristics of low cost, easy processing, low toxicity, low radioactivity and the like; the organic zinc catalyst is a polyurethane material catalyst with medium activity, can be used as a main catalyst or a cocatalyst for an MDI system and other isocyanate systems, and is mostly matched with an organic bismuth catalyst for use; the organic zirconium catalyst is a non-toxic safe environment-friendly catalyst (application research, coating technology and abstract, 31-34 pages in 2 years in 2013, permission to fly and the like) of the environment-friendly organic zirconium catalyst in a two-component waterborne polyurethane coating. The application of organic bismuth, zinc, zirconium and other catalysts can greatly reduce the residual quantity of tin in the synthesized degradable biological material, but the synthesized degradable biological material has another defect that the mechanical properties and the like of the synthesized material are far inferior to those of polyurethane obtained by the organic tin catalyst. And the organic nickel, organic neodymium and organic cerium catalysts can generate toxic damage to human bodies.

Therefore, it is necessary to find an organic metal catalyst without containing heavy metal tin and improve the preparation method of the degradable biological material, which can not only reduce the residual quantity of tin heavy metals in the degradable biological material, but also ensure that the mechanical and other properties of the material are not lower than those of the existing degradable biological material prepared by using the organic tin catalyst.

Disclosure of Invention

The technical problem to be solved by the invention is to provide an organic metal catalyst, a preparation method and application of a degradable biological material prepared by using the catalyst, so that the prepared degradable biological material can simultaneously meet the following requirements: 1. the content of heavy metal tin is low; 2. the mechanical and mechanical properties are not lower than those of the material prepared by adopting the organic tin catalyst; 3. the melting point is 50-56 ℃. The degradable biological material meeting the conditions has the advantages of high biological safety, strong mechanical property, no melting in human body, multiple sterilization modes and the like, and is more suitable for preparing implantable and non-implantable medical devices.

In order to achieve the purpose, the technical scheme adopted by the invention is as follows:

the invention discloses a preparation method of a degradable biological material, which comprises the following steps:

s1, carrying out catalytic reaction on polyether polyol and diisocyanate which are subjected to water removal and serve as raw materials by using an organic metal catalyst, reacting for 6-30h at 45-60 ℃, and carrying out reduced pressure distillation after the reaction is finished to obtain a product a;

s2, taking the polyester polyol subjected to water removal and the product a obtained in the step S1 as raw materials, reacting for 23-50h at 65-80 ℃, stopping heating after the reaction is finished, cooling to 45-55 ℃, and carrying out reduced pressure distillation to obtain a product b;

and S3, cooling the product b obtained in the step S2 to 20-35 ℃, cleaning and filtering to obtain the degradable biological material, and performing vacuum drying at 40 ℃ for 24-49 hours to obtain a relatively dry degradable biological material solid.

Preferably, the organometallic catalyst in step S1 is at least one of organobismuth, organozinc and organozirconium;

the organic bismuth is at least one of bismuth neodecanoate, bismuth isooctanoate, bismuth metasilicate and bismuth naphthenate; the organic zinc is at least one of zinc isooctanoate, zinc neodecanoate and zinc acetylacetonate; the organic zirconium is at least one of zirconium isooctanoate and zirconium acetylacetonate.

Preferably, the organometallic catalyst in step S1 is at least two of organobismuth, organozinc and organozirconium;

the organic bismuth is at least one of bismuth neodecanoate, bismuth isooctanoate, bismuth monthly silicate and bismuth naphthenate; the organic zinc is at least one of zinc isooctanoate, zinc neodecanoate and zinc acetylacetonate; the organic zirconium is at least one of zirconium isooctanoate and zirconium acetylacetonate.

Preferably, the mass ratio of the organic bismuth to the organic zinc is 14;

wherein, the mass ratio of the new bismuth decanoate to the bismuth laurate is 16-19, preferably 3;

the mass ratio of the new bismuth decanoate to the bismuth naphthenate is (11-1), preferably (5);

the mass ratio of the bismuth laurate to the bismuth naphthenate is 29-2, preferably, the mass ratio is 9;

the mass ratio of the new bismuth decanoate to the bismuth laurate to the bismuth naphthenate is 24-7, preferably, the mass ratio is 3.

Preferably, the mass ratio of the organic bismuth to the organic zirconium is 9;

wherein the mass ratio of the new bismuth decanoate to the bismuth laurate is (19-10);

the mass ratio of the new bismuth decanoate to the bismuth naphthenate is (3);

the mass ratio of the bismuth laurate to the bismuth naphthenate is 3;

the mass ratio of the new bismuth decanoate to the bismuth laurate to the bismuth naphthenate is (wt ratio) from 10 to 11.

Preferably, the mass ratio of the organic zinc to the organic zirconium is 15-2.

