JPH1028727A - Medical material - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a medical material which restricts plasma leakage and moreover, offers a material for an artificial lung film having a sufficiently gas permeability performance while being usable for a medical apparatus contacting blood of an extracorporeal blood circulation device or the like. SOLUTION: A material employs as one component a high polymer epoxy resin produced by polycondensation of bisphenol fluoride (bisphenol AF or the like) and epoxyhalide (epichlorohydrine or the like) and is made dissolvable in an organic solvent such as DMSO or DMAc. The angle of contact with pure water is more than 90 deg. while the angle of contact with plasma is higher than the angle of contact with the pure water. Thus, the material thus obtained is excellent in the gas permeability performance and plasma leakage as non- symmetrical porous film for an artificial lung.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a medical material used for a medical device that can be brought into contact with blood, such as an in vitro blood circulation device. The present invention also relates to an asymmetric porous membrane for an artificial lung for oxygenating blood and removing carbon dioxide.

[0002]

2. Description of the Related Art Recent advances in medical technology have made it possible to treat heart diseases such as heart transplants, but such advanced open heart surgery requires an extremely long operation time. After surgery, extracorporeal circulation extends for a long time until the heart is removed from the heart-lung machine.

At present, a commercially available artificial lung used for open heart surgery uses a silicon homogeneous membrane or a porous membrane. The gas is exchanged by dissolving and diffusing gas molecules in the silicon homogeneous membrane, and thus the gas permeation amount is extremely small, and particularly, the carbon dioxide gas exchange ability is insufficient. In addition, polytrimethylsilylpropyne homogenous membranes, which have higher gas permeability than silicon homogenous membranes, and non-porous membranes made of fluorinated polyimide used for gas separation membranes, have a low gas permeability as an artificial lung membrane. It is enough. On the other hand, in the case of a porous artificial lung membrane,
Since gas exchange is performed through pores of about 2000 °, the gas permeation amount is large. However, in long-term extracorporeal circulation, pores of this size cause a so-called plasma leak in which blood cells do not pass but plasma does.

[0004] The cause of the above-mentioned plasma leak is closely related to the contact angle of the membrane material with the plasma. When the pores are regarded as capillaries as shown in FIG. 1, if the contact angle with plasma is 90 ° or more, the surface tension F acting between the pore walls acts in a direction to suppress the invasion of plasma.

[0005]

FIG.

However, during prolonged extracorporeal circulation, adsorption of plasma protein into the pores of the artificial lung membrane occurs, and the pore walls become hydrophilic. Therefore, a plasma leak occurs, the gas exchange ability is reduced, or replacement of the artificial lung membrane is required, and the burden on the patient is increased, healing is delayed, and it is difficult to withdraw from the heart-lung machine.

[0007] Various membrane materials have been tried to suppress plasma leak.

For example, polypropylene (PP, Japanese Patent Application Laid-Open No. 54-160098) and polytetrafluoroethylene (PTFE, Japanese Patent Application Laid-Open No.
No. 3) and poly (4-methylpentene-1) (PM
P, Japanese Patent Application Laid-Open No. 1-10427) and the like, a porous artificial lung membrane using a hydrophobic material has been studied. However, even when these materials are used, a porous membrane having a pore diameter of several hundred mm or more has a smaller diameter than the pore. In a long-term extracorporeal circulation, it was impossible to avoid a plasma leak because small plasma proteins penetrated into the pores.

On the other hand, an asymmetric porous membrane having a pore diameter of several hundred degrees or less (hereinafter asymmetric membrane) having a molecular weight cut-off of 10,000 to 5
About 10,000 ultrafiltration membranes are used for plasma proteins such as albumin and γ.
-It does not transmit globulin, so that plasma leak can be suppressed. Since the PP, PTFE, PMP, and silicone resin are not dissolved in general organic solvents, it is difficult to obtain an ultrafiltration membrane.
For example, polysulfone is relatively hydrophobic and has a D
MAc (N, N-dimethylacetamide) and NMP (N
-2-methylpyrrolidone), it is possible to produce an asymmetric membrane by wet membrane formation.

