JPH0128777B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel resin composition, and more particularly, it relates to a copolymer of (A) maleic anhydride and an aliphatic vinyl ether or aliphatic vinyl ester copolymerizable therewith [hereinafter abbreviated as component (A)]. . ] and (B) a copolymer of maleic anhydride and an aromatic vinyl monomer or olefin monomer copolymerizable therewith [hereinafter abbreviated as component (B). ] This relates to a resin composition consisting of the following. Component (A) has been known for a long time, and includes various copolymerization components, copolymerization forms (block, random, etc.),
Those having a copolymerization ratio have been synthesized. For example, block copolymers of maleic anhydride and methyl vinyl ether in a copolymerization ratio of 1:1 are industrially produced. Component (A) has excellent solubility in water and organic solvents, excellent compatibility with resins, plasticizers, and metal salts, good moldability, high reactivity, etc., and is used in a variety of applications. It is used for this purpose.
Among these, there are many advantages when using it as a carrier for solidifying physiologically active substances by taking advantage of its high reactivity. In the past, many attempts have been made to immobilize physiologically active substances on carriers and make them insoluble, thereby stabilizing or sustaining their activity or making them easier to use. It is important to use an appropriate carrier in order to effectively exert the various activities of a physiologically active substance. Conventional methods for immobilization include preparing a physiologically active substance in a solution state and spraying this solution onto a carrier, and immersing the carrier in this solution.The latter method is particularly simple and reliable. Because of this, it is overwhelmingly adopted. In most cases, water is used as the solvent. Although there are rare special cases where alcohol or other organic solvents are used, it is extremely important not to reduce the activity of physiologically active substances, so it may not be preferable to use solvents other than water. many. Therefore, a carrier for immobilization is required to have the following functions. In other words, it must be water resistant for the time necessary to carry out the immobilization reaction;
Immobilized carriers are often used in places where they come into contact with water, body fluids, blood, etc., so they must maintain water resistance for a long time in such places.
High ability to immobilize physiologically active substances,
The immobilization reaction does not require high temperatures to the extent that the activity of the physiologically active substance is lost, and molded products of various shapes such as films, filaments, and granules can be obtained. Component (A) fully satisfies the function of a carrier for immobilizing a physiologically active substance. This indicates that activated cephadex, which is a typical conventional carrier,
Compared to activated glass beads, activated carbon, etc., which cannot be molded and can only be obtained in fixed shapes, such as granules or gels, there are major limitations on where they can be used. It means that. However, component (A) has problems with water resistance, and not only is it impossible to use in areas where it is constantly in contact with water, body fluids, blood, etc. There is also a problem with water resistance over a short period of time, i.e., about 5 to 10 minutes, and normal immobilization operations such as immobilization by immersing the carrier in an aqueous solution of a physiologically active substance cannot be used. As a method to solve the above problems that occur when using component (A), (1) a polyfunctional compound that can cause a crosslinking reaction with component (A) is blended, and heat treatment is performed. By rubbing, etc., component (A) crosslinks with each other to impart water resistance. (2) Component (A) is blended with other highly hydrophobic polymers to impart water resistance. Possible methods include: Many methods are known for method (1), but when glycol or alkylene diamine is used as a crosslinking agent, as disclosed in U.S. Pat. No. 3,810,468, the molded product obtained is hard and brittle, making it impossible to use it as a carrier, column packing material, filter, etc. Furthermore, in general, new problems arise with such crosslinking reactions, such as a decrease in functionality if the reaction is carried out in a manner that satisfies the functionality. Method (2) is a method that has not received much attention in the past. The present inventors focused on a method of blending other polymers with component (A), and obtained a resin composition with improved water resistance without reducing the excellent function of component (A) as a carrier. In order to achieve this goal, we conducted intensive research on the blending system of component (A) and various polymers. That is, homopolymers made of monomers having acidic groups other than acids other than maleic anhydride, such as carboxyl groups, sulfone groups, phosphonic groups, phosphine groups, and phenolic hydroxyl groups, and other monomers copolymerizable with these monomers. Select polymers such as copolymers of (A)