Preferably, the mass ratio of the organobismuth to the organozinc to the organozirconium is 7;

wherein, the mass ratio of the new bismuth decanoate to the bismuth laurate is 17-3, preferably, the mass ratio is 13;

the mass ratio of the new bismuth decanoate to the bismuth naphthenate is 3;

the mass ratio of the bismuth laurate to the bismuth naphthenate is 16-4, preferably, the mass ratio is 17;

the mass ratio of the new bismuth decanoate to the bismuth laurate to the bismuth naphthenate is 19-11, preferably, the mass ratio is 8.

Preferably, the amount of the organic metal catalyst used in the step S1 is 0.1-5% of the total mass of the diisocyanate and the polyether polyol.

Preferably, the polyether polyol in the S1 step is one of polyethylene glycol (PEG), polypropylene glycol (PPG) and polytetrahydrofuran glycol (PTMEG).

Preferably, the diisocyanate in the step S1 is one of Hexamethylene Diisocyanate (HDI), isophorone diisocyanate (IPDI), dicyclohexylmethane diisocyanate (HMDI), lysine Diisocyanate (LDI), trimethyl-1, 6-hexamethylene diisocyanate (TMDI), tetramethyl diisocyanate (TMXDI), methylcyclohexane diisocyanate (HTDI).

Preferably, in the step S2, the polyester polyol is one of polybutylene adipate glycol (PBGA), 1, 6-hexanediol adipate (PHA), 1, 6-hexanediol methyl-1, 3-propanediol adipate (PMHA), 1, 6-neopentyl glycol sebacate (PHS) and Polycaprolactone (PCL).

Preferably, the molar ratio of the polyether polyol and the diisocyanate in the S1 step is 1.

Preferably, the molar ratio of the polyether polyol in the S1 step and the polyester polyol in the S2 step is 1.

Preferably, the solvent for dissolving the polyether polyol, the metal catalyst solvent and the diisocyanate in the step S1 is one of dichloroethane, toluene, xylene, dioxane, methyl isobutyl ketone and toluene cyclohexanone.

The invention also discloses a degradable biological material, which is prepared by the preparation method of the degradable biological material, and the molecular formula is as follows:

further, the degradable biomaterial has the following properties:

the heavy metal tin is not contained;

tensile strength at break: 15-28MPa;

elongation at break: 500-1700 percent;

maximum force: 16-39N;

the weight average molecular weight is 80000-110000Da;

the melting point is 50-56 ℃.

The invention also provides application of the degradable biological material in preparing implantable and non-implantable medical devices.

Preferably, the above implantable and non-implantable medical devices comprise: medical equipment for soft tissue regeneration and repair, anti-adhesion materials, cartilage repair scaffolds, bone composite repair scaffolds, medical beauty products implantable in vivo, medical catheters, biodegradable coatings, wound repair films and dressings or absorbable surgical sutures.

Preferably, the medical device for soft tissue regeneration and repair comprises a peripheral nerve repair sleeve, a peripheral nerve repair coating film, a peripheral nerve repair sleeve, a peripheral nerve protection cap and artificial skin.

The invention also discloses an organic metal catalyst, which is at least one of organic bismuth, organic zinc and organic zirconium;

Preferably, the organometallic catalyst is at least two of organobismuth, organozinc and organozirconium.

Preferably, the mass ratio of the organic bismuth to the organic zinc is 14;

wherein, the mass ratio of the new bismuth decanoate to the bismuth laurate is 19-10, preferably 5;

the mass ratio of the new bismuth decanoate to the bismuth naphthenate is (3);

the mass ratio of the bismuth laurate to the bismuth naphthenate is 3;

Preferably, the mass ratio of the organic zinc to the organic zirconium is 15.

Preferably, the mass ratio of the organic bismuth, the organic zinc and the organic zirconium is (7);

wherein the mass ratio of the new bismuth decanoate to the bismuth laurate is (17-3);

the mass ratio of the new bismuth decanoate to the bismuth naphthenate is 3;

The invention also discloses an application of the organic metal catalyst in preparation of a degradable biological material.

Preferably, the degradable biological material comprises biodegradable polylactic acid, biodegradable polycaprolactone, biodegradable polyhydroxyalkanoate, biodegradable polybutylene succinate, biodegradable polybutylene terephthalate-adipate, biodegradable polyvinyl alcohol and biodegradable polycarbonate.

Compared with the prior art, the invention has the following beneficial effects:

1. the invention provides a preparation method of a degradable biological material, which takes polyether glycol and polyester glycol group as soft segments and diisocyanate as hard segments, and improves the preparation method of the degradable biological material by screening the type and the proportion of non-tin organic metal catalysts, changing the type, the molecular weight, the reaction temperature and the reaction time of the soft segments, so that the mechanical property of the prepared degradable biological material is not lower than that of the material prepared by adopting the tin organic metal catalysts.

