JP2000080189A - Surface-hydrophilic molding and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a highly hydrophilic highly biocompatible molding by forming on the surface of a molding a hydrophilic layer comprising a polymerizable compound having a hydrophilic group except a heparin residue and a polymerizable compound having a heparin residue. SOLUTION: The polymerizable compound (A) having a hydrophilic group except a heparin residue is a polymerizable compound having a hydrophilic group such as a sulfone group, a quat. ammonium group, or a carboxyl group, and the polymerizable compound (B) having a heparin residue is a heparin derivative of the formula (wherein R is a direct bond, -O-, -CONHCH2CH2O-, or the like; and Hep is a heparin residue). A hydrophobic photopolymerizable composition is molded into a shaping, and the shaping is brought into contact with a hydrophilic liquid containing components A and B and irradiated with an actinic light, whereupon the shaping is cured, and the hydrophobic compound and the hydrophilic compound are copolymerized at the interface between the shaping and the hydrophilic liquid to chemically bond molecules of the hydrophilic compound to the surface. No photopolymerization reaction takes place in the hydrophilic liquid except the interface of contact. The surface- hydrophilic molding does not suffer from swelling.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a surface hydrophilic molded article which is applied in the medical field and has low protein adsorption and excellent biocompatibility, and a method for producing the same. A compound having a hydrophilic group other than a heparin residue, a surface hydrophilic molded article having a compound having a heparin residue bonded to the surface, and a method for producing the same.

[0002]

2. Description of the Related Art A large problem in molded articles used in the medical field is often caused by lack of biocompatibility, such as occurrence of thrombus, hemolysis, sensitization, and immune reaction. Among them, especially thrombus (blood coagulation)
Is a fatal problem for long-term use medical materials (eg, cardiopulmonary bypass, blood circuit, etc.).

[0003] In order to solve such problems, the surface of a molded product is usually subjected to a hydrophilic treatment or a biocompatible treatment. For example, JP-A-10-53658 discloses that a polymerizable composition comprising a vinyl-based compound and a photopolymerization initiator is shaped, and the obtained uncured shaped product is treated with a vinyl-based compound having a hydrophilic group. By irradiating them with actinic rays in the contacted state, the uncured excipient is cured, and at the surface of the excipient, the vinyl compound and a part of the vinyl compound having a hydrophilic group are shared. A method for producing a surface hydrophilic molded article to be polymerized has been proposed. JP-A-5-177119 discloses that a copolymer comprising methacrylate and methacrylate having a quaternary amine and a phosphate anion group is dissolved in a solvent, and the solution is dispersed on the surface of the pores of a hydrophobic porous membrane. After coating, a method has been proposed in which the solvent is volatilized to retain the copolymer on the pore surfaces of the membrane. Further, Japanese Patent Application Laid-Open No. 7-724
No. 30 and JP-A-54-63025 propose a method of graft-polymerizing a vinyl monomer having a phospholipid-like structure on the surface of a material. On the other hand, as a surface treatment of a material with a compound having a heparin residue, Japanese Patent Application Laid-Open No. 55-158055 proposes a method of treating the surface of a material with active rays in the presence of a heparin derivative having an unsaturated double bond. Have been.

[0004]

Problems to be Solved by the Invention Japanese Patent Laid-Open No. 10-5365
8, JP-A-5-177119, JP-A-7-179
No. 72430 and JP-A-54-63025 disclose a surface hydrophilic molded product having biocompatibility and selective adsorption, in which those hydrophilic groups have low protein adsorption and biological inactivity. Although it contributes to imparting the property (inert), it does not have the effect of promoting the thrombin inhibition reaction by antithrombin (ATIII) or the like, so that the obtained surface hydrophilic molded article has antithrombotic (blood coagulation) properties. In terms of the above, it did not have sufficiently satisfactory performance.

The above-mentioned thrombin has a molecular weight of about 37,00.
0, a double-stranded glycoprotein having the property of activating blood coagulation factors. Antithrombin (AT
III) is a single-chain glycoprotein having a molecular weight of about 59,000 and has a function of forming a complex with thrombin and inhibiting blood coagulation.

On the other hand, Japanese Patent Application Laid-Open No. 55-158055 discloses that an excellent antithrombotic effect can be imparted to the surface of a material by using a heparin derivative having an unsaturated double bond. The antithrombotic effect of heparin is that heparin binds to antithrombin (ATIII), whereby the higher-order structure of ATIII is slightly changed, making it easier to bind to thrombin. ATIII promotes thrombin inhibition by more than 10,000 times with heparin.
However, the surface to which heparin is bound, especially when it comes into contact with blood for a long time, causes adsorption of other proteins, adhesion of blood cells, platelets, etc., and gradually causes protein denaturation and activation of platelets. In addition, there is a problem that thrombus and blood coagulation are caused by a coagulation factor other than thrombin.

An object of the present invention is to provide a surface hydrophilic molding having properties such as antithrombotic properties of heparin, low protein of hydrophilic group, low platelet adhesion and biological inertness of hydrophilic layer. Object (antithrombotic material or biocompatible material).

[0008]

Means for Solving the Problems The present inventors have made intensive studies to solve the above-mentioned problems, and as a result, (A) a polymerizable compound having a hydrophilic group other than a heparin residue; By providing a hydrophilic layer made of a polymerizable compound having a residue on the surface of the molded article, together with an antithrombotic effect,
The inventors have found that they exhibit an effect of preventing protein adsorption and platelet adhesion, and have completed the invention.

That is, in order to solve the above-mentioned problems, the present invention provides (I) a polymerizable compound having a hydrophilic group other than (A) a heparin residue on its surface and (B) a polymerizable compound having a heparin residue. The present invention provides a surface hydrophilic molded article having a hydrophilic layer comprising:

In order to solve the above-mentioned problems, the present invention provides (II) (1) wherein a polymerizable unsaturated double bond is contained in one molecule.
A shaped article (b) obtained by shaping a hydrophobic photopolymerizable composition containing at least one hydrophobic compound (a) and a photopolymerization initiator into a thin film, a thread, a bead, or any other shape. A first step of molding; and (2) a second step of bringing the surface of the excipient (b) into contact with a hydrophilic liquid (d) containing a hydrophilic compound (c) having a polymerizable unsaturated bond, (3) By irradiating actinic rays to the excipient (b) in the contact state, (a) the excipient (b) is cured, and (b) the excipient (b) and the hydrophilic liquid At the interface with (d), the hydrophobic compound (a) and the hydrophilic compound (c) are copolymerized to form molecules of the hydrophilic compound (c) on the surface of the hydrophobic excipient (b). (C) in the hydrophilic liquid (d), except that the photo-polymerization reaction does not occur except for the contact interface in the hydrophilic liquid (d). The method of manufacturing a shaped product, polymerizable unsaturated hydrophilic compound having a double bond as (c),
(A) A method for producing a surface hydrophilic molded article, characterized by using a polymerizable compound having a hydrophilic group other than a heparin residue, and (B) a polymerizable compound having a heparin residue.

In order to solve the above-mentioned problems, the present invention provides (III) (1) a hydrophobic compound (a) having two or more polymerizable unsaturated double bonds in one molecule, and a photopolymerization initiator. A first step of forming an excipient (b) by shaping a hydrophobic photopolymerizable composition containing a film into a thin film, a thread, a bead, or any other shape; and (2) an excipient (b) ) Is irradiated with an actinic ray to pre-cure the excipient (b), but the polymerizable unsaturated double bond remains at least on the surface of the excipient (b), a second step; 3) a third step of bringing the surface of the precured excipient (b) into contact with a hydrophilic liquid (d) containing a hydrophilic compound (c) having a polymerizable unsaturated double bond, and (4) By irradiating the pre-cured excipient (b) under the contact state with actinic rays,
(A) The immobilized product (b) is cured, and (b) the hydrophobic compound (a) and the hydrophilic compound (c) are mixed at the interface between the excipient (b) and the hydrophilic liquid (d). The hydrophilic compound (c) is chemically bonded to the surface of the hydrophobic excipient (b) by copolymerization. (C) In the hydrophilic liquid (d), the light is removed except for the contact interface. In the method for producing a surface hydrophilic molded product, which does not cause a polymerization reaction and comprises the fourth step, as the hydrophilic compound (c) having a polymerizable unsaturated double bond,
(A) A method for producing a surface hydrophilic molded article, characterized by using a polymerizable compound having a hydrophilic group other than a heparin residue, and (B) a polymerizable compound having a heparin residue.

