JPS5950168B2 - Method for producing non-blood clotting material - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a block polymer that is substantially free from blood coagulation.

The use of artificial organs (artificial kidneys, artificial lungs, artificial blood vessels, etc.) and blood processing tools (syringes, blood bags, cardiac catheters, blood circuit tubes, blood transfusion tubes, etc.) is rapidly progressing, and the use of synthetic polymer materials to Application to this area is being considered. However, the big problem here is that many of the conventional medical synthetic polymer materials have the ability to induce or promote blood coagulation when they come into contact with blood. This is hindering the expansion of its application. For this reason, methods of attaching or coating anticoagulant substances such as heparin to the surface of the synthetic polymer material have been considered, but the binding strength between heparins and synthetic polymer materials is generally weak, and heparin Since the drugs are released slowly, the duration of the effect is short. The present invention has been made in view of these circumstances, and aims to provide a synthetic polymer material (hereinafter referred to as a non-blood coagulating material) that exhibits extremely little blood coagulation potential.

The non-blood coagulating material to be provided here not only maintains its effect for a long time, but also contains additives such as plasticizers, stabilizers, and polymerization catalysts in the blood, or a part of the polymer material itself. It must not elute and cause harmful effects on living organisms. Naturally, it must also have excellent mechanical properties and chemical stability, and must not be easily degraded in vivo. The present inventors have conducted extensive research in order to provide materials that satisfy each of the above conditions, and have developed a linear oligopeptide and polyether U whose both ends have amino groups. We were able to arrive at a non-blood coagulable block polymer obtained by reacting urethane prepolymer. In other words, the non-blood coagulating material of the present invention does not use additives such as plasticizers, and the material itself has low solubility, so it is unlikely that these materials will elute into the blood and have a harmful effect on living organisms. do not have. Furthermore, since the polymerization reaction for producing the polymer proceeds as an addition reaction, there are no reaction by-products and there is less risk of harmful effects associated with the elution described above. Since it has good mechanical properties and chemical stability, and especially excellent elastic properties, it is suitable as a material for artificial organs itself, and in some cases can be used as a coating for other polymeric materials. It can also be used as a drug), and its range of applications is extremely wide. The linear oligopeptide, which is one of the raw materials for producing the polymeric material of the present invention, has amino groups at both ends.

Although the method for producing it is not intended to limit the present invention, the amino acid N-carboxylic anhydride (1
) and () can be obtained by reacting this with divalent amines. The reaction when the amino acid is glycine and the divalent amine is ethylenediamine is shown by the following formula. (However, M.n is a positive integer and (m+n) is in the range of 3 to 30.

(more preferably in the range of 5 to 20) The types of amino acids used here do not limit the present invention, but typical ones are exemplified. and aliphatic α-amino acids such as glycine, alanine, leucine, isoleucine, valine, serine, threonine, cysteine, cystine, methionine, aspartic acid, and glutamic acid: phenylalanine, tyrosine, histidine, tryptophan, phosphorus, and oxyamino acids. Aromatic (or heterocyclic) such as proline
α-amino acids; non-α-amino acids such as β-alanine, γ-amino acids, and anthranilic acid; and esters and amides thereof.

Note that trifunctional amino acids such as lysine and arginine can be applied to the present invention if one functional group is protected. The type of divalent amine that is the other component also does not limit the present invention, but representative examples include hydrazine, aliphatic diamine, aromatic diamine, nitrogen-containing heterocyclic diamine, carboxylic acid dihydrazide, and the following general Diamines as shown by the formula () or () can be mentioned. (However, Rl in the formula
(FR2R3'R42R5R67R7 and R8 are the same or different divalent alkylene groups, P, q, r, s represent 0 or a positive integer) and more specific examples of the above divalent amines include ethylenediamine, 1,2-propylene diamine, 1,3-propylene diamine, 1,4-tetramethylene diamine, 1,6-hexamethylene diamine, m-xylylene diamine, p-xylylene diamine,
In addition to piperazine, N,N-di(2-aminoethyl)piperazine, oxalic acid dihydrazide, succinic acid dihydrazide, adipic acid dihydrazide, sebacic acid dihydrazide, etc., polyoxyalkylene glycols have amino groups or acid hydrazide groups at both ends. Some (polyoxyalkylene glycol moiety includes polyethylene glycol,
Polypropylene glycol, polytetramethylene alone, or random or block copolymers) are used.

