JPH0735402B2 - Method for producing fine polymer beads having heat-sensitive properties - Google Patents

Description

The present invention relates to a method for producing fine polymer beads having novel heat-sensitive properties. More specifically,
The present invention relates to a method for producing fine polymer beads having heat-sensitive properties which can be used for diagnostic microbeads, sustained-release preparations, adsorbents, cosmetics and the like.

[Conventional technology]

The production of heat-sensitive submicron gel beads was by reverse phase suspension polymerization consisting of solvent-surfactant-pregel aqueous solution (Miji Hirose, Takeyuki Amiya, Notsugu Hirokawa, Toyoichi Tanaka, 1st Takataka). Molecular gel research forum material, 39 (1989)). N-Hexane was used as the solvent, and sorbitan monolaurate was used as the surfactant. The pregel aqueous solution is N-isopropylacrylamide, N- which is an ionizable monomer.
Acryloyloxysuccinimide, N, N'-methylenebisacrylamide, which is a crosslinking monomer, and ammonium persulfate. Sorbitan monolaurate was dissolved in nitrogen-substituted n-hexane, a pregel aqueous solution containing an initiator was injected, and after stirring, a small amount of tetramethylenediamine was added to carry out polymerization. In this method, the hydrodynamic diameter is about 800 nm in the swollen state and 200-30 in the contracted state.
It is 0 nm.

It is also possible to produce non-heat-sensitive nanometer-order ultramicrospheres and their colloids. Dendrimer (dend
rimer) (DATomalia, et al.:Macromoleciles,19,2466
(1986)) and single molecule microsphere (J. Kumaki: Macromo
lecules, 19, 2258 (1986)), etc., but these have complicated synthesis methods, are not easy to separate, and the particle size does not change due to temperature change.

[Problems to be Solved by the Invention]

If it is possible to produce fine beads having a heat-sensitive property having a particle size smaller than that of the submicron beads described above, it is expected to be used for higher performance diagnostic microbeads, sustained-release preparations, adsorbents, cosmetics and the like. The present invention has been made for the purpose of providing a method for producing fine polymer beads having a thermosensitive property with a smaller particle size.

[Means for Solving the Problems]

As a result of intensive studies, the present inventors have found that in a heat-sensitive polymer compound aqueous solution system in which a cationic surfactant or an anionic surfactant is added at a concentration equal to or higher than the critical micelle concentration, the polymer is Since the phase transition occurs in the micelles and the particles are deposited as fine particles, the phase transition phenomenon appears to be slow with the naked eye. Taking this knowledge as a hint, the homopolymer obtained by adding a cationic surfactant or an anionic surfactant at a concentration above the critical micelle concentration exhibits hydrophilic-hydrophobic thermoreversible dissolution characteristics, and an acrylamide vinyl compound and a crosslinking agent. A cationic or anionic surfactant is added to the aqueous solution consisting of at a concentration of the critical micelle concentration or higher to prepare a uniform aqueous solution, and after intra-micellar copolymerization at a temperature of the cloud point or higher, methanol or ethanol is added. It was found that the above-mentioned problems can be achieved by a method for producing fine polymer beads having a heat-sensitive property characterized by removing a surfactant by using an ultrafiltration membrane after destroying the micelle structure in addition, and based on this finding. Based on this, the present invention has been completed.

That is, the present invention has the general formula (Wherein R ¹ is a hydrogen atom or a methyl group, at least one of R ² and R ³ is an alkyl group or an alkoxyalkyl group, and the rest are hydrogen atoms), among the acrylamide or methacrylamide vinyl compounds A cationic surfactant or anionic surfactant in an aqueous solution containing at least one selected from the group consisting of at least one cross-linking agent selected from compounds having two vinyl groups and having a concentration of at least the critical micelle concentration. Added in
After the intra-micellar copolymerization was performed at a temperature above the cloud point,
Disclosed is a method for producing polymer beads which cause a thermosensitive particle size change, which is characterized by removing the used surfactant.