Furthermore, the present invention solves the above-mentioned problems by providing (A) an ionic group, a carboxyl group, a phosphoric acid residue, Amine, sugar residue, polymerizable compound having a functional group selected from the group consisting of amino acid residues and zwitterions,
And (B) generating radicals in the presence of a polymerizable compound having a heparin residue, thereby reacting the radicals generated on the surface of the molded article with the polysynthetic compound (A) and the polysynthetic compound (B), A method for producing a surface hydrophilic molded product, comprising grafting a polymerizable compound (A) having a hydrophilic group other than a heparin residue and a polymerizable compound (B) having a heparin residue on the surface of a molded product. provide.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION The polymerizable compound (A) having a hydrophilic group other than a heparin residue constituting the hydrophilic layer provided on the surface of the surface hydrophilic molded article of the present invention may be either organic or inorganic. Any polymer may be used as long as it is polymerized by irradiation with heat or actinic rays, for example, ultraviolet light, visible light, infrared light, or the like, and may be any one such as radical polymerization, anionic polymerization, or cationic polymerization. Such compounds include, for example,
In the molecule, a vinyl group, a vinylidene group, an acryloyl group, a methacryloyl group [hereinafter, an acryloyl group and a methacryloyl group are collectively referred to as a (meth) acryloyl group. The same applies to (meth) acryl, (meth) acrylate, etc.], and the like. Among them, compounds having a (meth) acryloyl group because of a high polymerization rate by irradiation with actinic rays Is preferred.

Examples of the hydrophilic group other than heparin in the polymerizable compound (A) include, for example, a sulfone group, a quaternary ammonium group, a carboxyl group, a phosphoric acid residue, an amine residue, a polyethylene glycol chain, and a heparin residue. Sugar residues, amino acid residues, zwitterionic groups, and the like, among them, sulfone group, quaternary ammonium group, phosphoric acid residue,
Polyethylene glycol chains, sugar residues other than heparin residues, and zwitterionic groups are preferred.

Examples of the polymerizable compound having a sulfone group include sodium ethoxy sulfonate (meth) acrylate.

The polymerizable compound having a quaternary ammonium group includes, for example, trimethylammonioethyl (meth) acrylate.

Examples of the polymerizable compound having a carboxyl group include ω-carboxycaprolactone (meth)
Examples include acrylate, 2- (meth) acryloyloxyethyl hexahydrohydrogen phthalate, 2- (meth) acryloyloxyethyl succinic acid, 2- (meth) acryloyloxypropyl hydrogen phthalate, and (meth) acrylic acid dimer.

The polymerizable compound having a phosphoric acid residue includes
For example, trimethyl [2- (meth) acryloyloxyethyl] phosphonium chloride, tri-n-butyl [2- (meth) acryloyloxyethyl] phosphonium chloride, (meth) acryloyloxyethyl phosphoric acid, (meth) acryloyloxydecyl phosphoric acid, β- (meth) acryloyloxyethylphenylphosphoric acid, and the like.

Examples of the polymerizable compound having an amine residue include (meth) acrylamide, N, N-dimethyl (meth) acrylamide, and N, N-diethyl (meth) acrylamide.
Acrylamide, N-isopropyl (meth) acrylamide, N, N-dimethylaminopropyl (meth) acrylamide, (meth) acryloylmorpholine, N, N
-Dimethylaminoethyl (meth) acrylate, N-methylenebis (meth) acrylamide, and the like.

Examples of the polymerizable compound having a polyethylene glycol chain include methoxydiethylene glycol (meth) acrylate, methoxytetraethylene glycol (meth) acrylate, methoxynonaethylene glycol (meth) acrylate, and methoxypolyethylene glycol (meth) acrylate. Is mentioned.

Examples of the polymerizable compound having a sugar residue other than the heparin residue include 6- (meth) acrylol (1
—O) n-butylglucoside, 6- (meth) acrylolglucose, 6- (meth) acrylolcellobiose, and the like.

Examples of the polymerizable compound having an amino acid residue include N- (meth) acryloyl asparagine,
N- (meth) acryloyloxyethylaminoasparagine, N- (meth) acryloylglutamine, N-
(Meth) acryloyloxyethylaminoglutamine,
And the like.

Examples of the polymerizable compound having an amphoteric ion group include 2-[(meth) acryloyloxy] ethyl-2 ′-(trimethylammonio) ethyl phosphate and (meth) acryloyloxybutyl-2- (trimethylammonium). E) Ethyl phosphate, (meth) acryloyloxynonaethylene oxide-2- (trimethylammonio) ethyl phosphate, (meth) acryloyloxytripropylene oxide-2 ′-(trimethylammonio) ethyl phosphate, 2- (vinyloxy) ethyl -2 '-(trimethylammonio) ethyl phosphate, 2- (p-vinylbenzyloxy) ethyl-2'-(trimethylammonio) ethyl phosphate, 2- (allyloxy) ethyl-2 '-(trimethylammonio) ethylphosphate Eto, 2- (styryloxy) ethyl-2 '- (trimethylammonio) ethyl phosphate, 2- (ethoxy full Malo yl) ethyl-2' - (triethylsilyl ammonio) ethyl phosphate, and the like.

These polymerizable compounds having a hydrophilic group include
They can be used alone or as a mixture of two or more.

Polymerizable compound (B) having a heparin residue
Is a compound having a heparin residue and a polymerizable functional group. Among them, the general formula (1)

[0026]

Embedded image

[Wherein R is a direct bond, -O-, -CO
_{NHCH 2 CH 2 O -, -} (CH 2) m -O-, - (CH
₂ CH ₂ O) _m or _{- (CH 2 CH (CH 3} ) O) m -. Represents (wherein, m is an integer of 1 to 9), R ¹
And R ² each independently represent a hydrogen atom or a group having 1 to 6 carbon atoms.
R ³ represents a hydrogen atom or a methyl group, Hep represents a heparin residue, and n represents an integer of 1 or more. ] Is preferred.

Examples of the heparin derivative represented by the general formula (1) include mono [(meth) acryloyl] heparin, di [(meth) acryloyl] heparin, tetra [(meth) acryloyl] heparin, and hexa [(meth)
Acryloyl] heparin, deca [(meth) acryloyl] heparin, mono [(meth) acryloyloxyethylaminocarbonyl] heparin, di [(meth) acryloyloxyethylaminocarbonyl] heparin, tetra [(meth) acryloyloxyethylaminocarbonyl] Heparin, hexa [(meth) acryloyloxyethylaminocarbonyl] heparin, deca [(meth) acryloyloxyethylaminocarbonyl] heparin, mono [(meth) acryloyloxyethyl] heparin, di [(meth) acryloyloxyethyl] heparin, Tetra [(meth) acryloyloxyethyl] heparin, hexa [(meth) acryloyloxyethyl] heparin,
Deca [(meth) acryloyloxyethyl] heparin,
Tetradeca [(meth) acryloyloxyethyl] heparin, mono [(meth) acryloyloxybutyl] heparin, di [(meth) acryloyloxybutyl] heparin, tetra [(meth) acryloyloxybutyl] heparin, hexa [(meth) acryloyl Oxybutyl] heparin, deca [(meth) acryloyloxybutyl] heparin, mono [(meth) acryloyloxyhexyl]
Heparin, deca [(meth) acryloyloxyhexyl] heparin, mono [(meth) acryloyloxyethylene oxide] heparin, deca [(meth) acryloyloxyethylene oxide] heparin, mono [(meth) acryloyloxydiethylene oxide] heparin , Deca [(meth) acryloyloxydiethylene oxide] heparin, mono [(meth) acryloyloxytetraethylene oxide] heparin, deca [(meth)
Acryloyloxytetraethylene oxide] heparin, mono [(meth) acryloyloxynonaethylene oxide] heparin, deca [(meth) acryloyloxynonaethylene oxide] heparin, mono [(meth)
Acryloyloxypolyethylene oxide] heparin, deca [(meth) acryloyloxypolyethylene oxide] heparin, mono [(meth) acryloyloxypropylene oxide] heparin, deca [(meth) acryloyloxypropylene oxide] heparin, mono [(meth) acryloyloxy Dipropylene oxide] heparin, deca [(meth) acryloyloxytetrapropylene oxide] heparin, and the like. These compounds can be used alone or in combination of two or more.