When we investigated the compatibility, stability of the composition, and suitability as a carrier for immobilizing physiologically active substances, we found that some polymers had poor compatibility with component (A), making it difficult to mix the two. It is difficult to even mix uniformly because agglomeration occurs just by mixing, and even if it looks like it is mixed uniformly,
When a film is made from this composition by a casting method, layer separation often occurs. It was also found that even when homogeneous mixing was possible, the immobilization ability was significantly reduced and the moldability deteriorated, but surprisingly, maleic anhydride and aromatic vinyl monomers or olefin monomers that can be copolymerized with maleic anhydride. The inventors have discovered that only a composition containing a copolymer of (A) and (A) can improve the water resistance of component (A) without impairing its advantages as a carrier, and has thus arrived at the present invention. That is, the present invention comprises (A) 0.5 to 99.5 parts by weight of a copolymer of maleic anhydride and an aliphatic vinyl ether or aliphatic vinyl ester that can be copolymerized therewith;
(B) A resin composition comprising 0.5 to 99.5 parts by weight of a copolymer of maleic anhydride and an aromatic vinyl monomer or olefin monomer copolymerizable with maleic anhydride. The resin composition of the present invention is uniform, does not cause layer separation even when made into a film, and is stable for a long period of time. As component (B) of the present invention, any copolymer of maleic anhydride and an aromatic vinyl monomer or olefin compound that can be copolymerized therewith can be used, but maleic anhydride is preferable. and styrene or ethylene or isobutylene or polypropylene are used, particularly preferably copolymers of maleic anhydride and the abovementioned monomers, in a copolymerization ratio of 1:1 to 1:
5 and a molecular weight of 500 to 2,000,000 is used. As the uninvented component (A), any copolymer of maleic anhydride and an aliphatic vinyl monomer or aliphatic vinyl ester that can be copolymerized with maleic acid can be used, but anhydrous maleic anhydride is preferably used. Copolymers of maleic acid and vinyl acetate or methyl vinyl ether or ethyl vinyl ether or butanediol vinyl ether are used, particularly preferably copolymers of maleic anhydride and the monomers mentioned above, in a copolymerization ratio of 1:1 to 1. :5
and those with a molecular weight of 500 to 2,000,000 are used. In the resin composition of the present invention, if the amount of component (A) is less than 0.5% by weight based on the total amount of components (A) and (B), the moldability, film-forming property, and stringiness will be significantly deteriorated, and the physiological activity The ability to immobilize substances also decreases, and on the other hand, if it exceeds 99.5% by weight, water resistance becomes extremely poor.For example, when a film obtained from this material is immersed in water, it begins to dissolve and lose its shape within a few minutes. Therefore, it is impossible to immobilize this material by contacting it with an aqueous solution of a physiologically active substance. In order to provide more sufficient water resistance and to be suitable for use in places where there is constant contact with water, blood, body fluids, etc., component (A) is preferably 80% by weight or less, and more preferably 70% by weight. % or less is desirable. In addition, in order to have more sufficient moldability, film-forming properties, stringinability, and ability to immobilize physiologically active substances, component (A) is preferably 1% by weight or more, more preferably 3% by weight or more, Particularly preferably 5% by weight or more, most preferably 10% by weight
It is desirable that the above amount is blended. Therefore,
Component (A) is preferably blended in an amount of 1 to 80% by weight, particularly preferably 5 to 80% by weight, most preferably 10 to 70% by weight, but water resistance is particularly important. In this case, it is preferably blended in an amount of 1 to 10% by weight, particularly preferably 3 to 10% by weight, and particularly improves moldability, film-forming properties,
When stringability and the ability to immobilize physiologically active substances are important, it is desirable that the content be in the range of 50 to 80% by weight. The resin composition of the present invention can be prepared, for example, by mixing components (A) and (B) using an organic solvent as a medium. That is, a solution of (A) component and (B)
