CN114456358A - Medical anti-adhesion absorbable flexible polyester material, and preparation method and application thereof - Google Patents

Abstract

The invention provides an absorbable flexible polyester material for medical anti-adhesion and an application thereof, belonging to the field of medical polymer materials. The material in the present invention is amino-terminated polyester with a weight average molecular weight of 40,000-200,000 and a glass transition temperature of 34°C to 39°C. When used, the amino-terminated polyester is made into a fiber film, and the thickness of the fiber film is 0.06mm~0.14mm, mainly used for postoperative anti-adhesion isolation material. Compared with the prior art, the present invention introduces polycaprolactone and polyglycolic acid structure from the molecular structure, increases its flexibility, and the elongation at break of the fiber film reaches more than 600%; the amino group is introduced into the polylactic acid molecular structure, because The material of the present invention will produce acidic substances in the process of in vivo degradation, and will also produce amino basic groups. The basicity of the amino group can balance the acidity, maintain the surrounding degradation environment within a certain range, and make the degradation speed stable. The material of the present invention It has the advantages of excellent flexibility, suitable degradation time and reduced inflammation.

Description

Absorbable flexible polyester material for medical anti-adhesion, preparation method and application thereof

technical field

The invention belongs to the field of medical polymer materials, and in particular relates to an absorbable flexible polyester material for medical anti-adhesion, a preparation method and an application thereof.

Background technique

Adhesion is a common complication in surgery, which brings great pain to patients' lives. At present, the main method of treating adhesion is to use physical isolation, that is, a solid material is placed between the surgical wound and the surrounding normal tissue to set up a physical barrier, so as to isolate the tissue during the healing process and achieve the anti-adhesion effect. Effectively reduce the occurrence of bad adhesion. There are many kinds of commonly used materials, such as sodium hyaluronate, chitosan, polyethylene glycol, polylactic acid, polyglycolic acid, etc. Because polylactic acid has good biodegradability, histocompatibility and excellent mechanical properties, etc. One of the commonly used materials in the market at present, but due to high mechanical strength and limited flexibility, its degradation controllability is also poor. During the degradation process, acidic substances will be produced, which will cause inflammation in the body and affect tissue regeneration and recovery. Its clinical use effect Not ideal either. International patent WO2006/100895 discloses a medical film composed of lactide and caprolactone copolymer, which has good flexibility and strength, but the degradation rate of the material itself is relatively slow, and it takes 6 months for complete absorption, which may affect the film. Wound healing and tissue repair functions. Chinese patent CN1305928C discloses that lactic acid and polyethylene glycol are copolymerized to obtain lactic acid/polyethylene glycol copolymer; Chinese patent CN103055354 B discloses that lactide, glycolide and polyethylene glycol are copolymerized to obtain polyethylene glycol-polylactide Glycolide block copolymer. Although the introduction of polyglycolic acid and polyethylene glycol in the two patents can speed up the degradation rate of polylactic acid in vivo, acid substances are generated during the degradation process, which will affect the pH value of the surrounding environment and affect the degradation speed of the diaphragm, and at the same time, it is easy to cause inflammation. occur, thus limiting its broad application in the field of clinical medicine.

SUMMARY OF THE INVENTION

In order to solve the above technical deficiencies, the purpose of the present invention is to provide an absorbable flexible polyester material for medical anti-adhesion, a preparation method and an application thereof, the material has excellent flexibility, suitable degradation time and reduces the occurrence of inflammation.

In order to achieve the above object, the concrete technical scheme of the present invention is:

An absorbable flexible polyester material for medical anti-adhesion and application thereof, the material is amino-terminated polyester, its weight average molecular weight is 40000-200000, and the molecular formula is:

Wherein: -R- is one or more of (1), (2), (3),

-R ₁ - is:

-R ₂ - is:

Where w=(2~145); x=(0~576); y=(0~240); z=(0~92);

When in use, the amino-terminated polyester is made into a fiber film, and the thickness of the fiber film is 0.06 mm to 0.14 mm.