2. The invention provides a degradable biological material, which has low content of heavy metal tin and mechanical properties not lower than those of a material prepared by adopting an organic tin catalyst, and has a melting point of 50-56 ℃. Has the advantages of high biological safety, strong mechanical property, no melting in human body, multiple sterilization modes selection and the like, and is more suitable for preparing implantable and non-implantable medical devices.

3. The invention provides an organic metal catalyst which is at least one of organic bismuth, organic zinc and organic zirconium, the mechanical strength of a degradable biological material prepared by catalysis is not lower than that of a degradable biological material prepared by using an organic tin catalyst, and after the organic bismuth, the organic zinc and the organic zirconium are compounded in a specific proportion, the mechanical strength of the degradable biological material prepared by catalysis is superior to that of the degradable biological material prepared by single catalysis.

Detailed Description

The embodiments of the present invention are described below with reference to specific embodiments, and other advantages and effects of the present invention will be easily understood by those skilled in the art from the disclosure of the present specification. The invention is capable of other and different embodiments and of being practiced or of being carried out in various ways, and its several details are capable of modification in various respects, all without departing from the spirit and scope of the present invention.

Before the present embodiments are further described, it is to be understood that the scope of the invention is not to be limited to the specific embodiments described below; it is also to be understood that the terminology used in the examples is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention.

When numerical ranges are given in the examples, it is understood that both endpoints of each of the numerical ranges and any value therebetween can be selected unless the invention otherwise indicated. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

The degradable biological material comprises biodegradable polylactic acid, biodegradable polycaprolactone, biodegradable polyhydroxyalkanoate, biodegradable polybutylene succinate, biodegradable poly (terephthalic acid) -adipic acid-butylene glycol, biodegradable polyvinyl alcohol, biodegradable polycarbonate and the like.

It should be noted that the raw materials used in the present invention are all common commercial products, the sources thereof are not particularly limited, and some of the raw materials are shown in table 1.

TABLE 1

Commercially available high molecular weight PCLs are generally available as PCL60,000, PCL80,000, PCL100,000, and the like. In the present invention, commercially available PCLs with a large molecular weight can be used. The commercially available PCL with a large molecular weight used in the examples was PCL80,000.

Commercially available Polyhydroxyalkanoates (PHAs) are usually PHA6000, PHA4000, PHA5000, etc., and are suitable for use in the present invention, and PHA6000 is used in examples.

Commercially available polybutylene adipate (PBGA) is usually PBGA3000, PBGA2000, PBGA5000, etc., and is suitable for use in the present invention, and PBGA3000 is used in the examples.

Commercially available polylactic acid diols (PLA) are generally PLA2000, PLA3000, PLA4000, etc., and are suitable for use in the present invention, with PLA2000 being used in the examples.

Examples 1 to 3A degradable biomaterial and a method for preparing the same

Example 1

1. Adding PEG800 and bismuth isooctanoate into a reaction bottle, adding dichloroethane, controlling the mass ratio of the PEG800 and the bismuth isooctanoate to the dichloroethane to be 1. The remaining solution was charged into a dropping funnel.

2. Adding HDI into a reaction bottle by dissolving HDI in dichloroethane, controlling the volume ratio of the mass of the HDI to the dichloroethane to be 1. The reaction was carried out for 29h, distilled under reduced pressure for 20min, and the remaining solution was charged into the dropping funnel.

3. Dissolving PCL80000 in toluene, adding the solution into a reaction bottle, controlling the volume ratio of the PCL80000 to the toluene to be 1. The reaction was carried out at 75 ℃ for 5h. After the reaction product was cooled to room temperature, it was washed 3 times with ice-distilled water. Transferring the obtained lower layer liquid into a reaction bottle, distilling under reduced pressure for 30min, pouring the residual liquid into a mixed solution of methanol and ice distilled water to wash and precipitate, and controlling the volume ratio of the methanol to the distilled water to be 1. And filtering after twice washing to obtain PCL2000.

4. Adding PCL2000 into a reaction bottle, adding dichloroethane, controlling the mass ratio of the PCL2000 to the dichloroethane to be 1. And (3) when the temperature in the reaction bottle is cooled to 73 ℃, slowly adding the residual solution in the step (2) into the reaction bottle, and controlling the molar ratio of the PCL2000 to the PEG800 to be 1. The reaction was carried out at 73 ℃ for 41h. Stopping reaction, cooling the reaction product to 50 ℃, and distilling under reduced pressure for 30min.

5. After distillation is stopped, the reaction flask is cooled to 20 ℃, the polymer is poured into a petroleum ether/methanol mixed solution for cleaning, the volume ratio of petroleum ether to methanol is controlled to be 5.

Example 2

This example is different from example 1 in that the bismuth isooctanoate catalyst in the preparation method was replaced with the same amount of zinc isooctanoate, and the obtained degradable biomaterial was designated as S2, and the rest was the same as example 1.