The hydrophilic compound in the hydrophilic layer of the surface hydrophilic molded product is a polymer of a polymerizable compound (A) having a hydrophilic group,
It comprises a polymer of the polymerizable compound (B) having a heparin residue and a copolymer of (A) and (B), and these polymers are chemically bonded to the surface of the molded product. The ratio (weight ratio) of the polymerizable compounds (A) and (B) is not particularly limited, but from the viewpoint of biocompatibility (antithrombotic) of the whole material such as antithrombotic action, inhibition of protein adsorption, and inhibition of platelet adhesion.
The ratio (weight ratio) between (A) and (B) is 1/99 to 99 /
The range of 1 is preferable, and the range of 30/70 to 50/50 is particularly preferable.

The thickness of the hydrophilic layer is not particularly limited as long as the hydrophilic compound completely covers the surface of the material, and can be appropriately changed depending on the type of the material and its use. For example, in the case of a material such as an artificial lung in which oxygen needs to pass through the surface of the hollow fiber, the thickness of the hydrophilic layer is as follows.
It is preferable to make the thickness as thin as possible so as not to affect the oxygen permeation rate. In this case, the thickness is preferably in the range of several Å (monomolecular film) to several hundred Å. On the other hand, in the case of a blood circuit or a blood pump, the thickness of the hydrophilic layer may be large. In that case, the thickness may be, for example, in the range of several tens nm to several tens μm.

In order to sufficiently exert the antithrombotic effect of the heparin derivative represented by the general formula (1), the general formula (1)
It is preferable to use a long-chain spacer group R as the spacer group to increase the degree of freedom of heparin residues. However, from the viewpoint of suppressing protein adsorption and platelet adhesion, a hydrophilic chain such as polyethylene glycol is preferred. Is preferred.

Next, a method for producing the surface hydrophilic molded product of the present invention will be described. The hydrophobic compound (a) having two or more polymerizable unsaturated double bonds in one molecule, which is used in the production method of the present invention, is not limited to heat, actinic light such as ultraviolet light, visible light, and infrared light regardless of organic or inorganic. Any polymer may be used as long as it is polymerized by irradiation with the above, and any polymer such as radical polymerization, anionic polymerization, and cationic polymerization may be used. Examples of such a compound include compounds having a vinyl group, a vinylidene group, an acryloyl group, a methacryloyl group, and the like in the molecule. Is preferred.

As the hydrophobic compound (a) used in the production method of the present invention, for example, 1,6-hexanediol di (meth) acrylate, polypropylene glycol di (meth) acrylate, neopentyl glycol dihydroxypivalate ( Meth) acrylate, 3-acryloyloxyglycerin monomethacrylate, 2,2′-
Bis (4- (meth) acryloyloxy polyethyleneoxyphenyl) propane 2,2'-bis (4- (meth)
Acryloyloxypolypropyleneoxyphenyl) propane, dicyclopentanyldi (meth) acrylate,
Bifunctional compounds such as bis [(meth) acryloyloxyethyl] hydroxyethyl isocyanate, phenylglycidyl ether acrylate tolylene diisocyanate, divinyl adipate; trimethylolpropane tri (meth) acrylate, trimethylolethane tri (meth) acrylate, tris [ (Meth) acryloyloxyethyl] isocyanate, trifunctional compound such as pentaerythritol tri (meth) acrylate; tetrafunctional compound such as pentaerythritol tetra (meth) acrylate, glycerin di (meth) acrylate hexamethylene diisocyanate; dipentaerythritol monohydroxy Pentafunctional compound such as penta (meth) acrylate; hexafunctional compound such as dipentaerythritol hexa (meth) acrylate , And the like.

The hydrophobic compound (a) used in the present invention includes (meth) acrylic ester of epoxy resin such as bisphenol A diepoxy- (meth) acrylic acid adduct, and (meth) acrylic acid of polyether resin. Esters, (meth) acrylic acid esters of polybutadiene resins, polyurethane resins having (meth) acrylic groups at molecular terminals, and the like are also included.

These hydrophobic compounds (a) can be used alone or as a mixture of two or more compounds.

Further, the hydrophobic compound (a) having two or more polymerizable unsaturated double bonds in one molecule used in the production method of the present invention may optionally contain a polymerizable unsaturated double bond in one molecule. A compound having one saturated double bond may be used in combination.
Compounds having one polymerizable unsaturated double bond in one molecule used for such purpose include, for example, ethyl (meth) acrylate, butyl (meth) acrylate, hexyl (meth) acrylate, lauryl (meth) Examples include acrylate, stearyl (meth) acrylate, phenyl (meth) acrylate, phenyl cellosolve (meth) acrylate, nonylphenoxy polyethylene glycol (meth) acrylate, isobornyl (meth) acrylate, and dicyclopentanyl (meth) acrylate.

By selecting the above-mentioned hydrophobic compound (a) and a compound having one polymerizable unsaturated double bond in one molecule, a support molded product of a surface hydrophilic molded product (ie, a shaped product (b) ) Can be arbitrarily controlled. For example, in order to obtain a molded product having excellent heat resistance, solvent resistance, swelling resistance, hardness and strength, a hydrophobic compound (a) having two or more polymerizable unsaturated double bonds in one molecule is required. Among them, a method of selecting a polymer having a large number of functional groups and increasing the crosslink density of a polymer molded therefrom may be employed.
Conversely, when thermoplasticity, flexibility, elongation, etc. are required, a method of forming a polymer having no cross-linking structure without using a polyfunctional compound, or a method of forming a polymer with a polyfunctional compound in one molecule What is necessary is just to employ | adopt the method of making a polymer with a comparatively low crosslink density by using together the compound which has one polymerizable unsaturated double bond. These methods can be arbitrarily selected depending on the required characteristics of the target molded product.

The feature of using the hydrophobic compound (a) in the present invention resides in that a molded article of a support which is not swelled in water can be obtained.
The term “non-swellable in water” as used herein means that when immersed in water at 20 ° C., the weight increase relative to the dry weight is 5% by weight or less. By being non-swellable in water, the molded article has water resistance, and does not have a dimensional change or a decrease in strength even in a wet state.

In the production method of the present invention, the shaped article (b) obtained by shaping the hydrophobic photopolymerizable composition comes into contact with the hydrophilic liquid (d) containing the hydrophilic compound (c). Until the photopolymerization and curing, it is necessary to be able to substantially maintain the shaped state. Therefore, the hydrophobic compound (a), which is a main component of the hydrophobic photopolymerizable composition, does not dissolve in the hydrophilic liquid (d), or the hydrophobic photopolymerizable composition has a high viscosity. Are preferred.

The photopolymerization initiator in the hydrophobic photopolymerizable composition is active for actinic rays used in the present invention, and
If it is possible to polymerize a hydrophobic compound (a) having two or more polymerizable unsaturated double bonds in a molecule and a hydrophilic compound (c) having a polymerizable unsaturated double bond, There is no particular limitation, and for example, a radical polymerization initiator, an anionic polymerization initiator, or a cationic polymerization initiator may be used.
As such a photopolymerization initiator, for example, p-tert-
Butyltrichloroacetophenone, 2,2'-diethoxyacetophenone, 2-hydroxy-2-methyl-1-
Acetophenones such as phenylpropan-1-one;
Ketones such as benzophenone, 4,4'-bisdimethylaminobenzophenone, 2-chlorothioxanthone, 2-methylthioxanthone, 2-ethylthioxanthone and 2-isopropylthioxanthone; benzoin, benzoin methyl ether, benzoin isopropyl ether and benzoin isobutyl ether And benzyl ketals such as benzyl dimethyl ketal and hydroxycyclohexyl phenyl ketone.

The photopolymerization initiator can be used in a state of being dissolved or dispersed in a hydrophobic photopolymerizable composition.
It is preferably one that dissolves in the hydrophobic photopolymerizable composition. The photopolymerization initiator concentration in the hydrophobic photopolymerizable composition is preferably in the range of 0.01 to 20% by weight,
A range of 10% by weight is particularly preferred.

In addition to the photopolymerization initiator, a thermal polymerization initiator can be used. For example, dibutyl peroxide methyl ethyl ketone peroxide, t-hexyl hydroperoxide and the like can be mentioned.