The preparation method of the above-mentioned absorbable and flexible polyester material for medical anti-adhesion is obtained by polymerizing lactide, glycolide and caprolactone to obtain polyester diol, then capping with aliphatic diisocyanate, and obtaining chain extension through diamine. .

The preparation method of the above-mentioned absorbable flexible polyester material for medical anti-adhesion, the preparation method is as follows:

a. Polymerization: add lactide:glycolide:caprolactone in the mass ratio of (63~83):(8~28):(8~10.5) into the reactor, then add initiator and catalyst solution, Pour nitrogen into vacuum and repeat for several times, and react at 130~180°C for 4h~48h to obtain crude polyester diol;

b. Purification: after the crude polyester diol obtained in step a is completely dissolved in solvent A, slowly add solvent B dropwise to slowly separate out the polyester diol, and finally vacuum dry at 40°C to 60°C for more than 12 hours .

c, end capping: dissolving the polyester diol obtained in step b with 5～10 times weight of N,N-dimethylformamide, slowly drip aliphatic diisocyanate solution, and its consumption is NCO:OH is ( 2.1~2.2): 1. Add dibutyltin dilaurate, the amount of dibutyltin dilaurate is 0.001wt%~0.01wt% of the total mass of polyester diol and aliphatic diisocyanate added, and the reaction temperature is 60℃~85℃ , the reaction time is 4 h to 24 h.

d. Chain extension: add diamine monomer dropwise to the solution after the reaction in step c, the dosage of NH ₂ :NCO is (1.1~1.5): 1, add solvent B to separate out, and then vacuum dry to obtain amino-terminated polyamine. ester.

The above-mentioned preparation method of an absorbable flexible polyester material for medical anti-adhesion is characterized in that the weight-average molecular weight of the purified polyester diol in the step b is 20,000-100,000.

In the preparation method of the above-mentioned absorbable flexible polyester material for medical anti-adhesion, the initiator, lactide, glycolide and caprolactone monomers used in step a are all dried before use, and their water content is below 200ppm.

In the preparation method of the above-mentioned absorbable flexible polyester material for medical anti-adhesion, the initiator in step a is ethylene glycol, 1,4-butanediol, polyethylene glycol 400, polyethylene glycol 1000 or polyethylene glycol One of the diols 2000, the dosage of the initiator is 0.07wt%~7.5wt% of the total input of lactide, glycolide and caprolactone.

In the above preparation method of absorbable flexible polyester material for medical anti-adhesion, the solvent in the catalyst solution in step a is dichloromethane, the concentration is 0.1wt%~10wt%, and the catalyst dosage is lactide, glycolide 0.00015wt% to 0.001wt% of the total mass of caprolactone, and the catalyst used is one or more of aluminum isopropoxide, zinc divinyl, stannous chloride or stannous octoate.

The preparation method of the above-mentioned absorbable flexible polyester material for medical anti-adhesion, the solvent A in step b is one or more of dichloromethane, chloroform or acetone, and the amount thereof is 5% of polyester diol. ~15 times; solvent B is one or more of anhydrous methanol, anhydrous ethanol, n-hexane, diethyl ether or isopropyl ether.

The preparation method of the above-mentioned absorbable flexible polyester material for medical anti-adhesion, the aliphatic diisocyanate solution is aliphatic diisocyanate/N,N-dimethylformamide solution, the concentration is 1wt%~10wt%, and the aliphatic diisocyanate solution used is 1wt%~10wt%. The diisocyanate is one or more of hexamethylene diisocyanate (HDI), 1,4-cyclohexane diisocyanate (BDI) and L-lysine diisocyanate (LDI).

In the preparation method of the above-mentioned absorbable flexible polyester material for medical anti-adhesion, the diamine monomer is ethylenediamine; the initiator is preferably polyethylene glycol 400; the catalyst used is preferably stannous octoate; the aliphatic diamine used is preferably The isocyanate is preferably hexamethylene diisocyanate.

