JPH0131931B2 - - Google Patents

Description

[Detailed description of the invention]

INDUSTRIAL APPLICATION FIELD The present invention relates to microencapsulated magnetic ultrafine particles. More specifically, the present invention relates to microencapsulated magnetic ultrafine particles that have greatly improved corrosion resistance and environmental resistance. BACKGROUND OF THE INVENTION Currently, organic, inorganic, and metal fine particles are used in many industrial fields as ceramic materials, pigments, medicines, and electronic materials. In particular, magnetic ultrafine particles have characteristics such as being able to be induced by a magnetic field or selectively separated and collected by a magnetic field, so they can be used as components of magnetic fluids, magnetic inks, etc., or pharmaceutical substances, catalysts, and biopolymers. Various fields of use are being developed for use as carriers for microorganisms, cells, etc. With the increasing frequency of use of fine particles and magnetic fine particles in a wide variety of industries, there is an increasing need for improved performance of fine particles, and research and development thereof is attracting attention. For example, ultrafine particle formation is a method for improving the properties of fine particles, and methods for producing ultrafine particles with a particle diameter of several A to submicron have already been proposed. Ultrafine particles have improved or modified various physical and chemical properties compared to conventional fine particles. For example, the surface area per unit gram (specific surface area) becomes very large, resulting in a lower melting point, the surface tension is large and the internal pressure is high, ultrafine particles made of magnetic materials are extremely ferromagnetic, and heat Various properties such as good conductivity and light absorption result from ultra-fine graining. When applying ultrafine particles with such characteristics industrially, surface modification and functionalization through compositing (microencapsulation, etc.) of fine particle materials become important issues. For example, microencapsulation 1
One purpose is to improve corrosion resistance, particle dispersibility, etc. by protecting the surface of highly active fine particles with a polymer coating, etc. For example, in the case of magnetic fine particles, ferromagnetic particles are Magnetic ink is produced by dispersing it in a medium using
The above-mentioned corrosion resistance and dispersibility are essential conditions when producing ferromagnetic particles (No. -105468) or during a supporting operation when using ferromagnetic particles as a carrier. Another purpose is to add another function or characteristic to the characteristics of the fine particles by combining them with other materials. In particular, microencapsulated magnetic particles or composites thereof have attracted attention in recent years as carriers for pharmaceutical substances, biopolymers such as enzymes, and catalysts. Fine particles have a large surface area per gram compared to large agglomerates, and therefore their use as carriers is suitable for maintaining high activity and effectiveness of pharmaceutical substances, enzymes, catalysts, etc. be. Furthermore, by using ultrafine magnetic particles or composite particles thereof as carriers,
Benefits such as those described below can be achieved. For example, in the case of drugs, magnetic field induction allows a medicinal substance to selectively reach a lesion or a site near the lesion, where it can exert its medicinal efficacy. Among the various substances administered into the body as medicines, there are some that are desired to act only on the lesion, which is the site of direct medical treatment, and to minimize side effects on normal tissue.For example,
Anticancer drugs are typical examples. Therefore,
Microcapsules containing ultrafine magnetic particles are