Other components may be contained in the hydrophobic photopolymerizable composition in a dissolved or non-dissolved state.
As other components, for example, a polymer that functions as a thickener of the photopolymerizable composition, a polymer that functions as a physical property improver of the final molded product, an inorganic substance such as a filler, a reinforcing material such as an aramid fiber, a coloring agent, Examples include agents such as an antifungal agent, and poor solvents for forming a porous body.

The hydrophilic liquid (d) of the present invention comprises a hydrophilic compound (c) having a polymerizable unsaturated double bond as a main constituent. The hydrophilic liquid (d) may further contain a solvent, a polymerization inhibitor, a chain transfer agent, etc., but preferably does not contain a photopolymerization initiator active in the actinic ray used in the present invention. When containing such a photopolymerization initiator,
It is not preferable because the hydrophilic compound (c) having a polymerizable unsaturated double bond is homopolymerized, which causes inconvenience when the hydrophilic liquid (d) is repeatedly used. However, even when a photopolymerization initiator is contained, the inconvenience described above can be reduced by simultaneously containing a polymerization inhibitor and a chain transfer agent.

The liquid used for the hydrophilic liquid (d) is
Water, a water-soluble solvent, a surfactant or a mixture thereof is preferable, and in order to obtain a molded product having excellent surface hydrophilicity, water or a solvent containing water as a main component is more preferable, and Most preferably, it is a mixture of the agent and water.

The water-soluble solvent is a solvent that is miscible with water at an arbitrary ratio. Examples of such a water-soluble solvent include alcohol solvents such as methanol, ethanol, propanol, ethylene glycol and glycerin, and acetic acid. Acids, ketone solvents such as acetone, and amide solvents such as formamide.

The surfactant which can be added to the hydrophilic liquid (d) as required may be any one which can be dissolved in a solvent containing the hydrophilic compound (c). For example, anionic surfactants such as sodium n-dodecylbenzenesulfonate, cationic surfactants such as n-dodecyltrimethylammonium chloride, polyoxyethylene sorbitan monolaurate (trade name "Twin 20"), Examples include nonionic surfactants such as polyoxyethylene lauryl ether.

The concentration of the hydrophilic compound (c) having a polymerizable unsaturated double bond in the hydrophilic liquid (d) depends on the hydrophilicity (biocompatibility) required for the surface of the molded product and the reactivity at the interface. From the viewpoints of controlling the amount of hydrophilic groups and the amount of bonding of the hydrophilic groups, and the post-washing, the amount of 0.1.
A range of 5 to 80% by weight is preferred, and a range of 3 to 30% by weight is particularly preferred.

In general, the higher the concentration of the hydrophilic compound (c) having a polymerizable unsaturated double bond in the hydrophilic liquid (d), the more the hydrophilic layer fixed on the surface of the molded support is. Although the thickness increases, the thickness does not need to be particularly limited. For example, when the strength of the hydrophilic layer is not required, the hydrophilic layer may be in a gel state. However, when a certain strength is required for the hydrophilic layer, if the hydrophilic layer is too thick (for example, a thickness of 10 μm or more in a dry state), the surface strength is reduced when wet, and the hydrophilic layer is Deformation and peeling are likely to occur. By setting the concentration of the hydrophilic compound (c) in the hydrophilic liquid (d) in the above range, sufficient hydrophilicity (biocompatibility) is exhibited, and the hydrophilic molding is not excessively thick in the surface hydrophilic layer. You can get things.

An uncured excipient of a hydrophobic photopolymerizable composition containing a hydrophobic compound (a) having two or more polymerizable unsaturated double bonds in one molecule and a photopolymerization initiator; The method of contacting with the hydrophilic liquid (d) is arbitrary, for example, immersion of the excipient in the hydrophilic liquid (d), casting or spraying the hydrophilic liquid (d) on the surface of the excipient, Examples of the method include contacting the excipient with a bubble of the hydrophilic liquid (d) and coextruding the photopolymerizable composition with the hydrophilic liquid (d). Immersion is preferred. The hydrophilic liquid (d) to be brought into contact with the excipient of the photopolymerizable composition may be a gas phase (vapor).

When the uncured shaped product obtained by shaping the photopolymerizable composition was irradiated with light while being in contact with the hydrophilic liquid (d), it was generated inside or on the surface of the shaped product. radical,
Hydrophobic compounds (a) having two or more polymerizable unsaturated double bonds in one molecule are polymerized by active species such as anions and cations, and generated active species or hydrophobic compounds (a) are generated. These active species in the polymerization chain also induce polymerization of the hydrophilic compound (c) having a polymerizable unsaturated double bond contained in the hydrophilic liquid (d) on the surface of the excipient, and one active species is produced. The polymerization reaction started from is terminated almost instantaneously. That is, the polymerization reaction
Inside the excipient, between the hydrophobic compound (a) and the hydrophilic compound (c) on the contact surface between the hydrophobic compound (a) and the excipient and the hydrophilic liquid (d), and the contact In the hydrophilic liquid (d) phase near the surface, the hydrophilic compound (c)
This occurs between each other to form a block copolymer of the hydrophobic compound (a) and the hydrophilic compound (c). Therefore, the hydrophilic compound (c) or its polymer does not exist inside the support molded product formed by curing the excipient, and the hydrophilic compound (c) or its polymer is It is bonded only to the surface of the molded body. The amount of the hydrophilic group bonded to the surface of the support molded article (that is, the amount of the polymer composed of the hydrophilic compound (c)) depends on the concentration of the hydrophilic compound (c), the reaction temperature, and the amount of the photopolymerizable composition. Can be adjusted by the photopolymerization initiator concentration, light intensity and the like. The hydrophilic compound (c) fixed on the surface of the support mold may not be a polymer but may be the hydrophilic compound (c) itself.

In the production method of the present invention, a part of the used amount of the hydrophilic compound (c) having a polymerizable unsaturated double bond is a cured product of the excipient of the photopolymerizable composition. The remaining hydrophilic compound (c) bonded to the surface of the support molding
Will remain uncured in the hydrophilic liquid (d) phase.

The shape of the hydrophilic molded product of the present invention is not particularly limited as long as it can be molded by light irradiation. Examples of the shape include a filament, a hollow fiber, a tube, a cylinder, a particle, a capsule, a film, and the like. The shape may be a plate, a coating, or any other shape. From the viewpoint of ease of molding, the hydrophilic molded product is preferably in the form of a film or a coating. Further, a form in which the hydrophilic molded article is further integrated with another support or the like may be used. Further, the hydrophilic molded product may be a homogeneous product, a porous material, a patterned product, or a product having another structure.

In the case of producing a porous material, for example, as a photopolymerizable composition, it is compatible with a hydrophobic compound (a) having two or more polymerizable unsaturated double bonds in one molecule. A component that does not dissolve or swell the polymerized cured product comprising the hydrophobic compound (a) (also referred to as a poor solvent or a phase separator.
It is called "poor solvent". ) Is used, shaped, and then polymerized and cured by pre-polymerization as described below.
What is necessary is just to remove the poor solvent. Since the hydrophobic compound (a) is polymerized and loses compatibility with the poor solvent at the same time, it undergoes phase separation and solidifies in a network. By washing to remove the poor solvent, porous bodies communicating with each other can be obtained.

Examples of the poor solvent used for such purposes include alkyl esters of fatty acids such as diisobutyl adipate, methyl caprylate, methyl caprate and methyl laurate; ketones such as diisobutyl ketone; polyethylene glycol monolau And nonionic surfactants such as polyethylene glycol monolauryl ether.

A method for shaping a hydrophobic photopolymerizable composition containing a hydrophobic compound (a) having two or more polymerizable unsaturated double bonds in one molecule and a photopolymerization initiator includes: There is no particular limitation. For example, coating with a coater or spray, extrusion from a nozzle, casting into a mold, or when it is necessary to apply thin and uniform coating or an object with a complicated shape, a porous body (for example, a porous film), a nonwoven fabric, When applying to the surface of textiles (including pores and fiber surfaces), dissolve the hydrophobic photopolymerizable composition in a solvent, and apply, spray or immerse it. Except for the above, a method of volatilizing the solvent may be used. The solvent in this case may be any solvent as long as it can dissolve the hydrophobic photopolymerizable composition. However, since the molded product after application has to be dried, a solvent having a relatively high volatility is used. Is more preferred.
Examples of such a solvent include alcohols such as methanol, ethanol, 1-propanol and 2-propanol; ketones such as acetone and methyl ethyl ketone; ethers such as diethyl ether: esters such as ethyl acetate; hexane and toluene. Hydrocarbons such as;
And chlorinated solvents such as dichloromethane and dichloroethane.