Compared with the prior art, the present invention introduces the structure of polycaprolactone and polyglycolic acid from the molecular structure, increases its flexibility, the elongation at break of the fiber film reaches more than 600%, and the glass transition temperature is between 34°C and 39°C. , close to the human body temperature, and implanted into the patient's body has a good fit and comfort; the introduction of amino groups into the molecular structure of polylactic acid, because the material of the present invention produces acidic substances during the degradation process in the body, and also produces amino-basic radicals The alkalinity of the amino group can balance the acidity, make the pH value of the surrounding degradation environment neutral, and make the degradation speed stable. The glass transition temperature is 34℃~39℃, which is close to the human body temperature. Fit comfort. The anti-adhesion fibrous membrane prepared by using the polyester material disclosed in the present invention has excellent softness and compliance, can adapt to the operation of adhering tissue parts to avoid suture fixation and reduce irritation, and the degradation time is 6-9 weeks.

Detailed ways

In the preparation method of the absorbable flexible polyester material for medical anti-adhesion of the present invention, the polyester diol is obtained by polymerizing lactide, glycolide and caprolactone, and then end-capped by aliphatic diisocyanate, and expanded by diamine. chain get.

The specific preparation method is as follows:

a. Polymerization: add lactide:glycolide:caprolactone in the mass ratio of (63~83):(8~28):(8~10.5) into the reactor, then add initiator and catalyst solution, Pour nitrogen into vacuum and repeat for several times, and react at 130 ℃ ~ 180 ℃ for 4 h ~ 48 h to obtain crude polyester diol;

b. Purification: after completely dissolving the crude polyester diol obtained in step a in solvent A, slowly add solvent B dropwise to slowly separate out the polyester diol, and finally, vacuum dry at 40℃~60℃ for 12h above. The weight-average molecular weight of the purified polyester diol is 20,000 to 100,000.

c, end capping: dissolving the polyester diol obtained in step b with 5～10 times weight of N,N-dimethylformamide, slowly drip aliphatic diisocyanate solution, and its consumption is NCO:OH is ( 2.1~2.2): 1. Add dibutyltin dilaurate, the dosage is 0.001wt%~0.01wt% of the total mass of polyester diol and aliphatic diisocyanate, the reaction temperature is 60℃~85℃, and the reaction time is 4h~24h.

d. Chain extension: add diamine monomer dropwise to the solution after the reaction in step c, the dosage of NH ₂ :NCO is (1.1~1.5): 1, add solvent B to separate out, and then vacuum dry to obtain amino-terminated polyamine. The weight-average molecular weight of the amino-terminated polyester is 40,000-200,000.

When in use, the amino-terminated polyester is made into an anti-blocking polyester fiber film by using an electrospinning technology, and the thickness of the anti-blocking polyester fiber film is 0.06 mm to 0.14 mm.

The initiator, lactide, glycolide and caprolactone monomers used in step a are all dried before use, and their water content is below 200 ppm.

The initiator in step a is ethylene glycol, 1,4-butanediol, one of polyethylene glycol 400, polyethylene glycol 1000 or polyethylene glycol 2000, and the consumption of the initiator is The total input of lactide, glycolide and caprolactone is 0.07wt%~7.5wt%.

The solvent in the catalyst solution in step a is dichloromethane, the concentration is 0.1wt%～10wt%, the catalyst dosage is 0.00015wt%～0.001wt% of the total mass of the monomers used, and the catalyst used is aluminum isopropoxide, One or more of divinyl zinc, stannous chloride or stannous octoate.

The solvent A in the step a is one or more of methylene chloride, chloroform or acetone, and its consumption is 5 to 15 times that of the polyester diol; the solvent B is anhydrous methanol, anhydrous ethanol, One or more of n-hexane, diethyl ether or isopropyl ether.

The aliphatic diisocyanate solution is an aliphatic diisocyanate/N,N-dimethylformamide solution with a concentration of 1wt% to 10wt%, and the aliphatic diisocyanate used is hexamethylene diisocyanate (HDI), 1, One or more of 4-cyclohexane diisocyanate (BDI) and L-lysine diisocyanate (LDI).

