JPH041773B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing a novel polyurethane or polyurethaneurea, particularly a polyurethane or polyurethaneurea having excellent anticoagulant properties. Polyurethanes are obtained by polyaddition reactions between diols and diisocyanates, and polyurethaneureas are obtained by chain-extending prepolymers obtained by polyaddition reactions between diols and diisocyanates with diamines. Because of the low compatibility of the chains of heterogeneous segments (ether segment and urethane segment, or ether segment and urethane and urea segment), a heterogeneous surface structure appears in the polymer film, and this heterogeneous surface structure is relatively Expresses high anticoagulant properties. In order to give the polymer membrane even better anticoagulant properties, the present invention uses polyurethane or polyurethaneurea having an ester group in its side chain, saponifies the ester group, neutralizes it, and then couples heparin. While retaining the excellent properties of polyurethane or polyurethane urea, the anticoagulant properties of the surface of the molded product are further enhanced through surface treatment. In the present invention, it is also possible to adjust the properties of the soft segment by controlling the type, degree of polymerization, and content of the diol segment or diamine segment, and it is also possible to control the molecular weight of the entire polymer chain.
This means that the amount of heparin adsorbed and the size of each hydrophilic and hydrophobic domain can be adjusted, and has the advantage that the material can be set according to the purpose. The present invention will be explained in detail below. Synthesis of polyurethane having an ester group in the side chain: - Synthesizing a compound having two hydroxyl groups and one ester group in the molecule, and coexisting polyether or polyester diol with this as a chain extender. Alternatively, it can be obtained by carrying out a polyaddition reaction with an aliphatic or aromatic diisocyanate without coexistence. (A) Synthesis of diol having an ester group: In the present invention, dimethylolpropionic acid ester is used as the diol having an ester group in the side chain, and an example using its methyl ester will be explained below. This methyl ester is obtained by methyl esterifying dimethylolpropionic acid. To illustrate this specifically, 25g of dimethylolpropionic acid is suspended in methanol,
Add another 1 g of p-toluenesulfonic acid,
Reflux for approximately 6 hours. After cooling, Amberlite (anion exchange resin manufactured by Rohm and Haas)
is added to remove p-toluenesulfonic acid, and then methanol is distilled off. Distill the resulting liquid under reduced pressure (bp 115℃/3mmHg) to obtain 24.6g of methyl dimethylolpropionate, a colorless and transparent liquid.
(90% yield). Infrared (hereinafter referred to as IR) spectrum and elemental analysis confirmed that pure methyl dimethylolpropionate was obtained. This compound has the following chemical structure, and polyurethane can be synthesized by polyaddition reaction with diisocyanate as a diol component. In addition to the above-mentioned diols having an ester group in the side chain, other ester groups such as dimethylolpropionic acid esters such as ethyl group and benzyl group may also be used. (B) Synthesis of polyurethane having ester groups: The diol having ester groups obtained in (A) above is mixed with polyether diol or polyester diol, or is synthesized with various diisocyanates without mixing. Polyurethane is synthesized by carrying out an addition reaction. As polyether diols, all diols conventionally used in the production of polyurethane can be used in the method of the present invention. Specifically, polyols with a molecular weight of 200 to 8,000, such as polyoxyalkylene diols such as polyethylene glycol, polypropylene glycol, and polytetramethylene glycol; examples of polyester diols include sebacic acid, succinic acid, oxalic acid,
Examples include those synthesized from dicarboxylic acids and derivatives thereof such as azelaic acid, terephthalic acid, and isophthalic acid, and those obtained by ring-opening polymerization of ε-caprolactone. Similarly, all diisocyanates conventionally used in the production of urethanes can be used in the method of the present invention. Examples of preferred diisocyanates are ethylene diisocyanate, propylene diisocyanate, tetramethylene diisocyanate, pentamethylene diisocyanate, octamethylene diisocyanate, undecamethylene diisocyanate, dodecamethylene diisocyanate, 3. 3'-diisocyanate propyl ether, cyclopentylene-1,3-diisocyanate, cyclohexane-1,4-diisocyanate, 2,4-tolylene diisocyanate, 2,6-tolylene diisocyanate, 2 , a mixture of 4-tolylene diisocyanate and 2,6-tolylene diisocyanate, xylylene-1,4-diisocyanate, xylylene-1,3-diisocyanate,
4,4'-diphenylmethane diisocyanate (MDI), 4,4'-diphenylpropane diisocyanate, p-isocyanate benzyl isocyanate, m-phenylene isocyanate, p
-Phenylene isocyanate, naphthalene-
1,4-diisocyanate, naphthalene-1,
