KR20000000603A - Process for producing functional polyurethane hydrogel - Google Patents

Abstract

PURPOSE: A process for producing a functional polyurethane hydrogel which improves bio compatibility and excellent mechanical, physical properties, thus can be widely applied for medical materials is provided. CONSTITUTION: The process is characterized by simultaneously forming urethane bonding and allophanate by thermal cross linking of a polyol and a diisocyanate at a high temperature of 80-100°C. The polyol is PEG (polyethylene glycol) having a molecular weight of 3400 or 4600, and the diisocyanate is methylenebis-phenyl-isocyanate having high water-swelling power and LCST (lower critical solution temperature). The obtained functional polyurethane hydrogel has reversible water-swelling power in accordance with temperature and is sensitive to thermal stimulus.

Description

Method of producing functional polyurethane hydrogel

The present invention relates to a method for producing a functional polyurethane hydrogel having excellent biocompatibility through a new manufacturing process and having various physical and mechanical properties according to synthetic methods and conditions, and applicable to a wide range of medical materials. In order to use the polyol is a non-toxic, immune reaction does not occur and has a hydrophilic property of PEG (Polyethylene Glycol) is excellent.

Urethanes became known since 1849 when Wurtz and Hoffman of Germany announced the first reaction of isocyanates with hydroxy compounds. By 1937, Otto Bayer was used for commercial purposes, and polyester-based urethanes began to be produced industrially to compete with nylon. The development of urethane for textiles, paints and foams was activated by the start of World War II. After the end of World War II, extensive research and development began in the United States, the United Kingdom and Germany, with the German technology becoming known. Initially confined to diisocyanates and polyester-based polyols, it turned to other hydroxy compounds that could be replaced by problems such as processability, cost, and foam properties. By 1957, the foam properties were improved as well as cost advantages. Polyether based polyols have been produced for a wide variety of applications.

Currently, polyurethane is an indispensable polymer material for the core industry, starting from building insulation and forming a wide range of products such as automobiles, general machinery, ships, furniture, shoes, and clothing, and in the form of adhesives, coatings, rubber, engineering plastics, etc. It is a material widely used in the industrial field. In particular, it is stable in the blood for a long time, so it can be used for various medical materials such as artificial organs, blood vessels, urethral catheters, drug release systems, and film or foam wound dressings. The reason for having such a wide range of fields is due to the advantage of synthesizing polymer materials having various physical and mechanical properties depending on the properties of the polyol and diisocyanate used in the synthesis of polyurethane. That is, the molecular weight, the shape and interaction of the soft and hard segments, and the degree of crystallinity can be used to produce polyurethane products with the desired properties. In general, as the molecular weight of the polyol increases, the degree of phase separation and crystallinity increases, so that the mechanical properties up to a certain limit molecular weight have been reported to be excellent, and as the content of the hard segment increases, the stress increases and the deformation decreases.

Polyurethane is a polymer material that is very likely to be developed as a new type of product in addition to the known product range.

The reaction of isocyanates, which form the basis of polyurethane synthesis, takes place between compounds containing active hydrogen and compounds having isocyanate groups. to be. And sometimes the presence of water during the reaction has an adverse effect on the molecular weight and mechanical properties of the final product, but also acts as an important medium for the formation of the foam. Most of the reactions have the main reaction at almost 50 ℃ except for the highly reactive aromatic isocyanate, and the reactivity with isocyanate is about 10 amines superior to the primary alcohol.

As a side reaction, urethane bonds and urea bonds at each temperature cause nucleophilic immobilization reactions with isocyanates, resulting in allophanate and biuret bonds, which in turn form chemically crosslinked structures in the polymer chain. Often, polyurethane reactions cause crosslinking by inserting a slightly excess molar ratio of isocyanate than polyol and applying high heat after forming the final product. In particular, since the allopanate reaction is reversible at high temperatures, it is possible to mold by dissolving a polyurethane having a small amount of allopanate bond and then reforming the allopanate while cooling. Often such allopanate bonds are generally formed at 80 ° C. or higher.

Other side reactions include the formation of dimers and trimers of isocyanates, which are formed from aliphatic isocyanates, reversible above 150 ° C, and trimers are formed from aliphatic and aromatic isocyanates and at relatively high temperatures. It is stable.

Research into the development of a hydrogel type material using polyurethane widely used as a medical material due to its excellent physical and mechanical properties, relatively good blood compatibility and stability in vivo for a long time has been conducted for a long time.

Polyurethane hydrogels that have been studied so far are isocyanate and a crosslinking agent to grafted PEG (polyethylene glycol) to improve biocompatibility and water swelling. Hydrogels based on water-soluble polyetherurethanes made using polyethylene oxide (PEO). They are mainly used for immobilization of enzymes or biomass as well as medical fields such as artificial organs, catheters, and materials for drug shear.

In the present invention, the reaction time is shorter than that of the conventional polyurethane elastomer, and a new material different from that of the existing polyurethane gel may be synthesized through a new manufacturing process that is easy to mold.

