JP2004189915A - Material composed of acrylic polymer having functional group and method for producing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To readily provide a material having a functional group by adding a polyalkylene glycol having a functional group to a material composed of an acrylic polymer. <P>SOLUTION: The material is composed of an acrylic polymer having a functional group having ≥10 wt.% water content. The material is preferably composed of the acrylic polymer having the functional group in which porosity of the material is ≥30%. <P>COPYRIGHT: (C)2004,JPO&NCIPI

Description

[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a material composed of an acrylic polymer having a functional group and a method for producing the same, and by easily contacting an aqueous solution containing a polyalkylene glycol having a functional group with a material composed of an acrylic polymer, the functional group is easily formed. Can be provided.
[0002]
[Prior art]
In recent years, materials having a functional group have been used as research materials such as affinity, and as reactive materials for producing medical materials into which ligands have been introduced. As a carrier material of a material for introducing a functional group, a polymer compound such as cellulose, a cellulose derivative, agarose, polyolefin, polyester, polystyrene, polyacrylonitrile, polymethyl methacrylate, polysulfone-based polymer, chitin, and chitosan is used. Have been. As the shape of these carriers, beads, fibers, hollow fiber membranes, flat membranes, gels and the like are used.
[0003]
However, when introducing a functional group into these carriers, an active group is introduced into the surface with cyanogen bromide, or an active group such as α-chloroacetamidomethyl group is introduced into the surface, and the functional group is introduced by a surface chemical reaction. It was necessary to introduce a group (for example, see Patent Document 1). These methods are frequently used in research applications, but when used in mass production such as medical material applications, the synthesis operation is complicated and a large amount of reactants and solvents are used. There is a problem that the production cost is increased, such as the occurrence of a problem.
[0004]
Acrylic polymers, particularly polymethacrylate polymers, are excellent in biocompatibility and are used for various separation membranes, films, hydrogels and the like, including intraocular lenses, contact lenses, and artificial kidneys. However, when a functional group is introduced into an acrylic polymer that is currently used, the functional group may be hydrolyzed (for example, see Non-Patent Document 1) or copolymerized with a monomer having a functional group. Similarly, the cost of introducing a functional group is a major problem in production. On the other hand, there is known a technique relating to a composition utilizing an interaction between a synthetic substance such as an acrylic polymer and a substance bonded to a polyalkylene glycol (see Patent Document 2). Immobilization of a physiologically active substance is possible.
[0005]
[Patent Document 1]
WO 97/027878 pamphlet [0006]
[Non-patent document 1]
Yoshihiro Ito et al., "Proceedings of National Academy of Sciences", National Academy of Sciences of the United States of America, 1996, 93 Vol., P. 3598-3601
[0007]
[Patent Document 2]
JP 2001-527539 A
[Problems to be solved by the invention]
In view of the above problems, the present invention provides a method that can easily and efficiently introduce a functional group into a material composed of an acrylic polymer, which is widely used, and a material that does not require a manufacturing cost. The purpose is to do.
[0009]
[Means for Solving the Problems]
In order to achieve the above object, the present invention has the following configurations. That is, a material made of an acrylic polymer having a functional group and having a water content of 10% by weight or more, and an aqueous solution containing a polyalkylene glycol having a functional group are brought into contact with a material made of an acrylic polymer in a water-containing state Then, a polyalkylene glycol is immobilized on the acrylic polymer to introduce a functional group into the acrylic polymer.
[0010]
BEST MODE FOR CARRYING OUT THE INVENTION
The acrylic polymer in the present invention is a polymer mainly composed of acrylic acid, methacrylic acid and derivatives thereof, specifically, polymethyl methacrylate, polymethyl acrylate, polyethyl methacrylate, polyethyl acrylate, polypropyl methacrylate. , Polypropyl acrylate, polybutyl methacrylate, polybutyl acrylate, polyphenyl methacrylate, polyphenyl acrylate, etc., and polymethyl methacrylate is preferable from the viewpoint of biocompatibility. The acrylic polymer used in the present invention may be appropriately used as a copolymer by copolymerizing other monomers.
[0011]
Polymethyl methacrylate preferably used in the present invention has an isotactic structure portion and a syndiotactic structure portion, but may use an isotactic-rich polymer alone or a syndiotactic-rich polymer alone. May be used. However, polymethyl methacrylate with high isotacticity and polymethyl methacrylate with high syndiotacticity can form a structural entanglement under certain conditions, that is, a so-called stereo complex. Those having a complex structure are desirable.