The diamine monomer is ethylenediamine; the initiator is preferably polyethylene glycol 400; the catalyst used is preferably stannous octoate; the aliphatic diisocyanate used is preferably hexamethylene diisocyanate.

The following examples serve to illustrate the invention.

Example 1

The required monomers are dried by a laboratory routine, and the water content is controlled below 200 ppm.

Add 70g of lactide, 10.5g of caprolactone, and 19.5g of glycolide into the reactor, 0.5g of 3% stannous octoate/dichloromethane solution, 1.5g of polyester diol (400), and nitrogen- Vacuuming was repeated 3 times, the tube was sealed under vacuum, and the reaction was carried out in an oil bath at 145 °C for 24 h to obtain crude polyester diol,

Dissolve with 1000 g of dichloromethane, then slowly add anhydrous ethanol dropwise to slowly separate out polyester diol, vacuum dry at 50°C for 12 hours to obtain polyester diol with a molecular weight of 50,000;

Take another four-necked bottle and add 800g N,N-dimethylformamide and 80g polyester diol. After it is completely dissolved, slowly add hexamethylene diisocyanate (HDI)/N,N-diisocyanate with a concentration of 1wt% dropwise. 56.52 g of methylformamide solution was added, 0.0008 g of dibutyltin dilaurate was added, and the reaction time was 24 hours at 80°C.

Then add 0.32g of ethylenediamine for chain extension, finally add absolute ethanol, and vacuum dry to obtain amino-terminated polyester with a molecular weight of 100,000, a glass transition temperature of 37.5°C, a total solvent residue below 0.15%, and a tin content of 27ppm.

Using electrospinning technology, the amino-terminated polyester was prepared into an anti-adhesion polyester fiber film with a film thickness of 0.120 mm, an elongation at break of 658%, and a degradation time of 8 to 9 weeks. The film has good flexibility and flexibility. suitable degradation time.

Example 2

The required monomers are dried by a laboratory routine, and the water content is controlled below 200 ppm.

Add 63 g of lactide, 9 g of caprolactone, and 28 g of glycolide monomers into the reactor, 0.5 g of 3% stannous octoate/dichloromethane solution, 3.5 g of polyester diol (2000), and nitrogen-evacuated Repeat the operation 3 times, seal the tube under vacuum, and react at 130 °C for 4 h to obtain crude polyester diol,

Dissolve with 1500 g of dichloromethane, then slowly add anhydrous ethanol dropwise to slowly separate out polyester diol, vacuum dry at 50°C for 12 hours to obtain polyester diol with a molecular weight of 100,000;

Take another four-necked bottle, add 800g N,N-dimethylformamide and 80g polyester diol, and slowly add L-lysine diisocyanate (LDI)/N,N- 3.98g of dimethylformamide solution, 0.0040g of dibutyltin dilaurate was added, the reaction time was 24h at 65°C,

Then add 0.159g ethylenediamine for chain extension, finally add absolute ethanol, vacuum dry to obtain amino-terminated polyester, its properties are as follows, its molecular weight is 200000, glass transition temperature is 35 ℃, total solvent residue is 0.45%, tin Content 36ppm.

Using electrospinning technology, the amino-terminated polyester was prepared into an anti-adhesion polyester fiber film with a film thickness of 0.050 mm, an elongation at break of 612%, and a degradation time of 8 to 9 weeks. The film has good flexibility and flexibility. suitable degradation time.

Example 3

The required monomers are dried by a laboratory routine, and the water content is controlled below 200 ppm.

