JPH03275071A - Antithrombogenic medical polymer material and device - Google Patents

Abstract

PURPOSE:To provide excellent mechanical physical properties, melt moldability and excellent antithrombogenic properties by setting the content of a polyether repeating unit to 5-75wt.% and forming a terminal from NH2 and COOH. CONSTITUTION:The first component of polyetheramide is a polyamide part and the polyamide part may be any polyamide obtained by polycondensation of lactam, polymerizable omega-amino acid or dibasic acid and diamine. However, from the viewpoint of antithrombogenic properties, it is necessary that the polyamide part is aliphatic saturated polyamide and the number of atoms of the alkylene chain thereof is 2-22, pref., 2-11 and lactam among the raw materials of polyamide is a 4-membered ring or more and epsilon-caprolactam, enanthlactam, capryllactam, layryllactam, alpha-pyrrolidone and alpha-piperidone are designated. Since a polyether part and the polyamide part are bonded by an amide group, a macroscopic phase separation structure generated when both parts are bonded by an ester bond is not developed and high mechanical strength is obtained.

Description

[Detailed Description of the Invention] <Industrial Field of Application> The present invention relates to antithrombotic medical polymeric materials and devices, especially mechanical properties! The present invention relates to antithrombotic medical polymer materials and devices.

<Prior Art> Synthetic polymer materials exhibiting excellent antithrombotic properties are indispensable in medical fields such as artificial blood vessels and artificial organs, and are desired to be stable during long-term residence in vivo.

As such an antithrombotic synthetic polymer, a polyether ester amide resin is known, in which the terminal hydroxyl group of a polyether segment and the terminal carboxyl group of a polyamide segment are bonded through an ester bond (Japanese Patent Application Laid-open No. 61-1111). -155426), there are difficulties in melt molding and mechanical properties after melt molding, and further improvements are desired.

<Problems to be Solved by the Invention> The purpose of the present invention is to provide a medical polymer material that has excellent mechanical properties, can be melt-molded, and has excellent antithrombotic properties, and a device using the same. do.

Means for Solving the Problems> These objects are achieved by the present invention described in (1) and (2) below.

(1) It has a repeating structural unit represented by the following structural formula (I) or (II), the content of polyether repeating units is 5 to 75 wt%, and the terminal is -NH and/or -COOH. An antithrombotic medical polymer material characterized by:

Structural formula (I) 1 set'0 (7R" collar. R3 廚帷R4 黚子5÷2M÷□mark R4 mark - Structural formula (II) -Cf) R'0 (-R2 call. R3C0-E-NH (-R
5NHCO-)-, R'C0-),, NHR5NH-(
In the above structural formula (1) or (II), R', R2
and R3 each represent a straight chain or branched alkylene group having 2 to 4 carbon atoms, R4 and R5 each represent a straight chain or branched alkylene group having 2 to 22 carbon atoms, n is O~180, m is 1 to 400, and p is O or 1. ) (2) An antithrombotic medical device that is a molded article of the polymeric material described in (1) above.

Effect> The polymeric material of the present invention is a polyetheramide resin produced from a polyether having an amino group or a carboxyl group at the end and a polyamide having a carboxyl group or an amino group at the end, and can be easily injection molded or extruded. Melt forming such as molding is possible, and the mechanical properties of the obtained molded piece are greatly improved.

<Specific structure of the invention> Hereinafter, a specific configuration of the present invention will be explained in detail.

The polymeric material of the present invention is a polyetheramide.

The first component of the polyether amide in the present invention is a polyamide part, and the polyamide part includes lactam,
It may be either a polymerizable ω-amino acid or a polyamide obtained by polycondensation of a dibasic acid and a diamine.

However, from the viewpoint of antithrombotic properties, the polyamide part needs to be an aliphatic saturated polyamide, and the alkylene group has 2 to 22 carbon atoms, preferably 2 to 11 carbon atoms.