[0012]
As the isotactic polymethyl methacrylate, those having an isotactic structure (triad display) of 50% or more, preferably 70% or more are used. The three-dimensional structure of polymethyl methacrylate can be quantitatively determined by a nuclear magnetic resonance absorption method. Isotactic polymethyl methacrylate is generally obtained by polymerization using a Grignard reagent or an organometallic compound such as alkyl lithium. According to such a method, it is possible to obtain a polymer having an isotactic structure content of 90% or more. is there.
[0013]
On the other hand, syndiotactic polymethyl methacrylate having high syndiotacticity can be obtained by ordinary radical polymerization. In this case, a vinyl group containing an anionic group such as a carboxyl group or a sulfonic acid group, a quaternary ammonium group, a cationic group such as an amino group, and a nonionic group such as hydroxyethyl methacrylate or acrylamide. It is also possible to copolymerize one or more monomers and the like. If necessary, a mixture of several kinds of polymethyl methacrylate homopolymers, polymers having different molecular weights, or different types of copolymers may be used.
[0014]
The average molecular weight of the polymethyl methacrylate-based polymer is usually preferably 100,000 or more in consideration of the structure, mechanical properties, and spinnability of the target material.
[0015]
The form of the material is not particularly limited, such as fibrous, spherical, flat membrane, or hollow fiber membrane.
[0016]
The polymethyl methacrylate polymer used in the present invention can be produced, for example, by a known dry-wet spinning method. As the solvent for the stock solution of the polymethyl methacrylate polymer, any solvent that dissolves the polymethacrylate polymer showing a sol-gel change can be used, but a solvent that gels at an appropriate temperature when the stock solution is cooled is preferable. used. Furthermore, water is preferably used as a coagulant for removing the solvent during coagulation to obtain a product, and therefore, a solvent that can be easily replaced with water is particularly preferable. For this purpose, dimethyl sulfoxide, dimethylformamide, acetonitrile, acetic acid, acetone, methyl ethyl ketone, and a mixture thereof are used.
[0017]
In addition, the polymer concentration of the stock solution of polymethyl methacrylate-based polymer also contributes to the structure, mechanical properties, or spinnability of the material in the same manner as the molecular weight. It is preferable that the polymer concentration in the medium is set in the range of 5 to 30% by weight, more preferably 10 to 30% by weight.
[0018]
Further, in order to control the pore size of the material, it is a common practice to add a third additive such as polyhydric alcohol, water, salt, or the like.
[0019]
The viscosity of the stock solution of the polymethyl methacrylate-based polymer obtained in this way is a factor that is closely related to spinnability when producing a fibrous or hollow fiber membrane, and the shape and dimensions of the die used or the controllable temperature It is preferable to determine in consideration of the range, the sol-gel change temperature, and the like. Usually, it is preferably 10 to 8000 poise, more preferably 100 to 3000 poise. That is, by appropriately selecting the polymer concentration and the molecular weight, it becomes possible to set optimal spinning stock solution conditions.
[0020]
Next, an example of producing a hydrated polymethyl methacrylate-based material in the form of a hollow fiber membrane preferably used in the present invention will be described.
[0021]
Usually, the dry-wet spinning method used for spinning the hollow fiber membrane is a method in which the discharged yarn is stretched in the air, set to a predetermined size, and then guided to a coagulation bath for coagulation and desolvation, Generally used widely.
[0022]
The hollow fiber uses a multi-slit that allows the flow of a liquid or gas for forming a hollow part inside and a spinning solution in which a polymer is dissolved in a solution on the outside, and discharges these liquids and gases to a coagulation bath. Is obtained by Examples of the liquid injected into the inside include, for example, a solvent for the spinning dope and a coagulant such as water or alcohol, a mixture thereof, or a hydrophobic liquid such as a non-solvent for the copolymer or a mixture thereof. For example, aliphatic hydrocarbons such as n-octane and liquid paraffin, and fatty acid esters such as isopropyl myristate can be used. When a hydrophilic coagulant is used, a hydrophilic polymer component having a high affinity for the coagulant moves to the inner surface of the membrane and solidifies. In addition, when the discharged yarn gels due to a temperature change in the air or quickly forms a strong structure by solidification, an inert gas such as nitrogen gas or air can be used by self-suction or press-fitting. . Such a gas injection method is a very advantageous method from the viewpoint of the process. In the case of a stock solution in which gelation is caused by a change in temperature, cold air can be blown in the dry portion to promote gelation. In general, the thickness of the hollow fiber is controlled by the discharge amount of the spinning solution, and the inner diameter is controlled by the amount of the injected liquid or gas.