After shaping the photopolymerizable composition,
The shaped object may be preliminarily incompletely cured by irradiating the shaped object with light. When the viscosity of the photopolymerizable composition is low,
The excipient comprising the photopolymerizable composition is converted into a hydrophilic compound (c).
Alternatively, it may be difficult to maintain the shape when brought into contact with those solutions. In such a case, a method of pre-curing (incompletely curing) the excipient with actinic rays, and then contacting the excipient with the hydrophilic compound (c) or a solution thereof, followed by light irradiation, is used. This is preferable because the smoothness of the product is improved. Excessive pre-curing reduces the amount of hydrophilic groups introduced to the surface of the molded product, so it is necessary to limit the amount of polymerizable functional groups of the photopolymerizable composition to the extent that they remain. Can be determined by a simple experiment. Precuring can be performed in a short time in a nitrogen atmosphere,
A method in which the photopolymerizable composition is incompletely cured for a short period of time in air which is susceptible to polymerization inhibition by utilizing the property of not being completely polymerized is preferable.

The actinic rays used in the production method of the present invention include ultraviolet rays, visible rays and infrared rays. Among these actinic rays, ultraviolet rays and visible lights are preferred from the viewpoint of polymerization curing speed, and ultraviolet rays are particularly preferred. The main wavelength of the ultraviolet light is preferably at least 300 nm, particularly preferably at least 350 nm. In addition to actinic rays, it is possible to use energy rays such as electron beams, X-rays, and γ-rays. The use of actinic rays is most preferred to reduce the amount of generation. The intensity of the irradiating actinic ray is 1 to 5000 mW / cm ² (10 to 50,000).
W / m ² ), preferably 10 to 2000 mW / cm ²
The range of (100 to 20,000 W / m ² ) is particularly preferable. For the purpose of accelerating the polymerization curing speed and performing the polymerization completely, it is preferable that the light irradiation is performed in an inert gas atmosphere, and the hydrophilic compound (c) having a polymerizable unsaturated double bond is used.
Is dissolved in water, a water-soluble solvent, a surfactant or a mixture thereof, it is preferable to remove oxygen dissolved therein. It is preferable that the hydrophobic compound (a) having two or more polymerizable unsaturated double bonds in one molecule also has dissolved oxygen removed therefrom.

The temperature at the time of photopolymerization is not particularly limited.
In the range up to about 0 ° C., it is preferable that the temperature at the time of polymerization be higher, because the hydrophilicity of the molded article increases. In consideration of working conditions, the range is preferably from room temperature to about 50 ° C. Of course, curing by light irradiation may be performed in a batch system or a continuous system. When curing by light irradiation is performed batchwise,
After shaping, it may be pre-cured by irradiating it with light as it is, and then the obtained pre-cured product may be brought into contact with the hydrophilic compound (c) and irradiated with light again to perform full curing.

When it is necessary to remove unreacted substances, polymerization initiator, and the like in the molded product after polymerization and curing, such as when the molded support is a porous material, washing, drying, suction, and replacement are performed. Etc. can be adopted. After removing these residuals, it is also possible to further irradiate (after cure) ultraviolet rays. It is also possible to perform a heat treatment after curing by light irradiation or after removing the residue. The unreacted monomer and the remaining solvent can be completely removed by the heat treatment.

The fact that the hydrophilic layer is formed on the surface of the hydrophilic molded article obtained by the production method of the present invention means that the element analysis, the contact angle with water on the surface is reduced, and that heparin activity is present. Can be determined by It is preferable that the surface hydrophilic molded article produced by the production method of the present invention has a contact angle with water reduced by 5 degrees or more as compared with the case where the hydrophilic layer is not formed on the surface. For example, when the surface hydrophilic molded product is used for applications requiring prevention of adsorption of a hydrophobic substance, the degree of decrease in the contact angle with water is preferably as large as possible, and preferably at least 10 degrees. More preferably, it is lowered by 20 degrees or more. In this case, the contact angle with water of the surface hydrophilic molded article of the present invention is preferably as small as possible, preferably 45 degrees or less, more preferably 30 degrees or less, and still more preferably 10 degrees or less. Is most preferred. On the other hand, from the viewpoint of antithrombotic properties, it is preferable that the heparin activity is 5 IU / cm ² or more.
/ Cm ² or more is more preferable. Since the value of heparin activity differs depending on the measurement method, the above-mentioned heparin activity value is a value measured by Test Team Heparin S manufactured by Daiichi Pure Chemicals Co., Ltd.

In the surface hydrophilic molded article produced by the production method of the present invention, the hydrophilic polymer is substantially present only on the surface of the support molded article, and is internally provided with, for example, a copolymer or a blend. It is preferably not present in a state. When the support body is a porous body, the inside of the support body means the inside of the resin constituting the support body, and the surface of the pores is regarded as the surface of the support body. Since the support molded article is composed of a polymer different from the surface hydrophilic layer, the physical properties of the support do not decrease particularly in a wet state.

[0063]

The present invention will be described in more detail with reference to the following Examples and Comparative Examples, but the present invention is not limited to the scope of these Examples. In the following examples, “parts” and “%” represent “parts by weight” and “% by weight”, respectively, unless otherwise specified.

[Definition of Measurement Items] Measurements in the following Examples and Comparative Examples were performed according to the following methods.

(1) Measurement of Water Contact Angle The water contact angle of the surface hydrophilic molded product was measured using a drop method CA-D type contact angle meter manufactured by Kyowa Kagaku Co., Ltd.

(2) Elemental Analysis of Molded Product Surface The elemental components on the surface of the molded product that has been hydrophilized are elemental compositions measured by photoelectron spectroscopy (ESCA) using X-ray excitation, and all are composition ratios of the number of atoms. . The measurement was performed using an X-ray photoelectron analyzer ESCA850 manufactured by Shimadzu Corporation under the condition that the angle (θ) between the surface of the molded product and the photoelectron detector was 90 °.

(3) Measurement of Heparin Activity Heparin activity was measured using “Test Team Heparin S” for measuring plasma heparin manufactured by Daiichi Pure Chemicals Co., Ltd. according to the measurement method.

(4) Blood compatibility test After treating the surface of the material with a phosphate buffer solution (PBS) overnight,
Human fresh blood (human whole blood) or human platelet-rich plasma (human
PRP) is placed on the surface of the material and incubated for 180 minutes. Next, the cells were rinsed three times with PBS, and the cell components adhered with 2.5% by weight of glutaraldehyde were fixed for 2 hours. After fixing, the cells were rinsed with distilled water, freeze-dried, and the surface was observed with an electron microscope (SEM). did.

Example 1 (Preparation of hydrophobic photopolymerizable composition) Hydrophobic compound (a)
Ethylene oxide-modified bisphenol A diacrylate having two acrylic groups in one molecule (“New Frontier BPE-4” manufactured by Daiichi Kogyo Seiyaku Co., Ltd.)
40 parts, 60 parts of a urethane acrylate having an average of three acrylic groups in one molecule (“Unidick V-4263” manufactured by Dainippon Ink and Chemicals, Inc.), and further as a photopolymerization initiator (Ciba Geigy) 2 parts of “Irgacure 184” manufactured by the company were uniformly mixed to obtain a hydrophobic photopolymerizable composition (1).

(Preparation of hydrophilic liquid (d)) Mono (2-acryloyloxyethyl) acid phosphate (“Light Ester PA” manufactured by Kyoeisha Chemical Co., Ltd.) was used as the hydrophilic compound (c) having a phosphoric acid residue. 10 parts, distilled water 8
9.5 parts and 0.5 part of polyethylene glycol mono-4-nonylphenyl ether (surfactant) were uniformly mixed to obtain a hydrophilic liquid (d-1).

Hydrophilic compound having heparin residue (c)
As methacrylated heparin (JP-A-55-1580).
Compound No. 55 described in Example 2) 5 parts and distilled water 95
The parts were uniformly mixed to obtain a hydrophilic liquid (d′-1).