Example 3

This example is different from example 1 in that the bismuth isooctanoate catalyst in the preparation method was replaced with the same amount of zirconium isooctanoate, and the obtained degradable biomaterial was designated as S3, and the rest was the same as example 1.

Comparative example 1

This comparative example differs from example 1 in that the bismuth isooctanoate catalyst in the preparation process was replaced with the same amount of dibutyltin dilaurate, and the resulting degradable biomaterial was designated as B1, as in example 1.

And (4) performance testing:

1. test method

( 1) Mechanical property determination (method reference: determination of tensile Properties of GB/T1040.1-2018 plastics part 1: general rule P13-15 )

a. Sample preparation

(1) Shape and size

The material was made into a straight strip shape with a length of about 15cm and a width of about 1 cm. The middle part of the sample should have two parallel marked lines with a 5cm separation.

(2) Sample preparation

The above-sized specimens were prepared using a cutting method so that the edges of the specimens were smooth and unnotched.

(3) Marking line

An ink stamp having a strong color contrast and not adversely affecting the sample to be tested is used to stamp the mark region.

b. Condition conditioning

The conditions of 23. + -. 2 ℃ and 50. + -. 10% relative humidity were chosen to condition the sample for 24h.

c. Test of

The test was performed under the same environment as the conditioning of the specimen.

The sample is placed in the fixture with the long axis of the sample in line with the axis of the tester. The clamp is clamped stably and firmly to prevent the sample from slipping and the clamp from moving in the test. The test was carried out at a sample speed of 50 mm/min.

( 2) Sample molecular weight determination (method reference: polylactic acid for YY/T1678-2019 surgical implant and molecular weight distribution detection method P5-P9 of copolymer of polylactic acid )

a. Mobile phase equipment

The chromatographic grade tetrahydrofuran was degassed under vacuum and added to the GPC bottle.

b. Preparation of Polymer sample solution

Preparing a polymer sample into a solution with the concentration of 0.5mg/ml by using chromatographic grade tetrahydrofuran, standing the solution overnight after the polymer sample is completely dissolved, and filtering the solution by using an organic phase microporous filter membrane to remove insoluble impurities.

c. Test conditions

The flow rate was 1ml/min, and the column temperature was 35 ℃.

( 3) Melting point determination (method reference: GB/T19466.1-2004 plastics Differential Scanning Calorimetry (DSC) part 1: general rule P6-P9 )

a. Sample preparation

About 10mg of the sample was weighed into a crucible having a hole in the lid and clamped by a clamp.

b. Equipment preparation

And opening the equipment and preheating for half an hour.

c. Loading sample

And putting the sample to be tested into the right side of the equipment, wherein the left side is blank.

d. Test flow

Cooling from room temperature to 0 deg.C at a rate of 30 deg.C/min, and maintaining at 0 deg.C for 3min.

Heating from 0 deg.C to 100 deg.C at a heating rate of 10 deg.C/min, and maintaining at 100 deg.C for 3min.

Cooling from 100 deg.C to 0 deg.C at a rate of 10 deg.C/min, and maintaining at 0 deg.C for 3min.

The temperature is increased from 0 ℃ to 100 ℃, and the heating rate is 10 ℃/min.

e. And after the test is finished, taking out the sample after the test is cooled. The crucible containing the sample was weighed and the data processed.

And (3) testing results: the physical and chemical performance tests of S1-3 and B1 are carried out, and the test results are shown in Table 2.

TABLE 2

The results show that S1-3 is a degradable biological material prepared by singly using organic bismuth, organic zinc and organic zirconium as organic metal catalysts, and the mechanical property of the degradable biological material is not lower than that of B1 prepared by using tin organic metal catalysts.

Examples 4 to 6A degradable biomaterial and a method for preparing the same

Example 4

1. Adding PEG400 and new bismuth decanoate/zinc isooctanoate into a reaction bottle, adding dichloroethane, controlling the mass ratio of the PEG400 and the new bismuth decanoate/zinc isooctanoate to the dichloroethane to be 1. The remaining solution was charged into the dropping funnel.

2. And (2) dissolving HDI in dichloroethane, adding the HDI into a reaction bottle, controlling the volume ratio of the mass of the HDI to the dichloroethane to be 1. The molar ratio of HDI to PEG400 was controlled to be 2. The reaction was carried out for 6h, distillation under reduced pressure was carried out for 20min, and the remaining solution was charged into a dropping funnel.

3. Adding PLA2000 into a reaction bottle, adding dichloroethane, controlling the mass of the PLA2000 and the volume ratio of the dichloroethane to be 1. And (3) after the temperature in the reaction bottle is cooled to 72 ℃, slowly adding the residual solution in the step (2) into the reaction bottle, and controlling the molar ratio of PLA2000 to PEG400 to be 1. The reaction was carried out at 72 ℃ for 30h. Stopping reaction, cooling the reaction product to 50 deg.C, distilling under reduced pressure for 30min, and charging the residual solution into dropping funnel.

