JP3207210B2 - Biocompatible membrane - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a membrane having excellent biocompatibility, and more particularly, to a membrane coated with a copolymer of 2-methacryloyloxyethyl phosphorylcholine and a hydrophobic monomer. It relates to a compatible porous membrane.

[0002]

2. Description of the Related Art A hydrophobic porous membrane has features such as (1) excellent gas permeability, (2) excellent mechanical strength, and (3) excellent filtration characteristics, and is characterized by an artificial lung and a plasma. Widely used in medical applications as separators and plasma component fractionation applications. In such applications, the problem of biocompatibility, especially antithrombotic properties, is important because the membrane material comes into contact with blood.
As a means therefor, a method of injecting an anticoagulant such as heparin into blood is commonly used.

[0003]

However, there has not yet been obtained a porous membrane having an essentially antithrombotic property. In view of the above-mentioned situation, the present inventors obtain a porous membrane excellent in biocompatibility, which is simpler as a method for imparting an essential antithrombotic property, has no toxicity to the human body, and is sufficiently stable for long-term storage. As a result, the present invention has been completed.

[0004]

The gist of the present invention is a copolymer of 2-methacryloyloxyethyl phosphorylcholine having a repeating unit represented by the following structural formula (I) and a methacrylate ester, wherein k is 0.03 to 0.70,
m represents 0.30 to 0.97, n represents an integer of 2 or more, and R represents H or OR ′ (R ′ represents an aliphatic hydrocarbon group or an aromatic hydrocarbon group)] at least in the hydrophobic porous membrane. It is a biocompatible membrane that is retained on some pore surfaces.

[0005]

Embedded image The material of the hydrophobic porous membrane used in carrying out the present invention includes polyethylene, polypropylene, poly-4-
Polyfluorinated olefins such as polyolefins such as methylpentene-1, poly (vinylidene fluoride), polytetrafluoroethylene, copolymers of hexafluoropropylene and tetrafluoroethylene, and copolymers of these fluorinated olefin monomers and olefin monomers Can be mentioned.

[0006] As a method for producing the porous membrane, various production methods such as a melt molding-stretching method, a melt molding-extraction method, and a wet molding method can be used.

The porosity of the porous film is preferably in the range of 20 to 90 vol (volume)%. 20 porosity
When the porosity is less than 1%, the microporous portion is blocked, and the filtration characteristics and gas permeability deteriorate.
If the content exceeds 0 vol%, the strength of the porous membrane itself is reduced, so that it is not preferable.

The porous membrane may be in any form such as a hollow fiber, a tube, or a film.

In the copolymer (MPC copolymer) used for obtaining the porous film excellent in biocompatibility according to the present invention, 2-methacryloyloxyethyl phosphorylcholine (MPC) is a compound represented by the following structural formula (II). It is.

[0010]

Embedded image This MPC reacts, for example, 2-bromoethyl phosphoryl dichloride with 2-hydroxyethyl methacrylate to obtain 2-methacryloyloxyethyl 2′-bromoethyl phosphate (MBP), and reacts the MBP in a methanol solution of trimethylamine. Let me get it.

The methacrylic acid ester as a copolymer component is a compound represented by the following structural formula (III).

[0012]

Embedded image [Where n is an integer of 2 or more, and R is H or OR '
(R ′: aliphatic hydrocarbon group or aromatic hydrocarbon group)], wherein the aliphatic hydrocarbon group is an alkyl group, an alkenyl group or the like, and the aromatic hydrocarbon group is a phenyl group or the like. n
Is less than 2, the hydrophobicity and the glass transition temperature of the copolymer with MPC become low. Therefore, when the composition ratio of MPC is increased to express the effect of using MPC, the obtained MPC The copolymer dissolves in water or swells significantly, reducing its strength.

Specific examples of methacrylates include ethyl methacrylate, propyl methacrylate, butyl methacrylate, pentyl methacrylate, hexyl methacrylate, heptyl methacrylate, octyl methacrylate, tridecyl methacrylate, 2-ethoxyethyl methacrylate, 2-ethoxypropyl methacrylate, 2-phenoxyethyl methacrylate, 2-butoxyethyl methacrylate and the like.

The MPC copolymer is obtained, for example, by reacting MPC with a methacrylic acid ester in a solvent in the presence of an initiator.

As the solvent, it is sufficient that the monomer is dissolved, and specific examples thereof include water, methanol, ethanol, propanol, t-butanol, benzene, toluene, dimethylformamide, tetrahydrofuran, chloroform, and mixtures thereof.

