KR100285238B1 - Medical Polyurethane with Polydimethylsiloxane (PDMS) and Polyethylene Glycol (PEG) - Google Patents

Abstract

The present invention relates to a polyurethane which is a medical polymer maximized biocompatibility using polydimethylsiloxane (PDMS) and polyethylene glycol (PEG) excellent in biocompatibility and a method for producing the same.

The present invention is prepared by crosslinking a hard part of polydimethylsiloxane, which is a soft part, and 4,4'-methylenediphenyl diisocyanate (MDI), in which ethylene glycol (EG) or diethylbishydroxymethylmalonate (DBM) is bonded. Copolymerization of hydrophilic polymer polyethylene glycol on the main chain of polyurethane produces biocompatible polymers with excellent physical properties even at room temperature.

An object of the present invention is to prepare a polyurethane that can be used as a medical polymer in the same manner as described above when the existing biomaterials are introduced into the human body as a major problem, thrombosis, infection by bacteria and polymers in vivo It is to solve toxic chemicals that are released.

Description

Medical Polyurethane with Polydimethylsiloxane (PDMS) and Polyethylene Glycol (PEG)

The present invention relates to a polyurethane which is a medical polymer maximized biocompatibility using polydimethylsiloxane (PDMS) and polyethylene glycol (PEG) excellent in biocompatibility and a method for producing the same.

One of the areas of research that has recently been of interest due to the rapid progress of science and technology is biomedical polymers. Typical biomedical polymers include polymethylmethacrylate, polyvinylchloride, polypropylene, polydimethylsiloxane, and polyurethane. They are applied to a wide range of areas such as artificial heart, kidney, blood vessel replacement material, various catheters and contact lenses. When biomaterials are used in the human body, the main problems to be considered are thrombosis, bacterial infections, and toxic chemicals released by polymers in vivo.

Conventional techniques for developing highly biocompatible polyurethane materials include the introduction of polyethylene glycol through chemical covalent bonds to the surface of polyurethane products such as pellets and biomers, which are already commercially available. Journal of Biomedical Material Research, 30, 30 (1996)), chemically treated commercial polyurethanes to form peroxides, and then using them as initiators, polyacrylic acid, polyacrylamide, poly-2-hydroxyethyl methacrylate, etc. Of dimethyl siloxane, known to have excellent biocompatibility, compared to polytetramethylene oxide (PTMO), which is currently used as a soft part of commercial polyurethanes (Journal of Biomedical Material Research, 27, 1559 (1993)). Or synthesis of polyurethane consisting of polyethylene glycol in soft parts [Biomaterials, 15, 408 (1994)], a hydrophilic multiblock type polymer (the triblock copolymer is polyethyleneglycol-polypropyleneglycol-polyethyleneglycol, and commercially available products include Pluronic) or a polyblock copolymer as an additive. Biomaterials, 15, 278 (1994), have been introduced into urethanes. However, these existing biomaterials have not been developed with satisfactory biocompatibility. I can't.

It is an object of the present invention to comprise 4,4′-methylenediphenyldiisocyanate (MDI) comprising a polydimethylsiloxane having a soft part of polyurethane having stability, proper mechanical properties, etc. which are not decomposed by heat and oxidation, in addition to excellent biocompatibility. And polyethylene glycol, a hydrophilic polymer, is branched through chemical reaction in the backbone of the polyurethane crosslinked with the hard part of the polyurethane, which is ethylene glycol (EG) or diethylbishydroxymethylmalonate (DBM). It is intended to invent a polymer having biocompatibility with suitable mechanical properties and excellent physical properties.

1 (a) is a graph showing DMA (Dynamic Mechanical Analysis) to confirm the viscoelasticity according to the temperature of the PUE series.

1 (b) is a graph showing DMA (Dynamic Mechanical Analysis) to confirm the viscoelasticity according to the temperature of the PUD series.

2 is a differential scanning calorimetry (DSC) graph showing thermal properties according to temperature of a polymer.

Figure 3 (a) is a graph showing the elongation of the dried polymer specimens and the polymer specimens hydrated for one day.

Figure 3 (b) is a graph showing the tensile strength of the dried polymer specimens and the polymer specimen hydrated for one day.