5-diisocyanate and the like. Production Example 1 Production of polyurethane containing methyl dimethylolpropionate, polytetramethylene glycol (hereinafter referred to as PTMG), and 4,4'-diphenylmethane diisocyanate (hereinafter referred to as MDI): 3.9 g of PTMG (molecular weight 1290) in 3 ml of dimethylformamide and 1.5 g of MDI (PTMG
(equivalent to 2 times the mole amount) in 2 ml of dimethylformamide, the atmosphere was replaced with nitrogen, and the mixture was reacted at 60°C for 3 hours. After that, 0.972g
A solution of methyl dimethylolpropionate (equimolar to PTMG) dissolved in 5 ml of dimethylformamide was added, and the mixture was reacted at 50°C for 24 hours. Then, add 0.06 ml of n-hexylamine (originally used
(equivalent to 10 mol% of MDI) was added to convert the isocyanate groups present at the ends of the reaction product into substituted urea and stabilize it. The obtained polyurethane solution was poured into distilled water and purified by precipitation. Upon drying, a white polyurethane was obtained. When this polyurethane was dissolved in dimethylformamide and its viscosity at 30°C was measured, it was found that [η]=0.420. Figure 1 shows the IR spectrum of the polyurethane obtained by this method. The absorption observed at 1730 cm ^-1 (A in the figure) is based on the ester group of methyl dimethylolpropionate, and it is thought that the absorption of the urethane bond that occurs with the formation of polyurethane is superimposed on this. 1100cm ^-1 (B in the diagram)
The absorption of alkyl ether group -CH ₂ -O-CH ₂ -
, which indicates the existence of PTMG. Based on these facts, it is thought that the polyurethane obtained by the above reaction has the following structure. Synthesis of polyurethane urea having an ester group in the side chain: In this method, a compound having two amino groups and one ester group in one molecule is synthesized, and this is used as a chain extender to form polyether diol or polyester diol. It can be obtained by carrying out a polyaddition reaction with an aliphatic or aromatic diisocyanate, with or without the coexistence of. (A) Synthesis of diamine having an ester group: In the present invention, L-lysine (hereinafter referred to as L-Lysine) is used as a diamine having an ester group in the side chain.
The methyl ester (abbreviated as L-
This will be explained using an example using Lys-OMe (abbreviated as Lys-OMe). To give a specific example, 5g of L-Lys・
2HCl is added to 200 ml of methanol saturated with dry hydrogen chloride, left to stand for 2 hours, and then refluxed.
After distilling off methanol, vacuum drying is performed. The white solid produced is purified by recrystallization from ethyl acetate and methanol. In this way, 4.79 g of L-Lys-MOe.2HCl was obtained. Pure L-Lys-OMe was determined by IR spectrum and elemental analysis.
It was confirmed that 2HCl was obtained. Next, 4.79 g of L-Lys-OMe・2HCl was dissolved in distilled water to make a saturated aqueous solution, and 3.45 g of sodium hydrogen carbonate (L-Lys-OMe・2HCl
(corresponding to twice the molar amount), stirred for 1 hour, and then freeze-dried. Add methanol, filter the soluble portion, and distill off the methanol. Furthermore, chloroform-methanol (2:1) solvent was added and the same operation was performed to obtain a colorless and transparent liquid with high viscosity (1.97 g of L-Lys-OMe) (yield:
60%). It was confirmed by IR spectrum and elemental analysis that it was pure L-Lys-OMe. This compound has the following chemical structure, and polyurethaneurea can be synthesized by polyaddition reaction with diisocyanate as a diamine component. (B) Synthesis of polyurethaneurea having an ester group: The diamine having an ester group obtained in (A) above is mixed with or without mixing with a polyether diol or a polyester diol, and various diisocyanates are mixed. Polyurethaneurea is synthesized by performing a polyaddition reaction with As the polyether diol, polyester diol, and diisocyanate, those mentioned in (B) above can be used. Production example 1 L-Lys-OMe, PTMG, and MDI in 1:
Preparation of polyurethaneurea with components in a 1:2 molar ratio: 2.61 g of PTMG (molecular weight 860) is dissolved in 3 ml of dimethylformamide, 1.5 g of MDI (PTMG
(equivalent to twice the mole of ) in 2 ml of dimethylformamide, and after purging with nitrogen
The reaction was carried out at 60°C for 1 hour. Then, 0.48 g of L-
A solution of Lys-OMe (equimolar to PTMG) dissolved in 5 c.c. of dimethylformamide was added, and the mixture was reacted at room temperature for 3 hours. Thereafter, 0.06 ml of n-hexylamine (corresponding to 10 mol % of the initially used MDI) was added to convert the terminal isocyanate groups of the reaction product into substituted hydrogen and stabilize it. The obtained polyurethaneurea solution was poured into distilled water and purified by precipitation. Upon drying, a white polyurethaneurea was obtained. When this was dissolved in dimethylformamide and the viscosity at 30°C was measured, [η]
=0.545. Polyurethaneureas were synthesized using PTMG with molecular weights of 1290 and 2100 in the same manner. The former had [η] = 0.622, and the latter had [η] = 0.615. Figure 2 shows the IR spectrum obtained by applying polyurethaneurea using PTMG with a molecular weight of 860.