As the initiator, any ordinary radical initiator may be used. Examples of the initiator include aliphatic azo compounds such as 2,2'-azobisisobutyronitrile (AIBN) and azobismalenonitrile; Organic peroxides such as benzoyl oxide, lauroyl peroxide, ammonium persulfate and potassium persulfate can be exemplified.

The ratio of the MPC component (k) to the methacrylate component (m) in the MPC copolymer is in the range of 0.03 to 2.33.
When k / m exceeds 2.33, the copolymer swells excessively in water, resulting in a decrease in strength.

The molecular weight of the MPC copolymer used in the present invention can be variously changed according to the purpose. However, from the viewpoint of the strength of the resulting copolymer, the molecular weight must be 5,000 or more. Is more preferable, and more preferably 10,000 or more. As a method for retaining the MPC copolymer in the porous membrane in the present invention, a method of treating the hydrophobic porous membrane with an organic solvent solution of the MPC copolymer can be mentioned. A coating layer of the MPC copolymer is formed on the pore surface. MP
MPC copolymer concentration in C copolymer solution is 0.1wt
(Weight)% or more is sufficient. The coating layer of the MPC copolymer does not necessarily need to completely cover the surface of the micropores of the porous membrane, but may cover at least about 30% of the surface, and should cover at least about 50%. Is more preferred. M
When the coating amount of the PC copolymer is 1 wt% or more with respect to the membrane, sufficient antithrombotic properties are exhibited. The coating amount is more preferably 2% by weight or more. From the viewpoint of the filtration performance and gas permeation performance of the membrane, the amount of MPC copolymer adhering to the membrane is 1
It is preferably at most 00 wt%.

The interaction between the hydrophobic porous membrane and the MPC copolymer is extremely strong, and the methacrylic acid ester portion, which is a hydrophobic component of the MPC copolymer, has a hydrophobic / hydrophobic interaction on the surface of the micropores of the hydrophobic porous membrane. It is held stably because it is strongly adsorbed by the action. Further, since the MPC portion similar to the phospholipid, which is a main component of the biological membrane, comes out on the surface, the biocompatibility is extremely excellent. This is an effect that cannot be obtained with a hydrophilic porous membrane.

[0020]

The present invention will be described in more detail with reference to the following examples.

Examples 1 to 3 and Comparative Example 1 A porous polyethylene hollow fiber membrane having an inner diameter of 300 μm, a thickness of 65 μm, and a porosity of 71 vol% was prepared by mixing 0.7 wt% (methanol / tetrahydrofuran = 1) of each polymer shown in Table 1.
/ 1) After immersion in the solution for 5 minutes, it was dried under reduced pressure. Using this hollow fiber membrane, a membrane module having a membrane area of 200 cm ² was produced.

On the other hand, by centrifuging rabbit fresh blood, platelet-rich plasma containing 1 × 10 ⁸ platelets / ml (P
RP).

Next, PRP obtained by adding 199 μl of a 1 mol / l calcium chloride solution to the hollow portion of the hollow fiber membrane of this membrane module was flowed at a flow rate of 0.23 ml / min for 20 minutes, and the liquid permeated through the membrane surface was not permeated. The liquid flowing out from the hollow at the other end was collected, the platelet count in the liquid was measured with a Coulter counter, and the platelet adhesion was calculated by the following equation.

[0024]

(Equation 1) The results are shown in Table 1. The platelet adhesion amount was extremely small in all the examples.

[0025]

[Table 1] Comparative Example 1 Poly-n-butyl methacrylate (molecular weight: 40,000) was used as a retaining polymer, and the other conditions were the same as in Example 1 to maintain this polymer at 6.2 wt% with respect to the porous membrane. . The platelet adhesion of this membrane was 39.5%.

[0026]

Industrial Applicability The porous membrane of the present invention has excellent biocompatibility due to the presence of the MPC-derived phospholipid polar group of the MPC copolymer held on the pore surface of the membrane. And almost no biological components are adsorbed, and thrombus formation can be suppressed.

Continuation of the front page (58) Field surveyed (Int. Cl. ⁷ , DB name) B01D 67/00-71/82 510 B01D 53/22 C02F 1/44

Claims (1)

(57) [Claims] 1. A copolymer of 2-methacryloyloxyethyl phosphorylcholine having a repeating unit represented by the following structural formula (I) and a methacrylate ester, wherein k is
Represents 0.03 to 0.70, m represents 0.30 to 0.97, n represents an integer of 2 or more, and R represents H or OR ′ (R ′ represents an aliphatic hydrocarbon group or an aromatic hydrocarbon group). ] On at least a part of the pore surface of the hydrophobic porous membrane. Embedded image