It can be suitably used as a carrier for this type of medicinal substance. Furthermore, after the enzymes and catalysts are used in a predetermined reaction, they can be selectively separated and recovered by applying a magnetic field, and can be used again. Enzymes and catalysts do not cause chemical changes themselves, speed up the chemical reaction of the target substance, and selectively produce the target substance. However, they are expensive, so they cannot be used in multiple reactions. It is often efficient and economical to use. However, enzymes are usually soluble and virtually impossible to reuse after separation. Therefore, in order to make the enzyme insoluble, it is desirable to have the enzyme supported on an insoluble substance. As the carrier, magnetic fine particles are excellent in terms of retention of specific activity, ease of separation, etc., and can be used effectively. In the case of a catalyst, it is also preferable to use magnetic fine particles as a carrier for reasons such as maintaining specific activity and ease of separation. Moreover, the characteristic that separation and collection using a magnetic field is possible can also be used for the separation of complementary DNA or the separation of microbial cells such as specific bacteria. In recent years, microcapsules made of magnetic particles and medical substances have been produced by coating the medical substances with organic polymer substances (ethyl cellulose, gelatin, albumin, etc.) and then fixing the magnetic particles. An example has been reported (Japanese Patent Laid-Open No. 51411/1983) in which fine particles made of a mixture were coated with an organic polymer substance. In addition, as a microcapsule consisting of magnetic particles and an enzyme, porous particles in which magnetic particles are dispersed are impregnated with a polyamine cross-linked with an excess of a bifunctional reagent, and an enzyme is further bonded to the polyamine ( JP-A No. 59-28477) has also been reported. Problems to be Solved by the Invention However, the above-mentioned conventional examples had problems as detailed below. That is, the microencapsulating agent disclosed in JP-A No. 56-51411 has a core made of a medicinal substance in which magnetic particles are dispersed and coated with an organic polymer material, or a core made of a medicinal substance, Because it is coated with an organic polymer material in which magnetic particles are dispersed,
The particle size must be relatively large. As a result, it is difficult to migrate to the capillaries, it cannot truly reach the lesion, the pharmacological effect at the lesion is weak, and there is a risk of causing side effects on normal tissues. ing. Furthermore, in this method, the magnetic particles are not completely protected;
In extreme cases, it is exposed to the outside. Therefore, the magnetic fine particles dissolve during movement within the body, and not only is magnetic field induction not performed effectively, but there is a risk that the dissolved fine particle elements may have some kind of adverse effect on the living body. Furthermore, the magnetic support matrix and immobilized enzyme disclosed in JP-A No. 59-28477 only have a porous refractory inorganic oxide core impregnated with polyamine; The bond strength is low;
Furthermore, there was a problem that the coating may be incomplete, resulting in poor corrosion resistance and environmental resistance. We have developed microencapsulated magnetic ultrafine particles that can solve these problems when conventional magnetic particles are used as carriers, have excellent corrosion resistance, environmental resistance, and are highly functional, and their production. Developing laws is very important. Therefore, one of the objects of the present invention is to provide microencapsulated magnetic fine particles having an ultrafine particle in its core and a coating strongly bonded to the core. Furthermore, another object of the present invention is to provide microencapsulated magnetic ultrafine particles that can be easily loaded with pharmaceutical substances, biopolymers such as enzymes, microbial cells, catalysts, etc., and can be used as strong carriers. It's about doing. Another object of the present invention is to provide a method for producing the above microencapsulated magnetic ultrafine particles. Means for Solving the Problems In order to solve the problems of the above-mentioned conventional example and achieve the object of the present invention, the present inventor carried out various research and studies.
