CN1191289C - Synthesis method of amphiphilic biodegradable polyurethane elastomer - Google Patents

Abstract

The present invention discloses a method for synthesizing a biodegradable polyurethane elastomer with amphipathicity in the field of biological materials. The polyurethane adopts polyethyleneglycol, polycaprolactone and 2, 6-diisocyanate ethyl caproate as raw materials, a biodegradable product is synthesized by a one-step copolycondensation method, and a biodegradable polyurethane elastomer with the amphipathicity is prepared. The present invention has hydrophilic and lipophilic performance, has no toxicity to an organism, and has fine biocompatibility; the hardness and the elasticity of the materials are adjusted by that a compounding ratio is changed so as to be suitable for the requirements of different purposes; the synthesizing process is simple, and a reaction condition is mild. Therefore, the polyurethane is suitably applied to the medical field, and the polyurethane elastomer has a wide development prospect on the application of biological materials.

Description

Synthesis method of amphiphilic biodegradable polyurethane elastomer

technical field

The invention belongs to the field of biomaterials, in particular to a method for synthesizing an amphiphilic biodegradable polyurethane elastomer.

Background technique

Because polyurethane elastomers have good mechanical properties, excellent biocompatibility and anticoagulant properties, polyurethane elastomers can be used in cardiovascular tissue engineering. At present, the synthesis of biodegradable polyurethane mainly has the following methods:

(1) Oligosaccharide derivative polyurethane.

(2) Lignin, tannin and bark derived polyurethane.

(3) Cellulose-derived polyurethane.

(4) Starch derived polyurethane.

The above biodegradable polyurethanes are synthesized by utilizing the high activity of isocyanate groups and the biodegradable properties of natural polymer compounds, and using natural polymer compounds containing multiple hydroxyl groups as one of the components of polyurethane polyols to make various Polyurethane material can endow it with better biodegradability and biocompatibility. However, there are three main problems with this type of polyurethane material as a bioabsorbable material: first, the bark, starch, and other raw materials used have not been purified and sterilized, and contain a large amount of harmful substances to the human body, and their degradation products are biologically toxic. It cannot meet the requirements of biomaterials for tissue engineering, and can only be used in the field of degradable polymers for industrial use. In addition, fully biodegradable polymers, such as polylactic acid, polycaprolactone, polyethylene carbonate, etc., can be used as polyol components of polyurethane to react with diisocyanate to synthesize biodegradable polyurethane. Such polyurethanes are particularly suitable for use in the medical field. However, the manufacturing process of polylactic acid and polyethylene carbonate is complicated and the cost is high, and it is not yet possible to achieve industrialized mass production. Polycaprolactone and polyethylene glycol are very mature industrial products, produced by many domestic manufacturers, and the price is relatively low. Therefore, it is an excellent raw material for the production of biodegradable polyurethane elastomers.

Contents of the invention

The purpose of the present invention is to provide a synthetic method of an amphiphilic biodegradable polyurethane elastomer suitable for the medical field. It is characterized in that: using completely biodegradable polyethylene glycol (PEG) and polycaprolactone (PCL) as polyol components and 2,6-diisocyanate (HDI) as raw materials, it adopts solution condensation polymerization reaction Synthetic biodegradable polyurethane. The specific steps are:

1). Add a certain molar ratio of PCL diol and PEG into a three-neck bottle at a ratio of 1:10-10:1. One bottle mouth is equipped with a condenser and a thermometer, and the other bottle mouth is equipped with a mechanical stirrer, and the stirring rod is stirred with the glass. The casings are connected with vacuum rubber tubes, and coated with vacuum silicone ester for lubrication and sealing; then placed in an electric heating mantle at 50°C-120°C, and stirred until the reactants are completely melted as polyol components: vacuum 1-3Pa, 3 hours. Then fill the mouth of the bottle with nitrogen protection at 10-40Pa, add dibutyltin dilaurate dropwise, add 50-300 milliliters of methyl ethyl ketone, add the molar ratio of HDI to polyol is 0.9:1-1.1:1, React at 90°C for 1-3 hours;

2). Under the protection of nitrogen, heat the product of 2 to 60-120°C, add 1-3 drops of dibutyltin dilaurate as a catalyst, and add an appropriate amount of butanediol dropwise. The general dosage is 1%-10% of the amount of HDI. Capping the polymer and reacting at this temperature for 0.5-3.5 hours;

3) Discharging: first cool down to about 60°C, then stop stirring, stop _N2 protection, lift the reaction bottle from the heating mantle, pour the solution into deionized water to precipitate milky white elastic polyurethane.