Examples of the acrylamide or methacrylamide vinyl compound represented by the above general formula (I) include N-ethylacrylamide, Nn-propylacrylamide,
N-n-propyl methacrylamide, N-isopropyl acrylamide, N-isopropyl methacrylamide,
N-cyclopropylacrylamide, N-cyclopropylmethacrylamide, N, N-diethylacrylamide,
N-methyl-N-ethylacrylamide, N-methyl-
N-n-propyl acrylamide, N-methyl-N-isopropyl acrylamide, N-acryloyl piperidine, N-acryloyl pyrrolidine, N-tetrahydrofurfuryl acrylamide, N-tetrahydrofurfuryl methacrylamide, N-methoxypropyl acrylamide, N-methoxy Propyl methacrylamide, N-ethoxypropyl acrylamide, N-ethoxypropyl methacrylamide, N-isopropoxypropyl acrylamide, N-isopropoxypropyl methacrylamide, N-ethoxyethyl acrylamide, N-ethoxyethyl methacrylamide, N- (2, 2-dimethoxyethyl) -N-methylacrylamide, N-1-methyl-2
-Methoxyethylacrylamide, N-1-methyl-2
-Methoxyethylmethacrylamide, N-1-methoxymethylpropylacrylamide, N-1-methoxymethylpropylmethacrylamide, N- (1,3-dioxolan-2-yl) -N-methylacrylamide, N-8-
Acryloyl-1,4-dioxa-8-azaspiro [4.5]
Decane, N-di (2-methoxyethyl) acrylamide, N-2-methoxyethyl-Nn-propylacrylamide, N-2-methoxyethyl-Nn-ethylacrylamide, N-methoxyethoxypropylacrylamide, and the like. be able to.

The compound used as the cross-linking agent in the method of the present invention may be a compound having two vinyl groups in one molecule, and examples of such a compound include divinylbenzene, N, N′-methylenebisacrylamide and the like. Mention may be made of functional vinyl compounds. These cross-linking agents are usually used in the range of 0.01 to 10% by weight with respect to the acrylamide or methacrylamide vinyl compound represented by the general formula (I).

Water used as a polymerization reaction medium is ion-exchanged water, distilled water, tap water or the like.

As a method for initiating the polymerization, any known method such as irradiation with radiation or electron beam, heating in the presence of a radical polymerization initiator, or light irradiation in the presence of a photosensitizer is used. be able to. As the polymerization initiator used in the present invention, any water-soluble radical initiator can be used. For example, ammonium persulfate,
Persulfates such as potassium persulfate, hydrogen peroxide, tert-butyl peroxide, sulfites, hydrogen sulfite, redox initiators such as ceric ammonium nitrate, 2,2'-azobis-2-amidinopropane hydrochloride Salt, 2,2'-azobis-2,4-dimethylvaleronitrile, 4,4'-azobis-4
Examples thereof include azo compounds such as cyanovaleic acid and its salts. It is also possible to use two or more of the above initiators in combination. The amount of radical polymerization initiator used is usually 0.01 to 10% by weight, preferably 0.05 to 8% by weight, based on the monomers. The polymerization temperature varies depending on the initiator used and the vinyl compound used, but it is usually 0 to 100 ° C. and the temperature above the cloud point of the resulting heat-sensitive polymer aqueous solution.