(Preparation of Surface-Hydrophilic Molded Product) A hydrophobic photopolymerizable composition (1) coated on a polystyrene sheet with a coater to a thickness of 250 μm was coated with a hydrophilic liquid (d-1). And immediately put in 50 mW / cm ² (50
After irradiating with UV light (0 W / m ² ) for 10 seconds, the sheet was taken out, put again into the hydrophilic liquid (d′-1), and irradiated with UV light for 30 seconds.

The cured product thus obtained was immersed in a 30% aqueous ethanol solution for 10 minutes, and then washed with running water for 10 minutes.
After washing for 1 minute, it was air-dried overnight to obtain a coated hydrophilic hydrophilic product.

Table 1 shows the results of the water contact angle, elemental analysis, heparin activity and blood compatibility of the surface of the surface hydrophilic molded product. In addition, the thickness of the surface hydrophilic layer of the obtained surface hydrophilic molded product was so thin that it could not be observed with a scanning electron microscope. In addition, the support molded product of the surface hydrophilic molded product obtained in Example 1 did not swell with water at 37 ° C.

Further, the hydrophilic liquids (d-1) and (d'-
1) Apply 50 mW / cm ² (500 W / m ² )
Even after irradiation for 0 seconds, no cured product or gelled product was precipitated in the aqueous solution. When the aqueous solution was measured by gel permeation chromatography (GPC), the hydrophilic compounds in the aqueous solution were present at almost the same concentration, and the amount of the polymer produced was negligible.

[Example 2] (Preparation of hydrophilic liquid (d)) Mono (2-acryloyloxyethyl) acid phosphate (manufactured by Kyoeisha Chemical Co., Ltd.) was used as the hydrophilic compound (c) having a phosphoric acid residue. Light ester PA ") 10 parts, as a hydrophilic compound (c) having a heparin residue, 5 parts of methacrylated heparin used in Example 1, 0.5 parts of polyethylene glycol mono-4-nonylphenyl ether as a surfactant, And 84.5 parts of distilled water were uniformly mixed to obtain a hydrophilic liquid (d-
2) was obtained.

(Preparation of Surface Hydrophilic Molded Product) In Example 1, except that the hydrophilic liquid (d-2) was used in place of the hydrophilic liquids (d-1) and (d'-1), In the same manner as in Example 1, a coated hydrophilic surface molded article was produced.

Table 1 shows the results of the water contact angle, elemental analysis, heparin activity and blood compatibility of the thus obtained surface hydrophilic molded product. In addition, the thickness of the surface hydrophilic layer of the obtained surface hydrophilic molded product was so thin that it could not be observed with a scanning electron microscope. In addition, the support molded product of the surface hydrophilic molded product obtained in Example 2 did not swell with water at 37 ° C.

From the results shown in Table 1, it is clear that the same surface as in Example 1 can be obtained even when an aqueous solution in which two kinds of hydrophilic compounds are mixed is used.

Example 3 (Preparation of hydrophobic photopolymerizable composition) Hydrophobic compound (a)
98 parts of hexanediol diacrylate having two acrylic groups in one molecule (“New Frontier HDDA” manufactured by Daiichi Kogyo Seiyaku Co., Ltd.) and “Irgacure manufactured by Ciba Geigy, Inc.” as a photopolymerization initiator. 184 ")
And 2 parts were uniformly mixed to obtain a hydrophobic photopolymerizable composition (3).

(Preparation of Hydrophilic Liquid (d)) As the hydrophilic compound (c) having an amphoteric ion, 2-methacryloyloxyethyl-2 ′-(trimethylammonio) ethyl phosphate (alias: 2-methacryloyloxyethyl phosphorylcholine) 10 parts of a hydrophilic compound (c) having a heparin residue as a methacrylated heparin (described in Example 2 of JP-A-55-158555). Compound 5)
Parts, a surfactant, 0.5 parts of polyethylene glycol mono-4-nonylphenyl ether, and 8 parts of distilled water.
4.5 parts were uniformly mixed to obtain a hydrophilic liquid (d-3).

(Preparation of Surface-Hydrophilic Molded Product) After applying a hydrophobic photopolymerizable composition (3) to a thickness of 250 μm on a polystyrene sheet using a coater, it was pre-cured in air for 2 seconds and then cured. This pre-cured product is treated with a hydrophilic liquid (d-
3), and immediately put in 50 mW / cm ² (500 W /
m ² ) was irradiated for 40 seconds.

The cured product thus obtained was immersed in a 30% aqueous ethanol solution for 10 minutes, and then washed with running water for 10 minutes.
After washing for 1 minute, it was air-dried overnight to obtain a coated hydrophilic hydrophilic product.

Table 1 shows the results of the water contact angle, elemental analysis, heparin activity and blood compatibility of the thus obtained surface hydrophilic molded product. In addition, the thickness of the surface hydrophilic layer of the obtained surface hydrophilic molded product was so thin that it could not be observed with a scanning electron microscope. In addition, the support molded product of the surface hydrophilic molded product obtained in Example 3 did not swell with water at 37 ° C.

Example 4 (Preparation of hydrophobic photopolymerizable composition) Hydrophobic compound (a)
1 part of hexanediol diacrylate having two acrylic groups in one molecule (“New Frontier HDDA” manufactured by Daiichi Kogyo Seiyaku Co., Ltd.), and “Irgacure” manufactured by Ciba Geigy, Inc. as a photopolymerization initiator. 184 ")
0.05 parts and 99 parts of ethanol are mixed uniformly,
A hydrophobic photopolymerizable composition (4) was obtained.

(Preparation of Surface Hydrophilic Molded Product) Hollow Fiber for Artificial Lung Preliminarily Treated with Oxygen Plasma (Polyolefin Hollow Fiber “P-106” manufactured by Dainippon Ink and Chemicals, Inc.)
Was immersed in a hydrophobic photopolymerizable composition (4), irradiated with ultrasonic waves for 10 seconds, then the yarn was taken out, and ethanol was volatilized at room temperature to perform acrylate coating. Next, the coated yarn was immersed in the hydrophilic liquid (d-3) and immediately irradiated with 50 mW / cm ² (500 W / m ² ) ultraviolet light for 40 seconds.

The cured product thus obtained was immersed in a 30% aqueous ethanol solution for 10 minutes, and then immersed in running water for 10 minutes.
After washing for 1 minute, the mixture was air-dried overnight to obtain a hollow fiber-shaped surface hydrophilic molded product.

Table 1 shows the results of the water contact angle, elemental analysis, heparin activity and blood compatibility of the surface of the thus obtained surface hydrophilic molded product. In addition, the thickness of the surface hydrophilic layer of the obtained surface hydrophilic molded product was so thin that it could not be observed with a scanning electron microscope. In addition, the support molded product of the surface hydrophilic molded product obtained in Example 4 did not swell with water at 37 ° C.

[Example 5] (Preparation of hydrophilic liquid (d)) As a hydrophilic compound (c) having an ionic group, sodium sulfonate methacrylate ("Antox MS-2" manufactured by Nippon Emulsifier Co., Ltd.) was used.
N "20 parts, a hydrophilic compound having a heparin residue (c)
Methacrylated heparin “Hep-MO” previously synthesized from methacryloyloxyethyl isocyanate (“Karenz MOI” manufactured by Showa Denko KK) and heparin.
I ", 5 parts of polyethylene glycol mono-4-nonylphenyl ether as a surfactant, and 7 parts of distillation 7
4.5 parts were uniformly mixed to obtain a hydrophilic liquid (d-5).

(Preparation of Surface-Hydrophilic Molded Product) In Example 1, a hydrophilic liquid (d-5) was used in place of the hydrophilic liquids (d-1) and (d'-1). In the same manner as in Example 1, a coated hydrophilic surface molded article was produced.

Table 1 shows the results of the water contact angle, elemental analysis, heparin activity and blood compatibility of the surface of the surface hydrophilic molded product thus obtained. In addition, the thickness of the surface hydrophilic layer of the obtained surface hydrophilic molded product was so thin that it could not be observed with a scanning electron microscope. In addition, the support molded product of the surface hydrophilic molded product obtained in Example 5 did not swell with water at 37 ° C.

Example 6 (Preparation of hydrophobic photopolymerizable composition) Hydrophobic compound (a)
5 parts of hexanediol diacrylate having two acrylic groups in one molecule (“New Frontier HDDA” manufactured by Daiichi Kogyo Seiyaku Co., Ltd.) and “Irgacure 184 manufactured by Ciba Geigy Co., Ltd.” as a photopolymerization initiator. ") 0.
2 parts and 95 parts of ethanol were uniformly mixed to obtain a hydrophobic photopolymerizable composition (6).