Shown below. 1730cm ^-1 (A in the figure), and 1100cm ^-1
The absorption observed in (B in the figure) is the same as in Figure 1, but in Figure 2 it is 1650 cm ^-1
Absorption based on urea bonds is observed in the vicinity (C in the figure), indicating the presence of urea bonds in the polymer. Based on these facts, the polyurethane obtained in the above reaction is considered to have the following structure. Production example 2 L-Lys-OMe, PTMG, MDI in 3:1:4
Production of polyurethaneurea with components in molar ratio: Dissolve 2.61 g of PTMG (molecular weight 860) in 3 ml of dimethylformamide, dissolve 3.0 g of MDI (PTMG
(equivalent to 4 times the mole of
The reaction was carried out at 60°C for 1 hour. Then 1.44g L-
A solution of Lys-OMe (equivalent to 3 times the mole of PTMG) dissolved in 5 ml of dimethylformamide was added, and the mixture was reacted at room temperature for 3 hours. Thereafter, 0.12 ml of n-hexylamine (corresponding to 10 mol % of the initially used MDI) was added to convert the terminal isocyanate groups of the reaction product into substituted urea and stabilize it.
Pour the resulting polyurethaneurea solution into distilled water,
It was purified by precipitation. Upon drying, a white polyurethaneurea was obtained. When this was dissolved in dimethylformamide and the viscosity was measured at 30℃,
[η] = 0.317. Polyurethane ureas were synthesized in the same manner using PTMG with a molecular weight of 1290 and 2100, respectively. The former is [η] = 0.342, the latter is [η]
=0.470. L-Lys-OMe, PTMG, MDI 5:1:6
Polyurethane urea as components in molar ratios was synthesized in a similar manner. The molecular weight of PTMG is 860, 1290,
2100, the viscosity of synthetic polyurethaneurea is [η] = 0.280, 0.480 and 0.528, respectively.
It was hot. Using PTMG with a molecular weight of 860, L-Lys-
Figure 3 shows the IR spectrum obtained by the spreading method of polyurethaneurea when the molar ratio of OMe, PTMG, and MDI was 3:1:4. 1730cm ^-1 (A in the figure),
The assignment of absorption at 1100 cm ^-1 (B in the figure) is the same as in Figures 1 and 2. In Figure 3, from Figure 2
It can be seen that the absorption based on urea bonds at 1650 cm ^-1 (C in the figure) increases. This indicates that the urea bond content in the polymer is higher than in Production Example 1. The result obtained here is thought to have the following structure. Synthesis of heparinized polyurethane or polyurethaneurea having an ester group in the side chain: This product is the aforementioned polyurethane or polyurethaneurea [hereinafter, when referring to both collectively, it will be referred to as polyurethane (urea). ] by saponifying and neutralizing it, and coupling it with heparin. Saponification treatment is performed after molding the polyurethane (urea). Molding here refers to processing the polymer into a film shape, tube shape, etc. according to various uses. A polyurethane (urea) molded product is immersed in an alkaline solution and saponified. This treatment changes the side chain from an ester group to a carboxylate group. Neutralization treatment is performed by immersion in an acidic solution after saponification. This treatment turns the carboxylate group into a carboxyl group. Heparinization treatment is performed after neutralization treatment. A polyurethane (urea) molded product is neutralized and the side chains that have become carboxyl groups are reacted with water-soluble carbodiimide. Heparin is added here, and the amino group in the heparin molecule and the carboxyl group in the molded product are coupled to form a covalent bond with heparin. In the method of the present invention, heparin or a metal salt of heparin can be used to bind heparin. Examples Polyurethaneurea (L-Lys-OMe,
