JPS587254A - Selective separation film having anti- coagulation property of blood and production thereof - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a selective separation membrane having anticoagulant properties and a method for producing the same.

In recent years, many polymeric materials have been used in medical instruments. There are also examples, such as artificial kidneys, where the performance of organic polymer membranes is effectively utilized. On the other hand, things related to blood, such as heart-lung machines, F! Since membrane materials are required to have anticoagulant properties, no membrane material with sufficient performance has been found so far. For example, polyvinyl chloride, polyethylene, polyfluoroethylene, polyester-polyether block copolymers, polyamide, polyurethane, etc. are used in blood-related devices such as artificial blood vessels, blood bags, and auxiliary blood circulation devices. . However, these are not very good in terms of anticoagulant properties and toxicity; the present inventors found that they have good anticoagulant properties and are nontoxic.

As a result of repeated research to obtain a polymer material that is easy to mold and inexpensive, a specific composition has been discovered and proposed. (Patent application 1986-23760.Patent application 1984-24504
) A polymeric material having a specific composition, a polynisdel-polyether block copolymer and/or a segmented polyether urethane urea and a silicone resin are uniformly dispersed in a microphase-separated platform. It is.

The present invention is to manufacture more useful products using the above-mentioned polymeric materials. Specifically, one purpose is to manufacture an oxygen supply membrane useful for heart-lung machines.

Heart-lung machines currently use a method of blowing air into the blood. However, this method poses a problem of blood aging. Therefore, we use an oxygen-enriching membrane to efficiently add oxygen to the blood in a short time.

Methods of returning it to the body are being considered. Cellulose acetate, polysulfone membranes, and the like are known as these oxygen-enriching membranes. However, as mentioned above, these membrane materials
In terms of anticoagulant properties and toxicity.

The present inventors have discovered that the surface K of the homogeneous membrane or asymmetric porous membrane of the polymeric material having an oxygen enrichment effect, the polyester/polyether block copolymer and/or the segmented polyether urethane urea and the silicone resin By forming a homogeneous thin film of a material in which the We succeeded in obtaining a membrane useful for this purpose. Moreover, since the composition has a gas separation function,
It can also be applied to asymmetric porous membrane buttons with low oxygen enrichment function.

The polyester/polyether block copolymer used in the composition of the present invention is a block copolymer of linear polyester segments and polyalkylene ether segments. (b) at least one low molecular weight glycol or an ester-forming derivative thereof, and (c) at least one poly(alkylene oxide) glycol or an ester-forming derivative thereof (and K Therefore, it can be made.

Examples of the low molecular weight dicarboxylic acids include terephthalic acid, isophthalic acid, m s aromatic dicarboxylic acids such as 1,2-bis(p-carboxyphenoxy)methane, or adipic acid, decapacic acid, azefinic acid, 1, Examples include aliphatic dicarboxylic acids such as 4-cyclohexanedicarboxylic acid and dimer acid.

Ester-forming derivatives of these can also be used.

-Among the low molecular weight dicarboxylic acids forming the RK polyester segment, aromatic dicarboxylic acids are superior in mechanical strength, elasticity, etc. as molded articles (artificial organs and other medical devices) made from the composition of the present invention. It is preferable because you can get something.

Note that an aliphatic dicarboxylic acid may be used in combination if desired.

Examples of the low molecular weight glycol forming the polyester segment include Kliful having 2 to 8 carbon atoms, specific Kl-t ethylene glycol, fluoropylene gelylcol, and tetobumethylene glycol.

Examples include neopentyl glycol, V-chlorohexane dimetatool, and the like. Ester-forming derivatives of these can also be used. Among these, ethylene glycol and tetofumethylene glycol are preferred because they improve the mechanical strength and heat resistance of molded articles formed from the composition of the present invention.

Also, as a poly(alkylene oxide) glycol that forms a polyether segment.

The ratio of treated element to oxygen is preferably about 2.5 to 4.3,
Although those outside this range may be used, polyester-polyether block copolymers generally formed with a molecular weight of less than 2.5, and thus those within the above range formed from the composition of the present invention, are preferred. Specific examples include poly(tetramethylene oxide) glycol, random or block copolymers of ethylene oxide and 1,2-propylene oxide, and the like. These poly(alkylene oxide) glycols preferably have a number average molecular weight of 600 to 6,000 and are green.