(Preparation of hydrophilic liquid (d)) As a hydrophilic compound (c) having an amine, 15 parts of N, N-dimethylacrylamide (“DMAA” manufactured by Kojin Co., Ltd.) and a heparin residue As a hydrophilic compound (c), 5 parts of methacrylated heparin “Hep-MOI” previously synthesized from methacryloyloxyethyl isocyanate (“Karenz MOI” manufactured by Showa Denko KK) and heparin, and 80 parts of distilled water were uniformly mixed. Mix to form a hydrophilic liquid (d-6)
I got

(Preparation of Surface Hydrophilic Molded Product) Non-woven fabric cut into a circular shape having a diameter of 60 cm (MF manufactured by Japan Vilene Co., Ltd.)
-90 ") was immersed in the hydrophobic photopolymerizable composition (6), irradiated with ultrasonic waves for 20 seconds, the nonwoven fabric was taken out, and ethanol was volatilized at room temperature to coat the acrylate. Next, immediately after immersing this coated nonwoven fabric in the hydrophilic liquid (d-6), 50 mW / cm ² (50
(0 W / m ² ) of ultraviolet light for 40 seconds.

The cured product thus obtained was immersed in a 30% aqueous ethanol solution for 10 minutes, and then washed with running water for 10 minutes.
After washing for 1 minute, the mixture was air-dried overnight to obtain a non-woven surface hydrophilic molded product.

Table 2 shows the results of elemental analysis, heparin activity and blood compatibility of the thus obtained surface hydrophilic molded product. The water contact angle could not be measured because water drops dropped on the surface of the nonwoven fabric penetrated into the nonwoven fabric. In addition, the thickness of the surface hydrophilic layer of the obtained surface hydrophilic molded product was so thin that it could not be observed with a scanning electron microscope. In addition, the support molded product of the surface hydrophilic molded product obtained in Example 6 did not swell with water at 37 ° C.

[Example 7] (Preparation of hydrophilic liquid (d)) As a hydrophilic compound (c) having a sugar residue, 6-acryloyl (1-O-) n-butylglucoside (JP-A-10-53658) Example 8 of
10 parts, as a hydrophilic compound (c) having a heparin residue, methacryloyloxyethyl isocyanate ("Karenz MOI" manufactured by Showa Denko KK)
Methacrylated heparin “Hep”
-MOI ”5 parts, and 85 parts of distilled water were mixed uniformly,
A hydrophilic liquid (d-7) was obtained.

(Preparation of Surface-Hydrophilic Molded Product) In Example 1, a hydrophilic liquid (d-7) was used in place of the hydrophilic liquids (d-1) and (d'-1). In the same manner as in Example 1, a coated hydrophilic surface molded article was produced.

Table 2 shows the results of the water contact angle, elemental analysis, heparin activity and blood compatibility of the surface of the surface hydrophilic molded product thus obtained. In addition, the thickness of the surface hydrophilic layer of the obtained surface hydrophilic molded product was so thin that it could not be observed with a scanning electron microscope. Further, the support molded product of the surface hydrophilic molded product obtained in Example 7 did not swell with water at 37 ° C.

[Example 8] (Preparation of hydrophilic liquid (d)) As a hydrophilic compound (c) having an amino acid residue, methacryloyloxyethyl isocyanate ("Karenz MO" manufactured by Showa Denko KK) was used.
I ") and methacryloyloxyethylaminocarbonylglycine" Gly-MOI "1 synthesized from glycine
0 parts, as a hydrophilic compound (c) having a heparin residue, 5 parts of methacrylated heparin “Hep-MOI” synthesized from methacryloyloxyethyl isocyanate (“Karenz MOI” manufactured by Showa Denko KK) and heparin,
As a surfactant, polyethylene glycol mono-4-
0.5 parts of nonylphenyl ether and 84.5 of distilled water
Were uniformly mixed to obtain a hydrophilic liquid (d-8).

(Preparation of Surface Hydrophilic Molded Article) In Example 1, except that the hydrophilic liquid (d-8) was used instead of the hydrophilic liquids (d-1) and (d'-1), In the same manner as in Example 1, a coated hydrophilic surface molded article was produced. Table 2 shows the results of the water contact angle, elemental analysis, heparin activity, and blood compatibility of the surface of the thus obtained surface hydrophilic molded article. In addition, the thickness of the surface hydrophilic layer of the obtained surface hydrophilic molded product was so thin that it could not be observed with a scanning electron microscope. In addition, the support molded product of the surface hydrophilic molded product obtained in Example 8 did not swell with water at 37 ° C.

[Comparative Example 1] (Surface hydrophilic molded article having a hydrophilic layer composed of only a polymerizable compound having a phosphoric acid residue)
Example 1 on a polystyrene sheet using a coater
250 μm in thickness of the hydrophobic photopolymerizable composition (1) used in
m was applied to the hydrophilic liquid (d) used in Example 1.
-1), and immediately put in 50 mW / cm ² (500 W
/ M ² ) for 40 seconds.

The cured product thus obtained was immersed in a 30% aqueous ethanol solution for 10 minutes, and then washed with running water for 10 minutes.
After washing for 1 minute, it was air-dried overnight to obtain a surface hydrophilic molded product.

Table 2 shows the results of a water contact angle, an elemental analysis, a heparin activity and a blood compatibility test performed on the surface of the thus obtained surface hydrophilic molded product.

From the results shown in Table 2, it can be seen that the surface to which only the phosphoric acid residue is bound has a much higher number of blood cells and platelets,
It is clear that blood compatibility is lacking.

[Comparative Example 2] (Surface hydrophilic molded article having a hydrophilic layer consisting only of a polymerizable compound having a sulfone group) Sodium ethoxy methacrylate (20 parts of "Antox MS-2N" manufactured by Nippon Emulsifier Co., Ltd.) Then, 0.5 part of polyethylene glycol mono-4-nonylphenyl ether as a surfactant and 79.5 parts of distilled water were uniformly mixed to obtain a hydrophilic liquid.

Then, the hydrophobic photopolymerizable composition (1) used in Example 1 was applied to a thickness of 250 μm on a polystyrene sheet using a coater, and the resultant was coated in the hydrophilic liquid. Immediately after introduction, 50 mW / cm ² (500
(W / m ² ) for 40 seconds.

The cured product thus obtained was immersed in a 30% aqueous ethanol solution for 10 minutes, and then washed with running water for 10 minutes.
After washing for 1 minute, it was air-dried overnight to obtain a surface hydrophilic molded product.

The surface hydrophilic molded article thus obtained was subjected to water contact angle, elemental analysis, heparin activity and blood compatibility test, and the results are shown in Table 2.

From the results shown in Table 2, it is clear that the surface to which only the sulfone group is bonded has a far greater adhesion number of blood cells and platelets and lacks blood compatibility.

[Comparative Example 3] (Surface hydrophilic molded article having a hydrophilic layer consisting only of a polymerizable compound having a heparin residue) On a polystyrene sheet, using a coater, the hydrophobicity used in Example 1 was measured. Photopolymerizable composition (1) having a thickness of 25
After being applied to a hydrophilic liquid (d′-1), the composition applied to a thickness of 0 μm was irradiated with ultraviolet rays for 40 seconds.

The cured product thus obtained was immersed in a 30% aqueous ethanol solution for 10 minutes, and then washed with running water for 10 minutes.
After washing for 1 minute, it was air-dried overnight to obtain a surface hydrophilic molded product.

The surface hydrophilic molded article thus obtained was subjected to water contact angle, elemental analysis, heparin activity and blood compatibility test, and the results are shown in Table 2.

From the results shown in Table 2, it is clear that the surface to which only the heparin residue is bound also has a large adhesion number of blood cells and platelets and lacks blood compatibility.

[0115]

[Table 1]

[0116]

[Table 2]

1) Heparin reagent (Sodium Salt, Grade 1)
-A.SIGMA H-3393) ESCA elemental analysis results: [S] = 6.4%, [N] = 3.4%. 2) Measurement results by "Test Team Heparin S" manufactured by Daiichi Pure Chemicals Co., Ltd. 3) The number is directly counted from each electron microscope (SEM) photograph. Unit: Pieces / 10000μm ²

From the results shown in Tables 1 and 2, it can be understood that elements derived from heparin residues were detected on the surface of the surface hydrophilic molded product of each Example. Also, from the results of Comparative Example 3 shown in Table 2, it can be understood that elements derived from heparin residues were detected.