As the surfactant used in the present invention, a cationic surfactant and an anionic surfactant are used. As is specifically cationic surfactant, trimethyl stearyl ammonium chloride _{[(C 18 H 37 N (} CH 3) 3] Cl, trimethyl cetyl ammonium chloride _{[(C 16 H 33 N (} CH 3) 3] Cl,
Trimethyl cetyl ammonium bromide [(C ₁₆ H ₃₃ N (C
H _{3) 3]} Br, the chain length of the hydrophobic group of trimethyl n- tetradecyl ammonium chloride _{[(C 14 H 29 N (} CH 3) 3] Cl and cationic surfactants are those having a C12 or higher long chain especially Other long-chain cationic surfactants may be used as the anionic surfactant, such as sodium harddodecylbenzenesulfonate, sodium softdodecylbenzenesulfonate, and sodium 4-n-octylbenzenesulfonate. Acid salt, sodium dodecyl diphenyl ether disulfonate, sulfate ester salts such as nonylphenol sulfate sodium salt, sodium dioctylsulfosuccinate, sodium dodecyl sulfate, etc. Suitable, but other types of long chain A nonionic surfactant may be used, and one or more of these cationic surfactants and one or more of anionic surfactants may be used in combination. In the system added to, the heat-sensitive polymer compound undergoes a phase transition due to temperature rise,
At this time, a part of the polymer undergoes phase transition in the micelle of the surfactant and precipitates as fine particles, so that it is considered that the phase transition phenomenon due to temperature rise seems to be slow with the naked eye. Such a phenomenon does not appear in a system in which a short-chain ionic surfactant or a nonionic surfactant is added to an aqueous thermosensitive polymer compound solution. Further, it is not preferable to add a substance capable of remarkably changing the cloud point of the heat-sensitive polymer to these surfactants, and a substance which does not remarkably change the cloud point may be added.

The cationic micelle or the anionic surfactant is added to an aqueous solution containing one or more of the above-mentioned acrylamide vinyl compounds to which the cationic surfactant or the anionic surfactant is added at a concentration of the critical micelle concentration or more and the crosslinking agent. A uniform aqueous solution is prepared by adding it at a concentration equal to or higher than the concentration, and radical copolymerization is performed at a temperature equal to or higher than the cloud point to obtain a polymer emulsion having a crosslinked structure. After the addition of methanol or ethanol to destroy the micelle structure, the surfactant can be removed from such a polymer emulsion using an ultrafiltration membrane, and fine polymer beads having heat-sensitive properties can be obtained.

The hydrodynamic diameter D _M of the gel beads of the present invention was determined by photon correlation spectroscopy. This gel bead, depending on the manufacturing conditions, is about 75 nm to 150 nm in the swollen state and about 65 n in the contracted state.
m to 100 nm, and its distribution is close to that of a monodisperse system. The characteristics of these beads are obtained by reverse-phase suspension polymerization consisting of solvent-surfactant-pregel aqueous solution (Miji Hirose, Takeyuki Amiya, Yoshitsugu Hirokawa, Toyoichi Tanaka, 1st Polymer Gel Research Discussion Material, 39
(1989)), the hydrodynamic diameter D _M is much smaller than that of the beads of the method (the hydrodynamic diameter is about 800 nm in the swollen state and 200 to 300 nm in the contracted state). For the state of the phase transition,
The major difference was that nanometer-sized polymer beads were continuous and bulk gels were discontinuous.

〔The invention's effect〕

The polymer beads obtained by the method of the present invention have the property of expanding at a temperature lower than the phase transition temperature of the polymer constituting the polymer beads in water and contracting at a high temperature. Since this change is discontinuous and is accompanied by a change in hydrophilicity-hydrophobicity at the same time, these changes can be used to control the interaction of biological systems, such as oxygen consumption. Therefore, the fine polymer beads produced by the present invention exhibit sufficient performance as diagnostic microbeads, sustained-release preparations, adsorbents, cosmetics, etc., and are expected to have a wider range of applications.

Hereinafter, the present invention will be described with reference to examples, but the present invention is not limited thereto.

Example 1 10.04 g of N-isopropylacrylamide, N, in a 500 ml Erlenmeyer flask with a U-tube equipped with a capillary stopper.
N'-Methylenebisacrylamide 0.10g, distilled water 150.11
g ,, Sodium dodecylbenzene sulfonate 0.8
4 g (60% aqueous solution) was added, and nitrogen gas was vigorously passed for 30 minutes. Then, 43.3 mg of ammonium persulfate is added, and polymerization is carried out at 60 ° C. for 3 hours while stirring under a nitrogen stream. A bluish-colored polymer emulsion was formed as the polymerization proceeded.

