JPH02284901A - Production of porous polymer particles - Google Patents

Abstract

PURPOSE:To obtain the title particles of uniform and large particle size, being suitably used as a medical material by adding ricinolic acid ester to a monomer mixture containing a crosslinking vinyl monomer and a non-crosslinking vinyl monomer and subjecting the mixture to suspension polymerization in an aqueons medium. CONSTITUTION:A ricinolic acid ester as a poring solvent is added to a crosslinking vinyl monomer preferably divinylbenzene and a noncrosslinking vinyl monomer (preferably glycidyl methacrylate) and the mixture is subjected to suspension polymerization in an aqueous medium to give the subject polymer particles.

Description

Detailed Description of the Invention [Field of Industrial Application] The present invention relates to a method for producing porous polymer particles, and more particularly, to an adsorbent for adsorbing and removing various substances, particularly for use in blood purification in the medical field. The present invention relates to a method for producing porous polymer particles useful as adsorbents for industrial applications.

[Conventional technology and its problems]

Conventionally, adsorbents, separation agents, chromatography packing materials,
Porous polymer particles are used as carriers for immobilized enzymes, etc., and recently in the medical field, they have been used as adsorbents to remove harmful substances from blood or as adsorbents for cell separation. Its usefulness is attracting attention.

As a method for producing porous polymer particles used in the above applications, the present inventors added this mixed monomer to a mixed monomer of divinylbenzene, which is a crosslinkable vinyl monomer, and glycidyl (meth)acrylate, which is a non-crosslinkable vinyl monomer. 4-Methyl-2-pentanol, which is soluble in but not in the resulting polymer, is added as a pore-forming solvent, and after suspension polymerization in an aqueous dispersion medium, the porosity-forming solvent is removed. (Japanese Patent Laid-Open Publication No. 149712/1982).

The above method uses polymer particles that are useful as adsorbents or adsorbent carriers for various substances, from high molecular weight substances (e.g., biologically related substances such as bilirubin) to low molecular weight substances (e.g., carbon dioxide gas). Although this method is excellent in that it can be manufactured, this method or the porous polymer particles obtained by this method have the following problems.

(a) In order to obtain polymer particles with a large particle size, it is common to lower the stirring speed during suspension polymerization, but when the stirring speed is lowered in the above method, the mixing monomer and porous solvent The mixed liquid undergoes phase separation on the aqueous dispersion medium, making it difficult to maintain a good suspension state, and therefore difficult to stably obtain polymer particles with large particle diameters.

(b) The polymer particles obtained by this method are as described above (
For reasons such as a), the particle size is generally 150 to 4
Since it is small at 00 μm or less and has a wide particle size distribution, a classification operation is required to make the particle size uniform.
Therefore, the yield is not so high.

(C) When the polymer particles obtained by this method are used to fill a column for blood purification by direct blood perfusion, the voids in the column may become uneven or the packing may become too fine. As a result, the pressure of perfused blood increases significantly, making it easy to form a thrombus.

As a result of studies to solve the above-mentioned problems, the present invention has developed a porous polymer having a large particle size and uniform particle size by using a specific porous solvent. The present invention was completed based on the discovery that particles can be manufactured easily and the above problems can be solved.

[Means to solve the problem]

That is, in the method for producing porous polymer particles of the present invention, a porosity-forming solvent is mixed with a monomer mixture of a crosslinkable vinyl monomer and a non-crosslinkable vinyl monomer, and this is mixed in an aqueous medium! !
The method is characterized in that ricinoleic acid ester is used as a pore-forming solvent in producing porous polymer particles through turbidity polymerization.

In the method of the present invention, the crosslinkable vinyl monomer is
Various known crosslinkable vinyl monomers can be used, including (a) aromatic vinyl monomers having two or more unsaturated hydrocarbon groups in one molecule; and (b) two or more unsaturated hydrocarbon groups in one molecule. It is preferable to appropriately select and use a vinyl monomer consisting of a polyol ester of (meth)acrylic acid having a (meth)acryloyl group, and specific examples of the vinyl monomer include divinylbenzene, divinyltoluene, divinylnaphthalene, etc. aromatic polyvinyl compounds, and ethylene glycol di(meth)acrylate, triethylene glycol di(
meth)acrylate, polyethylene glycol di(meth)acrylate, propylene glycol di(meth)acrylate, trimethylolpropane tri(meth)acrylate, pentaerythritol tetra(meth)acrylate, 1,3-butylene glycol diacrylate,
It is a polyol ester of (meth)acrylic acid such as 1,6-hexanethiol di(meth)acrylate, and these crosslinkable vinyl monomers can be used alone or in a mixture of two or more, and in particular, divinylbenzene is used. is preferable.