As an artificial lung using this asymmetric polysulfone membrane, a polysulfone asymmetric membrane having high gas permeability (Japanese Patent Laid-Open No. 61-119272) has been proposed. Can not be suppressed. For this reason, water from which high molecular weight components have been removed from the plasma by ultrafiltration may block the pores, and the gas exchange capacity of the oxygenator may be reduced.

As described above, in order to solve the problem of plasma leak, a material having a high hydrophobicity and a contact angle larger than that of the plasma is used as the membrane material, and the membrane has a pore size at which plasma proteins cannot enter the pores. There was a need for an asymmetric membrane. Further, not only in the heart-lung machine, but also in a hemodialysis machine, a blood transfusion or a blood collection machine, a blood circuit in which prevention of blood coagulation and suppression of complement activation are essential in order to maintain a therapeutic effect.

[0012]

SUMMARY OF THE INVENTION An object of the present invention is to provide an asymmetric membrane for an artificial lung and a peripheral material thereof, which suppresses plasma leak and has sufficient gas permeability.

[0013]

Means for Solving the Problems As a result of intensive studies, the present inventors have reached the present invention.

(1) A medical material soluble in an organic solvent characterized by having a contact angle with pure water of 90 ° or more and a contact angle with plasma higher than that with pure water. A medical material characterized by comprising a polycondensed, copolymerized or alloyed polymer of a bisphenol containing at least one or more bisphenols and a halogenated epoxy or dichlorodiphenyl sulfone. (3) An asymmetric membrane (1) The medical material according to (1) or (2), wherein the material surface is provided with biocompatibility.

[0015]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail.

Since plasma contains a protein component and a lipid component and has a surfactant effect, the surface tension is lower than that of water. Therefore, the contact angle of plasma is generally smaller than that of pure water, even for highly hydrophobic PTFE, silicone resin or polypropylene, and for highly hydrophilic material such as polyamide. On the other hand, the medical material of the present invention is characterized in that the contact angle of plasma or plasma protein with an aqueous solution is specifically higher than the contact angle of water.

An example of such a material is 2,2 wherein all the methyl groups of bisphenol A are trifluoromethylated.
-Bis- (4-hydroxyphenyl) -hexafluoropropane (hereinafter referred to as bisphenol AF), 1,3-bis (2-hydroxyhexafluoro-2-propyl) benzene, octafluorobiphenyl-4,4'-diol, bis ( High molecular weight epoxy resin (hereinafter referred to as 2,3,5,6, -tetrafluoro-4-hydroxyphenyl) ether, 3,3 ', 5,5'-tetrabromobisphenol AF and a bisphenol containing a fluorine atom and epichlorohydrin Fluorinated phenoxy resin).

These polymers are prepared by using common organic solvents such as DMAc, NMP, DMSO (dimethyl sulfoxide) or DMF (N, N-dimethylformamide).
Thus, it is possible to obtain an asymmetric membrane type artificial lung membrane having sufficient gas permeability and a small pore diameter.

The asymmetric membrane obtained from this polymer has the following advantages: (1) its ability to prevent the invasion of plasma is greater than that of a porous membrane of PP or PMP due to its small pore size, compared to a conventional porous artificial lung membrane; The inside of the pores is not hydrophilized because plasma proteins do not penetrate. (3) The contact angle with water is 90 ° or more.

As a method for producing an asymmetric film from the material of the present invention, any method can be used as long as it is a wet film forming method such as an evaporation method and an immersion method. In addition, as a molded product other than a film, a method such as injection molding, extrusion molding, compression molding, or the like is possible. It is also possible to modify the surface by coating or graft polymerization on the surface of various molded products.

The pore size of the obtained asymmetric membrane is desirably 100 ° or less, and more desirably 10 to 90 ° to prevent the permeation of plasma components. In order to improve gas permeation performance, it is preferable to add a salt, various low molecular weight compounds or high molecular compounds to the polymer solution to make the pore size uniform, or to lower the polymer concentration to increase the porosity.

