JPH1180701A - Production of ph-sensitive and heat-sensitive microbead - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing a pH-sensitive and heat-sensitive microbead, sensitive to both pH and heat and capable of changing the grain diameter according to the changes thereof. SOLUTION: This pH-sensitive and heat-sensitive microbead is produced by further adding a cationic surfactant or an anionic surfactant at the critical micelle concentration thereof to an aqueous solution containing a mixture of 1-40 mol.% at least one polymer selected from polyacrylic acid and polymethacrylic acid with 99-60 mol.% at least one monomer selected from an unsaturated amide represented by the formula (R<1> is hydrogen atom or methyl group; at least either one of R<2> and R<3> is an alkyl group or an alkoxyalkyl group and the remaining other is hydrogen atom) and a cross- linking agent and carrying out the intramicellar reaction at a temperature of the cloud point or above thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel pH-sensitive and heat-sensitive microbead which is sensitive to both pH and heat, changes its particle size according to the change, and is useful as a functional material. It is about the method.

[0002]

2. Description of the Related Art In recent years, heat-sensitive microbeads whose particle size changes in response to changes in heat are expected to be used as functional materials, for example, for diagnostic microbeads, sustained-release preparations, adsorbents, cosmetics, and the like. ,Attention has been paid.

[0003] Such heat-sensitive microbeads are N-
Isopropylacrylamide is converted to a crosslinking monomer such as N,
The reverse phase suspension polymerization method which can be obtained by polymerizing in the presence of N'-methylenebisacrylamide and has been hitherto performed in the presence of an organic solvent and a surfactant ["Macromolecules", 20 volumes, first
342 (1987)], a precipitation polymerization method in water [“Colloid & Polymer Science (Colloid & Polymer Science)”
Polymer Science), Vol. 270, p. 53 (1992)] and a method of performing polymerization in a surfactant aqueous solution having a concentration equal to or higher than the critical micelle concentration [Japanese Patent Publication No. Hei 7 (1994)].
No. 35402, "Burethane of Research"
Institute of Polymer and Textiles (Bull. Res. Inst. Polymer)
r & Textiles), Vol. 167, 67-
80 (1991)].

However, conventional microbeads obtained by these methods are heat-sensitive microbeads whose particle size changes according to a change in temperature, and are pH-sensitive microparticles whose particle size changes according to a change in pH. No sexual function.

[0005]

SUMMARY OF THE INVENTION The present invention provides a novel method for producing pH-sensitive, heat-sensitive microbeads whose particle size changes not only with heat but also with pH. It was made for the purpose of.

[0006]

Means for Solving the Problems The present inventors have first prepared a surfactant in an aqueous solution containing a specific ratio of an N-substituted acrylamide or methacrylamide derivative and acrylic acid or methacrylic acid in the presence of a crosslinking agent. Was added at a concentration higher than the critical micelle concentration and copolymerization was carried out in the micelle at a temperature higher than the cloud point, thereby succeeding in obtaining pH-sensitive and heat-sensitive microbeads. ,
Even without forming such a copolymer, by reacting polyacrylic acid or polymethacrylic acid with acrylamide or methacrylamide in the same manner as a crosslinking agent in the presence of a surfactant, pH sensitivity, heat sensitivity The present inventors have found that microbeads can be obtained, and have accomplished the present invention based on this finding.

That is, the present invention relates to a polymer represented by the general formula: 1 to 40 mol% of at least one polymer selected from polyacrylic acid and polymethacrylic acid.

Embedded image (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 remainder is a hydrogen atom). At least one monomer 99 to 60
Mol% of the mixture and the aqueous solution containing the cross-linking agent, a cationic surfactant or an anionic surfactant is further added at a concentration higher than the critical micelle concentration. The present invention provides a method for producing pH-sensitive and heat-sensitive microbeads, which is characterized in that the method is performed.

The microbeads obtained by the above-mentioned copolymerization change the cloud point depending on the monomer composition, but the microbeads obtained by the present invention have the characteristic that the cloud point does not change depending on the proportion of the monomer used. have.

[0009]

DESCRIPTION OF THE PREFERRED EMBODIMENTS In the method of the present invention, polyacrylic acid or polymethacrylic acid, an unsaturated amide, and a crosslinking agent are used as raw materials for microbeads. The polyacrylic acid or polymethacrylic acid preferably has a weight average molecular weight in the range of 1,000 to 10,000,000, and particularly preferably has a weight average molecular weight in the range of 10,000 to 1,000,000. The weight average molecular weight was determined by gel permeation chromatography (GP
C). In the present invention, the polyacrylic acid may be used alone, the polymethacrylic acid may be used alone, or a mixture thereof may be used. )
Acrylic acid].