1 is a graph showing the change of water swelling degree according to the temperature of polyurethane hydrogel using PEG having a molecular weight of 3,400

2 is a graph showing the change of water swelling degree according to the temperature of polyurethane hydrogel using PEG having a molecular weight of 4,600

3 is a graph showing the change in water swelling degree (MDI: PEG = 3: 1) for thermal stimulation of polyurethane hydrogel

4 is a cross-sectional analysis (MDI: PEG = 3: 1) of the polyurethane gel using SEM

5 is a cross-sectional analysis (MDI: PEG = 5: 1) of the polyurethane gel using SEM

All.

In the present invention, since only hydrophilic linear (including polymer chain entanglement) polyurethane has a limitation in the water swelling and mechanical properties of the hydrogel, the polyurethane hydro having a chemical crosslinking structure is introduced by introducing allophanate into the urethane bond by thermal crosslinking. Gels were synthesized. In the production of conventional polyurethane elastomers, polyurethane prepolymers were synthesized and the chains were expanded using chain extenders and then crosslinked by high temperature. In this experiment, polyol and excess diisocyanate were used without using chain extenders. By reacting at a high temperature to form a urethane bond and allophanate at the same time, the reaction formula is as follows.

Synthesis of Polyurethane Hydrogels by Thermal Crosslinking.

Based on the result of the hydrophilic linear polyurethane as a monomer, the diisocyanate observed to have excellent water swelling and lower critical solution temperature (LCST) characteristics is MDI (Methylenebis-Phenyl-Isocynate) as a polyol, and molecular weight as a polyol. 3,400 and 4,600 PEG (Polyethylene Glycol), and a solvent was used as a solvent with a volume ratio of 9: 1 of THF (Tetrahydrofuran) and DMF (Dimethylformamide).

The description of the present invention will be described in more detail with the following examples and test examples. However, the following examples and test examples do not limit the technical scope of the present invention.

Example 1 Purification of Reactant

Diisocyanate MDI (4,4'-methylenebis-phenyl-isocyanate; ACORS) used in the synthesis of polyurethane hydrogel was stored at 50 ° C for 1 to 2 hours to prevent dimer precipitated while heating to prevent crystallization due to cooling. After filtration, it was precipitated in purified nucleic acid and dried in a vacuum oven for 3 to 4 days. PEG (polyethyleneglycol; Aldrich Chemical Co.) used as a polyol was used after removing water at 100 ° C. under reduced pressure for 30 minutes. THF (tetrahydrofuran; Fisher Scientific Co. GR grade) used as a solvent was refluxed for 4 hours in the presence of CaH ₂ and distilled. DMF (dimethylformamide; JT Baker, 99.9%) was reacted with sodium for 24 hours at room temperature. After purification by distillation under reduced pressure, 4A molecular sieve was put and stored for a week.

Na (Fluka Chemika), CaH ₂ (Sigma Chemical Co. 95%) and molecular sieves (4A, 4-8 mesh; ACROS) used for removing water were used without any treatment.

Example 2 Synthesis of Polyurethane Hydrogel by Thermal Crosslinking

First, a well-purified THF and DMF were mixed in a volume ratio of 9: 1, and then degassed for 1 hour, and then dissolved in 50 ml, and 10 g of PEG removed from water at 100 ° C. under reduced pressure was dissolved at 80 ° C. The furnace was put in a fixed temperature reactor and refluxed using a condenser. When all the devices were completed, the MDI corresponding to 10 g of PEG was dissolved at 80 ° C. in a 50 ml mixed solvent according to the molar ratio of MDI and PEG (2: 1, 3: 1, 4: 1, 5: 1) and the molecular weight of PEG. Do not use. The reaction time is adjusted within the range of 1 to 3 hours to control the viscosity of the solution and the physical properties of the prepared hydrogel.

After the synthesis was completed, the viscous solution was poured into a Teflon film-coated shale, dried at room temperature for 3 days, and dried under reduced pressure at 80 ° C. for 4 days to completely remove the reaction solvent, followed by casting to obtain an even film. During casting, peel off the film attached to the edge of the chaele with a knife and use a syringe to remove bubbles.

<Test Example 1> Water swelling measurement

When measuring the water swelling degree of the hydrogel, a film is produced by casting. The prepared material is cut to a width of about 1 cm ² without damage, and then measured under different conditions of time and temperature in a buffer solution having a pH of 7.4. Clean the swollen specimen with gauze to keep the surface dry. And water swelling degree is defined as the weight of water absorbed divided by the weight of the polymer matrix.

As the molecular weight of PEG was fixed at 1000, 2000, 3400, and 4600, and chemical crosslinking reaction, the water swelling degree was 9 times and 10 times, respectively, at 3,400 and 4,600. Below 2,000, the film was obtained with a very small water swelling degree, and it was found that the water swelling degree increased as the molecular weight of PEG increased. In addition, the water swelling degree is different depending on the molar ratio of MDI and PEG. The reason is that as the molar ratio of MDI to PEG increases, the content of PEG in the polyurethane gel decreases and the hydrophilicity decreases relatively.