[0023]
The distance from the discharge mouth to the bath liquid, the so-called dry portion length (hereinafter abbreviated as dry length), is set at a certain distance in the aerial portion in the state of the sol in order to stretch the shape of the discharged sol to the target size. It is preferable to draft. On the other hand, it is preferable to increase the dry length to some extent in order to reduce the yarn drafting stability due to a rapid draft. At the same time, if the dry length is too long, the deformation of the sol becomes unstable, and the dimensional stability of the hollow fiber tends to deteriorate. Therefore, the dry length is preferably 1 mm or more and 30 mm or less, and more preferably 2 mm or more and 20 mm or less.
[0024]
The liquid bath for gelling the discharged sol and fixing the shape of the hollow fiber may only perform gelation, but it is often advantageous in terms of the process to simultaneously perform the desolvation together with the gelation. Used as Thus, its composition and especially its temperature can also affect the permeation properties of the hollow fiber. In general, as the coagulation bath temperature increases, the permeability (pore size) of the membrane increases, but the dimensional stability tends to decrease. Therefore, conditions according to the characteristics of the target hollow fiber are selected. It is preferable that it is -70 degreeC, Furthermore, it is preferable that it is 20-50 degreeC. The coagulation bath usually consists of a coagulant such as water or alcohol, or a mixture with a solvent constituting the spinning dope. The composition of the coagulation bath affects the spinning stability and the membrane structure of the hollow fiber depending on its coagulability.
[0025]
The thus obtained hollow fiber gel is sufficiently washed with water to obtain a hydrogel structure containing water molecules in the pores of the membrane. Once the water-containing gel structure is dried, it is difficult to return to the original water-containing gel structure. Therefore, a humectant such as glycerin is applied to the film so that the film structure is not destroyed by drying, and modularization is performed.
[0026]
In the case of a dried polymethacrylate-based porous material, it does not become hydrated even when immersed in water, but after being immersed in ethanol or the like having a small surface tension once, it is gradually hydrated by being gradually replaced with water. It is possible.
[0027]
The water content in the present invention means that the water content is 10% by weight or more. The material composed of the acrylic polymer having a functional group of the present invention needs to have a water content of 10% by weight or more. is there. The water content refers to a value obtained by multiplying 100 by a value obtained by dividing the weight of water in a material containing water by the weight of a material in a water-containing state. Specifically, the water on the surface of the material containing water is wiped off, the weight is measured, the material is sufficiently dried, and the dry weight is measured to calculate the weight of the water contained.
[0028]
In the functional group-containing material of the present invention, the higher the moisture content of the material, the higher the immobilization efficiency of the functional group-containing polyalkylene glycol. Therefore, the water content needs to be 10% by weight or more, preferably 30% by weight or more.
[0029]
In order to make the material water-containing, the material is preferably porous. The higher the porosity of the porous material, the higher the water content can be achieved. The porosity here is calculated by the following equation.
A: Dry weight of actual material (g)
B: Weight (g) of the material assuming that the material has no pores (value obtained by multiplying the volume assuming that the material has no pores by the specific gravity of the material)
Porosity = {1− (A / B)} × 100
The porosity is preferably as high as possible, but is preferably 30% or more, more preferably 50% or more, in order to make the water content 10% by weight or more.
[0030]
The shape of the material may be anything such as a flat membrane, a particle, a hollow fiber, a fiber, a sponge, or a cut fiber.However, when a functional group is introduced, a ligand is immobilized, and the material is used for blood purification or cell culture. A hollow fiber membrane is preferred because it has the advantage of being able to circulate without damaging cells in a closed system without pressure loss. In addition, it is preferable that these materials are porous from the viewpoint of securing a surface area and a condition of containing water. When used as a porous material, it can impart dialysis and filtration functions, and can be used not only for blood purification but also for cell culture such as bioreactors. In the case of a porous material, the pores can be controlled by controlling the manufacturing conditions.
[0031]
The functional group in the present invention may be any one having a structural formula having various chemical properties, such as an amino group, a hydroxyl group, a carboxyl group, a succinimide group, and a mercapto group. , A pyridyl disulfide group, an imidazolyl carbamic acid group, an epoxy group, an aldehyde group, biotin and the like.