800-3000 is more preferable. Anything outside this range can be used, but if it is smaller than this range.

This is not preferable because it loses its performance as an elastic body, and if it becomes too large, it becomes difficult to form a polyester/polyether block copolymer, and it tends to have no elastic recovery. The content of polyether in the polyether/polyether block copolymer is from 5 to 85 tlb by weight, preferably from 20 to 80 tlb by weight. If the amount exceeds the above, the melting point of the polyester/polyether block copolymer will decrease, making it impractical, while if the amount is too low, it will lose its elasticity, making it hard and brittle, which is not preferable.

The segmented polyether urethane urea used in the composition of the present invention has a molecular weight of 500 to 3000 (preferably H
Terminals obtained by reacting polyalkylene diols such as polytetramethylene glycol, polypropylene glycol, and/or polyethylene glycol/polypropylene glycol (preferably polytetramethylene glycol and/or polypropylene glycol) with diisocyanates of 1000 to 2000 Obtained by chain-extending isocyanate prepolymers with diamines.

The above diisocyanates include 2,4'-)V diisocyanate%4,4'-diphenylmethane diisocyanate), 4,4'-diphenylpropane diisocyanate, xylylene diisocyanate, phenylene diisocyanate, naphthalene diisocyanate, ethylene diisocyanate, butylene diisocyanate. , hexamethylene diisocyanate, cyclohexylene diisocyanate, and 4,4'-dicyclohexylmethane diisocyanate, preferably #
i4. Aromatic diisocyanates such as 4'-diphenylmethane diiso V-anate and tolylene diisocyanate.

In addition, the above diamines include ethylenediamine,
1.2-propylene diamine, 1.3-propylene diamine, butylene diamine, benchlene diamine, cyclohexyne diamine, hexamethylene diamine,
4.4'-Aliphatic diamines and phenylenediamines such as diaminodiV-chlorohexylmethane, 4.4'-
Aromatic diamines such as diaminodiphenylmethane and quinolidendiamine can be used. However, it is preferred that at least 60 moles of the diamine used be ethylene diamine and/or 1,2-propylene diamine. In some cases, aliphatic diols having 2 to 15 carbon atoms, such as ethylene glycol, propylene glycol, butanediol, and hexanediol, may be used in place of a portion of the diamine as long as the total chain extender is less than 40 mol. good.

Segmented polyether urethane urea #i, which is one component of the composition of the present invention, contains the above polyoxyalkylene diol and diisocyanate in a ratio of 1/1.3 to 1/3.0.
(molar ratio), preferably t-j: 1/1.5-1
A prepolymer having isocyanate groups at both ends is synthesized at a ratio of /2.5 (molar ratio), and this is dissolved in a solvent that does not react with isocyanate groups such as dimethylformamide and/or dimethylacetamide. The silicone polymer used in the present invention is obtained by chain-extending with diamines, reacting with a primary or secondary monoamine, or a #-11 monovalent low molecular weight alcohol to terminate the chain. , woody general formula (wherein R1 and R3 are an alkyl group or an aryl group.

Each represents an alkenyl group and a halogenated hydrocarbon group.

) Consists of diorganosiloxane units represented by: R
The alkyl group represented by 1tRl includes, for example, a methyl group,
There are ethyl groups, propyl groups, aryl groups such as phenyl groups, and alkenyl groups such as vinyl groups,
For example, halogenated hydrocarbon groups include 3,
3.3- There is a trifluoroprobyl group.

A common diorganopolysiloxane consisting of units represented by the above general formula (I) is dimethylpolysiloxane, and other materials such as methylphenylpolysiloxane and methylvinylpolysiloxane are also used. It is preferable that the dimethylsiloxane unit in the product is 70 molti or more.