Among these polyamide raw materials, lactams have a four-membered ring or more, and specific examples thereof include ε-caprolactam, enantholactam, capryllactam, lauryllactam, α-pyrrolidone, α-piperidone, and the like.

In addition, the number of carbon atoms in the alkylene chain of ω-amino acids is 2 to 22.
Specific examples thereof include 6-aminocaproic acid, 7-amitshebutanoic acid, 9-aminononanoic acid, 11-aminoundecanoic acid, and the like.

In addition, when using a dibasic acid and a diamine, the number of carbon atoms is 2 to
The dicarboxylic acids of 22 include malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, superric acid, azelaic acid, sebacic acid, undecanedioic acid, dodecanedioic acid, tridecadionic acid, tetradecadionic acid, hexadecadionic acid, Examples include octadecadionic acid, eicosandioic acid, tocosandioic acid, and 2,2°4-trimethyladipic acid.

Examples of diamines having 2 to 22 carbon atoms include ethylenediamine, trimethylenediamine, tetramethylenediamine, pentamethylenediamine, hexamethylenediamine, heptamethylenediamine, octamethylenediamine, nonamethylenediamine, decamethylenediamine, and undecamethylenediamine. , dodecamethylene diamine, tridecamethylene diamine, hexadecamethylene diamine, octadecamethylene diamine, 2.2.4 (or 2.4.4)-)-limethylhexamethylene diamine, and the like.

Specific examples of such polyamides include nylon 4.6.7.8.11.12.6.6.6.9.6.
10.6.11.6.12.6T, 6/6.6.6/1
Examples include 2.6/6T.

In addition, the terminal end of the polyamide raw material used to form these polyamide parts is -COOH and/or -N
It is H2.

Such raw materials have the following structural formula: (Ia) is preferred.

Structural formula (I a) H[l+COR'÷C0NHR'-), N)I-)
, H In this case, R4 and R' are each an alkylene group having 2 to 22 carbon atoms, but R4 is an alkylene group having 2 to 22 carbon atoms.
, preferably 2 to 11. R5 is a straight or branched alkylene group having 2 to 22 carbon atoms, preferably 2 to 7 carbon atoms.

There are no particular restrictions on the combination of R' and R' carbon numbers, but examples of combinations that exhibit a micro phase separation structure (microdomain structure) for the polyether chain and have good antithrombotic properties include, for example, R4 being octamethylene. group, R8 is a straight-chain alkylene group with an even number of carbon atoms such as a hexamethylene group.

Moreover, m is 1-400, preferably 1-200.

Further, p is 0 or 1, p=l means a two-molecule reaction between a dibasic acid and a diamine, and p=Q means a one-molecule reaction.

On the other hand, the polyether moiety is a polyalkylene oxide having an alkylene chain having 2 to 4 carbon atoms, and specific examples thereof include polyethylene oxide, polypropylene oxide, polytetramethylene oxide, and the like.

A modified polyether in which the terminal hydroxyl group is directly aminated, cyanoethylated, reductively aminated, or oxidized and carboxylated is used as a raw material.

As such a raw material, a diamine or dicarboxylic acid having the following structural formula (Ie) or (IIe) is preferable.

Structural formula (I e) NH2R'0+R''0-), R3N) I2 Structural formula (T
ie) HOCOR'0 (-R"0 +, 1R3COOH In this case, R', R" and R3 are each a straight chain or branched chain having 2 to 4 carbon atoms, such as an ethylpropylene group, an isopropylene group, a tetramethylene group, etc.) It is an alkyl group.

In addition, n is not particularly limited, but 0 to 180, and the preferred range is about 0 to 60.

These raw material polyamides and raw material polyethers may be synthesized by known methods, or commercially available products may be used.

Then, these two raw materials were pressurized to about 10 kg while stirring,
The reaction was allowed to take place for about 2 hours, then the pressure was gradually released, and the
The reduced pressure reaction is carried out at a pressure of mHg or less for about 2 hours.

After that, the stirring is stopped, the pressure is restored in an inert atmosphere, and the mixture is formed into strands and further into pellets.