[0032]
Introduction of a functional group into the acrylic polymer can be achieved by adding an aqueous solution containing a polyalkylene glycol having a functional group to the water-containing acrylic polymer. It is considered that the polyalkylene glycol is immobilized on the material composed of the acrylic polymer by hydrophobic interaction and hydrogen bonding.
[0033]
The polyalkylene glycol having a functional group may be synthesized, but it is desirable to use a commercially available product. For example, those having a hydroxyl group, those having a carboxyl group, those having an amino group, those having a mercapto group, those having a succinimide group, those having a pyridyl disulfide group, those having an epoxy group, imidazolyl carbamic acid groups, and aldehydes Those having a group, an isocyanate group, biotin and the like are commercially available from Shearwater. The functional group may be at the terminal of the polyalkylene glycol, in the side chain, or in the main chain. In the case of a terminal functional group, it may be both terminals or one terminal.
[0034]
The polyalkylene glycol in the present invention is a hydrophilic chain polymer containing an oxygen atom in the main chain represented by, for example, polyethylene glycol or polypropylene glycol, but is a polymer in which a part of the polyalkylene glycol is modified. May be. The molecular weight of the polyalkylene glycol is not particularly limited, and those having a number average molecular weight of about 1,000 to 20,000 are used. The optimum molecular weight in consideration of the adsorption ability to the substrate is, for example, 2,000 to 2,000. Those having about 10,000 are preferably used.
[0035]
When the material is used as a blood purification column, particularly when a hollow fiber is used, it is produced as follows, but is not particularly limited. An example is as follows. First, the hollow fiber membrane is cut into a required length, bundled in a required number, and then placed in a cylindrical case. Thereafter, temporary caps are put on both ends, and a potting agent (for example, a two-component polyurethane adhesive) is put into both ends of the hollow fiber membrane. At this time, a method of adding the potting agent while rotating the module with a centrifuge is a preferable method because the potting agent is uniformly filled. After the potting agent is solidified, both ends are cut so that both ends of the hollow fiber membrane are open, and a hollow fiber membrane module is obtained.
[0036]
【Example】
Examples are shown below, but the present invention is not limited to these.
[0037]
The concentration of the polyethylene glycol having a functional group was measured by high performance liquid chromatography (eluent: 0.2 M phosphate buffer, pH 8.0, column: Tosoh G3000SWXL, apparatus: Tosoh Corporation, HPLC system, flow rate: 1. 0 ml / min).
[0038]
The immobilization rate was determined from the concentration of polyethylene glycol having a functional group by the following equation.
Immobilization rate = concentration of polyethylene glycol having a functional group before mixing−concentration after mixing / concentration before mixing
[Preparation Example 1 Preparation of stereocomplex polymethyl methacrylate (PMMA) hollow fiber]
137 g of syndiotactic (syn) -PMMA having a weight average molecular weight of 400,000 by polystyrene conversion, 80 g of syn-PMMA having a weight average molecular weight of 1.4 million, and 35 g of isotactic (iso) -PMMA having an average molecular weight of 500,000 were converted into dimethyl sulfoxide. The mixture was mixed with 1185 g and stirred at 110 ° C. for 8 hours to prepare a spinning dope.
[0039]
The obtained spinning stock solution was discharged into the air at a rate of 1.1 g / min from an annular slit type hollow die having an outer diameter / inner diameter of 2.1 / 1.95 mmφ kept at 99 ° C. At the same time, nitrogen gas was injected into the hollow interior. The length of the dry portion was 60 cm, and water at 40 ° C. was used for the coagulation bath. After the coagulated hollow fiber was washed with water, it was subjected to a 5% relaxation heat treatment at 75 ° C. and a 73% aqueous glycerin solution and sampled. The inner diameter / film thickness of the hollow fiber was 200/30 μm. The obtained hollow fiber was sterilized by gamma irradiation at 25 kGy.
[0040]
[Production Example 2 Production of stereo complex non-forming PMMA hollow fiber]
198 g of syn-PMMA having a weight-average molecular weight of 400,000 by polystyrene conversion and 154 g of syn-PMMA having a weight-average molecular weight of 1.4 million were mixed with 1655 g of dimethyl sulfoxide, and stirred at 110 ° C. for 8 hours to prepare a spinning dope.