As a result of measuring the water swelling degree of the hydrogel synthesized by changing the molar ratio of MDI and PEG at 3,400 and 4,600 of the molecular weight of PEG, the water swelling degree decreased with increasing temperature, and the water swelling degree was reversible with temperature. Changed to.

Test Example 2 Measurement of Mechanical Properties

Mechanical properties of polyurethane hydrogels were tested using an Instron testing machine and the specimens were cut to ASTM D638M-V type. Preparation of the film was cast after synthesis and stored at room temperature for one week, and soaked in distilled water at room temperature for 48 hours when measuring the water-swelled hydrogel. The thickness of the film was 0.1-0.3 mm and the specimens were pulled at a rate of 50 mm / min.

Overall, when the molecular weight of PEG was 4,600 rather than 3,400, the shear stress, modulus of elasticity, and deformation increased due to the increase of crystallinity and phase separation as in the previous paper. In addition, the effect of the molar ratio of MDI and PEG showed that the shear stress, modulus of elasticity and deformation decreased with increasing molar ratio (Table 1). This is in contrast to the tendency of shear stress and modulus to increase and deformation to decrease as the amount of hard segments increases. This is because in the synthesis method, as the molar ratio of MDI increases, allophanate formation takes place together with the synthesis of the polyurethane prepolymer, which makes it difficult to synthesize the linear polymer. Therefore, since the proportion of linear urethane bonds in the total crosslinked structure becomes small, the segmental form of polyurethane disappears, and instead, it appears that many allophanate bonds forming an irregular crosslinked structure are distributed.

<Test Example 3> SEM (Scanning electron microscope) measurement

In order to observe the cross section of the polyurethane hydrogel through a scanning electron microscope (SEM), the surface of the sample was weakly formed in a straight line, frozen in liquid nitrogen for about 5 minutes, broken, coated with gold, and observed at 1500 times.

From the overall shape of the polyurethane gel measured by SEM, it is estimated that allophanate is more likely to be formed when the molar ratio of MDI and PEG is 5: 1 than that of 3: 1. . In addition, the formation of allophanate is not a role of connecting linear prepolymers in the form of trapezoids, but it is assumed that allopanate bonds are formed as soon as urethane bonds are formed, so that the chains are formed in a radial form that cannot predict the crosslinking structure. . Therefore, it was confirmed that when the polymer chain is charged during casting, the molar ratio is composed of a more dense spider web in the case of 3: 1. In addition, due to these effects, the mechanical properties and water swelling of the MDI and PEG in the molar ratio of 3: 1 are better than that of 5: 1.

In the measurement of the mechanical properties of water-swelled hydrogels, the difference between the dried gels was that the modulus of elasticity increased with the influence of water in the gel as the molar ratio of MDI and PEG increased. Silver was significantly reduced compared to the dried gel (Table 2).

Table 1. Mechanical Properties of Polyurethane Gel

Polymer Shear stress (MPa) % Strain Elasticity (MPa) PEG molecular weight MDI: PEG 3400 2: 1 8.13 1240 19.46 3400 3: 1 7.28 856 13.54 3400 4: 1 5.28 591 5.17 3400 5: 1 2.85 158 2.73 4600 2: 1 16.71 1856 32.87 4600 3: 1 13.51 1533 25.49 4600 4: 1 8.68 954 14.47 4600 5: 1 6.66 674 10.50

Table 2. Mechanical Properties of Polyurethane Hydrogels

Polymer Shear stress (MPa) % Strain Elasticity (MPa) PEG molecular weight MDI: PEG Water swelling degree (hours) 3400 2: 1 9.04 0.7235 434.56 0.2998 3400 3: 1 6.15 0.6486 253.90 0.4189 3400 4: 1 4.35 0.3976 86.43 0.6021 3400 5: 1 3.23 0.2678 32.33 0.8460 4600 2: 1 10.20 0.9756 687.45 0.2576 4600 3: 1 7.27 0.8304 463.80 0.3097 4600 4: 1 5.35 0.6596 118.70 0.5107 4600 5: 1 3.51 0.5676 93.16 0.8040

The present invention is a functional polyurethane hydrogel synthesized through a new manufacturing process, the water swelling degree changes with temperature and exhibits a thermosensitive and reversible water swelling sensitivity sensitive to thermal stimulation, and thus has a different mechanical property from that of the conventional polyurethane gel. Hydrogels can be synthesized.

Claims (2)

A hydrogel using a polyurethane, wherein the polyol and diisocynate are thermally crosslinked at high temperature to simultaneously form a urethane bond and an allophanate. The method of claim 1, wherein the polyol is a polyethylene glycol (Polyethylene Glycol) molecular weight of 3,400 and 4,600 is used, the diisocyanate is reacted at a temperature of 80 ~ 100 ℃ using Methylenebis-Phenyl-Isocyanate Method for producing a functional polyurethane hydrogel, characterized in that.