On the other hand, as the unsaturated amide, a compound represented by the above general formula (I) is used. In the unsaturated amide represented by the general formula (I), R ² and R ³
Among them, preferred as the alkyl group are linear, branched and cyclic alkyl groups having 1 to 10 carbon atoms.
Examples of such a compound include a methyl group, an ethyl group,
n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, hexyl group, octyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, etc. Can be Further, as the alkoxyalkyl group of R ² and R ³ , a straight-chain having 2 to 10 carbon atoms,
Preferred are branched and cyclic alkoxyalkyl. Such compounds include, for example, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, isopropoxymethyl, isopropoxyethyl, isopropoxypropyl, cyclopropoxymethyl Group,
Examples thereof include a 2,2-dimethoxyethyl group, a 1-methyl-2-methoxyethyl group, a 1-methoxymethylpropyl group, and a methoxyethoxypropyl group. This R ² and R ³
Each may be the same or different, and may be bonded to each other to form a heterocyclic ring having a nitrogen atom as a hetero atom.

Examples of such unsaturated amides represented by the general formula (I) include N-ethylacrylamide and N-ethylacrylamide.
-N-propylacrylamide, N-isopropylacrylamide, N-cyclopropylacrylamide, N,
N-diethylacrylamide, N-methyl-N-ethylacrylamide, N-methyl-Nn-propylacrylamide, N-methyl-N-isopropylacrylamide, N-acryloylpiperidine, N-acryloylpyrrolidine, N-acryloylmorpholine, N -Methoxypropylacrylamide, N-ethoxypropylacrylamide, N-isopropoxypropylacrylamide, N-ethoxyethylacrylamide, N- (2,2
-Dimethoxyethyl) -N-methylacrylamide, N
-1-methyl-2-methoxyethylacrylamide, N
-1-methoxymethylpropylacrylamide, N-di (2-methoxyethyl) acrylamide, N-2-methoxyethyl-NNn-propylacrylamide, N-2
-Methoxyethyl-N-ethylacrylamide, N-methoxyethoxypropylacrylamide, and the like, and methacrylamide derivatives corresponding to these acrylamide derivatives. These unsaturated amides may be used alone or in combination of two or more.

Further, as the crosslinking agent, a polyfunctional monomer, preferably a compound having two vinyl groups in the molecule is used. Such compounds include, for example, N,
N'-methylenebisacrylamide, 1,4-diacloylpiperazine, divinylbenzene and the like can be mentioned. These may be used alone or in combination of two or more.

In the method of the present invention, first, an aqueous solution containing 1 to 40 mol% of poly (meth) acrylic acid and 99 to 60 mol% of the unsaturated amide represented by the above general formula (I) together with the crosslinking agent. Is prepared. When the amount of the poly (meth) acrylic acid and the unsaturated amide is less than 1 mol%, the pH sensitivity is not sufficiently exhibited, and when the amount exceeds 40 mol%, the heat sensitivity is poor. Will be enough. From the viewpoint of the balance between pH sensitivity and heat sensitivity, the proportion of poly (meth) acrylic acid is preferably 5 to 30 mol%, and the proportion of unsaturated amide is preferably 95 to 70 mol%. Also,
The amount of the crosslinking agent to be used is not particularly limited and may be appropriately selected depending on the situation. In general, the amount of the crosslinking agent is 0.1 to the total amount of the poly (meth) acrylic acid and the unsaturated amide.
It is used at a rate of 01 to 100 mmol%. further,
In the preparation of the aqueous solution, water used as a reaction medium may be any of ion-exchanged water, distilled water, tap water and the like.

In the method of the present invention, a cationic surfactant or an anionic surfactant is further added to the aqueous solution containing poly (meth) acrylic acid, unsaturated amide and the cross-linking agent thus obtained, in a critical micelle. Add at a concentration higher than the concentration to prepare a uniform aqueous solution. Examples of the cationic surfactant include trimethyl stearyl ammonium chloride, trimethyl cetyl ammonium chloride, trimethyl cetyl ammonium bromide, and trimethyl n-
Preferred examples of the hydrophobic group include those having a long chain of 12 or more carbon atoms, such as tetradecyl ammonium chloride. These cationic surfactants may be used alone or in combination of two or more. On the other hand, examples of anionic surfactants include, for example, sodium hard dodecylbenzenesulfonate, sodium soft dodecylbenzenesulfonate, alkylbenzene sulfonates such as sodium 4-n-octylbenzenesulfonate, and sulfates such as sodium nonylphenol sulfate. Salts, and also those having 1 carbon atom such as sodium dioctyl sulfosuccinate, sodium dodecyl sulfate, etc.
Those having two or more hydrophobic groups are preferred. These anionic surfactants may be used alone,
Two or more kinds may be used in combination.

