JPH0224543B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to anticoagulant materials. BACKGROUND ART Anticoagulant materials are in demand as constituent materials for medical equipment used in direct contact with blood, such as artificial organs, artificial blood vessels, and blood transfusion devices. Various polymeric materials have been proposed as such materials, and some of them have been put into practical use, but the conventional materials still have insufficient anticoagulability, low durability, and However, there were disadvantages such as poor mechanical strength, stiffness, and difficulty in molding. In addition, there are few examples of research on materials that have anticoagulant properties and have special functions for specific purposes. For example, there are no reports regarding materials with anticoagulant properties and high gas permeability intended for membranes for oxygenators. The present inventors have conducted intensive research based on the recognition of the above problems, and have found that a segmented polymer having a specific structure and containing an organopolysiloxane segment and a fluorine-containing segment has anticoagulant properties and durable mechanical properties. It has been found that the material has excellent mechanical strength and moldability, and can also be made into a material with high oxygen permeability by adjusting the siloxane content. Thus, the present invention has been completed based on the above findings, and provides a novel anticoagulant material comprising a segmented polymer in which organopolysiloxane segments and fluorine-containing segments are regularly incorporated into the main chain. It is something. In the present invention, it is important that the segmented polymer consists of an organopolysiloxane segment and a fluorine-containing segment, and that both segments are regularly incorporated into the main chain. Such segmented polymers exhibit excellent anticoagulant properties due to their microphase-separated structure, excellent durability and biocompatibility due to the contribution of fluorine-containing segments, and excellent oxygen permeability due to the contribution of organopolysiloxane segments. It becomes a great material for sex. It also has advantages in terms of molding, such as excellent solvent solubility and ease of application using coating methods.
Furthermore, it has excellent mechanical strength. On the other hand, even if a polymer has organopolysiloxane segments, it is difficult to form a microphase-separated structure in a polymer that is not regularly incorporated into the main chain, such as a graft copolymer, and its anticoagulant properties are reduced. Not only is it insufficient, but it is also inferior in terms of durability, mechanical strength, etc. In addition, when fluorine-containing segments are not included, durability and biocompatibility are inferior,
If it does not contain an organopolysiloxane segment, it is not preferable because it will be inferior in terms of oxygen permeability and the like. In the present invention, the segment polymer includes radical polymerization of vinyl compounds, ionic polymerization,
Coordination polymerization or polycondensation of difunctional monomers,
Products obtained by various methods such as polyaddition and ring-opening polymerization of epoxide etc. can be used, but the arrangement of the organopolysiloxane segment and the fluorine-containing segment is completely regulated.
Since it is possible to obtain the desired polymer with good reproducibility, polycondensation is performed by applying a chain extender to a prepolymer in which organopolysiloxane segments and fluorine-containing segments are regularly arranged. Polyadducts or polyadducts can be preferably employed. Bonding modes in such suitable segmented polymers include polyurethane, polyurethaneurea, polyurea, polyester, polyamide,
Various forms such as polyamide-imide, polyimide, polycarbonate, and polyether sulfone types can be adopted, but polyurethane, polyurethane urea, and polyurea types are preferable from the viewpoint of polymer durability, mechanical properties, and biocompatibility. The mode of attachment is preferred. Furthermore, it is possible to introduce an oxyalkylene chain as a third segment in order to impart hydrophilicity to the polymer and increase its strength. The oxyalkylene chains are preferably introduced into the polymer by being regularly arranged with fluorine-containing segments instead of organopolysiloxane segments. Such segmented polymers contain as repeating units (a) (-RNHCONHCH ₂ R _f CH ₂ NHCOO-A-OCONHCH ₂ R _f CH ₂ NH
CONH)− and () (b) (−RNHCONHCH ₂ R _f CH ₂ NHCOO−B−CONHCH ₂ R _f CH ₂ NHC
ONH）− (a) (−R−OCONHCH ₂ R _f CH ₂ NHCOO−A−OCONHCH ₂ R _f CH ₂
NHCONH)− and () (b) (−R−OCONHCH ₂ R _f CH ₂ NHCOO−B−CONHCH ₂ R _f CH ₂ N
HCONH)− (a) (−RNHCONHCH ₂ R _f CH ₂ NHCONH−A−NHCONHCH ₂ R _f CH ₂
NHCONH)− and () (b) (−RNHCONHCH ₂ R _f CH ₂ NHCOO−B−CONHCH ₂ R _f CH ₂ NHC
ONH)- and the like are exemplified, among which those represented by the general formula () are particularly suitable from the viewpoints of durability, mechanical properties, availability of raw materials, etc. In the above general formula, R is pear or a divalent organic group having 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, specifically ( _-CH2 ) _-1 (1=1 to 10),

Examples include those represented by [Formula] or -CH ₂ (-CF ₂ )- ₁ CH ₂ -.