The reaction of the above amino acid N-carboxylic acid anhydride and divalent amine is usually carried out in the presence of a solvent, and the solvent is
Rogenated hydrocarbons such as methylene chloride, chloroform, and tetrachloroethane; Amide polar solvents such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone, and hexamethylphosphoamide; Polar solvents such as dimethylsulfoxide and sulfolane; Other solvents that do not adversely affect the progress of the reaction are used.

In addition, a compound produced by this reaction, a preferred sequence of structural units in a linear oligopeptide having amino groups at both ends.
The number of reactions is as described above, but it is controlled by the reaction molar ratio of the amino acid N-carboxylic anhydride and the divalent amine. Next, the polyether urethane prepolymer, which is another reaction component used in the present invention, is obtained by reacting polyether diol and diisocyanate, and is made of polytetramethylene glycol (V).
An example of the reaction between 4,4'-diphenylmethane diisocyanate () and 4,4'-diphenylmethane diisocyanate is shown below. (x is a positive integer, y is 0 or a positive integer) That is, 1..
By reacting 2 to 4 equivalents, preferably 1.5 to 3 equivalents, a very convenient polyether-urethane polymer is prepared.

However, there are no particular restrictions on the reaction conditions, and the reaction is generally allowed to proceed at a temperature of 30 to 80°C, preferably 30 to 80°C. Although a catalyst and a solvent are not required, if desired, the reaction can be carried out using tin octylate, dibutyltin dilaurate, etc. as a catalyst and a solvent inert to isocyanate groups. Examples of the polyether diol used here include polyethylene glycol, polypropylene glycol, polytetramethylene glycol, or random or block copolymers thereof.

The molecular weight of these diols is usually 500.
Although it is desirable to use polyether diols having a molecular weight of 6,000 to 6,000, polyether diols other than the exemplified diols may be used. On the other hand, there are no special limitations on diisocyanates, but typical examples include ethylene diisocyanate, tetramethylene diisocyanate, and diisocyanate.
, 4-tolylene diisocyanate, 2,6-tolylene diisocyanate and other aliphatic diisocyanates; xylene-1,4-diisocyanate, xylene-1,3-
Examples include aromatic (or alicyclic) diisocyanates such as diisocyanate, 4,4-diphenylmethane diisocyanate, 4,4'-dicyclohexanylmethane diisocyanate, m-phenylene diisocyanate, and p-xylene diisocyanate, and these may be mixed. It can also be used as

As described above, an oligopeptide having amino groups at both ends and a polyether urethane prepolymer are prepared, and the present invention is carried out by reacting these.

The reaction is usually carried out in the presence of a solvent. Preferably, the solvent is one that is inert to isocyanate groups and can dissolve the oligopeptide and polyether urethane prepolymer. Specifically, chloroform is used as the solvent. , halogenated hydrocarbons such as methylene chloride and tetrachloroethane; amide polar solvents such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone and hexamethylphosphoamide; and aprotic polar solvents such as dimethylsulfoxide and sulfolane. These solvents are usually used in an amount of 0.5 to 20% per polyether/urethane prepolymer.
Used in the ratio of times (by weight). The reaction polarity is -20 to 80°C, preferably -5 to 50°C. The reaction procedure is not limited, but usually polyether diol and diisocyanate are reacted.
The urethane prepolymer is directly added to the solvent, and the oligopeptide is added while adjusting the reaction polarity as described above. The amount of the latter is 0.8 to 1.0 equivalent, preferably 0.95 to 1.0 equivalent, based on the amount of residual diisocyanate in the former.
It is 1.0 equivalent. The composition ratio of the polyether/urethane prepolymer and the oligopeptide in the addition polymer thus obtained is not limited, but the composition ratio of the polyether/urethane prepolymer in the polymer is 15 to 8.
5% by weight, preferably 30-75% by weight E. The reason for this is that when the amount of polyether-urethane prepolymer is too small, the resulting polymer has poor solution stability, resulting in phase separation or gel formation. Furthermore, if the amount of the polyether-urethane prepolymer is too large, the anticoagulant property, which is a feature of the present invention, will be reduced. Therefore, when carrying out the present invention, it is extremely important to adjust in advance the molar ratio of the terminal hydroxyl group in the polyether diol to the isocyanate group in the diisocyanate, the number of repeating units in the oligopeptide, etc. It is. The polymerization reaction is usually carried out in solution as described above, but
In order to ensure the stability of the obtained polymer solution, unreacted isocyanate groups may need to be protected. For this reason, a conventional amine may be added during or after the polymerization reaction, and such embodiments are also included in the scope of the present invention, and addition of other modifications that do not hinder the progress of the reaction is within the scope of the present invention. Those who carry out the measures are also left to their own discretion. The polymer produced? The liquid can be formed into any shape by wet or dry methods, and can be formed into sheets, tubes, or hollow fibers depending on the application, and can also be used as a coating material for other polymeric materials. It is also possible to use