The PEG has a molecular weight from 200 to 4600, and the PCL-diol has a molecular weight from 500 to 6000.

The beneficial effect of the present invention is to use the fully biodegradable polymer as the polyol component of polyurethane, and react with diisocyanate to synthesize non-toxic, safe, bioabsorbable and biodegradable polyurethane elastomers, while having good biological properties. compatibility. The hardness and elasticity of the material can be adjusted by changing the ratio to meet the needs of different purposes. The synthesis method of this product is a one-step co-condensation method, the synthesis process is simple, the reaction conditions are mild, the reaction is stable, and it is easy to control. Such polyurethanes are particularly suitable for use in the medical field.

Detailed ways

The purpose of the present invention is to provide a synthetic method of an amphiphilic biodegradable polyurethane elastomer suitable for the medical field. It is characterized in that: using completely biodegradable polyethylene glycol (PEG) and polycaprolactone (PCL) as polyol components and 2,6-diisocyanate (HDI) as raw materials, it adopts solution condensation polymerization reaction Synthetic biodegradable polyurethane. The specific steps are:

1). Add a certain molar ratio of PCL diol and PEG into a three-neck bottle at a ratio of 1:10-10:1. One bottle mouth is equipped with a condenser and a thermometer, and the other bottle mouth is equipped with a mechanical stirrer, and the stirring rod is stirred with the glass. The casings are connected with vacuum rubber tubes, and coated with vacuum silicone ester for lubrication and sealing; then placed in an electric heating mantle at 50°C-120°C, and stirred until the reactants are completely melted as polyol components: vacuum 1-3Pa, 3 hours. Then fill the mouth of the bottle with nitrogen protection at 10-40Pa, add dibutyltin dilaurate dropwise, add 50-300 milliliters of methyl ethyl ketone, add the molar ratio of HDI to polyol is 0.9:1-1.1:1, React at 90°C for 1-3 hours;

2). Under the protection of nitrogen, heat the product of 2 to 60-120°C, add 1-3 drops of dibutyltin dilaurate as a catalyst, and add an appropriate amount of butanediol dropwise. The general dosage is 1%-10% of the amount of HDL. Capping the polymer and reacting at this temperature for 0.5-3.5 hours;

3). Discharging: first cool down to about 60°C, then stop stirring, stop _N2 protection, lift the reaction bottle from the heating mantle, pour the solution into deionized water to precipitate milky white elastic polyurethane.

In the present invention, polyethylene glycol (PEG, molecular weight from 200 to 4600), polycaprolactone diol (PCL-diol, molecular weight from 500 to 6000) and ethyl 2,6-diisocyanate caproate (HDI ) for raw material preparation. The intervention of polyethylene glycol segment (PEG) in its PCL series makes the crystallinity of the copolymer rise first and then decrease with the increase of its content, and the spherulite size becomes smaller, thus greatly improving the mechanical properties of the copolymer; the tensile strength can be as high as 14MPa; the elongation at break increased from 1210% of PCL to 2044%; the melting point decreased from 44.8°C to 37.7°C with the composition change; the equilibrium water absorption increased from 8% to 70%; the water contact angle of the material surface decreased from 80° to 40 degrees, the hydrophilicity is greatly improved. The biodegradability of this series is affected by its own chain flexibility, crystallization properties, molecular weight and its molecular weight distribution, and the external conditions are affected by the thickness of the degraded film and the environment. When the mass percentage of PEG reaches 50%, the crystallinity is the smallest and the degradation is fastest. In the phosphate buffer solution, the weight loss rate of the film with a thickness of 0.14mm was 25% (PCLPEG-30), 30% (PCLPEG-50), and 20% (PCLPEG-70) after 10 weeks of degradation with different PEG contents.