[0041]
The obtained spinning dope was discharged into the air at a rate of 1.1 g / min from an annular slit-type hollow die having an outer diameter / inner diameter of 2.1 / 1.95 mmφ kept at 99 ° C. At the same time, nitrogen gas was injected into the hollow interior. The length of the dry portion was 60 cm, and water at 40 ° C. was used for the coagulation bath. The coagulated hollow fiber was washed with water, subjected to a 5% relaxation heat treatment at 75 ° C. and a 73% glycerin aqueous solution, and sampled. The inner diameter / film thickness of the hollow fiber was 200/30 μm. The obtained hollow fiber was sterilized by gamma irradiation at 25 kGy.
[0042]
[Preparation Example 3 Preparation of stereo complex non-formed PMMA flat membrane]
10% by weight of syn-PMMA having a polystyrene-equivalent weight average molecular weight by GPC method of 400,000 was mixed with dimethyl sulfoxide and stirred at 80 ° C. for 8 hours to prepare a stock solution. This solution was applied to a glass plate at 80 ° C. with a 0.1 mm spacer, and the solution obtained by stretching the solution with a doctor blade was placed in water and solidified to produce a flat film material made of PMMA. The obtained flat membrane was sterilized by gamma irradiation at 25 kGy.
[0043]
[Preparation Example 4 Preparation of PEG Having Mercapto Group]
N-succinimidyl 3 was added to aminated methoxy PEG (Shearwater, molecular weight 5000, one terminal amino group, one terminal methoxy group) dissolved at 5 mg / ml in 20 mM phosphate buffer (pH 7.5) containing 0.15 mM NaCl 3 A 5-fold molar amount of a solution of-(2-pyridyldithio) -propionate (SPDP, manufactured by Pierce, Inc.) dissolved in 20 mM was added thereto, and reacted at room temperature for 30 minutes. Then, dithiothreitol (Pierce) was added. The solution was added to a concentration of 25 mM to obtain methoxy PEG having a mercapto group at one end.
[0044]
<Example 1, Comparative Example 1>
0.36 g (dry weight: 0.1 g) of the PMMA flat membrane (water content: 75% by weight) obtained in Preparation Example 3 was added to 1 ml of a 500 ppm aqueous solution of commercially available aminated methoxy PEG (molecular weight: 5,000, Shearwater). However, the aminated methoxy PEG was immobilized (80%), and a material having an amino group could be produced. On the other hand, it was not immobilized on the dried flat membrane (Comparative Example 1).
[0045]
<Example 2, Comparative Example 2>
0.86 g (dry weight 0.15 g) of the hollow fiber obtained in Preparation Example 1 (water content: 83% by weight, porosity: 80%) was added to 1 ml of a 5100 ppm aqueous solution of commercially available biotin PEG (molecular weight: 3400, Shearwater). Upon addition, the biotinylated PEG was immobilized (95%), and a biotin-immobilized material could be produced. On the other hand, it was not immobilized on the dried hollow fiber (Comparative Example 2).
[0046]
<Example 3, Comparative Example 3>
0.96 g (dry weight: 0.2 g) of the hollow fiber (water content: 79% by weight, porosity: 75%) obtained in Preparation Example 2 in 1 ml of a 500 ppm aqueous solution of a commercially available antibody made of epoxy PEG (molecular weight: 5000, Shearwater) ) Was added, the epoxidized PEG was immobilized (95%), and a material having an epoxy group introduced could be produced. On the other hand, it was not immobilized on the dried hollow fiber (Comparative Example 3).
[0047]
<Example 4>
After filling Toray's artificial kidney “Filt Riser” (BK-1.0F) made of PMMA hollow fiber membrane sterilized with 25 kGy with γ-ray with 500 ppm of methoxy PEG having a mercapto group at one end obtained in Preparation Example 4 , Washed with water. 120 mg of PEG having a mercapto group was immobilized per module, and a column comprising a material into which the mercapto group had been introduced could be prepared.
[0048]
【The invention's effect】
According to the present invention, a material having a functional group can be easily provided by adding a polyalkylene glycol having a functional group to a material composed of an acrylic polymer.

Claims (5)

A material comprising an acrylic polymer having a functional group, wherein the material has a water content of 10% by weight or more. 2. The material comprising an acrylic polymer having a functional group according to claim 1, wherein the porosity of the material is 30% or more. The material comprising an acrylic polymer having a functional group according to claim 1, wherein the acrylic polymer is polymethyl methacrylate. The material comprising a functional group-containing acrylic polymer according to any one of claims 1 to 3, wherein the material contains a polyalkylene glycol. A method for producing a material comprising an acrylic polymer having a functional group, comprising contacting an aqueous solution containing a polyalkylene glycol having a functional group with a material comprising an acrylic polymer.