The synthetic polymer material obtained by the present invention has virtually no blood coagulation effect, does not elute harmful substances into living organisms, and has excellent mechanical properties and chemical stability. Therefore, it is extremely convenient as a material for the aforementioned artificial organs and medical instruments.

Examples of the present invention will be shown below, but these and the embodiments described in the claims are not intended to limit the present invention. In the Examples, all parts mean parts by weight, and the logarithmic viscosity was measured using dimethylacetamide as a solvent at a polymer concentration of C10.59/dl (3'C).
Example 1 A silica gel tube was attached to an Erlenmeyer flask (capacity: 500 m0), and L-methylglutamate-N-carboxylic acid anhydride (37.49 g) was charged therein.

Dimethylacetamide (350m0) was added to this to make a homogeneous solution with stirring. Next, ethylenediamine (1.2
g) dimethylacetamide (50m0 solution) was added all at once, and then stirred at room temperature for 20 hours.
An oligomer solution of 0.02 mol/400 ml (dimethylacetamide) was prepared. The number average degree of polymerization of the oligopeptide was 10. Next, prepare a polymerization container with a capacity of 11, and use polytetramethylene glycol (409) with a molecular weight of 2000.
and 4,4 diphenylmethane diisocyanate (109
) and heated on a 65°C oil bath for 45 minutes.

Dimethylacetamide (30 ml) was added to this to obtain a homogeneous solution, which was then transferred onto an ice water bath and cooled for 30 minutes. The ice water bath was removed and the oligomer solution was slowly added (required 1.5 hours). It was stirred at room temperature for 12 hours. The logarithmic viscosity of the obtained polymer was 1.21. The inner wall of a test tube with an inner diameter of 10 mm was coated with this polymer solution, and the solvent was evaporated off. Test tube 5 thus obtained Approximately 2 me of fresh blood was added to the book and the coagulation time was measured at 37°C. The measurement results are listed together with other Examples and Comparative Examples.
Example 2 A similar test tube was prepared using poly(1,2-propylene glycol) 409 having a molecular weight of 2000 in place of polytetramethylene glycol in Example 1.

The logarithmic viscosity of the obtained polymer was 1.15. Example 3 Adipic acid dihydrazide (3.48 f!) was used in place of ethylene diamine in Example 1 to obtain an oligomer solution similar to that in Example 1.

The number average degree of polymerization of the oligopeptide is 10. On the other hand, polytetramethylene glycol was treated in the same manner as in Example 1 using 56f1, and then the oligomer solution (24
0 m0 was added over 1 hour. The logarithmic viscosity of the obtained polymer was 1.18. Thereafter, the same procedure as in Example 1 was carried out to obtain five test tubes. Comparative example 1 molecular weight 2000
A polyether urethane was obtained by reacting poly(1,2-propylene glycol), methylene diphenyl diisocyanate, and ethylene diamine in a dimethylacetamide solution.

Claims (1)

[Claims] 1. Obtaining a non-blood coagulable block polymer by reacting a linear oligopeptide having amino groups at both ends and having a repeating number of structural units of 3 to 30 with a polyether urethane prepolymer. A method for producing a non-blood clotting material characterized by: 2. The manufacturing method according to claim 1, wherein the linear oligopeptide is obtained by reacting an amino acid N-carboxylic anhydride with a divalent amino acid. 3. The manufacturing method according to claim 1 or 2, wherein the composition ratio of the polyether/urethane prepolymer in the block polymer is 15 to 85% by weight.