Select the degradation intermediate of 2,6-diisocyanate ethyl caproate, and use biodegradable polyethylene glycol (PEG) and polycaprolactone (PCL) as polyol components to synthesize non-toxic small molecules or Non-toxic and safe bioabsorbable materials for human metabolic products; choosing a cross-linked network structure can more freely adjust the mechanical properties and degradation rate of bioabsorbable materials. The amphiphilic biodegradable polyurethane elastomer can be prepared, which is hydrophilic and lipophilic, and its equilibrium water absorption can be adjusted between 8% and 100%. The following examples are given to further illustrate the present invention.

Example 1

1). Add 20 grams of PCL (molecular weight 1000) and 80 grams of PEG (molecular weight 1000) into a three-neck bottle, vacuum seal, mechanically stir, vacuumize at 3Pa for 3 hours, then place it in an electric heating mantle at 100°C, and stir until The reactant is completely melted to obtain a polyol component prepolymer, and then filled with a nitrogen protection of 10-40Pa from one of the bottle mouths, and three drops of dibutyltin dilaurate are added dropwise, and 16.84 grams of HDI are added to react at 100°C for 3 Hour.

2). Under the protection of nitrogen, heat the product of ① to 120°C, add 300 ml of methyl ethyl ketone, add 1 drop of dibutyltin dilaurate catalyst, add 0.94 g of butanediol dropwise to cap the polymer, and react at this temperature 0.5-3.5 hours.

3). Discharging: first cool down to 60°C, then stop stirring, stop _N2 protection, lift the reaction bottle from the heating mantle, pour the solution into deionized water to precipitate milky white elastomer.

Example 2

1). Add 40 grams of PCL (molecular weight 1000) and 60 grams of PEG (molecular weight 1000) into a three-necked bottle, vacuum seal, mechanically stir, vacuumize 3 Pa, 3 hours, then place in an electric heating mantle at 100 ° C, and stir until The reactant is completely melted to obtain a polyol component prepolymer, and then filled with a nitrogen protection of 10-40Pa from one of the bottle mouths, and three drops of dibutyltin dilaurate are added dropwise, and 16.84 grams of HDI are added to react at 100°C for 3 Hour.

2). Under the protection of nitrogen, heat the product of ① to 120°C, add 300 ml of methyl ethyl ketone, add 1 drop of dibutyltin dilaurate catalyst, add 0.94 g of butanediol dropwise to cap the polymer, and react at this temperature 0.5-3.5 hours.

3). Discharging: first cool down to 60°C, then stop stirring, stop _N2 protection, lift the reaction bottle from the heating mantle, pour the solution into deionized water to precipitate milky white elastomer.

Example 3

1). Add 50 grams of PCL (molecular weight 1000) and 50 grams of PEG (molecular weight 1000) into a three-neck bottle, vacuum seal, mechanically stir, vacuumize at 3 Pa for 3 hours, then place it in an electric heating mantle at 100°C, and stir until The reactant is completely melted to obtain a polyol component prepolymer, and then filled with a nitrogen protection of 10-40Pa from one of the bottle mouths, and three drops of dibutyltin dilaurate are added dropwise, and 16.84 grams of HDI are added to react at 100°C for 3 Hour.

2). Under the protection of nitrogen, heat the product of ① to 120°C, add 300 ml of methyl ethyl ketone, add 1 drop of dibutyltin dilaurate catalyst, add 0.94 g of butanediol dropwise to cap the polymer, and react at this temperature 0.5-3.5 hours.

3). Discharging: first cool down to 60°C, then stop stirring, stop _N2 protection, lift the reaction bottle from the heating mantle, pour the solution into deionized water to precipitate milky white elastomer.

Example 4

1). Add 60 grams of PCL (molecular weight 1000) and 40 grams of PEG (molecular weight 1000) into a three-neck bottle, vacuum seal, mechanically stir, vacuumize at 3Pa for 3 hours, then place in an electric heating mantle at 100°C, and stir until The reactant is completely melted to obtain a polyol component prepolymer, and then filled with a nitrogen protection of 10-40Pa from one of the bottle mouths, and three drops of dibutyltin dilaurate are added dropwise, and 16.84 grams of HDI are added to react at 100°C for 3 Hour.