4. And after the distillation is stopped, cooling the reaction bottle to 25 ℃, pouring the polymer into a petroleum ether/methanol mixed solution for cleaning, controlling the volume ratio of petroleum ether to methanol to be 5.

Example 5

The difference between the present example and example 4 is that the mass ratio of the new bismuth decanoate to the zinc isooctanoate in the preparation method is 14.

Example 6

The difference between this example and example 4 is that the mass ratio of the new bismuth decanoate to the zinc isooctanoate in the preparation method is changed from 14 to 2, and the obtained degradable biomaterial is marked as S6, and the rest is the same as example 4.

Comparative example 2

The comparative example is different from example 4 in that the mass ratio of the new bismuth decanoate to the zinc isooctanoate in the preparation method is 14, and the ratio is replaced by 5.

Comparative example 3

The comparative example is different from example 4 in that the mass ratio of the new bismuth decanoate to the zinc isooctanoate in the preparation method is 14, the mass ratio is replaced by 3, the obtained degradable biological material is marked as B3, and the rest is the same as example 4.

Comparative example 4

This comparative example is different from example 4 in that the same amount of dibutyltin dilaurate was substituted for bismuth neodecanoate and zinc isooctanoate in the preparation method, and the obtained degradable biomaterial was designated as B4, and the rest of the same procedure was used in example 4.

And (4) performance testing:

1. the test method comprises the following steps: the same test method as above

2. And (3) testing results: the physical and chemical performance tests of S4-6 and B2-4 are carried out, and the test results are shown in Table 3.

TABLE 3

The above results show that the catalyst used in examples 4-6 is obtained by compounding organic bismuth and organic zinc within the proportion range protected by the present invention, and the mechanical properties of the prepared S4-6 are not lower than those of B4 prepared by using the tin-based organometallic catalyst in comparative example 4; the catalysts used in comparative examples 2 to 3 were obtained by compounding organic bismuth and organic zinc in proportions not covered by the present invention, and the resulting B2-3 had lower mechanical properties than B4 obtained in comparative example 4 using a tin-based organometallic catalyst.

Examples 7 to 9A degradable biomaterial and a method for preparing the same

Example 7

1. Adding PTMEG600 and bismuth naphthenate/zirconium isooctanoate into a reaction bottle, adding toluene, controlling the mass ratio of PTMEG600 and bismuth naphthenate/zirconium isooctanoate to toluene to be 1. The remaining solution was charged into a dropping funnel.

2. The preparation method comprises the following steps of dissolving LDI in toluene, adding the solution into a reaction bottle, controlling the volume ratio of the mass of the LDI to the toluene to be 1.

3. Adding PHA6000 into a reaction bottle, adding toluene, controlling the mass ratio of PHA6000 to toluene to be 1. And (3) when the temperature in the reaction bottle is cooled to 75 ℃, slowly adding the residual solution in the step (2) into the reaction bottle, and controlling the molar ratio of the PHA6000 to the PTMEG600 to be 1. The reaction was carried out at 65 ℃ for 50h. Stopping the reaction, cooling the reaction product to 50 ℃, and distilling under reduced pressure for 30min.

4. After stopping the distillation, the reaction flask was cooled to 30 ℃, the polymer was poured into a petroleum ether/methanol mixed solution for washing, the volume ratio of petroleum ether to methanol was controlled to be 5.

Example 8

The difference between this example and example 7 is that the mass ratio of bismuth naphthenate/zirconium isooctanoate in the preparation method is 9.

Example 9

Comparative example 5

The comparative example differs from example 7 in that the mass ratio of bismuth naphthenate/zirconium isooctanoate in the preparation method is changed from 9 to 5, the obtained degradable biomaterial is marked as B5, and the rest is the same as example 7.

Comparative example 6

The comparative example differs from example 7 in that the mass ratio of bismuth naphthenate/zirconium isooctanoate in the preparation method is replaced by 3.

Comparative example 7

This comparative example differs from example 7 in that the preparation process was replaced with bismuth naphthenate/zirconium isooctanoate for dibutyltin dilaurate and the resulting degradable biomaterial was designated B7, as in example 7.

And (4) performance testing:

1. the test method comprises the following steps: the same test method as above

2. And (3) testing results: the above physical and chemical properties were measured for S7-9 and B5-7, and the results are shown in Table 4.

TABLE 4

The above results show that the catalysts used in examples 7-9 are obtained by compounding organic bismuth and organic zirconium in the proportion range protected by the present invention, and the mechanical properties of the prepared S7-9 are not lower than those of B7 prepared by using the tin-based organic metal catalyst in comparative example 7; the catalysts used in comparative examples 5 to 6 were obtained by compounding organobismuth and organozirconium in a ratio not within the range of the present invention, and the mechanical properties of B5-6 obtained were all lower than those of B7 obtained in comparative example 7 using a tin-based organometallic catalyst.