Further, Rf is a barfluoroalkylene group having 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, and 0 to 10 ether bonds, preferably 0 to 4 carbon atoms, specifically (-CF ₂ )-
₁ , −CF ₂ CF ₂ OCF ₂ CF ₂ −, CF ₂ CF ₂ O (CF ₂ ) _o
OCF ₂ CF ₂ −(n=1 to 5), −CF(CF ₃ )O(CF ₂ ) _o
OCF (CF ₃ ) - or -CF ₂ CF ₂ OCF ₂ CF (CF ₃ )
Examples include O( _CF2 ) _oOCF ( _{CF3 ) CF2OCF2CF2- .} In the above general formula, A is (However, P and Q are alkylene groups having 1 to 10 carbon atoms, and R ¹ , R ² , R ³ and R ⁴ are 1 to 3 carbon atoms.
represents an alkyl group or a substituted alkyl group, and n is 1 to 50), and is a divalent organic group containing an organopolysiloxane segment. On the other hand, B is the molecular weight
It has an oxyalkylene chain of 40 to 10,000, preferably 400 to 4,000, but one or more ester bonds, aromatic rings, or some fluorine-containing alkylene groups may be introduced. Specifically, ( _-CH2CH2O ) _-p (p ₌ 8 to 70),
(−CH ₂ CH ₂ CH ₂ CH ₂ O) − _q (q=5 to 42), [−CH
(CH ₃ ) CH ₂ O] − _r (r = 6 to 54), (−CH ₂ CH ₂ O) − _a
[CH (CH ₃ ) CH ₂ O] − _b (CH ₂ CH ₂ O) − _c (a, c=
1 to 5, b=4 to 50), [ _-CH2CH2OCO ( _{CH2 ) s}
COOCH ₂ CH(CH ₃ )O〕 _−t (s=1~5, t=2
~30) or (u=2 to 30), etc. can be exemplified. Further, it is desirable that the polymer contains (a) and (b) in a molar ratio of 1:0 to 1:20. In the present invention, the molecular weight of the segmented polymer is determined to be 0.5 g/concentration in dimethylformamide from both the solvent solubility and mechanical properties of the polymer.
dl, the intrinsic viscosity (ηinh) measured at a temperature of 30℃ is
It is preferably about 0.1 to 1.5 dl/g, particularly about 0.2 to 0.9 dl/g. The fluorine-containing block polymer of the present invention can be produced by various methods as described above, but as an example, a polymer having a repeating unit of the general formula () has the general formula (a') OCN-CH ₂ R _f CH ₂ NHCOO−A−OCONH−CH ₂ R _f CH ₂ NC
(a'), (b') represented by O and (b') OCN-CH ₂ R _f CH ₂ NHCOO-B-CONHCH ₂ R _f CH ₂ NCO (where Rf, A, and B are the same as above) The general formula H ₂ N is added to the fluorine-containing diisocyanate containing in a molar ratio of 1:0 to 1:20.
It can be produced by reacting with a diamine represented by -R-NH ₂ (R is the same as above). The anticoagulant material of the present invention can be used as a single raw material by directly forming it into a tube, film, sheet, or complex-shaped product by extrusion, rolling, casting, dipping, injection molding, or other methods. It is also possible to use it as a covering material by applying it to various pre-formed polymer materials, glass, metals, ceramics, etc. Next, the present invention will be explained in more detail with reference to Examples. In each Example, the evaluation of anticoagulability was
The method was based on the method proposed by RILee and PD White [Am.J.Med.Sci., 145 , 495 (1913)]. That is, the segment polymer is 50μm
Pour 1 ml of fresh goat blood into two test tubes with an inner diameter of 10 mm coated on the front and back. After 3 minutes, tilt one test tube every 60 seconds, and when the blood stops flowing, pour the other test tube. Perform the same operation on the test tube, and the end point is the point at which the blood in the test tube no longer flows even when the test tube is gently completely reversed. The time required was defined as the blood coagulation time. In addition, the test tubes in which the blood had coagulated were centrifuged, and the color tone of the upper layer was observed to determine the presence or absence of hemolysis. Furthermore, the tensile breaking strength and elongation of the segmented polymer were approximately
Measurements were made using a 300μ thick film as a test piece. Gas permeability was measured using a Seikagaku-style gas permeation measuring device using a 50-80 μm thick membrane as a test piece. Example 1 Capacity with thermocouple, stirrer and reflux tube installed
in a 200 ml three-necked flask under nitrogen atmosphere. (average molecular weight: 1250) 9.31 g (7.45 m
mol), 45 ml of n-butyl acetate and 2,2,3,
3,4,4,5,5-octafluorohexamethylene diisocyanate [OCNCH ₂
(CF ₂ ) ₄ CH ₂ NCO] 4.65 g (14.9 mmol) were charged in this order. Heat in an oil bath to adjust the solution temperature.