2). Under the protection of nitrogen, heat the product of ① to 120°C, add 300 ml of butanone, add 1 drop of dibutyltin dilaurate as a catalyst, add 0.94 g of butanediol dropwise to cap the polymer, and react at this temperature 0.5-3.5 hours.

3). Discharging: first cool down to 60°C, then stop stirring, stop _N2 protection, lift the reaction bottle from the heating mantle, pour the solution into deionized water to precipitate milky white elastomer.

Example 5

1). Add 80 grams of PCL (molecular weight 1000) and 20 grams of PEG (molecular weight 1000) into a three-neck bottle, vacuum seal, mechanically stir, vacuumize 3Pa, 3 hours, then place in an electric heating mantle at 100 °C, and stir until The reactant is completely melted to obtain a polyol component prepolymer, and then filled with a nitrogen protection of 10-40Pa from one of the bottle mouths, and three drops of dibutyltin dilaurate are added dropwise, and 16.84 grams of HDI are added to react at 100°C for 3 Hour.

2). Under the protection of nitrogen, heat the product of ① to 120°C, add 300 ml of methyl ethyl ketone, add 1 drop of dibutyltin dilaurate catalyst, add 0.94 g of butanediol dropwise to cap the polymer, and react at this temperature 0.5-3.5 hours.

3). Discharging: first cool down to 60°C, then stop stirring, stop _N2 protection, lift the reaction bottle from the heating mantle, pour the solution into deionized water to precipitate milky white elastomer.

Example 6

1). Add 100 grams of PCL (molecular weight 2000) and 100 grams of PEG (molecular weight 2000) into a three-neck bottle, vacuum seal, mechanically stir, vacuumize 3Pa, 3 hours, then place in an electric heating mantle at 100 °C, and stir until The reactant is completely melted to obtain a polyol component prepolymer, and then filled with a nitrogen protection of 10-40Pa from one of the bottle mouths, and three drops of dibutyltin dilaurate are added dropwise, and 16.84 grams of HDI are added to react at 100°C for 3 Hour.

2). Under the protection of nitrogen, heat the product of ① to 120°C, add 300 ml of methyl ethyl ketone, add 1 drop of dibutyltin dilaurate catalyst, add 0.94 g of butanediol dropwise to cap the polymer, and react at this temperature 0.5-3.5 hours.

3). Discharging: first cool down to 60°C, then stop stirring, stop _N2 protection, lift the reaction bottle from the heating mantle, pour the solution into deionized water to precipitate milky white elastomer.

Example 7

1). Add 40 grams of PCL (molecular weight 2000) and 160 grams of PEG (molecular weight 2000) into a three-neck bottle, vacuum seal, mechanically stir, vacuumize at 3Pa for 3 hours, then place it in an electric heating mantle at 100°C, and stir until The reactant is completely melted to obtain a polyol component prepolymer, and then filled with a nitrogen protection of 10-40Pa from one of the bottle mouths, and three drops of dibutyltin dilaurate are added dropwise, and 16.84 grams of HDI are added to react at 100°C for 3 Hour.

2). Under the protection of nitrogen, heat the product of ① to 120°C, add 300 ml of methyl ethyl ketone, add 1 drop of dibutyltin dilaurate catalyst, add 0.94 g of butanediol dropwise to cap the polymer, and react at this temperature 0.5-3.5 hours.

3). Discharging: first cool down to 60°C, then stop stirring, stop _N2 protection, lift the reaction bottle from the heating mantle, pour the solution into deionized water to precipitate milky white elastomer.

Example 8

1). Add 180 grams of PCL (molecular weight 2000) and 20 grams of PEG (molecular weight 1000) into a three-neck bottle, vacuum seal, mechanically stir, vacuumize at 3 Pa for 3 hours, then place in an electric heating mantle at 100°C, and stir until The reactant is completely melted to obtain a polyol component prepolymer, and then filled with a nitrogen protection of 10-40Pa from one of the bottle mouths, and three drops of dibutyltin dilaurate are added dropwise, and 16.84 grams of HDI are added to react at 100°C for 3 Hour.

2) Under the protection of nitrogen, heat the product of ① to 120°C, add 300 ml of methyl ethyl ketone, add 1 drop of dibutyltin dilaurate as a catalyst, add 0.94 g of butanediol dropwise to end the polymer, and react at this temperature for 0.5 -3.5 hours.