Figure 3 (c) is a graph showing the tensile modulus of the dried polymer specimens and the polymer specimens hydrated for one day.

Figure 4 (a) is a graph showing the blood compatibility between the control and PUE series.

Figure 4 (b) is a graph showing the blood compatibility between the control and PUD series.

5 is a graph showing the bacterial adsorption results of the control, PUE211, PUE211PEG.

Figure 6 (a) is a graph showing the drug release behavior of the control, PUE211PEG, PUE311PEG.

Figure 6 (b) is a graph showing the drug release behavior of the control, PUD211PEG, PuD311PEG.

Hereinafter, the present invention will be described in more detail with reference to the following examples and test examples. However, these examples and test examples are provided only to facilitate understanding of the present invention, but the scope of the present invention is not limited by these examples and test examples.

Example 1

[Synthesis of Polyurethane Polydimethylsiloxane Consisting of Soft Part]

60% polydimethylsiloxane in a solution of tetrahydrofuran: dimethylacetamide (3: 1v / v%) in which monomeric amount of 0.2w / v% of stenos octoate and 4,4′-methylenediphenyldiisocyanate are dissolved. Charged under anhydrous conditions at atmospheric pressure and reacted for 2 hours to synthesize polydimethylsiloxanes in which both ends were terminated with isocyanate groups (-NCO) and to obtain high molecular weight polymers such as ethylene glycol or diethyl bishydride. Charge oxymethylmalonate and react at 8O < 0 > C for 8 hours at atmospheric pressure. The reaction solution was precipitated in distilled water two times, dried in vacuo at 50 ° C. for two days, and modified with polydimethylsiloxane, 4,4′-methylenediphenyl diisocyanate and chain extender to modify the molar ratio of polyurethane. Was obtained and the details are shown in Table 1 below. Each polymer was named as PUE series using ethylene glycol as chain extender and PUD series when diethylbishydroxymethylmalonate was used as chain extender.

Example 2

[Polyethylene Glycol Synthesis in PUE Series]

92w of monomer amount in a solution in which hexamethylenediaisocyanate (HMDI) using 5 times of polyethyleneglycol-OH group was dissolved in 10w / v% tetrahydrofuran (THF) to replace the chain terminal group of polyethyleneglycol. Polyethylene glycol was charged with / v% dibutyltin diauate and reacted under anhydrous conditions at room temperature for 12 hours. After the reaction was terminated, the solution was precipitated in anhydrous ether and dried in vacuo at room temperature for 2 days to obtain polyethylene glycol (PEG-NCO) in which the chain ends were terminated with isocyanate groups.

Polyethylene glycol and polyurethane (PUE series) terminated by an isocyanate group at the end of the chain. Polyethylene glycol: Polyurethane = 1: 1, and monomer content of 0.2w / v% stenos octoate is 10w / v% tetrahydrofuran. After dissolving in, reacted for two days at 50 ° C. under anhydrous conditions, the reaction solution was precipitated in hexane, washed twice with distilled water, and dried in vacuo at 50 ° C. for two days to obtain a final polymer having a yield of 90% (PUE-PEG). The structural formula is as follows, where R is a chain extender and R 'is ethylene glycol.

If R is ethylene glycol and R 'is polyethylene glycol, the compound is specified as follows.

Example 3

[Polyethylene Glycol Synthesis on PUD Series]

A solution of 1N sodium hydroxide (NaOH) was added to a solution of polyurethane (PUD series) in 10w / v% tetrahydrofuran until the pH was 11, and the pH was fixed at 11. After hydrolysis at room temperature and atmospheric pressure for 1 hour. After induction of 1N hydrochloric acid (HCI) aqueous solution was added until the pH is 4 to fix the pH to 4 to obtain a polyurethane containing carboxylic acid in the main chain. This was vacuum dried at 50 ° C. for 2 days and then to polyethylene glycol using 2 times of carboxylic acid in polyurethane, 1,3-dicyclohexylcarbodiimide and 1.2 using 1.2 times of carboxylic acid in polyurethane. It was dissolved in 10 w / v% tetrahydrofuran together with 4-dimethylaminopyridine using 0.2-fold of the carboxylic acid, and reacted for 12 hours under anhydrous conditions at 50 ° C. Thereafter, the reaction solution was precipitated in hexane, washed in distilled water, and dried in vacuo at 50 ° C for 2 days to obtain a final product (PUD-PEG) having a yield of 90%. The structural formula is as follows: R is a chain extender and R ′ is Ethylene glycol is shown.