Through such a reaction, the polyamide part and the polyether part are connected through the acid amide group -NHCO- to form a structural unit represented by structural formula (I) or (II).

Structural formula (T) Kazutsugu 1 low 12 calls. R3N) l÷markR4÷ωtanugin,■÷J
R4ω-Structural formula (II)-COR discharge R2 name. 83 minutes (a) + (-R'NH snore R4
By connecting the snore J5 sweet parts with -NHCO-, moldability and mechanical strength are significantly improved compared to when connecting with -COO-.

In addition, the polymeric material of the present invention may be a one-molecule reaction of a raw material polyamide and a modified polyether, or may have about 2 to 3 polyamide parts and polyether parts, respectively.

And the molecular weight is about 1.000 to 200.000, more preferably 2,
000 to 50,000 is preferable.

However, both ends of this linear polymer are usually in a mixed state, and the NH,/C0OH ratio is about 1.

Further, the content of polyether repeating units, preferably -R'0-(-R20+, R''- in the above structural formula, is 5 to 8
5 wt%, preferably 10 to 70 wt%.

If the content is at a value other than this, the antithrombotic properties will decrease.

The biomaterial of the present invention more preferably has a microdomain structure having a crystalline phase and an amorphous phase with an average length of about 5 to 10 nm.

This is because this also improves antithrombotic properties.

In addition, in providing such a microdomain structure,
The above polyether contents are preferred.

Note that the microdomain structure is confirmed by a transmission electron microscope and a scanning electron microscope.

To obtain the final molded product, it is fed to various molding machines such as injection, extrusion, blow, and compression, and molded according to conventional methods.

Furthermore, so-called multicolor molding is also possible.

Furthermore, on the surface (blood contact surface) of the polymer material of the present invention,
It is preferable to form spherulites (spherical crystals). This exhibits excellent antithrombotic properties.

Here, spherulite refers to the form of a polymer that grows fibrils around a nucleus and is crystallized into a single spherical shape, and when observed with an electron microscope (SEM), protrusions of a hemispherical or similar shape are observed. It appears as.

The principle by which excellent antithrombotic properties are obtained by forming spherulites is not clear, but it is presumed that it is because the arrangement of crystalline and non-crystalline parts is arranged, resulting in a clear microphase-separated structure. .

The average diameter of the spherulites is not particularly limited, but is 0.5 to 50-
It is preferable that Moreover, it is preferable that the height is 0.1 to 5-.

In order to form such spherulites on the surface, it is preferable to do the following.

In order to form spherulites by molding, it is preferable to cool slowly after melting. In this case, gas, water, etc. are used for cooling, but considering that gases may oxidize,
Oxygen-free is preferred. In addition, when water is used as a medium, 80
Preferably, the temperature is between 5°C and 5°C.

The polymeric material of the present invention has excellent moldability, exhibits extremely good mold releasability during various moldings, and does not cause peeling of molded pieces.

The material of the present invention has a high compatibility between the polyether component and the nylon component, and therefore has excellent strength.

It also exhibits extremely high tensile strength, bending strength, and impact strength.

Furthermore, it exhibits good antithrombotic properties.

Therefore, the medical device using the polymeric material of the present invention is applied to a component of an extracorporeal blood circulation circuit. The components of this circuit include various tubes such as blood feeding tubes and pump tubes, different diameter connectors for connecting tubes, arterial and venous insertion catheters, gas exchange membranes and dialysis membranes of artificial organs such as artificial lungs and artificial kidneys H, Examples include bubble traps, blood bags, chambers, mixed injection ports, centrifugal pumps, etc.

In addition, we also provide blood transfusion and other equipment such as artificial blood vessels, artificial hearts, intravascular indwelling catheters, catheters that house pacemaker lead wires, etc., as well as syringes, blood collection tubes, blood bags, and their accessories. It can also be applied to blood sampling instruments.

Furthermore, it can be used as an adsorbent for biological substances and as a bioadhesive material.