PTMG860, MDI=1:1:2) was dissolved in dimethylformamide at 10% by weight, cast on a glass plate, heated with an infrared lamp to distill off the dimethylformamide, and further vacuum-dried. Dimethylformamide was completely distilled off to form a membrane. This membrane is immersed for 3 hours at room temperature in a solution of 4N aqueous sodium hydroxide and methanol in a 1:3 solubility ratio. After this, wash thoroughly with distilled water. Next, this membrane is immersed in a solution of 10% citric acid aqueous solution and methanol in a 1:3 solubility ratio for 3 hours at room temperature, and then thoroughly washed with distilled water. The thus treated membrane was further treated with a 10% aqueous 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide solution [0.1M MES {this MES was
(N-morpholino) ethanesulfonic acid (adjusted to pH 4.75 with a buffer solution) for 30 minutes at room temperature. After thoroughly washing with distilled water, it is immersed in a 5% aqueous heparin solution (adjusted to PH4.75 with 0.1M MES buffer) at room temperature for 12 hours. Finally, it was thoroughly washed with distilled water to obtain heparinized polyurethane urea. The ATR-IR spectra of the saponified polyurethaneurea membrane, the polyurethaneureas neutralized after saponification, and the heparinized polyurethaneurea membrane are shown in a, b, and c of FIG. 4, respectively. In Figure 4a, absorption due to carboxylate groups was observed at 1663 cm ^-1 (A in the figure) due to saponification treatment, and in Figure 4b, this peak disappeared due to citric acid treatment, and absorption due to carboxyl groups was observed in urethane. The absorption of the bond overlapped with 1730 cm ^-1 . In FIG. 4c, when the heparinization treatment was performed, absorption based on the ether bond of the sugar moiety of heparin was newly observed at 1051 and 1016 cm ^-1 (B in the figure). Anticoagulant Test The heparin-bound polyurethane (urea) obtained by the method of the present invention has excellent anticoagulant properties, and the test results are shown below together with comparative examples. The samples used in this test are as follows. Sample (1) Glass sample (2) Polyurethaneurea (L-Lys-OMe:
PTMG2100:MDI=1:1:2) Sample (3) Polyurethaneurea (L-Lys-OMe:
PTMG860:MDI=1:1:2) Sample (4) Polyurethaneurea (L-Lys-OMe:
PTMG1290:MDI=1:1:2) Sample (5) Polyurethaneurea (L-Lys-OMe:
PTMG1290:MDI=3:1:4) Sample (6) Polyurethaneurea (L-Lys-OMe:
PTMG1290:MDI=5:1:6) Sample (7) Surface saponified polyurethaneurea (L-
Lys-OMe:PTMG2100:MDI=1:1:2) Sample (8) Surface saponified polyurethaneurea (L-
Lys-OMe:PTMG860:MDI=1:1:2) Sample (9) Surface saponified polyurethaneurea (L-
Lys-OMe:PTMG1290:MDI=1:1:2) Sample (10) Surface saponified polyurethaneurea (L-
Lys-OMe:PTMG1290:MDI=3:1:4) Sample (11) Surface saponified polyurethaneurea (L
-Lys-OMe:PTMG1290:MDI=5:1:
6) Sample (12) Surface neutralized polyurethaneurea (L-
Lys-OMe:PTMG2100:MDI=1:1:2) Sample (13) Surface neutralized polyurethaneurea (L-
Lys-OMe:PTMG860:MDI=1:1:2) Sample (14) Surface neutralized polyurethaneurea (L-
Lys-OMe:PTMG1290:MDI=1:1:2) Sample (15) Surface neutralized polyurethaneurea (L-
Lys-OMe:PTMG1290:MDI=3:1:4) Sample (16) Surface neutralized polyurethaneurea (L-
Lys-OMe:PTMG1290:MDI=5:1:6) Sample (17) Heparinized polyurethaneurea (L
-Lys-OMe:PTMG2100:MDI=1:1:
2) Sample (18) Heparinized polyurethaneurea (L
-Lys-OMe:PTMG860:MDI=1:1:
2) Sample (19) Heparinized polyurethaneurea (L
-Lys-OMe:PTMG1290:MDI=1:1:
2) Sample (20) Heparinized polyurethaneurea (L
-Lys-OMe:PTMG1290:MDI=3:1:
4) Sample (21) Heparinized polyurethaneurea (L
-Lys-OMe:PTMG1290:MDI=5:1:
6) Sample (22) Polyurethane (methyl dimethylolpropionate: PTMG1290:MDI=1:1:2) Sample (23) Saponified polyurethane (methyl dimethylolpropionate: PTMG1290:MDI=
1:1:2) Sample (24) Neutralized polyurethane (methyl dimethylolpropionate: PTMG1290: MDI=
1:1:2) The above samples (2) to (24) were made into a dimethylformamide solution, placed in a watch glass made of the same glass as the above sample (1), the solvent was distilled off using an infrared lamp, and the solution was dissolved under reduced pressure. Dry it overnight and use it as a test sample. Saponification, neutralization, and heparinization treatments were then performed.