If R is diethylbishydroxymethylmalonate and R 'is polyethylene glycol as follows.

Physical properties of the polymer materials obtained in Examples 1, 2 and 3 were measured by the following test examples.

[Test Example 1]

[Molecular Weight and Solubility of Synthetic Polymer]

The molecular weight of the polymer synthesized in Example 1 was measured by Gel Permeation Chromatography (GPC), and the weight average molecular weight had a value of 35,000 or more (see Table 1 above), and the PUE synthesized in Examples 2 and 3 The molecular weights of the -PEG and PUD-PEG polymers measured by NMR are shown in Table 2 below. The solubility in organic solvents was commonly dissolved in most organic solvents such as acetone, methylene chloride, dimethylformamide, dimethyl sulfoxide, dimethylacetamide and tetrahydrofuran. The PUD series was dissolved in ethanol, chloroform, benzene, toluene and the like, whereas the PUE series was not dissolved in them. This is shown in detail in Table 3 below.

[Test Example 2]

Hydrophilicity of Synthetic Polymers

The hydrophilicity of each polymer was observed using a dynamic contact angle meter. The test specimen was made by repeatedly immersing 1 mm x 1 mm x 1 mm slide glass treated with chromic acid in 20 µm of dimethylacetamide solution in which 2.5w / v% polymer was dissolved. As a control, Pelethane, a commercial polyurethane product, showed that the polyurethane using the polydimethylsiloxane as a soft part was much more hydrophobic, and in particular, as the composition of the polydimethylsiloxane was increased, the hydrophobicity was strengthened. Polyethylene glycol-branched polyurethane showed higher hydrophilicity than the control polyurethane product, pelletane.

[Test Example 3]

[Viscoelasticity of Synthetic Polymers]

Dynamic mechanical analysis (DMA) was used to confirm the viscoelasticity according to the temperature of the polymer. 10W / v% of the polymer dissolved in the tetrahydrofuran solution was applied on a glass plate and dried at room temperature and atmospheric pressure for 24 hours or at room temperature and vacuum for 12 hours or longer to prepare a specimen having a thickness of 0.8 mm. Used for the test.

As the composition of the hard part increased, the storage modulus increased and the polydimethylsiloxane used as the soft part of the polyurethane had little compatibility with other components such as the hard part or polyethylene glycol, and the hard part of the PUE series was not compatible with the polyethylene glycol. The hard part of the PUD series was confirmed to be compatible with polyethylene glycol and is shown in FIGS. 1 (a) and (b).

[Test Example 4]

[Thermal Properties of Synthetic Polymers]

The thermal properties of the polymers were observed using differential scanning calorimetry (DSC). As mentioned in Test Example 3, since polyethylene glycol is incompatible with the hard part of the PUE series, an independent crystal phase was formed and melted at about 50 ° C. However, in the case of the PUD series having the polyethylene glycol branched with the hard part, Due to the compatibility, polyethylene glycol did not form an independent crystal phase and did not exhibit melting points. Details are shown in FIG.

[Test Example 5]

[Mechanical Properties of Synthetic Polymers]

After the film was made in the same manner as in Test Example 3, a dogbone specimen according to ASTM D638M was prepared and used for the test. Tensile modulus and tensile strength tended to increase with increasing hard part composition of polyurethane, while elongation tended to decrease. Polyurethane with branched polyethylene glycol showed tensile elastic modulus and tensile strength compared to polyurethane without polyethylene glycol. Although elongation was decreased, elongation was increasing. Tensile test after one day hydration of the specimen reduced mechanical properties such as tensile modulus, tensile strength, elongation, and especially the degree of reduction of polyethylene glycol-branched polyurethane. It was confirmed that it had various mechanical properties according to the composition of each polymer. At least 150% to 1,500% for elongation, 1.5 MPa to 13 MPa for tensile strength, and 2 MPa to 30MPa for tensile modulus Desired physical properties could be obtained until the details are shown in Figures 3 (a), (b), (c).