Hemolysis refers to the release of hemoglobin due to deformation and damage of red blood cells. Platelet adhesion and cohesive deformation are the largest causes of thrombus and blood coagulation.

[0120]

The surface hydrophilic molded article of the present invention exhibited good blood (bio) compatibility because the hydrophilic group and heparin residue coexist on the surface of the molded article.

The surface-hydrophilic molded product obtained by the production method of the present invention does not have a hydrophilic group and a heparin residue inside the molded product, so that the molded product does not swell and the original structure and physical properties of the molded product can be improved. There is an advantage that no loss occurs and no separation of the hydrophilic group and the heparin residue occurs. According to the method for producing a surface hydrophilic molded article of the present invention, a hydrophilic group and a heparin residue are covalently bonded only to the surface of the molded article,
In addition, the density and the like of hydrophilic groups bonded to the surface of the molded product can be easily controlled, and a molded product having high hydrophilicity and biocompatibility can be easily produced. Furthermore, according to the method for producing a surface hydrophilic molded product of the present invention, a molded product having high moldability and an arbitrary shape can be produced.

Continued on front page F-term (reference) 4C081 AB32 AB35 AC15 BA03 BA05 BB01 BB02 BB04 CA021 CA031 CA082 CA102 CA282 CB042 CC05 CC06 CC07 CD062 DA01 DA02 DA03 DA04 DA05 DC02 DC03 DC05 DC06 DC14 EA06 4F006 AA15 AA23 A03 A03 BA04 BA18 BA48 BB01 BB02 BB03 CA45 EA01 EA11 EA21 EA22 EA23 EA24 EA36 EA77 FA03 FA05 FA06 FA12 4J011 AC04 QA03 QA06 QA07 QA12 QA13 QA17 QA18 QA22 QA23 QA24 QA33 QA34 QA35 QA27 QA30 QA37 QA38 SA12 SA14 SA16 SA20 SA22 SA25 SA28 SA32 SA34 SA54 SA61 SA64 SA76 UA01 VA01 VA04 WA07 WA10

Claims (12)

[Claims] 1. A surface hydrophilicity comprising: (A) a polymerizable compound having a hydrophilic group other than a heparin residue, and (B) a hydrophilic layer comprising a polymerizable compound having a heparin residue on its surface. Moldings. 2. A polymerizable compound (A) having a hydrophilic group other than a heparin residue, comprising a sulfone group, a quaternary ammonium group,
The surface hydrophilic molding according to claim 1, which is a polymerizable compound having a hydrophilic group selected from the group consisting of a carboxyl group, a phosphoric acid residue, an amine residue, a polyethylene glycol chain, a sugar residue, an amino acid residue and a zwitterionic group. object. 3. The polymerizable compound (B) having a heparin residue is represented by the following general formula (1): [Wherein, R represents a direct bond, -O-, -CONHCH ₂ C
_{H 2 O -, - (CH} 2) m -O-, - (CH 2 CH 2 O) m
Or _{- (CH 2 CH (CH 3} ) O) m - (. Wherein, m is an integer of 1-9) represents, R ¹
And R ² each independently represent a hydrogen atom or a group having 1 to 6 carbon atoms.
R ³ represents a hydrogen atom or a methyl group, Hep represents a heparin residue, and n represents an integer of 1 or more. 3. The surface hydrophilic molded product according to claim 1, which is a heparin derivative represented by the following formula: 4. A thin film of a photopolymerizable composition containing a hydrophobic compound (a) having two or more polymerizable unsaturated double bonds in one molecule and a photopolymerization initiator. A first step of forming a shaped article (b) shaped into a thread, a bead, or any other shape; and (2) a hydrophilic property having a polymerizable unsaturated bond on the surface of the shaped article (b). A second step of contacting the hydrophilic liquid (d) containing the compound (c), and (3) irradiating the excipient (b) under the contact state with actinic rays to obtain (a) an excipient. (B) is cured, and (b) the hydrophobic compound (a) and the hydrophilic compound (c) are copolymerized at the interface between the excipient (b) and the hydrophilic liquid (d). The molecules of the hydrophilic compound (c) are chemically bonded to the surface of the excipient (b) of (a). (C) In the hydrophilic liquid (d), the contact interface A method for producing a surface hydrophilic molded article comprising a third step that does not cause a photopolymerization reaction except for the step (A), wherein the hydrophilic compound (c) having a polymerizable unsaturated double bond is a hydrophilic compound other than a heparin residue. A method for producing a surface hydrophilic molded product, comprising using a polymerizable compound having a group and (B) a polymerizable compound having a heparin residue. 5. The polymerizable compound (A) having a hydrophilic group other than a heparin residue comprises a sulfone group, a quaternary ammonium group,
The surface hydrophilic molding according to claim 4, which is a polymerizable compound having a hydrophilic group selected from the group consisting of a carboxyl group, a phosphoric acid residue, an amine residue, a polyethylene glycol chain, a sugar residue, an amino acid residue and a zwitterionic group. Method of manufacturing a product. 6. The method for producing a surface hydrophilic molded product according to claim 4, wherein the polymerizable compound (B) having a heparin residue is a compound represented by the general formula (1). 7. A thin film of a hydrophobic photopolymerizable composition containing a hydrophobic compound (a) having two or more polymerizable unsaturated double bonds in one molecule and a photopolymerization initiator. A first step of forming a shaped article (b) shaped into a thread, a bead, or any other shape; and (2) a shaped article (b) by irradiating the shaped article (b) with actinic rays. Is pre-cured, but a second step of maintaining at least the polymerizable unsaturated double bond on the surface of the excipient (b), and (3) A third step of contacting with a hydrophilic liquid (d) containing a hydrophilic compound (c) having a polymerizable unsaturated double bond, and (4) a pre-cured excipient (b) in the contact state ) Is irradiated with an actinic ray to (a) cure the excipient (b) and (b) excipient (b) and the hydrophilic liquid (d) At the interface with the polymer, the hydrophobic compound (a) and the hydrophilic compound (c) are copolymerized to chemically bond the molecules of the hydrophilic compound (c) to the surface of the hydrophobic excipient (b). (C) a method for producing a surface hydrophilic molded product comprising: a fourth step in which a photopolymerization reaction does not occur except for the contact interface in the hydrophilic liquid (d), wherein a polymerizable unsaturated double bond is formed. (A) a polymerizable compound having a hydrophilic group other than a heparin residue, and (B) a polymerizable compound having a heparin residue as the hydrophilic compound (c). Production method. 8. The polymerizable compound (A) having a hydrophilic group other than a heparin residue comprises a sulfone group, a quaternary ammonium group,
The surface hydrophilic molding according to claim 7, which is a polymerizable compound having a hydrophilic group selected from the group consisting of a carboxyl group, a phosphoric acid residue, an amine residue, a polyethylene glycol chain, a sugar residue, an amino acid residue and a zwitterionic group. Method of manufacturing a product. 9. The method according to claim 7, wherein the polymerizable compound (B) having a heparin residue is a compound represented by the general formula (1). 10. A molded article having a thin film, thread, bead, or other arbitrary shape, comprising (A) an ionic group, a carboxyl group,
Generating a radical in the presence of a polymerizable compound having a functional group selected from the group consisting of a phosphoric acid residue, an amine, a sugar residue, an amino acid residue and a zwitterion, and (B) a polymerizable compound having a heparin residue Thereby, the radical generated on the surface of the molded article reacts with the polysynthetic compound (A) and the polysynthetic compound (B), and the polymerizable compound (A) having a hydrophilic group other than heparin residue on the surface of the molded article ) And a polymerizable compound (B) having a heparin residue. 11. The polymerizable compound (A) having a hydrophilic group other than a heparin residue is a sulfone group, a quaternary ammonium group, a carboxyl group, a phosphoric acid residue, an amine residue, a polyethylene glycol chain, a sugar residue, and an amino acid. The method for producing a surface hydrophilic molded product according to claim 10, which is a polymerizable compound having a hydrophilic group selected from the group consisting of a residue and a zwitterionic group. 12. The method according to claim 10, wherein the polymerizable compound (B) having a heparin residue is a compound represented by the general formula (1).