In addition, the molded product of the polymeric material of the present invention includes reinforcing materials such as glass fiber and carbon fiber, core materials such as clay, silica, alumina, silica alumina, silica magnesia, glass peas, graphite, and gypsum, and dyes and pigments. Well-known additives such as , antistatic agents, and antioxidants can be used within a range that is not harmful in practical terms.

<Examples> Hereinafter, the present invention will be explained in more detail with reference to Examples.
The present invention is not limited to these examples.

The physical properties of the test pieces described in Examples and Comparative Examples were measured according to the following method.

1) Tensile test; compliant with ASTM D638 2) Bending test;
Based on ASTM D 790 Ni'J 3) Izot impact test; Based on ASTM D256 4) Relative viscosity: Determined at 1% concentration in m-cresol using an Ubbelohde viscosity tube (30''C).

5) Moldability The state of peeling of the molded piece from the mold during injection molding is visually judged. If the mold release property is good, the molded piece can be easily removed from the mold, but if the mold release property is poor, the resin itself will be pulled off or the resin will remain in the mold.

Examples 1 to 5 The polyamide raw materials listed in Table 1.2 were placed in a 200°C autoclave, sealed in a N2 atmosphere, heated to 250 to 260°C under constant pressure (10 kg), and stirred for 2 hours. The reaction was carried out under pressure.

After this, the modified polyether listed in Table 1.2 is added,
Further, a pressurized reaction was carried out for 2 hours while stirring. The pressure was gradually released to the predetermined pressure shown in Table 1.2, and the reaction was carried out under reduced pressure for 2 hours.

After polycondensation, wash the pellet with a large amount of hot water for 50 minutes.
Repeatedly.

The stirring was stopped, N2 was introduced to restore the pressure to normal pressure, and the mixture was extracted as a strand and pelletized.

After drying the pellet thus obtained, the resin temperature was 240°C and the mold temperature was 60°C using a 3.6 oz injection molding machine (manufactured by Toshiba Machine ■) and a test piece mold specified by ASTM. The material was molded and various physical properties were investigated.

Comparative Example 1.2 The polyamide raw materials listed in Table 2 were placed in a 200°C autoclave, sealed in a N2 atmosphere, and maintained at a constant pressure (10 kg).
), the temperature was raised to 250-260°C, the reaction was carried out under pressure for 2 hours with stirring, and then the pressure was gradually released and the temperature was raised to 250-260°C under reduced pressure (700 torr).
) The reaction was carried out for 1 hour. After adding the polyether and esterification catalyst listed in Table 2, the pressure was gradually released to a predetermined pressure, and the reaction was carried out under reduced pressure for 8 hours.

The same operations as in Examples 1 to 5 were performed below.

These results are shown in Table 1.2.3.

In addition, in Table 1.2, the raw materials used are as follows.

Diaminopolypropylene oxide (Jeffamine D-2000, manufactured by Jefferson Chemical Company) H2N(-CH,CH20(,0-)T(α2),-N
l(.

(Molecular weight 2000) Bis(3-aminopropyl)polytetrahydrofuran [
manufactured by BASF] 82N-1-(:H,), (-C1(2CH2CH2
CH70÷o(CH2) 3-NH2 (molecular weight 2000
) Polytetrahydrofuran [Mitsubishi Kasei Corporation 27MG20
00] HO(-CI(, CH201201,0 or-(molecular weight 2
000) Polypropylene [manufactured by Mitsubishi Kasei Corporation] Sebacic acid HOOC + CH2), t-C0OH Azelaic acid HOOC (-CH2), -COOH Adipic acid HOOC + CHz) s-COOH ε-caprolactam is different from Comparative Example 1 due to the absence of an ester group. -3, the presence of an ester group was confirmed.

In addition, in Table 3, the molecular weight is determined from the amount of terminal NH2 and C02H.
It was estimated to be between 18,000 and 28,000.