As a result of our studies, we have developed the present invention. That is, the microencapsulated magnetic ultrafine particles according to the present invention include: a core material made of magnetic ultrafine particles; a coupling layer made of a binder chemically bonded to the surface of the core material and having a polymerizable functional group; the above polymerizable functional group and at least one
A polymer coating layer obtained by polymerization with a species of polymerizable monomer. Various known magnetic core materials can be used as the magnetic core material useful in the microencapsulated magnetic ultrafine particles of the present invention. However, since it is necessary to chemically bond the core material and the binding material to the surface thereof, the core material is required to have a hydroxyl group on its surface. Therefore, the magnetic core material used in the microencapsulated magnetic ultrafine particles of the present invention is specifically shown as follows:
Examples include ferromagnetic iron, nickel, cobalt, or magnetite, and ferromagnetic alloys or compounds thereof. Further, the magnetic core portion is an ultrafine particle, and the magnetic ultrafine particle can be obtained by, for example, heating and evaporating a magnetic substance in a rare gas, and condensing the resulting vapor in a rare gas to form ultrafine particles. It can be obtained by various known techniques such as evaporation in gas (evaporation method in gas), electrolytic antibody, plasma jet, and induction laser. Next, the polymerizable binder used in the present invention has the general formula R-Si-X ₃ [where X is a halogen, an alkoxy group, an alkyloxyalkyleneoxy group, or an alkylcarbonyloxy group (three X's are the same). ) and R is a vinyl group or a substituted vinylcarbonyloxyalkyl group], such as vinyltriethoxysilane, vinyltriacetoxysilane, vinylbis(β-methoxyethoxy)silane. , vinyltrichlorosilane, γ-methacryloxypropyltrimethoxysilane, vinyltrimethoxysilane, and the like. These binders chemically bond to the inorganic core material through a condensation reaction with hydroxyl groups present on the surface of the inorganic core material or chemically adsorbed water molecules. This reaction mechanism is described below using vinyltrimethoxysilane as an example: becomes. Furthermore, as is clear from this reaction formula, the above-mentioned binder also provides a polymerizable functional group R for forming a polymeric coating layer through polymerization with a polymerizable monomer. Furthermore, examples of the polymerizable monomer include acrylic acid esters such as methyl acrylate, ethyl acrylate, and benzyl acrylate; functional monomers having functional groups such as acrolein and 2-hydroxyethyl methacrylate;
-, p-methylstyrene, o-, m-, p-ethylstyrene, vinylnaphthalene, vinyltoluene, styrene, etc., and it is also possible to use a mixture of two or more of these. These polymerizable monomers can be appropriately selected or specific functional groups can be introduced depending on the drug, enzyme, catalyst, etc. to be supported on the microencapsulated magnetic ultrafine particles. For example, when the substance to be supported is a protein having an amino group such as an enzyme, if a polymerizable monomer having an aldehyde group such as acrolein is used and copolymerized, an aldehyde group will be present on the surface. , a surface that easily reacts specifically with amino groups is obtained. In addition, when the microencapsulated magnetic ultrafine particles of the present invention are used as carriers to support proteins such as enzymes, the acids, coenzymes, microbial cells, etc., intervening molecules called spacers may be attached to specific groups or sites in these substances. It is generally considered desirable to couple the functional groups on the microcapsule layer through the spacer. As such a spacer, an acylating agent, an alkylating agent, a diamine, etc. are used. For example, examples of the alkylating agent include halocarboxylic acids; cyclic compounds such as lactones and epoxy; aldehydes; examples of the halocarboxylic acids include 4-halovaleric acid and 5-halocaproic acid. In addition, as a lactone,
β-, γ-, σ- and ε-lactones, aldehydes such as critalaldehyde and terephthalaldehyde, and epoxys such as ethylene oxide and trimethylene oxide can be used effectively. Further, examples of the acylating agent include acid chloride, acid anhydride, lactam, aliphatic diisocyanate, and the like. Examples of the acid chloride include terephthyl chloride and β-formylpropionic acid chloride, and examples of the lactam include β-propiolactam and δ-valerolactam. Further, examples of the diamine include hexamethylene diamine, heptamethylene diamine, and the like. Microencapsulated magnetic ultrafine particles according to the present invention are manufactured by the following steps. That is, the method for producing microencapsulated magnetic ultrafine particles according to the present invention involves (i) performing a coupling reaction between the core material of magnetic ultrafine particles obtained by a conventionally known method and a binder, and then (ii) It consists of polymerizing the binder on the surface of the core material and at least one kind of polymerizable monomer. The coupling reaction between the magnetic core material and the binder is carried out by first mixing the core material, which is ultrafine magnetic particles, the binder, and an inert solvent, and heating and stirring the mixture for a predetermined period of time. The obtained reaction product is washed with the solvent and dried. Inert solvents that can be used here include:
Any solvent may be used as long as it is non-reactive and compatible with the magnetic core material and binder, such as isooctane, petroleum benzine, benzene, toluene, petroleum ether, n-hexane,
Examples include cyclohexane, methanol, ethanol, isopropanol, acetone, and ethyl ether. In the next polymerization reaction between the binder on the surface of the core material and the polymerizable monomer, first, the reaction product obtained by the coupling reaction, an inert solvent, and at least one polymerizable monomer are mixed together. After heating to a predetermined temperature, add a polymerization initiator and continue stirring for a predetermined time while maintaining the above temperature to polymerize the polymerizable functional group of the binder and the polymerizable monomer on the surface of the core material. Consists of. In this step, inert solvents that can be used are:
It only needs to be non-reactive and compatible with the binder, polymerizable monomer and polymerization initiator, and non-reactive with the core material and the polymerization reaction product, such as amyl alcohol, liquid paraffins,
Methylisocarbitol, heptane, butanol, toluene and the like can be mentioned. Furthermore, as a polymerization initiator, benzoyl peroxide,
Examples include lauroyl peroxide, azobisisobutyronitrile, t-butyl peroxide, t-butylperoxyisopropyl carbonate, and 2,2'-azobis-2,4-dimethyl. The inert solvent and reaction initiator used in these two reactions are preferably combined appropriately depending on the core material, binder, and polymerizable monomer used in the microencapsulated magnetic ultrafine particles. The thus obtained microencapsulated magnetic ultrafine particles of the present invention have excellent dispersibility and corrosion resistance,
The hydrophilicity of the surface can be controlled and is very fine. Furthermore, when used as a carrier, the coating can be changed as appropriate depending on the substance to be supported. Function In the industrial use of ultrafine particles, magnetic ultrafine particles are attracting attention due to their ability to be induced by a magnetic field or selectively separated and recovered by a magnetic field, and the microencapsulated magnetic ultrafine particles of the present invention , ultrafine magnetic particles are used as the core material. As mentioned above, effective and widespread industrial application of ultrafine particles requires clever modification and modification of their surfaces. In order to modify or modify the surface of ultrafine particles, it is effective to coat the surface with a polymer compound, and in the present invention, as a method to do so, the ultrafine particle that is the core material and the coating polymer are coated. A method of chemical bonding is used. Most of the conventional coatings of ultrafine particles are based on impregnation or wrapping the surface with polymers, but with this method, the coating formed easily peels off or the coating is incomplete. There were many cases. Therefore, there was a problem with the corrosion resistance or environmental resistance of the microencapsulated fine particles. The method of coating ultrafine particles according to the present invention involves chemically bonding the hydroxyl groups on the surface of the ultrafine particles, which are the core material, with a silane coupler, which is the binder, and then chemically bonding them to the surface of the ultrafine particles through this coupling reaction. The surface of the ultrafine particles is coated by polymerizing the polymerizable functional group of the bonded silane coupler and the polymerizable monomer. The microencapsulated magnetic ultrafine particles according to the present invention are capable of guiding a specific substance to a predetermined location with a magnetic field, or selectively separating and recovering a specific substance by using the magnetic ultrafine particles. However, by using the configuration as described above, the following effects can be further achieved. That is, since the diameter of the target magnetic ultrafine particles ranges from several tens of Å to several thousand Å, the produced microencapsulated magnetic ultrafine particles are extremely fine and are effective as carriers for pharmaceutical substances. be. In addition, due to microencapsulation, the surface charge of the ultrafine particles becomes positive, making them highly dispersible in solutions.