For comparison, a sample watch glass without any treatment was taken.
It was used as (1). The test was conducted as follows. Take 30 ml of blood from the femoral artery of an adult female dog, add 4.5 ml of ACD solution (a solution consisting of citric acid, sodium citrate, and glucose), and pour 0.2 ml of this onto a watch glass as described above. 0.02 ml of a 0.1 M calcium chloride aqueous solution is added to each sample prepared in 1 to initiate clotting. Distilled water is added every time a set period of time elapses to stop blood clots, and the formed blood clots are fixed with formalin and replaced with distilled water.
Remove the wet clot with a spatula, place it between tissue papers to absorb excess water, and weigh. The results of the thrombus formation test are shown in Table 1.

【table】

【table】

【table】

[Table] In Table 1, the weight is in mg, and the % value is the weight of blood clot when using glass (sample 1) as 100%.
and the relative weight % to this is shown. According to this table, blood completely coagulates within 10 minutes on glass (sample 1). The untreated polyurethaneurea of samples (2) to (6) was saponified (sample (7) to
(11)) and neutralization (samples (12) to (16)) tend to improve anticoagulability. This is thought to be because the polymer surface becomes hydrophilic through saponification and neutralization. Furthermore, when samples (17) to (21) were heparinized, very excellent anticoagulant properties were obtained. In particular, no thrombus formation was observed in samples (18) and (21) with a high ester group content and a large amount of heparin bound. Polyurethane membranes are flexible and have smooth surfaces, and also exhibit fairly good antithrombotic properties based on their microphase-separated structure. The present invention has shown that by supporting heparin on a polyurethane (urea) membrane, its antithrombotic properties can be further improved. Based on the excellent mechanical properties of polyurethane (urea), the polyurethane material obtained by the present invention can be used for various medical equipment materials that require antithrombotic properties,
For example, vascular catheters, cannulae, shunts,
It can be used in all parts that come into contact with blood vessels, such as extracorporeal blood transport circuits and blood pumps for artificial hearts.
In addition, by changing the types and composition of the constituent components of the microphase-separated structure of polyurethane (urea), the interaction with blood components such as blood proteins and platelets can be adjusted. It can also be used for beta etc. What has been explained above and shown in the specific examples of implementation is related to typical examples to aid understanding of the present invention, and the present invention is not limited to these examples, but is intended to be understood according to the scope of the claims. However, other modifications and variations can be made within that range.

[Brief explanation of drawings]

Figure 1 shows the IR spectrum of the polyurethane produced in Production Example 1 in Section B of the text by the spreading method.
Figure 2 shows the IR spectrum of the polyurethaneurea produced in Production Example 1 of Section B in the text by the spreading method, and Figure 3 shows the IR spectrum of the polyurethaneurea produced in Production Example 2 of Section B by the spreading method.
Figure 4 shows the membrane during surface treatment of the polyurethaneurea molded product described in the Examples section of the text.
It is an ATR-IR spectrum, and in the figure, a, b,
c are ATR-IR spectra of surface-saponified polyurethaneurea, surface-neutralized polyurethaneurea, and heparinized polyurethaneurea, respectively. In FIGS. 1 to 4, the vertical axis represents absorption, and the horizontal axis represents wave number (cm ⁻¹ ).

Claims (1)

[Claims] 1 Dimethylolpropionate or L-
Anti-blood coagulant property characterized by molding polyurethane or polyurethaneurea obtained by polyaddition reaction of lysine ester and diisocyanate, saponifying the surface of the molded product, further neutralizing it, and then binding heparin. Method of manufacturing materials.