Method of mixing component solutions, method of adding (B) component to (A) component solution and mixing, method of adding (A) component to (B) component solution and mixing, (A) component It can be prepared by adding a solvent to component (B) and mixing them. In order to enhance the mixing effect and shorten the mixing time, it is desirable to heat or stir as necessary. Examples of organic solvents that can be used in producing the resin composition of the present invention include ketones such as acetone and methyl ethyl ketone, aldehydes such as benzaldehyde, formaldehyde, and dimethyl formaldehyde, ethers such as tetrahydrofuran, methyl acetate, and ethyl acetate. and alcohols such as methanol, ethanol, propanol, isopropanol, and butanol, but ketones and alcohols are preferably used. From the resin composition of the present invention prepared in this way using an organic solvent as a medium, when the solvent is vaporized by heating etc., a solid resin composition can be obtained, and in particular, it can be formed into a film, sheet-like object, or filament-like object. A solid resin composition can be easily obtained. As shown in the examples, the resin composition of the present invention
It has superior water resistance compared to component (A) alone, and its ability to immobilize physiologically active substances far exceeds the ability expected when components (A) and (B) are mixed. . Therefore, the resin composition of the present invention can be used in a wide range of fields due to its high reactivity, good moldability, and water resistance, but it is particularly preferably used as a carrier for immobilizing various physiologically active substances. be able to. What is the physiologically active substance mentioned here?
It means a substance that has some kind of pharmacological effect or physiological influence on a living body, and more specifically, for example, amylase, trypsin, chymotrypsin, aminoacylase, galactosidase, invertase, pectinase, L-asparaginase, glucose oxidase, uriase. , various enzymes such as cellulase, various antigens, antibodies, enzyme inhibitors, various hormones, coenzymes, various anticancer drugs, anticancer drugs, antibiotics such as amikacin, dibekacin, kanamycin, streptomycin, gentamicin, fradiomycin, polymyxin, acrinol , acrylflavin, benzalkonium chloride, benzethonium chloride, bactericidal agents such as cyclohexidine, etc., and various enzymes, antigens, antibodies, antibiotics, bactericidal agents, etc. are preferably used in the resin composition of the present invention. Fixed. Other components can be mixed into the resin composition of the present invention as needed. A typical example of such a component is a crosslinking agent that can cause a crosslinking reaction with component (A) or component (B) used in the present invention. The method of mixing other components into the resin composition of the present invention can be carried out according to the method of preparing the resin composition of the present invention, and the method of mixing component (A), component (B), and other components can be carried out according to the method of preparing the resin composition of the present invention. The order is arbitrary. Examples of crosslinking agents that can be mixed into the resin composition of the present invention include hexamethylene diisocyanate,
Polyisocyanates such as toluene diisocyanate, polyvinyl alcohol and its derivatives,
Polyols such as ethylene glycol, propylene glycol, butylene glycol, and polyethylene glycol, natural polymers such as starch, gelatin, and dextran, hexamethylene diamine,
Examples include polyamines such as ethylenediamine and trimethylenediamine, and aminoalcohols such as monoethanolamine and triethanolamine, with polyvinyl alcohol, polyols, and the like being preferably used. The present invention will be explained in more detail with reference to Examples below. Note that "parts" in the examples mean "parts by weight." Examples 1 to 5, Comparative Examples 1 to 2 A 10% by weight acetone solution of Gantrez AN169 (manufactured by GAF, a copolymer of maleic anhydride and methyl vinyl ether) and SMA3000 (ARCO Chemical
Copolymer of maleic anhydride and styrene)
Create a 10% by weight acetone solution of and mix both solutions so that the solid weight ratio of Gantrez 169 and SMA3000 is 5/95, 20/80, 50/50, 80/20, 95/5. It was adjusted. The resin composition thus prepared remained transparent and stable without phase separation even after being left at 35°C for one month. This resin composition was cast onto a polyester film and dried with hot air at 100°C to produce a film with a thickness of 50μ. For comparison, the solid content weight ratios of Gantrez 169 and SMA3000 are 100/0, 99.7/0.3, 0.3/99.7,
It was cast and dried in the same manner as the acetone solution adjusted to 0/100. The film forming properties of Examples 1 to 5 and Comparative Examples 1 to 4 and the water resistance observed by immersing these films in 25°C water are as shown in Table 1.