Therefore, when used as a carrier, uniform dispersion of the substance to be supported is ensured. Furthermore, since it has a strong coating chemically bonded to the surface of the ultrafine particles, it has excellent corrosion resistance and environmental resistance, and is effective when used as a magnetic ink or as a carrier. Moreover, the surface coating may optionally include OH groups,
Since it can have an amino group or an aldehyde group introduced into it, the surface can be made reactive and can be functionalized to support various substances by chemically bonding it. Examples Next, the manufacturing method and characteristics of the microencapsulated magnetic ultrafine particles of the present invention will be specifically explained using the following examples and experimental examples. Example 1 Production of microencapsulated magnetic ultrafine particles Ferromagnetic ultrafine iron particles were used as the core material. There are two types of shapes: short chain-like particles of about 0.04 x 0.5 μm (ultrafine particles A) and isolated ultrafine particles of about 0.03 x 0.04 μm (ultrafine particles B). Both were microencapsulated using the same steps below. After introducing 1 g of ultrafine particles as a core material into a round bottom flask equipped with a stirrer, 0.5 ml of vinyltrimethoxysilane as a binder and 100 ml of toluene as an organic solvent were added, heated to 60°C to 80°C, and the mixture was heated to 60°C to 80°C. The coupling reaction is carried out while maintaining the temperature and stirring for 30 minutes to 1 hour. The product obtained by the above reaction was then washed with the organic solvent and dried. Next, the reaction product, 100 ml of ethyl acetate as an organic solvent, and ~5000 mg of vinyl monomer as a polymerizable monomer were added to the flask while stirring.
Heated to 60-80℃ and further used as a polymerization initiator.
Add 100 mg of AIBN (azobisisobutyronitrile). The polymerization reaction is carried out while maintaining this temperature and stirring for 30 minutes to 3 hours. In this example, styrene was used as the polymerizable monomer (vinyl monomer).
HEMA (2-hydroxyethyl methacrylate)
A mixture of the following was used in a weight ratio of 1:1. The obtained polymerization reaction product was washed with the above organic solvent and then dried. The thus obtained microencapsulated magnetic ultrafine particles were examined for their dispersibility, film thickness, etc. using a dark field optical microscope and an electron microscope. The obtained electron micrographs are shown in the attached FIGS. 1 and 2. Attached Figure 1 is an electron micrograph of a microcapsule made of ultrafine particles B;
The figure is an electron micrograph of microcapsules made of ultrafine particles A. The results of each measurement are shown in Table 1.

[Table] To evaluate the dispersibility, 1 mg of ultrafine particles was suspended in 150 ml of solvent, irradiated with ultrasound, and then dispensed into 10 ml test tubes to perform a sedimentation test. The dispersibility was evaluated semi-quantitatively, with those producing coarse secondary particles after 1 minute as (±), after 3 minutes as (+), and after 5 minutes as (++). Experimental Example 1: Dispersibility in water and organic solvents 1 mg each of the microencapsulated ultrafine particles (based on ultrafine particles A) and non-microencapsulated ultrafine particles (material of ultrafine particles A) obtained as above.
was dispersed in 100 ml of water and an organic solvent, and its dispersibility was measured. Dispersibility is evaluated by measuring the zeta potential of particles in the neutral region and by sedimentation tests. The sedimentation test is conducted under the same conditions and criteria as the sedimentation test described above. The zeta potential was measured by suspending each ultrafine particle in water at an appropriate concentration and measuring it by microelectrophoresis using a Mark model manufactured by Rank Brothers. The results obtained are summarized in Table 2. The good dispersibility of the microcapsules according to the present invention can be understood from the fact that the ζ potential changes to positive after encapsulation.

[Table] Experimental Example 2: Acid Resistance 1 mg each of microencapsulated ultrafine particles according to the present invention and non-microencapsulated ultrafine particles (according to ultrafine particles A) were left in 5 ml of a strong acidic solvent with a pH of 2.0, and Acid resistance was measured by measuring the change in iron concentration over time. The presence of solvent iron due to the dissolution of ultrafine particles was detected and measured using visual observation or color reaction using the orthophenanthroline method. In the microencapsulated ultrafine particles according to the present invention, no dissolution of iron was detected even after being left for one week. On the other hand, the non-microencapsulated ultrafine particles were dispersed in the aqueous solution, started to dissolve immediately upon shaking, and exhibited coloration due to divalent iron ions. The presence of divalent iron ions was also confirmed by the orthophenanthroline method. Experimental example 3: Adjustment of hydroxyl group concentration Using styrene and HEMA as monomers,
During the polymerization reaction conditions, the ratio of styrene to HEMA charge and the solvent were varied, and the surface hydroxyl group concentration was measured for each. The hydroxyl group concentration can be measured using Otsugu Porter.