In order to prevent plasma leakage from the pores, the contact angle with water must be 90 ° or more, and the contact angle with plasma must be larger. The contact angle with plasma is desirably 92 ° or more, and more desirably 95 ° or more. If it is at least 92 °, the adsorption of plasma proteins can be sufficiently suppressed. Further, the difference from the contact angle with water is desirably 2 ° or more,
More preferably, it is 5 or more. If it is 2 ° or more, the possibility of plasma leakage due to a decrease in the contact angle is reduced even if the adsorption of plasma protein occurs slightly in long-term extracorporeal circulation.

If the contact angle with water and plasma is 90 ° or more, a phenoxy resin and / or polysulfone containing no fluorine and a fluorinated phenoxy resin and / or fluorinated polysulfone are blended to control various physical properties. It is also possible to use a polymerized or alloyed product, or a polymer obtained by a polycondensation reaction from a mixture of a fluorinated bisphenol and a bisphenol containing no fluorine, and a halogenated epoxy or dichlorodiphenyl sulfone. Further, the contact angle can be further increased by copolymerizing with silicone, polyolefin, polyfluoroalkylene, or polyoxyfluoroalkylene, or by reacting a low molecular compound with a functional group such as a hydroxyl group, epoxy group or aromatic ring of a phenoxy resin.

Furthermore, a biocompatible compound or material is combined, mixed or coated with the material of the present invention to impart biocompatibility, and to suppress blood coagulation and complement activation, thereby enabling extracorporeal circulation. It is possible to reduce the burden on the body in. Therefore, biocompatibility can be imparted to the surface of the asymmetric membrane produced using the material of the present invention, which does not block pores or hydrophilize, on the side that comes into contact with blood. In addition to the heart-lung machine, the material of the present invention is applied to a filter, a housing, a blood port, a connector, a tube, a pump, etc. of a hemodialysis device, a blood transfusion device, a blood collection device, and other blood circulation devices, or a modification of an existing product. Is possible.

[0025]

Next, the present invention will be described in more detail by way of examples, but the present invention is not limited thereto.

(Example 1) USP 3,305,528
A polymer was prepared by the following method according to Example 1 described in Example 1.

8.41 g of commercially available bisphenol AF
(25 mmol), 2.31 g of epichlorohydrin
(25 mmol), 5.31 g of ethanol, 4.
0 g and 1.0 g (25 mmol) of NaOH were placed in a 50 ml three-necked flask equipped with a stirrer and a reflux condenser.
Stir at room temperature under nitrogen for 16 hours. USP3,305,5
According to the method described in Item 28, 0.15 g of NaOH, water
Add 0.60 g and reflux at 80 ° C. 1.5 ml of chlorobenzene was added 30 minutes after the start of reflux, and 0.1 ml after 45 minutes.
Add 75 ml, 0.75 ml after 60 minutes. 4 as it is
The mixture was refluxed for 2 hours, and 0.235 g of phenol and 1.5 ml of chlorobenzene were added. The mixture was further refluxed for 2 hours, and the reaction was completed. The remaining NaOH was neutralized, and the resulting precipitate was sufficiently washed with water, dissolved in chloroform, reprecipitated in hexane, filtered and dried at 80 ° C. under reduced pressure to obtain a white powder polymer. Chloroform solution concentration 0.2 g /
The converted viscosity measured at dl and a temperature of 25 ° C. was 0.3.

This polymer was dissolved in chloroform to prepare a 5 wt% solution, and a film was formed by a dry casting method. The membrane was dried at 60 ° C. for 24 hours, and the static contact angle with respect to the obtained membrane was measured.
° and the contact angle of water was 92 °. This polymer is DM
It was dissolved in a water-soluble organic solvent such as SO, DMF, DMAc and NMP at room temperature.

A solution of 3.3 g of this polymer, 2.1 g of propylene glycol, and 9.6 g of NMP was prepared, and an asymmetric membrane was obtained by a wet casting method. This film is kept at 60 ° C, 2
After drying for 4 hours and measuring the static contact angle, the contact angle of bovine plasma was 98 ° and the contact angle of water was 92 °. The oxygen permeability of this membrane can be changed to 6 × 10
^-3 to 2 × 10 ^-2 cm ³ / cm ² · sec · cmHg. Observation of the outer surface in contact with blood with a scanning electron microscope (SEM) revealed no pores of 100 ° or more.