[Table] 1 g each of the films obtained in Examples 1 to 5 and Comparative Examples 2 to 3 was immersed in an aqueous dibekacin sulfate solution [50 mg (potency)/100 ml] at 25°C for 15 minutes. All of the five films immobilized 35 mg of dibekacin sulfate, and the activity of the immobilized dibekacin sulfate remained unchanged even after one month had passed. Regarding the film of Comparative Example 2, its shape began to collapse 5 minutes after immersion, and when it was taken out at that point, the amount immobilized was 5 mg. The film of Comparative Example 3 was taken out at the same time as the other five films, and the amount of immobilization was 8 mg. When 1 g of each of the films obtained in Examples 1 to 5 was immersed in an aqueous solution [250 mg/100 ml] of Hebsbrin (manufactured by Midori Juji Co., Ltd., dried anti-hepatitis B human immunoglobulin) at 7°C for 10 hours, 5 films were obtained. friend
100 mg of hebusbrin was immobilized. The activity of immobilized hebusbulin remained stable even after storage for 3 months in air at 7°C. The films of Examples 1 to 5 were treated in the same manner as described above, except that an aqueous urokinase solution [250 mg/100 ml] was used instead of an aqueous hebusbrin solution, and 90 mg of urokinase was immobilized on each film. The activity of immobilized urokinase was conserved over a long period of time. Examples 6 to 10 Films were prepared in the same manner as in Examples 1 to 5, except that a copolymer of maleic anhydride and ethylene (copolymerization ratio 1:1, molecular weight 500,000) was used instead of SMA3000. Examples 1 to 3 about the obtained films
When dibekacin sulfate was immobilized in the same manner as in step 5, 30 mg (titer) of dibekacin sulfate was immobilized on all five films. The activity of immobilized dibekacin sulfate was retained for a long time. Examples 11-15 Instead of Gantrez AN169, a copolymer of maleic anhydride and ethyl vinyl ether (copolymerization ratio 1:
Films were prepared in the same manner as in Examples 1 to 5, except that 1, molecular weight: 500,000) was used. The obtained film was mixed with a sulfuric acid polymyxin B aqueous solution [500,000 units/100mg]
When immersed in water for 20 minutes at 7°C, 350,000 units of polymyxin B sulfate were immobilized on the five films.
The activity of immobilized polymyxin B sulfate is maintained for a long period of time. Example 16 Gantrez AN169 50 parts and SMA3000 50 parts to 300
A 10 d thread was prepared from this solution by a dry spinning method. The obtained thread had excellent water resistance and ability to immobilize physiologically active substances as in Example 3. Comparative example 3 Gantrez AN169 0.3 parts and SMA3000 99.7 parts
It was dissolved in 300 parts of acetone and spinning was attempted in the same manner as in Example 16 using this solution, but spinnability was poor and spinning was impossible.

Claims (1)

[Claims] 1 (A) 0.5 to 99.5 parts by weight of a copolymer of maleic anhydride and an aliphatic vinyl ether or aliphatic vinyl ester copolymerizable therewith; (B) maleic anhydride and an aromatic vinyl monomer copolymerizable therewith; or Copolymer with olefin monomer 0.5-99.5
A resin composition consisting of parts by weight.