[Test Example 6]

[Compatibility of Blood of Synthetic Polymer]

20 ml of each solution of dimethylacetamide in which a polyurethane composed of 2.5 parts by weight of polydimethylsiloxane is composed of soft parts in a glass beads having a diameter of 200 µm treated with chromic acid and a polyurethane in which polyethylene glycol is branched therein. Was applied to the blood compatibility test based on the determination of how the platelet, the main component of the thrombus adsorbed on the polymer surface.

Compared to the pellets used as a control group, the polyurethane composed of the polydimethylsiloxane synthesized in the present invention had less adsorption of platelets, and the polyethylene glycol-branched polyurethane showed the best blood compatibility. ) and (b).

[Test Example 7]

[Bacterial Adsorption of Synthetic Polymers]

After the film was made by the method of Test Example 3, a disk-shaped specimen having a diameter of 12 mm was made, and E. coli. And S.epidermidis were selected to observe the degree of adsorption on the specimen. In the case of E. coli, polyurethane, which consists of soft parts of polydimethylsiloxane, adsorbed more than the control group due to strong hydrophobic interaction with bacteria. In the case of S. epidermidis, polymers composed of polydimethylsiloxane soft parts showed more adsorption than the control group, and polyethylene glycol-branched polyurethane showed almost the same level of adsorption as the control group. Indicated.

[Test Example 8]

[Drug Release Behavior of Synthetic Polymers]

After dissolving 10 wt% of rifampicin in tetrahydrofuran in the polymer produced by the present invention, a specimen was prepared by the method described in Test Example 7 to observe the drug release behavior. In the case of the control group, the release of the drug is about 80% or more within about 10 days, while the polymer synthesized in the present invention was released from the minimum 30% to the maximum 60% despite the release of the drug over 40 days. Especially, the PUD series branched with polyethylene glycol showed less burst effect than other specimens due to hydrogen bonding between the hard part of the polyurethane and the drug, and it was confirmed that the decrease of the hard part increased as the composition of the hard part increased. The details are shown in Figures 6 (a) and (b).

The present invention consists of a polydimethylsiloxane composed of a soft part of polyurethane, and by copolymerizing polyethylene glycol by covalent bond, dissolving it in various organic solvents to prepare a thermoplastic biopolymer that is maximized in biocompatibility, the conventional biomaterial is a human body The main problems that can occur in the body, such as thrombosis, bacterial infections, toxic chemicals released from the biological material can be solved. In addition, by changing the composition of the polyurethane according to the needs of the application, it is possible to adjust the biocompatibility, mechanical performance, drug release behavior, etc. as desired can be used in various medical supplies.

Claims (5)

Polydimethylsiloxane (PDMS) as a soft part, 4,4'- methylenediphenyl diisocyanate (MDI) and a chain extender characterized in that the covalently branched polyethylene glycol (PEG) in a polyurethane composed of a hard part Medical polyurethane combined with polydimethylsiloxane and polyethylene glycol which can be represented by the following general formula. R is a chain extender, R 'is polyethylene glycol, x and y are determined according to molecular weight PUD-PEG R is a chain extender, R 'is polyethylene glycol, and x and y are molecular weights. The medical polyurethane according to claim 1, wherein the polyethylene glycol and polydimethylsiloxane have a molecular weight of 300 or more and 10,000 or less. The method of claim 1, wherein the chain extender is ethylene glycol, diethylbishydroxymethylmalonate, 1,4-butanediol, ethylenediamine, hexanediol, polydimethylsiloxane and polyethylene glycol combined medical poly urethane. In the synthesis of polyethylene branched polyethylene glycol, polydimethylsiloxane terminated at both ends with an isocyanate (-NCO) group is reacted with a chain extender to make a polyurethane, and then the polyethylene glycol terminated with an isocyanate group is 1: 1. Method for producing a medical polyurethane combined with polydimethylsiloxane and polyethylene glycol, characterized in that the reaction. The method according to claim 4, wherein the polydimethylsiloxane and polyethylene glycol combined medical use, characterized in that the polyurethane containing carboxylic acid in the main chain is made and then reacted with polyethylene glycol using twice the carboxylic acid in the polyurethane. Method for producing polyurethane