Examples 10 to 12A degradable biomaterial and a method for preparing the same

Example 10

1. Adding PPG600 and new zinc decanoate/zirconium isooctanoate into a reaction bottle, adding dichloroethane, controlling the mass ratio of the PPG600 and the new bismuth decanoate/zirconium isooctanoate to the dichloroethane to be 1. The remaining solution was charged into the dropping funnel.

2. Dissolving TMDI in dichloroethane, adding the mixture into a reaction bottle, controlling the mass ratio of TMDI to dichloroethane to be 1/5, slowly adding the rest solution obtained in the step 1 into the reaction bottle by using a dropping funnel at 52 ℃, wherein the total amount of the new zinc caprate and the zirconium isooctanoate is 2% of the total mass of PPG600 and TMDI, and the mass ratio of the new zinc caprate/the zirconium isooctanoate is 15. The molar ratio of TMDI to PPG600 was controlled to 2. The reaction was carried out for 22h, distillation under reduced pressure was carried out for 30min, and the remaining solution was charged into a dropping funnel.

3. Adding PBGA3000 into a reaction bottle, adding dichloroethane, controlling the mass of PBGA3000 to the volume ratio of dichloroethane to be 1. After the temperature in the reaction flask cooled to 74 ℃, the remaining solution in step 2 was slowly added to the reaction flask, controlling the molar ratio of PBGA3000 to PPG600 to 1. The reaction was carried out at 80 ℃ for 23h. Stopping the reaction, cooling the reaction product to 40 ℃, and distilling under reduced pressure for 30min.

4. And after the distillation is stopped, cooling the reaction bottle to 35 ℃, pouring the polymer into a petroleum ether/methanol mixed solution for cleaning, controlling the volume ratio of petroleum ether to methanol to be 5.

Example 11

The difference between this example and example 10 is that the mass ratio of zinc neodecanoate/zirconium isooctanoate in the preparation method 15 is replaced by 3.

Example 12

The difference between this example and example 10 is that the mass ratio 15 of the new zinc decanoate/zirconium isooctanoate in the preparation method is replaced by 2.

Comparative example 8

The comparative example is different from example 10 in that the mass ratio of the new zinc decanoate/zirconium isooctanoate in the preparation method is changed from 15 to 5, the obtained degradable biomaterial is marked as B8, and the rest is the same as example 10.

Comparative example 9

The comparative example is different from example 10 in that the mass ratio of the new zinc decanoate/zirconium isooctanoate in the preparation method is changed from 15 to 2, the obtained degradable biomaterial is marked as B9, and the rest is the same as example 10.

Comparative example 10

This comparative example differs from example 10 in that the new zinc/zirconium octoate was replaced by dibutyl tin dilaurate in the preparation method and the resulting degradable biomaterial was marked B10, the rest being the same as example 10.

And (4) performance testing:

1. the test method comprises the following steps: the same test method as above

2. And (3) testing results: the above physical and chemical properties were measured for S10-12 and B8-10, and the results are shown in Table 5.

TABLE 5

The above results show that the catalysts used in examples 10 to 12 were obtained by compounding organic zinc and organic zirconium in the ratio range protected by the present invention, and that the mechanical properties of the resulting S10-12 were not lower than those of B10 obtained in comparative example 10 using a tin-based organometallic catalyst; the catalysts used in comparative examples 8 to 9 were obtained by compounding organic zinc and organic zirconium in proportions not covered by the present invention, and the resulting B8-9 had lower mechanical properties than B10 obtained in comparative example 10 using a tin-based organometallic catalyst.

Examples 13 to 15A degradable biomaterial and a method for preparing the same

Example 13

1. Adding PEG800 and new bismuth decanoate/bismuth laurate/bismuth naphthenate/zinc isooctanoate/zirconium acetylacetonate into a reaction bottle, adding dichloroethane, controlling the mass ratio of the PEG800 and the new bismuth decanoate/bismuth laurate/bismuth naphthenate/zinc isooctanoate/zirconium acetylacetonate to the dichloroethane to be 1. The remaining solution was charged into a dropping funnel.

2. Adding HDI into a reaction bottle, controlling the volume ratio of the mass of HDI to dichloroethane to be 1. The reaction was carried out for 29h, distilled under reduced pressure for 20min, and the remaining solution was charged into the dropping funnel.

3. Dissolving PCL80000 in toluene, adding the solution into a reaction bottle, controlling the volume ratio of the PCL80000 to the toluene to be 1. The reaction was carried out at 75 ℃ for 5h. After the reaction product was cooled to room temperature, it was washed 3 times with ice-distilled water. Transferring the obtained lower layer liquid into a reaction bottle, distilling under reduced pressure for 30min, pouring the residual liquid into a mixed solution of methanol and ice distilled water to wash and precipitate, and controlling the volume ratio of the methanol to the distilled water to be 1. After washing twice, filtering is carried out to obtain PCL2000.