By keeping it at 120℃ and stirring for 3 hours, cooling it to room temperature. An n-butyl acetate solution of a prepolymer having the following structure and having m as 1 as a main component was obtained. To the prepolymer solution obtained above, while stirring, 0.45 g (7.5 mmol) of ethylenediamine dissolved in 80 ml of n-butyl acetate was added dropwise at such a rate that the solution temperature was maintained below 15°C. At the end of the dropwise addition, a viscous and slightly cloudy solution was obtained. After further stirring at room temperature overnight, the solvent was distilled off under reduced pressure. The dried polymer was washed with ethanol and ion-exchanged water in that order, then vacuum-dried at 40℃, purified by reprecipitation method, and vacuum-dried again at 40℃ overnight to obtain 10.37g of white purified polymer. (yield 72%). The intrinsic viscosity (ηinh) of the thus obtained polymer measured in N,N-dimethylformamide at a concentration of 0.5 g/dl at 30°C was 0.20 dl/g. Also,
The oxygen permeability coefficient P (O ₂ ) is 28×10 ^-9 cc-cm/sec-cm ²
-cmHg, carbon dioxide permeability coefficient P (CO ₂ ) is 160×
10 ^-9 cc−cm/sec−cm ² −cmHg, and Lee−
Blood coagulation time by White method was over 60 minutes. Example 2 The amount of the organopolysiloxane bond-containing diol used in Example 1 was 4.66 g (3.73 mmol), and 4.02 g of polytetramethylene glycol (PTG200 manufactured by Nippon Polyurethane Industries: average molecular weight 1079) was added.
The same operation as in Example 1 was carried out except that (3.73 m mol) was mixed and used, and 10.47 g of white purified polymer was obtained.
(yield 76%). ηinh was 0.33 dl/g, tensile strength at break was 70 Kg/cm ² , and elongation was 480%. Also, P(O ₂ ) and P(CO ₂ ) are each 5.7×
10 ^-9 cc−cm/sec−cm ² −cmHg and 37×10 ⁻⁹ cc−
cm/sec- ^cm2 -cmHg, indicating good anticoagulability. Examples 3-5 Organopolysiloxane bond-containing diol and
A white purified polymer was obtained in the same manner as in Example 1 except that the ratio of PTG200 was changed. The results are summarized in Table 1. In addition, in all of Examples 1 to 5, the formation of a microphase-separated structure with a domain size of approximately 20 Å was observed, and no hemolysis after completion of coagulation was observed in any of them.

【table】

Claims (1)

[Scope of Claims] 1. An anticoagulant material comprising a segmented polymer in which organopolysiloxane segments and fluorine-containing segments are regularly incorporated into the main chain. 2. The material according to item 1, wherein the segmented polymer contains an oxyalkylene chain in the main chain as the third segment. 3. Material according to paragraphs 1 and 2, in which the segmented polymer has a bonding mode selected from polyurethane and polyurethaneurea types. 4 The segmented polymer is (a) -RNHCONHCH ₂ R _f CH ₂ NHCOO-A-OCONHCH ₂ R _f CH ₂ NHCO
NH− and (b) −RNHCONHCH ₂ R _f CH ₂ NHCOO−B−CONHCH ₂ R _f CH ₂ NHCON
H- (However, R is pear or a C ₁ to C ₂₀ divalent organic group, R _f is a C ₁ to _{C 20} perfluoroalkylene group with 0 to 10 ether bonds, and A is [However, P and Q represent an alkylene group having 1 to 10 carbon atoms, R ¹ , R ² , R ³ and R ⁴ represent an alkyl group or substituted alkyl group having 1 to 3 carbon atoms, and n is 1
50], and B has a molecular weight of 40 to 10,000
(representing an oxyalkylene group) as a constitutional unit, and the material is contained in a molar ratio of (a):(b)=1:0 to 1:20. 5. The material according to item 4, which has good oxygen permeability and has an organopolysiloxane segment content of 10 to 80% by weight of the polymer. 6. The material of claim 5, wherein the organopolysiloxane segment content is from 40 to 70% by weight of the polymer.