Since the polymer synthesized in this way exists in micelles, methanol is added little by little to the extent that the polymer does not precipitate, and after destroying this micelle structure, it is repeatedly treated with an ultrafiltration membrane. The surfactant was removed. It was confirmed by the measurement of electric conductivity that no surfactant was present in the polymer emulsion.

The hydrodynamic radius of the gel beads thus obtained R _M
Was measured by photon correlation spectroscopy. The aqueous solution containing gel beads was diluted 2 to 5 times and transferred to a 1 × 1 × 5 cm light scattering cell through a 5 μm filter. The temperature of the cell was controlled in the range of 24-35 ° C. The time correlation function obtained by the digital correlator was fitted by the Cumulant method. From the average diffusion constant obtained,
The hydrodynamic diameter D _M was obtained from the Einstein-Stokes equation. The results are shown in Table 1.

Example 2 N-isopropylacrylamide 9.76 g, N, N'into a 500 ml Erlenmeyer flask with a U-shaped tube equipped with a capillary stopper.
-Methylenebisacrylamide 0.095g, distilled water 150.13
g ,, Nonipol S-40 (nonylphenol EO 4 mol adduct sulfate Na salt) C ₉ H ₁₉ C ₆ H ₄ O (CH ₂ CH ₂ O) _n SO ₃ Na 1.61 g (31% aqueous solution) was added, and nitrogen gas was added. I ran hard for 30 minutes. Then, 49.6 mg of ammonium persulfate is added, and polymerization is carried out at 60 ° C. for 2 hours while stirring under a nitrogen stream. As the polymerization progressed, a bluish-white polymer emulsion formed. The surfactant in the polymer emulsion was removed in exactly the same manner as in Example 1, the same measurement as in Example 1 was carried out, and the relationship between the hydrodynamic diameter D _M and temperature is shown in Table 1.

Example 3 13.35 g of N-isopropylacrylamide, N, in a 500 ml Erlenmeyer flask with a U-tube equipped with a capillary stopper.
N'-Methylenebisacrylamide 0.14g, distilled water 200.07
g ,, 4-n-octylbenzene sulfonic acid sodium salt
0.73 g was added and nitrogen gas was vigorously passed through for 30 minutes. Then, 8.8 mg of ammonium persulfate is added, and polymerization is carried out at 60 ° C. for 3 hours while stirring under a nitrogen stream. A white polymer emulsion was formed as the polymerization proceeded. The surfactant in the polymer emulsion was removed in exactly the same manner as in Example 1, the same measurement as in Example 1 was carried out, and the relationship between the hydrodynamic diameter D _M and temperature is shown in Table 1.

Example 4 10.06 g of N-isopropylacrylamide, N, in a 300 ml Erlenmeyer flask with a U-tube equipped with a capillary stopper.
N'-Methylenebisacrylamide 0.10g, distilled water 150.06
g and 0.51 g of trimethylstearyl ammonium chloride were added, and nitrogen gas was passed through for 2 hours. Then, 15.2 mg of ammonium persulfate is added, and polymerization is carried out at 60 ° C. for 3 hours while stirring under a nitrogen stream. As the polymerization proceeded, a pearlescent polymer emulsion formed. In the same manner as in Example 1, the surfactant in the polymer emulsion was removed, and Example 1
Table 1 shows the relationship between the hydrodynamic diameter D _M and temperature, which was measured in the same manner as in.

Claims (1)

[Claims] 1. A general formula (Wherein R ¹ is a hydrogen atom or a methyl group, at least one of R ² and R ³ is an alkyl group or an alkoxyalkyl group, and the rest are hydrogen atoms), among the acrylamide or methacrylamide vinyl compounds A cationic surfactant or anionic surfactant in an aqueous solution containing at least one selected from the group consisting of at least one cross-linking agent selected from compounds having two vinyl groups and having a concentration of at least the critical micelle concentration. Added in
After the intra-micellar copolymerization was performed at a temperature above the cloud point,
A method for producing a polymer bead which causes a thermosensitive particle size change, which comprises removing the used surfactant.