Furthermore, as the non-crosslinkable vinyl monomer, various vinyl monomers other than the above-mentioned crosslinkable vinyl monomers can be used, but (a) (meth)acrylic acid having one (meth)acryloyl group in one molecule; It is preferable to appropriately select and use esters and (b) aromatic vinyl monomers having one unsaturated hydrocarbon group in one molecule. Specific examples thereof include methyl (meth)acrylate, ethyl ( meth)acrylate, butyl(meth)acrylate, glycidyl(meth)acrylate, (represented by the following general formula [1])
meth)acrylic acid ester oligomer (wherein R is a hydrogen atom or a methyl group, which may be the same or different, and Z is a divalent organic group having 2 to 20 carbon atoms; each may be the same or different, and n is an integer of 1 to 100), and (meth)acrylic esters such as
There are aromatic monovinyl monomers such as styrene, methylstyrene, chlorostyrene, and vinylnaphthalene, and these vinyl monomers can be used alone or in a mixture of two or more, and among them, (meth)acrylic esters, In particular, it is preferable to use glycidyl (meth)acrylate and/or (meth)acrylic acid ester oligomers represented by the above general formula [I].

The non-crosslinkable vinyl monomer includes glycidyl (meth)acrylate and (meth)acrylate represented by the general formula [I].
When using a mixture of acrylic ester oligomers,
Such a combination of monomers is particularly preferred in the present invention, since the antithrombotic properties of the resulting porous polymer particles are maintained well, and selective adsorption properties for adsorbing only specific components in blood are imparted. .

In addition, among the (meth)acnolic acid ester oligomers represented by the above general formula [I], it is preferable that the organic group represented by Z has 2 to 10 carbon atoms, particularly 2 to 5 carbon atoms. Preferably, 2 to 3 ethylene or propylene groups are most preferred. Specific examples of such (meth)acrylic acid ester oligomers include hydroxyethyl (meth)acrylate oligomer, hydroxypropyl (meth)acrylate oligomer, hydroxybutyl (meth)acrylate oligomer, and hydroxyhexyl (meth)acrylate. These oligomers can be used alone or in combination of two or more.

There is no particular limitation on the mixing ratio of the (meth)acrylic ester oligomer when mixed with the above-mentioned glycidyl (meth)acrylate, but as the amount of the (meth)acrylic ester oligomer increases, the resulting porous particles become smaller. Although antithrombotic properties are good, water resistance, mechanical strength, etc. tend to decrease, so glycidyl (meth)acrylate: (meth)acrylic acid ester oligomer
0 to 95% by weight: preferably in the range of 50 to 5% by weight.

The above crosslinkable vinyl monomer and non-crosslinkable vinyl monomer,
The mixing ratio is not particularly limited in the present invention, and depends on the use of the obtained copolymer particles.
For example, when used as an adsorbent for blood purification, the mixing ratio of crosslinkable vinyl monomer and non-crosslinkable vinyl monomer is 50% by weight.
~99% by weight: preferably in the range of 50 to 1% by weight.

In the present invention, ricinoleic acid ester used as a porosity-forming solvent is an important component for obtaining uniform porous polymer particles with a large particle size through suspension polymerization. Specific examples include methyl ricinoleate, ethyl ricinoleate,
These include ricinoleic acid alkyl esters such as 0-butyl ricinoleate, and esterified products of ricinoleic acid and dihydric alcohol such as ethylene glycol monoricinolate and brobylene glycol monoricinoleate.

In the method of the present invention, porous polymer particles having large particle diameters and uniform particle sizes can be obtained by using the above-mentioned ricinoleic acid ester as a porosity-forming solvent. This is thought to be due to its relatively high specific gravity and high viscosity.

That is, when a ricinoleic acid ester having a large specific gravity is mixed as a pore-forming solvent with the crosslinkable and non-crosslinkable vinyl monomers, the specific gravity of the mixed solution of the vinyl monomer and the ricinoleic acid ester will inevitably increase, and as a result,
The difference in specific gravity with the aqueous dispersion medium during suspension polymerization is relatively reduced,
Even when the stirring speed is reduced, the problem of phase separation of the monomer mixture is eliminated, and a stable suspension state can be maintained. In addition, due to the high viscosity of the porous solvent,
Stirring during suspension polymerization does not cause the monomer mixture to be finely dispersed more than necessary, and in combination with low-speed stirring, polymer particles with large particle diameters and uniformity are formed.

The porosity-forming solvent used in the present invention refers to a "solvent that is completely compatible with the mixed monomers but does not dissolve the polymer produced by polymerization," and is used to suspend the mixed monomers in the presence of the solvent. When polymerized, extremely fine secondary polymer particles, most of which have a diameter of 1 μm or less, are produced, which aggregate to form polymer particles with a porous structure generally referred to as macroreticular porous resin.