The silicone polymer used in the present invention can be used in the form of a soluble high molecular weight silicone rubber. In this case, it is also possible to use a room temperature vulcanization type that is crosslinked to become rubber-like. In this case, the diorganopolysiloxane with terminal silanol groups and R"5iXs as a crosslinking agent
(Here, Rs is the same group as R1 and R1 above, or #
'ix, and X represents an alkoxy group such as an acetoxy group, a methoxy group, or an ethquin group, or a hydrolyzable group such as an oxime group. ) can be made by reacting.

Furthermore, vinyl group-containing diorganopolysiloxanes and methylhydrodiene polysiloxanes are platinum-catalyzed. Furthermore, it can also be produced by radically crosslinking methylvinylpolysiloxane in the presence of an organic peroxide such as benzoyl peroxide or dicumyl peroxide.

The molecular weight of the silicone polymer is not particularly limited, but it is preferable to use a molecular weight of 100 CS (centistokes) or more.

In the composition of the present invention, a polyester-polyether block copolymer and/or a 4C5/licone polymer (B) in a segmented polyether urethane urea (A)
) must exist in a microphase-separated state,
Generally, the above (A) has a weight of 70 to 99 qb1, preferably Vi
From the viewpoint of blood compatibility and physical properties of the final product, a ratio of so to 97% by weight and (B) of 30 to 1% by weight, preferably 20 to 3% by weight, is preferable.

Further, the composition of the present invention includes a silicone polymer in the polyester/polyether block copolymer and/or segmented polyether urethane urea phase, and has a weight average particle size of 0.01 to 20 microns.

Preferably, the temperature is 0.05 to 5 microns to cause microphase separation and uniform dispersion. In order to form such a dispersed state, it is preferable to mix the above-mentioned seven peripheral components in their respective solutions and use them as a complete solution or a finely dispersed solution. Examples of solvents that dissolve or finely disperse the surrounding components include one or more selected from dimethylacetamide, dimethylformamide, dimethylsulfoxide, hexamethylphosphoamide, methylene chloride, chloroform, and tetophhydrofuran. A mixed solvent with one or more selected from , dioxane, etc. may be mentioned.

Regarding the homogeneous membrane, symmetrical or asymmetrical porous membrane used as a support in the present invention, there are no particular restrictions on the type of polymer material, membrane shape, membrane thickness, etc. However, asymmetric porous membranes having a homogeneous surface layer made of cellulose acetate, polysulfone, polyester, polyamide, etc. are particularly effective. Furthermore, it is more effective for these supports to have a hollow fiber shape in view of miniaturization of the device, efficiency of oxygenation to blood, and the like.

A thin film of the composition is composited onto the support.

As a method, it is possible to adhere a thin film of the composition prepared in advance onto the support by a method such as thermocompression bonding, but it is also possible to apply a solution of the composition onto the support and dry it. However, it is possible to easily combine Km.

In this case, the solution concentration is preferably about 0.1% to 10% by weight. As the solvent, the solvents listed in 1IfJ can be used, but depending on the type of support, the solvent may be diluted to near the cloudy point with a solvent that does not dissolve the polymer material serving as the support, such as methanol.

The composite membrane thus obtained is very useful, especially as a selective separation membrane for heart-lung machines.

The effects of the present invention will be explained below with reference to Examples, but the present invention is not limited thereto.

The anticoagulant and toxicity tests were evaluated according to the methods described below.

Anticoagulant properties were evaluated using the circumferential kinetic method of Imai et al.
Biomed, Mater, Re5-L 165 (
1972)) as follows. That is, a film with a thickness of 100 μm was cut into three squares, and it was attached to the surface of a watch glass with a stopper.
250 ml of blood was placed therein, and 25 μj of a 0.1 M calcium chloride aqueous solution was added to initiate a blood coagulation reaction. 37
After 12 minutes of contact at °C, water was added to stop the coagulation reaction, and the resulting clot was fixed with formalin. After removing moisture using F paper, the weight is measured using a chemical balance. A similar operation is carried out using only a glass watch glass, and the amount of blood clot produced is set as 100, and the anticoagulability is evaluated based on the relative weight (coagulation rate) to this.