A modified Siggia method was used based on Ogg, Porter and Willite, Ind.Eng.Anal. Ed., 17, 394-397 (1945). This method is a method for determining the amount of OH- groups in a polymer through esterification. A mixed solution of acetic anhydride and pyridyl was used as the acetylating agent, and 0.1 g of ultrafine iron particles after the reaction was used as a single analysis sample.
The acetic acid produced as a result of the reaction was titrated with 0.1N NaOH using 1% phenolphthalein as an indicator.
OH- group was calculated. The results obtained are shown in Table 4.

Table 4 shows that when microencapsulated magnetic ultrafine particles are applied to biological systems, their hydrophilicity and affinity can be adjusted as necessary. Experimental Example 4: Introduction of a functional group with good binding properties to proteins Using acrolein as a polymerizable monomer, microencapsulation was performed by the method described in Example 1.
The microencapsulated ultrafine particles obtained by this method were observed to have very good binding properties with proteins. Effects of the Invention The thus obtained microencapsulated magnetic ultrafine particles can be selectively separated and recovered by magnetic field induction inherent in magnetic particles, and also have a strong polymer membrane around them. It has excellent corrosion resistance, environmental resistance, and high separability, so it is effectively used in magnetic fluids and magnetic inks. Furthermore, since the surface properties can be changed, various carriers can be used, such as binding carriers for microorganisms such as bacteria, carriers for biomolecules such as enzymes, carriers for pharmaceutical substances such as anticancer drugs, and embolic agents for cancer treatment. It can be advantageously used as In particular, when used as these carriers, the specific surface area is large and the activity of the supported substance can be maintained sufficiently high, so it is possible to obtain high activity as a carrier for pharmaceutical substances, enzymes, or catalysts. Further, since the microencapsulated magnetic ultrafine particles according to the present invention are fine, they can easily migrate into capillary tubes and are effective as carriers for anticancer drugs.

[Brief explanation of drawings]

FIGS. 1 and 2 are electron micrographs of microencapsulated magnetic ultrafine particles according to the present invention, respectively.

Claims (1)

[Scope of Claims] 1. A core material made of ultrafine magnetic particles, a coupling layer made of a binder chemically bonded to the surface of the core material and having a polymerizable functional group, and the above-mentioned polymerizable functional group of the binder. Microencapsulated magnetic ultrafine particles characterized by comprising a polymer coating layer obtained by polymerization with at least one kind of polymerizable monomer. 2. The microencapsulated magnetic ultrafine particles according to claim 1, wherein the magnetic ultrafine particles are selected from the group consisting of iron, cobalt, nickel, magnetite, and ferromagnetic alloys and compounds thereof. Fine particles. 3 The above-mentioned binder has the general formula R-Si-X ₃ [where X is a halogen, an alkoxy group, an alkyloxyalkyleneoxy group, or an alkylcarbonyloxy group (the three Xs do not need to be the same), 3. The microencapsulated magnetic ultrafine particles according to claim 1 or 2, wherein R is a silane compound having a vinyl group or a substituted vinylcarbonyloxyalkyl group. 4. The silane compound is selected from the group consisting of vinyltriethoxysilane, vinyltriacetoxysilane, vinylbis(β-methoxyethoxy)silane, vinyltrichlorosilane, γ-methacryloxypropyltrimethoxysilane, and vinyltrimethoxysilane. Microencapsulated magnetic ultrafine particles according to claims 1 to 3, characterized in that: 5 The polymerizable monomer is methyl acrylate,
Ethyl acrylate, benzyl acrylate, acrolein, 2-hydroxyethyl methacrylate, o-, m-, p-methylstyrene, o-, m
-, p-ethylstyrene, vinylnaphthalene, vinyltoluene, and styrene. .