Add 83 g of lactide, 9 g of caprolactone, and 8 g of glycolide into the reactor, 0.5 g of 3% stannous octoate/dichloromethane solution, 1.0 g of polyester diol (400), and nitrogen-pumping The vacuum operation was repeated 3 times, the tube was sealed under vacuum, and the reaction was carried out in an oil bath at 180 °C for 48 h to obtain crude polyester diol,

Dissolve with 1500 g of dichloromethane, then slowly add anhydrous ethanol dropwise to slowly separate out polyester diol, vacuum dry at 50°C for 12 hours to obtain polyester diol with a molecular weight of 50,000;

Take another four-necked bottle, add 800g N,N-dimethylformamide, 80g polyester diol, and slowly dropwise add 1,4-cyclohexanediisocyanate (BDI)/N with a concentration of 5wt% after it is completely dissolved. 11.7g of N-dimethylformamide solution, 0.0061g of dibutyltin dilaurate was added, the reaction time was 12h at 80°C,

Then add 0.27g ethylenediamine for chain extension, finally add absolute ethanol, vacuum dry to obtain amino-terminated polyester, its molecular weight is 100000, glass transition temperature is 39°C, total solvent residue is 0.24%, and tin content is 42ppm.

Using electrospinning technology, the amino-terminated polyester was prepared into an anti-adhesion polyester fiber film with a film thickness of 0.120 mm, an elongation at break of 620%, and a degradation time of 7 to 8 weeks. The film has good flexibility and flexibility. suitable degradation time.

Example 4

The required monomers are dried by a laboratory routine, and the water content is controlled below 200 ppm.

Add 66g of lactide, 8g of caprolactone, and 26g of glycolide monomers into the reactor, 0.5g of 3% stannous octoate/dichloromethane solution, 3.75g of polyester diol (1000), and nitrogen-evacuated Repeat the operation 3 times, seal the tube under vacuum, and react in an oil bath at 130 °C for 4 h to obtain crude polyester diol,

Dissolve with 500g of dichloromethane, then slowly add anhydrous ethanol dropwise to slowly separate out polyester diol, vacuum dry at 50°C for 12h to obtain polyester diol with a molecular weight of 20,000;

Take another four-necked bottle and add 400g N,N-dimethylformamide and 80g polyester diol. After it is completely dissolved, slowly add L-lysine diisocyanate (LDI)/N,N with a concentration of 10 wt% dropwise. -19g of dimethylformamide solution, 0.0082g of dibutyltin dilaurate was added, and the reaction time was 24h at 65°C.

Then add 0.76g ethylenediamine for chain extension, finally add absolute ethanol, and vacuum dry to obtain amino-terminated polyester with molecular weight of 50,000, glass transition temperature of 34°C, total solvent residue of 0.15%, and tin content of 45ppm.

Using electrospinning technology, the amino-terminated polyester was prepared into an anti-adhesion polyester fiber film with a film thickness of 0.080 mm, an elongation at break of 650%, and a degradation time of 6 to 7 weeks. The film has good flexibility. and suitable degradation time.

There are ester groups and urethane groups in the polyester structure of the present invention, and the ester groups generate acidic substances (such as lactic acid, lactic acid oligomers, glycolic acid, glycolic acid oligomers, and oligomers of COOH, etc.) during the degradation process. , amine substances (oligomers containing amino groups) are generated during the degradation of the urethane group, and the acidic substances undergo a neutralization reaction with the amine substances and the amino groups at both ends of the polyester molecular chain. This balances the pH of the degradation products and avoids inflammation and discomfort.

The above are only the preferred embodiments of the present invention. It should be pointed out that for those skilled in the art, without departing from the technical principles of the present invention, several improvements and modifications can also be made. These improvements and modifications It should also be regarded as the protection scope of the present invention.