3). Discharging: first cool down to 60°C, then stop stirring, stop _N2 protection, lift the reaction bottle from the heating mantle, pour the solution into deionized water to precipitate milky white elastomer.

Example 9

1). Add 40 grams of PCL (molecular weight 2000) and 80 grams of PEG (molecular weight 1000) into a three-neck bottle, vacuum seal, mechanically stir, vacuumize at 3Pa for 3 hours, then place it in an electric heating mantle at 100°C, and stir until The reactant is completely melted to obtain a polyol component prepolymer, and then filled with nitrogen protection at 10-40Pa from one of the bottle mouths, and three drops of dibutyltin dilaurate are added dropwise, and 16.84 grams of HDI are added to react at 100°C for 3 Hour.

2). Under the protection of nitrogen, heat the product of ① to 120°C, add 300 ml of butanone, add 1 drop of dibutyltin dilaurate as a catalyst, add 0.94 g of butanediol dropwise to cap the polymer, and react at this temperature 0.5-3.5 hours.

3). Discharging: first cool down to 60°C, then stop stirring, stop _N2 protection, lift the reaction bottle from the heating mantle, pour the solution into deionized water to precipitate milky white elastomer.

Example 10

1). Add 20 grams of PCL (molecular weight 2000) and 80 grams of PEG (molecular weight 4000) into a three-neck bottle, vacuum seal, mechanically stir, vacuumize at 3Pa for 3 hours, then place it in an electric heating mantle at 100°C, and stir until The reactant is completely melted to obtain a polyol component prepolymer, and then filled with nitrogen protection at 10-40Pa from one of the bottle mouths, and three drops of dibutyltin dilaurate are added dropwise, and 16.84 grams of HDI are added to react at 100°C for 3 Hour.

2) Under the protection of nitrogen, heat the product of ① to 120°C, add 300 ml of methyl ethyl ketone, add 1 drop of dibutyltin dilaurate catalyst, add dropwise 0.94 g of butanediol to end the polymer, and react at this temperature for 0.5 -3.5 hours.

3). Discharging: first cool down to 60°C, then stop stirring, stop _N2 protection, lift the reaction bottle from the heating mantle, pour the solution into deionized water to precipitate milky white elastomer.

Claims (2)

1. A synthetic method of amphiphilic biodegradable polyurethane elastomer, characterized in that: with fully biodegradable polyethylene glycol, polycaprolactone as polyol component and 2,6-diisocyanate as raw material Materials, take the solution condensation polymerization reaction to synthesize biodegradable polyurethane; the specific steps are: 1). Add a certain molar ratio of polycaprolactone and polyethylene glycol into a three-necked bottle at a ratio of 1:10-10:1. One bottle is equipped with a condenser and a thermometer, and the other bottle is equipped with a mechanical stirrer. The rod and the glass stirring sleeve are connected with a vacuum rubber tube, and coated with vacuum silicon ester for lubrication and sealing; then placed in an electric heating mantle at 50°C-120°C, stirred until the reactant is completely molten, and used as a polyol component; . Vacuum at 1-3Pa for 3 hours, then fill one of the bottles with nitrogen protection at 10-40Pa, add dibutyltin dilaurate dropwise, add 50-300ml methyl ethyl ketone, add 2,6-diisocyanate hexanoic acid The molar ratio of ethyl ester to polyol is 0.9:1-1.1:1, reacting at 90°C for 1-3 hours; 2). Under the protection of nitrogen, heat the product of 2 to 60-120°C, add 1-3 drops of dibutyltin dilaurate as a catalyst, and add an appropriate amount of butanediol dropwise. The general dosage is 1% of the dosage of 2,6-diisocyanate -10%, for polymer capping, react at this temperature for 0.5-3.5 hours; 3). Discharging: first cool down to about 60°C, then stop stirring, stop nitrogen protection, lift the reaction bottle from the heating mantle, pour the solution into deionized water to precipitate milky white elastic polyurethane. 2. according to the synthetic method of the described amphiphilic biodegradable polyurethane elastomer of claim 1, it is characterized in that: described polyethylene glycol, molecular weight is from 200 to 4600, polycaprolactone diol, molecular weight is from 500 to 6000 .