In addition, as the porosity-forming solvent used in the present invention, other porosity-forming solvents may be used in combination with the above ricinoleic acid ester as needed. Monohydric alcohol (however, ter
(excluding t-amyl alcohol), and specific examples include n-amyl alcohol, n-octyl alcohol, 4-methyl-2-pentanol, 3,5.5-)limethylhexanol, lauryl alcohol, - Ethylhexyl alcohol, diisobutyl carbinol, etc., and these may be mixed alone or in combination of two or more with the ricinoleic acid ester. In addition,
When mixing the above-mentioned -hydric alcohol with ricinoleic acid ester, there is no particular limitation on the mixing ratio. tends to phase separate in the upper part, making it impossible to obtain particles with a large particle size. For this reason, it is preferable that the mixing ratio of alcohols be limited to 50% by weight.

Is the above porosity forming solvent made of the above crosslinkable vinyl monomer and non-crosslinkable vinyl monomer? It is preferable to use the mixture in an amount of 40 to 200 parts by weight, particularly 80 to 120 parts by weight, per 100 parts by weight of the monomer. If the mixing ratio is less than 40 parts by weight, a good porous structure may not be formed and preferred adsorption performance may not be obtained; on the other hand, if it exceeds 200 parts by weight, the strength of the porous particles obtained becomes weak,
There may be a drawback that it cannot withstand handling during use.

The suspension polymerization in the present invention is not special per se, and can be carried out by a conventionally known suspension polymerization method. - An example is a method in which a conventional amount of polymerization initiator is added to the above mixed monomer and porous solvent mixture, if necessary, and suspension polymerization is carried out in an aqueous dispersion medium according to a conventional method. The combined particles are treated with an appropriate purification step to remove the porous solvent and unreacted monomers remaining in the particles, resulting in porous polymer particles useful for uses such as adsorbents. It can be done.

The method of the present invention has been explained above using the adsorbent used in the direct blood reflux method as an example. However, the method of the present invention is not limited to the method for manufacturing the adsorbent described above, and the method can be applied from low molecular weight substances to high molecular weight substances. It goes without saying that the present invention can be applied to the production of porous polymer particles useful as adsorbents for various substances with a wide range of molecular weights, or as adsorbent carriers.

[Example] Hereinafter, the present invention will be described in further detail based on Examples.

Example-1 In a separable flask equipped with a stirring blade and a condenser installed in a water bath, 1200 g of ion-exchanged water, 24 g of a dispersant (6% polyvinyl alcohol aqueous solution), and
NaCl Bog was added and dissolved to form an aqueous phase. This is divinylbenzene (divinylbenzene content 5
A mixture of 204 g of 5% industrial divinylbenzene) and 136 g of glycidyl methacrylate, 240 g of methyl ricinoleate (porous solvent), and 3.6 g of benzoyl peroxide (polymerization initiator) was stirred. In addition, suspension polymerization was carried out over 7 hours while stirring at 150 rpm while raising the external temperature stepwise from 60°C to 90°C.

After filtering the particles from the resulting reaction solution, the particles are first mixed with water,
Next, it was thoroughly washed with methanol, further purified by Soxhlet extraction with acetone until it reached a constant weight, and dried. Porous polymer particles were obtained with a yield of 93% based on the monomers charged. In addition, this polymer particle has a surface area of 419.7 g and a pore volume of 1°34 m.
It had a porous structure of Q/g.

In addition, the stirring speed during suspension polymerization was set to 130 and 1100 r.
Except that p was used, suspension polymerization was carried out with the same composition and under the same conditions as above, and porous polymer particles were produced under conditions with different stirring speeds.

Each of the porous polymer particles obtained as described above was tested using the test method below, and the results are shown in Table 1 below.
It was shown to.

1) Particle size distribution: Sample a part of the obtained porous polymer particles, measure the particle size of the sieved portion by a method, and plot it on a logarithmic probability diagram to obtain the "mass-based 50% diameter (
Ds@(μm)], and geometric standard deviation [σ,
] and evaluate the particle size distribution based on this value.

(2) Antithrombotic properties: Antithrombotic properties are evaluated using the following procedures (a) to (c).

(a) Hydrophilization treatment of porous polymer particles; dried porous polymer particles have poor affinity with water, and even when immersed in an aqueous solution, it is difficult for the air in the pores to replace the aqueous solution. The particles are placed in ethanol and thoroughly washed with degassed water,
The particles are filtered to form a wet powder with a moisture content of about 60% by weight.

(b) Preparation of a column packed with porous polymer particles; Using physiological saline, the porous particles hydrophilized in the above (a) were packed into a column with a capacity of 200Q, and sterilized using high-pressure steam (118°C
x 30 minutes) and subjected to the following animal test.