In addition, the ratio of carbon, hydrogen, and nitrogen was determined by elemental analysis measurement, and the polyether content was measured.

Furthermore, when the surfaces of these samples were observed using an electron microscope, the diameters ranged from 0.5 to 50. o, a, spherulites with a height of 0.1 to 5.0 were observed.

Note that FIG. 1 shows the surface state of Example 10.

In addition, from the results of TIR, the effects of the present invention are clear from the results shown in Tables 1 to 3 for Examples 1 to 5.

Test example 1 Platelet dilatation test was conducted by the following method.

First, samples A to C were prepared as base material samples.

A: Polypropylene film B: EVAL FILM C: Film of Example 1 In addition, the dimensions of each sample A to C are 8×8 mm.

Next, 20011j of PPP prepared to have a platelet count of 105/++j as a specimen was dropped onto each sample, left at room temperature for 30 minutes, and fixed with glutaraldehyde.

After washing and drying, the number of adherent platelets and morphological classification (1, n, ■) were calculated by electron microscopic observation.

<Morphological classification> ■・Disc shape in normal state■: It has become spherical from the normal state but has not deformed to the point where it produces pseudopods■: It has elongated pseudopods Table 4 I II III Total A (Comparison ) 5 2 115 122B
(Comparison) 5 12 16 33C
95519 As is clear from Table 4, Sample C of the present invention has a smaller number of adherent platelets and less morphological change than Samples A and B, which are comparative examples.

Note that the same results as C were obtained for Examples 2 to 5 as well.

Test Example 2 In the same manner as Test Example 1, a platelet diastolic ability test was conducted using the following samples.

D. Sheet E with no rare item formation in Example 1: Sheet of Example 1 (with rare item formation) table
5 I II I total D 7 3 36
461 2 12
15. In preparing the sample, molding was performed as follows, and spherulites were not formed.

D is a heat press machine, and molding E is at 240℃.
Spherulites can be formed by press molding.

The surface conditions of samples E and D are shown in Figures 1 and 2, respectively.
As shown in the figure. In FIG. 2, it can be seen that there is no formation of spherulites.

Effect〉 The polymer material of the present invention exhibits extremely excellent antithrombotic properties.

In other words, the adhesion of platelets to the material surface is extremely low.
It was also observed that no morphological change of adherent platelets occurred.

Similar results are also obtained for lymphocytes in the blood.

Furthermore, since the bond between the polyether part and the polyamide part is an amide group, there is no macroscopic phase separation structure that occurs when they are combined with an ester group, and they exhibit high mechanical strength and physical properties necessary for manufacturing processing. In addition to being promising, it also has high stability for long-term implantation in vivo.

[Brief explanation of drawings]

Both FIGS. 1 and 2 are photographs substituted for drawings showing the crystal structure. Figure 1 is an electron micrograph (2000x magnification) showing the state of the surface of the polymer material of the present invention with spherulites formed on the surface.
It is. FIG. 2 is an electron micrograph (2000x magnification) showing the state of the surface of the polymer material of the present invention on which no spherulites are formed. Applicant Teru Doshin Technical Agent Patent Attorney Patent Attorney Mo Co., Ltd. Yomasu Taniishi 1) Engraving of Tatsuya's drawing G, 10 +tn] ■ C1, -f-M *m JE 'il' (g rishiheisei)
May 16, 2018

Claims (2)

[Claims] (1) It has a repeating structural unit represented by the following structural formula (I) or (II), the content of polyether repeating units is 5 to 75 wt%, and the terminals are -NH_2 and /
or -COOH.An antithrombotic medical polymer material. Structural formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Structural formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the above structural formula (I) or (II), R^1,
R^2 and R^3 each represent a straight chain or branched alkylene group having 2 to 4 carbon atoms, and R^4 and R^5 each represent a straight chain or branched alkylene group having 2 to 22 carbon atoms. where n is 0 to 180,
m is 1 to 400, and p is 0 or 1. ) (2) An antithrombotic medical device which is a molded article of the polymeric material according to claim 1.