4. Adding PCL2000 into a reaction bottle, adding dichloroethane, controlling the mass ratio of the PCL2000 to the dichloroethane to be 1. And (3) when the temperature in the reaction bottle is cooled to 73 ℃, slowly adding the residual solution in the step (2) into the reaction bottle, and controlling the molar ratio of the PCL2000 to the PEG800 to be 1. The reaction was carried out at 73 ℃ for 41h. Stopping the reaction, cooling the reaction product to 50 ℃, and distilling under reduced pressure for 30min.

5. After distillation was stopped, the reaction flask was cooled to 20 ℃, the polymer was poured into a petroleum ether/methanol mixed solution for washing, the volume ratio of petroleum ether to methanol was controlled at 5.

Example 14

This example differs from example 13 in that the mass ratio of bismuth neodecanoate/bismuth laurate/bismuth naphthenate/zinc isooctanoate/zirconium acetylacetonate in the preparation process is 17.

Example 15

This example differs from example 13 in that the mass ratio of bismuth neodecanoate/bismuth laurate/bismuth naphthenate/zinc isooctanoate/zirconium acetylacetonate in the preparation process is changed from 17.

Comparative example 11

This comparative example differs from example 13 in that the mass ratio of bismuth neodecanoate/bismuth laurate/bismuth naphthenate/zinc isooctanoate/zirconium acetylacetonate in the preparation process was replaced with 7.

Comparative example 12

This comparative example differs from example 13 in that the mass ratio of bismuth neodecanoate/bismuth laurate/bismuth naphthenate/zinc isooctanoate/zirconium acetylacetonate in the preparation process was replaced with 15.

And (4) performance testing:

1. the test method comprises the following steps: the same test method as above

2. And (3) testing results: the above physical and chemical properties were measured for S13-15 and B11-12, and the results are shown in Table 6.

TABLE 6

The above results show that the catalysts used in examples 13 to 15 were obtained by compounding organobismuth, organozinc and organozirconium in the ratio range protected by the present invention, and that none of the mechanical properties of the obtained S13 to 15 was lower than that of B1 obtained by using the tin-based organometallic catalyst in comparative example 1; the catalysts used in comparative examples 11 to 12 were obtained by compounding organobismuth, organozinc and organozirconium in proportions not protected by the present invention, and the mechanical properties of the prepared B11 to 12 were all lower than those of B1 prepared in comparative example 1 using a tin-based organometallic catalyst; and the results of comparing S1-3 with S13-15 show that the mechanical property of the prepared degradable biological material is superior to that of the degradable biological material prepared by singly using the organic bismuth, the organic zinc and the organic zirconium are compounded in the protection proportion range of the invention.

Examples 16 to 17A degradable biomaterial and a method for preparing the same

Example 16

This example differs from example 14 in that the amount of bismuth neodecanoate/bismuth laurate/bismuth naphthenate/zinc isooctanoate/zirconium acetylacetonate used in step 2 of the preparation method was changed to 0.1% of the total mass of PEG800 and HDI instead of 2% of the total mass of PEG800 and HDI, and the resulting degradable biomaterial was denoted as S16, and the rest was the same as example 14.

Example 17

This example differs from example 14 in that the amount of bismuth neodecanoate/bismuth laurate/bismuth naphthenate/zinc isooctanoate/zirconium acetylacetonate used in preparation process step 2 was changed to 2% of the total mass of PEG800 and HDI and the resulting degradable biomaterial was designated as S17, which was otherwise the same as example 14.

Comparative example 13

This example differs from example 14 in that the amount of bismuth neodecanoate/bismuth laurate/bismuth naphthenate/zinc isooctanoate/zirconium acetylacetonate used in step 2 of the preparation method was changed to 0.05% of the total mass of PEG800 and HDI instead of 2% of the total mass of PEG800 and HDI, and the resulting degradable biomaterial was denoted as B13, and the rest was the same as example 14.

Comparative example 14

This example differs from example 14 in that the amount of bismuth neodecanoate/bismuth laurate/bismuth naphthenate/zinc isooctanoate/zirconium acetylacetonate used in preparation process step 2 was changed to 2% of the total mass of PEG800 and HDI, to 6% of the total mass of PEG800 and HDI, and the resulting degradable biomaterial was designated B14, which was otherwise the same as in example 14.

And (3) performance testing:

1. the test method comprises the following steps: the same test method as above

2. And (3) testing results: the above physical and chemical properties were measured for S16-17 and B13-14, and the results are shown in Table 7.

TABLE 7

The above results show that the organic metal catalysts used in examples 14 and 16-17 are within the scope of the present invention, and that neither S14 nor S16-17 obtained has lower mechanical properties than B1 obtained by using the tin-based organic metal catalyst in comparative example 1; the amount of the organometallic catalyst used in comparative examples 13 to 14 is out of the range protected by the present invention, and B13 to 14 obtained were all inferior in mechanical properties to B1 obtained in comparative example 1 using the tin-based organometallic catalyst.