(c) Animal test: A shunt was placed between the carotid arteries and veins of domestic rabbits, and a direct blood perfusion experiment was performed using the packed column in (b) above at a flow rate of 5 @ ρ/min, and the column pressure was changed over time. and the number of platelets in the blood, and the antithrombotic properties are evaluated by the increase in column pressure and the change in platelet count (reduction rate %).

Example-2 The composition of the mixed monomer used in Example-1 above was: ethylene glycol dimethacrylate
132 g glycidyl methacrylate 36 g hydroxyethyl acrylate oligomer (manufactured by Nippon Shokubai Kagaku Kogyo Co., Ltd., HE-20) 36 g, and the porosity solvent was replaced with ethyl ricinoleate. Porous polymer particles were produced in the same manner as above, and the particle size distribution was measured in the same manner. The results are shown in Table 1 below.

Comparative Example-1 The pore-forming solvent in Example-1 above was replaced with 4-methyl-2-pentanol instead of methyl ricinoleate.
Porous polymer particles were produced in exactly the same manner as in the examples, and each of the obtained particles was tested in the same manner, and the results are shown in Table 1 below.

(Left below) As is clear from the results in Table 1 above, the methods of Examples 1 and 2, which correspond to the present invention, can produce large-sized particles with a uniform particle size distribution even when the stirring speed during suspension polymerization is changed. Particles were stably obtained, there was almost no pressure increase in the perfused blood even after long-term direct blood perfusion, and only a small amount of thrombus formation was observed, indicating that the porous polymer particles had extremely excellent performance. .

On the other hand, in the conventional method in which ricinoleic acid ester is not used as the pore-forming solvent in the comparative example, the stirring speed during suspension polymerization is reduced to 1
When 5Orpm was used, porous polymer particles were obtained in high yield, but the particle size was as small as 243 μm, and only particles with a wide particle size distribution were obtained as shown by the standard deviation value, and suspension polymerization When the stirring speed was set to 130 rpm, relatively large particles were obtained, but the yield was low and the particle size distribution was wide. The mixed liquid layer of the porosity-forming solvent phase-separated and a good suspension state could not be maintained, resulting in a yield of 8%.
As shown, almost no polymer particles were obtained. Furthermore, even in the evaluation of antithrombotic properties of polymer particles obtained by Ii polymerization at stirring speeds of 150 and 130 rpm, there was a drawback in that the pressure of perfused blood increased in a short period of time and the formation of thrombi was observed. However, it has not been a preferred method for producing adsorbents for use in the medical field, particularly in direct blood perfusion methods.

〔Effect of the invention〕

A major feature of the method for producing porous polymer particles of the present invention is the use of ricinoleic acid ester as a porosity-forming solvent. This is an extremely excellent method that can easily produce large polymer particles.

Claims (6)

[Claims] (1) When a porosity-forming solvent is mixed with a monomer mixture of a crosslinkable vinyl monomer and a non-crosslinkable vinyl monomer, and this is suspended polymerized in an aqueous medium to produce porous polymer particles, ricinol is used as the porosity-forming solvent. A method for producing porous polymer particles, characterized by using an acid ester. (2) the crosslinkable vinyl monomer is an aromatic vinyl monomer having two or more unsaturated hydrocarbon groups in one molecule;
and at least one vinyl monomer selected from polyol esters of (meth)acrylic acid having two or more (meth)acryloyl groups in one molecule. Method. (3) The method for producing porous polymer particles according to claim 2, wherein the aromatic vinyl monomer is divinylbenzene. (4) The non-crosslinkable vinyl monomer is a (meth)acrylic acid ester having one (meth)acryloyl group in one molecule, and an aromatic compound having one unsaturated hydrocarbon group in one molecule. The method for producing porous polymer particles according to claim 1, wherein the vinyl monomer is at least one kind selected from vinyl monomers. (5) The above (meth)acrylic acid ester is glycidyl methacrylate and the following general formula [I]▲There are mathematical formulas, chemical formulas, tables, etc.▼……[I] (However, in the formula, R is a hydrogen atom or a methyl group. Each may be the same or different, Z is a divalent organic group having 2 to 20 carbon atoms and may be the same or different, and n is 1 to 100. The method for producing porous polymer particles according to claim 4, which is a (meth)acrylic acid ester oligomer represented by (an integer). (6) The ricinoleic acid ester is methyl ricinoleate, ethyl ricinoleate, n-butyl ricinoleate,
6. The method for producing porous polymer particles according to claim 1, wherein the porous polymer particles are at least one selected from ethylene glycol monoricinolate and propylene glycol monoricinolate.