Furthermore, Imai et al. [Artificial Organs 9, 260 (198
0)) The initial cell adhesion rate in cell culture tests is related to platelet adhesion9. Although it has been stated that the smaller the size, the more antithrombotic properties are expected, a similar test was conducted for the material of the present invention. That is, 9X9cI11 was added to the Lab-TeK cell culture chamber/spheroid (8 chambers).
Insert a film sample with a thickness of 100μ.

After irradiation with a germicidal lamp for 3 hours, a cell suspension containing 20% calf serum (Ca cell line derived from human gingival cancer) was prepared.

9.22) 0.3g/ was added and cultured in a carbon dioxide incubator at 37°C for 16 to 18 hours. After culturing, the cells were briefly washed twice with phosphate buffer, stained with 0.5% tigristal violet (CV) for 3 minutes, and washed with water for 7 minutes.

The dyed sheet was placed in a bottle containing 1% sodium dodecyl sulfate (3851) and Cv was extracted.

The absorbance at *598 nin was measured using a spectrophotometer to quantify the concentration of CV. It is known that the concentration of Cv and the number of cells are proportional.

Y, et al, Trans, Amer-5oe, A
rtif, Intern. Qrgans.

25 (1979)) The initial adhesion rate was determined from the concentration of CV using the following equation.

Note that a plastic sheet for cell culture (Wako Pure Chemical Industries, Ltd.) was used as a control sample.

Example 1 97 parts of dimethyl terephthalate, 68 parts of tetramethylene glycol and 0.3 parts of tetra-n-butyl titanate
5 parts were charged into a transesterification reactor, heated while stirring,
The internal temperature was raised from 140°C to 225°C in 60 minutes to carry out the transesterification reaction.

Thereafter, 0.7 parts of a commercially available antioxidant (trade name Ionox 330) and an average molecular weight of 2000 were added to the reaction mixture.
poly(tetramethylene oxide) glycol 251
After adding 1 part, the mixture was transferred to a polymerization reactor.

Anti-F) While increasing the temperature of the mixture from 225°C to 245°C, gradually reduce the pressure KL, 0.1111 in 35 minutes.
KL was 1 Hf or less, and the polymerization reaction was further carried out for 80 minutes under these conditions. The reduced specific viscosity of the polymer thus obtained is 2.
It was 15. 100 tons of this polymer was dissolved in 300 g of chloroform, and 20 tons of hydroxyl-terminated boridimethylsiloxane (viscosity 100,000 centistokes) was added to the solution.
? , Methyltriacetoxysifun0.6 fwo15 C
A solution of a5t in chloroform, and 0.06
Dioctyl-tin acid (F) was added and stirred well. After adding 250 d of chloroform, 1400 g of methanol/
was gradually added to obtain a homogeneous solution.

It was prepared in advance. The above-mentioned solution was uniformly applied to a 200 μ thick asymmetric porous membrane made of cellulose triacetate having a dense thin film layer on its surface using a spray, and then dried.

When the coated surface was observed under an electron microscope, it was found that the silicone resin was dispersed in the polyester/polyether block copolymer with an average particle size of 0.5 to 5 microns. The coagulation rate on this surface was 5696. The cell attachment rate Vi was 50%. In addition, the separation coefficient of oxygen from air (PO
s/PN s ) is 5.0. Oxygen permeability coefficient (POg)
Id: 8 x 10” CIA-ex/z, cj
-cxxHf.

Patent applicant: Toyobo; ★Madai Company

Claims (2)

[Claims] (1) A selective separation membrane having anti-blood coagulability consisting of membrane (A), membrane (B) and/or membrane (C). (A) Symmetrical or asymmetric porous membrane made of organic polymer material (B) Thin membrane in which polyester/polyether block copolymer and silicone resin are uniformly separated from each other in a state of microphase separation (C) Segment A thin film in which polyether urethane urea and silicone resin are uniformly dispersed in a microphase-separated state. (2) After applying a solution containing a polyester/polyether block copolymer and/or segmented polyether urethane urea and silicone resin to the surface of a symmetric or asymmetric porous membrane made of an organic polymer material, A method for producing a selective separation membrane having anti-blood coagulation properties, which comprises forming a homogeneous membrane by removing a solvent.