In conclusion, the degradable biomaterial prepared according to the technical scheme of the invention does not contain heavy metal tin, has high biological safety, and the mechanical property of the finally obtained degradable biomaterial is higher than that of the degradable biomaterial obtained by adopting a tin organic metal catalyst, the melting point is 50-56 ℃, and the degradable biomaterial is more suitable for the medical field.

Finally, it should be noted that the above-mentioned contents are only used for illustrating the technical solutions of the present invention, and not for limiting the protection scope of the present invention, and that the simple modifications or equivalent substitutions of the technical solutions of the present invention by those of ordinary skill in the art can be made without departing from the spirit and scope of the technical solutions of the present invention.

Claims

1. The preparation method of the degradable biological material is characterized by comprising the following steps:

s1, using the dehydrated polyether polyol and diisocyanate as raw materials, carrying out catalytic reaction by using an organic metal catalyst, reacting for 6-30h at 45-60 ℃, and carrying out reduced pressure distillation after the reaction is finished to obtain a product a;

s2, reacting the polyester polyol subjected to water removal and the product a obtained in the step S1 at 65-80 ℃ for 23-50h, stopping heating after the reaction is finished, cooling to 45-55 ℃, and distilling under reduced pressure to obtain a product b;

and S3, cooling the product b obtained in the step S2 to 20-35 ℃, and cleaning and filtering to obtain the degradable biological material.

2. The preparation method according to claim 1, wherein the organometallic catalyst in step S1 is at least one of organobismuth, organozinc and organozirconium;

the organic bismuth is at least one of bismuth neodecanoate, bismuth isooctanoate, bismuth metasilicate and bismuth naphthenate; the organic zinc is at least one of zinc iso-octoate, zinc neo-caprate and zinc acetylacetonate; the organic zirconium is at least one of zirconium isooctanoate and zirconium acetylacetonate.

3. The preparation method according to claim 2, wherein the mass ratio of the organic bismuth to the organic zinc is 14.

4. The preparation method according to claim 2, wherein the mass ratio of the organobismuth to the organozirconium is 9.

5. The preparation method according to claim 2, wherein the mass ratio of the organozinc to the organozirconium is 15-2.

6. The preparation method according to claim 2, wherein the mass ratio of the organobismuth, the organozinc and the organozirconium is 7.

7. The method according to any one of claims 1 to 6, wherein the organometallic catalyst in the step S1 is 0.1 to 5% by mass of the total mass of the diisocyanate and the polyether polyol.

8. A degradable biomaterial produced by the production method according to any one of claims 1 to 7.

9. The degradable biomaterial of claim 8, wherein the melting point of the degradable biomaterial is 50-56 ℃.

10. Use of a degradable biomaterial according to claim 9 in the preparation of implantable and non-implantable medical devices comprising: medical instruments, anti-adhesion materials, cartilage repair scaffolds, bone composite repair scaffolds, medical beauty products implantable in vivo, medical catheters, biodegradable coatings, wound repair films and dressings or absorbable surgical sutures for soft tissue regeneration repair; the medical apparatus for soft tissue regeneration and repair comprises a peripheral nerve repair sleeve, a peripheral nerve repair coating film, a peripheral nerve repair sleeve, a peripheral nerve protective cap and artificial skin.

11. An organic metal catalyst, characterized in that the organic metal catalyst is at least one of organic bismuth, organic zinc and organic zirconium;

the organic bismuth is at least one of bismuth neodecanoate, bismuth isooctanoate, bismuth metasilicate and bismuth naphthenate; the organic zinc is at least one of zinc iso-octoate, zinc neodecanoate and zinc acetylacetonate; the organic zirconium is at least one of zirconium isooctanoate and zirconium acetylacetonate.

12. The organometallic catalyst according to claim 11, wherein the mass ratio of the organobismuth to the organozinc is 14.

13. The organometallic catalyst according to claim 11, wherein the mass ratio of the organobismuth to the organozirconium is 9.

14. The organometallic catalyst according to claim 11, wherein the mass ratio of the organozinc to the organozirconium is 15-2.

15. The organometallic catalyst according to claim 11, wherein the mass ratio of the organobismuth, the organozinc and the organozirconium is 7.

16. The use of the organometallic catalyst according to any one of claims 11 to 15, wherein the use is a use of the organometallic catalyst in preparing a degradable biomaterial, and the degradable biomaterial comprises biodegradable polylactic acid, biodegradable polycaprolactone, biodegradable polyhydroxyalkanoate, biodegradable polybutylene succinate, biodegradable polybutylene terephthalate-adipate, biodegradable polyvinyl alcohol, and biodegradable polycarbonate.