Comparative Example 1 The contact angle of bovine plasma with commercially available polypropylene was 94 °, and the contact angle of water was 103 °. Polypropylene is DMSO, DMF, DMAc,
It did not dissolve in water-soluble organic solvents such as NMP. Using this polypropylene, a porous hollow fiber membrane was produced by the method described in Japanese Patent Publication No. 4-39371. The oxygen permeability of the obtained membrane was 2 × 10 ^-2 cm ³ / cm ² · sec · cmHg. Observation of the outer surface in contact with blood with a scanning electron microscope (SEM) revealed a large number of pores of several hundreds to 1,000 degrees.

Comparative Example 2 A film was prepared from commercially available poly (4-methylpentene-1), and the contact angle was measured. The contact angle of bovine plasma was 94 ° and the contact angle of water was 10 °.
3 °. This polymer is DMSO, DMF, DM
It did not dissolve in water-soluble organic solvents such as Ac and NMP.

Using this poly (4-methylpentene-1), a porous hollow fiber membrane was produced by a melt drawing method in accordance with the method of Example 2 described in JP-A-6-210146. The resulting membrane has an oxygen permeability of 1 × 10 ⁻³ cm ³ / cm ² · se.
c · cmHg. Observation of the outer surface in contact with blood by SEM revealed a large number of pores of several hundreds to 1,000 degrees.

Comparative Example 3 A film was prepared from commercially available polysulfone by a dry casting method. When the contact angle was measured, the contact angle of bovine plasma was 92 ° and the contact angle of water was 88 °. Example 1 of JP-A-61-119272
, A porous hollow fiber membrane was produced by a wet method. The obtained membrane has an oxygen permeability of 2 × 10 ^-2 cm ³ / cm ² · sec · cmH
g. Observation of the outer surface in contact with the blood by SEM revealed no pores of 100 ° or more.

Comparative Example 4 USP 3,305,528
A phenoxy resin was synthesized using bisphenol A and epichlorohydrin according to the method described. The reduced viscosity was 0.51. The contact angle of bovine plasma to the phenoxy resin was 92 °, and the contact angle of water was 88 °. A porous hollow fiber membrane was produced according to the method described in JP-A-61-119272. The resulting membrane has an oxygen permeability of 2 × 1
It was 0 ^-2 cm ³ / cm ² · sec · cmHg. Observation of the outer surface in contact with the blood by SEM revealed no pores of 100 ° or more.

[0035]

The medical material of the present invention has a high hydrophobicity as a membrane material, a contact angle with pure water of 90 ° or more, and a contact angle with plasma of more than that. And the surface tension acting between them acts in the direction of suppressing the invasion of plasma, so that the permeation of the plasma filtrate does not occur, and the plasma leak can be avoided. Further, it is an ultrafiltration membrane having a molecular weight cut-off of about 10,000 to 50,000, and has a small pore diameter of 100 ° or less, so that it has a large ability to prevent invasion of plasma. Albumin and γ-globulin do not permeate in the pores, so there is no adsorption of plasma proteins. Since the proteins are not hydrophilized, plasma leakage due to a decrease in the contact angle with the pore walls hardly occurs.

The asymmetric porous membrane according to the present invention makes it possible to suppress plasma leak even in a long-term extracorporeal circulation as compared with a conventional porous artificial lung membrane, and reduces the burden on the patient and accelerates healing. In addition to the heart-lung machine, the material of the present invention can be applied to a filter, a housing, a blood port, a connector, a tube, a pump, and the like of a hemodialysis device, a blood transfusion device, a blood collection device, and other blood circulation devices. .

Claims (4)

[Claims] 1. A medical material dissolvable in an organic solvent, wherein the contact angle with pure water is 90 ° or more, and the contact angle with plasma is higher than the contact angle with pure water. 2. A medical product comprising a polycondensed, copolymerized or alloyed polymer of a bisphenol containing at least one kind of bisphenol containing a fluorine atom and a halogenated epoxy or dichlorodiphenylsulfone. material 3. The medical material according to claim 1, which is an asymmetric membrane. 4. The medical material according to claim 1, wherein the surface of the material is made biocompatible.