Claims (10)

1. An absorbable flexible polyester material for medical anti-adhesion and application thereof, is characterized in that, this material is amino-terminated polyester, and its weight-average molecular weight is 40000～200000, and the molecular formula is:

Wherein: -R- is one or more of (1), (2), (3),

-R ₁ - is:

-R ₂ - is:

Where w=(2~145); x=(0~576); y=(0~240); z=(0~92); When in use, the amino-terminated polyester is made into a fiber film, and the thickness of the fiber film is 0.06 mm to 0.14 mm. 2. A preparation method of an absorbable flexible polyester material for medical anti-adhesion, characterized in that, polyester diol is obtained by polymerization of lactide, glycolide and caprolactone, and then end-capped by aliphatic diisocyanate, Obtained through diamine chain extension. 3. The preparation method of the absorbable flexible polyester material for medical anti-adhesion as claimed in claim 2, wherein the preparation method is as follows: Polymerization: add lactide:glycolide:caprolactone in the mass ratio of (63~83):(8~28):(8~10.5) into the reactor, then add the initiator and catalyst solution, pass through Nitrogen-evacuation and repeated several times, react at 130 ℃ ~ 180 ℃ for 4 h ~ 48 h to obtain crude polyester diol; Purification: after the crude polyester diol obtained in step a is completely dissolved in solvent A, slowly add solvent B dropwise to slowly precipitate the polyester diol, and finally, vacuum dry at 40 ℃ ~ 60 ℃ for more than 12 hours; End capping: dissolving the polyester diol obtained in step b with 5~10 times the weight of N,N-dimethylformamide, slowly dripping the aliphatic diisocyanate solution, the amount of which is NCO:OH is (2.1~ 2.2): 1. Add dibutyltin dilaurate, the amount of dibutyltin dilaurate is 0.001wt%~0.01wt% of the total mass of polyester diol and aliphatic diisocyanate added, the reaction temperature is 60 ℃ ~ 85 ℃, the reaction Time 4h ~24h; Chain extension: add diamine monomer dropwise to the solution after the reaction in step c, the dosage of NH ₂ :NCO is (1.1~1.5): 1, add solvent B to separate out, and then vacuum dry. 4 . The method for preparing an absorbable flexible polyester material for medical anti-adhesion according to claim 3 , wherein the weight-average molecular weight of the purified polyester diol in the step b is 20,000 to 100,000. 5 . 5. The preparation method of the absorbable flexible polyester material for medical anti-adhesion as claimed in claim 4, wherein the initiator, lactide, glycolide and caprolactone monomers used in the step a are before use All are dried, and the water content is below 200ppm. 6. The method for preparing an absorbable flexible polyester material for medical anti-adhesion as claimed in claim 5, wherein the initiator in step a is ethylene glycol, 1,4-butanediol, polyethylene glycol One of glycol 400, polyethylene glycol 1000 or polyethylene glycol 2000, and the dosage of the initiator is 0.07wt% to 7.5wt% of the total input of lactide, glycolide and caprolactone. 7. The preparation method of the absorbable flexible polyester material for medical anti-adhesion as claimed in claim 6, wherein the solvent in the catalyst solution in step a is dichloromethane, and the concentration is 0.1wt%～10wt %, the catalyst dosage is 0.00015wt%~0.001wt% of the total mass of the monomers used, and the catalyst used is one or more of aluminum isopropoxide, divinyl zinc, stannous chloride or stannous octoate. 8. The preparation method of the absorbable flexible polyester material for medical anti-adhesion as claimed in claim 7, wherein the solvent A in step b is one of methylene chloride, chloroform or acetone or The dosage is 5-15 times that of the polyester diol; the solvent B is one or more of anhydrous methanol, anhydrous ethanol, n-hexane, diethyl ether or isopropyl ether. 9. The preparation method of the absorbable flexible polyester material for medical anti-adhesion as claimed in claim 8, wherein in the step c, the aliphatic diisocyanate solution is aliphatic diisocyanate/N,N-dimethyl Formamide solution, the concentration is 1wt%~10wt%, the aliphatic diisocyanates used are hexamethylene diisocyanate (HDI), 1,4-cyclohexane diisocyanate (BDI), L-lysine diisocyanate (LDI) ) one or more of them. 10. The method for preparing an absorbable flexible polyester material for medical anti-adhesion according to claim 9, wherein the diamine monomer is ethylenediamine; the initiator is preferably polyethylene glycol 400; The catalyst used is preferably stannous octoate; the aliphatic diisocyanate used is preferably hexamethylene diisocyanate.