As a method for initiating polymerization, a conventionally known method, for example, a method of irradiating with radiation or an electron beam, a method of heating in the presence of a radical polymerization initiator, a method of irradiating light in the presence of a photosensitizer However, among these methods, a method of heating in the presence of a radical polymerization initiator is preferable. The radical polymerization initiator may be any one as long as it is water-soluble, and is not particularly limited. For example, ammonium persulfate, potassium persulfate, hydrogen peroxide, tert-
Butyl hydroperoxide, or a redox initiator such as sulfite, hydrogen sulfite, ceric ammonium nitrate, and the like; 2,2'-azobis-2-amidinopropane hydrochloride; , 4-
Azo compounds such as dimethylvaleronitrile and 4,4'-azobis-4-cyanovaleric acid and salts thereof can be used. These radical polymerization initiators may be used alone or in combination of two or more, and the amount used is usually from 0.01 to 100% by weight based on the total amount of the monomers. %, Preferably in the range of 0.05 to 8% by weight. The polymerization temperature varies depending on the type of the monomer and the initiator used, but is usually in the range of 0 to 100 ° C. and higher than the cloud point of the aqueous polymer solution produced by polymerization.

In such a polymerization mode, the copolymerization reaction takes place in the micelle, and a copolymer emulsion having a crosslinked structure can be obtained efficiently. After the polymerization is completed, methanol and ethanol are added to destroy the micelle structure, and then the surfactant and unreacted monomer are removed by using an ultrafiltration method or a dialysis method to obtain a desired pH sensitivity, Thermosensitive microbeads can be obtained.

The microbeads thus obtained have a characteristic that the particle size changes according to changes in both pH and heat. That is, when the pH is changed from acidic to alkaline, the particle size increases, and when the temperature is lowered, the particle size sharply increases below a certain temperature. Although the size of the microbeads varies depending on the manufacturing conditions, the hydrodynamic diameter (Ds) obtained by photon correlation spectroscopy is usually about 150 to 1000 nm in a swelled state and about 20 to 200 nm in a contracted state in a neutral state. It is.

[0018]

According to the present invention, it is possible to efficiently produce pH-sensitive and heat-sensitive microbeads which are sensitive to both pH and heat, and have a property that the particle size changes according to the change. Can be. The microbeads include, as functional materials, for example, diagnostic microbeads, sustained-release preparations,
Useful for adsorbents, cosmetics, etc.

[0019]

EXAMPLES Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples. The hydrodynamic diameter (Ds) of the obtained microbeads was determined by photon correlation spectroscopy.

That is, the dispersion liquid of microbeads is
Dilute 1-fold, pass through a 5 μm filter, 1 × 1 × 5
cm light scattering cell. Cell temperature 15-70
The temperature was controlled in the range of ° C. The time correlation function obtained by the digital correlator was fitted by the cumulant method. From the obtained average diffusion constant, Einste
From the in-Stokes equation, the hydrodynamic diameter (D
s) was determined. Further, LPA3000 / 3100 manufactured by Otsuka Electronics Co., Ltd. was used as a measuring device.

Example 1 In a 500 ml Erlenmeyer flask equipped with a U-tube equipped with a capillary stopper, 200.70 g of distilled water, 8.07 g of N-isopropylacrylamide, and 25 weights of polyacrylic acid (weight average molecular weight: 150,000) % Aqueous solution 2.28 g,
0.12 g of N, N'-methylenebisacrylamide and 0.70 sodium harddodecylbenzenesulfonate
g was added and nitrogen gas was passed vigorously for 30 minutes. Then
0.05 g of ammonium persulfate was added, and the mixture was heated to 60 ° C. while stirring under a nitrogen stream to initiate polymerization. 60
After polymerization was performed at 2 ° C. for 2 hours, air was blown in to stop the polymerization, and a copolymer emulsion was formed. Since the copolymer thus obtained is present in the micelle, dialysis is performed for 4 days against pure water using a dialysis membrane to obtain a pH 5.5 at which the surfactant and unreacted monomers are completely removed. About 7 copolymer microbead dispersions were obtained.

Next, a part of the microbead dispersion liquid was taken, and 0.1 M hydrochloric acid was added thereto to adjust the pH to 2.9 in which the side chain acrylic acid groups were not dissociated. Was added to dissociate the side-chain acrylic acid groups, and the pH was adjusted to 10.2 by diluting with distilled water to obtain three types of microbead dispersions having different pH values. These three
The temperature of the microbead dispersion liquid was changed in the range of 20 to 50 ° C., and the hydrodynamic diameter (Ds) of the microbeads at each temperature was determined. Table 1 shows the results.
The molar ratio between N-isopropylacrylamide units and acrylic acid units in this dispersion was 90:10.

Example 2 In Example 1, the amount of N-isopropylacrylamide was changed to 8.45 g and polyacrylic acid (weight average molecular weight 1
50,000) was obtained in the same manner as in Example 1 except that the amount of the 25% by weight aqueous solution was changed to 6.84 g. The molar ratio between N-isopropylacrylamide units and acrylic acid units in this dispersion was 70:30. Using this microbead dispersion, three kinds of microbead dispersions having different pH values obtained in the same manner as in Example 1 were used.
The temperature was changed in the range of 0 to 50 ° C., and the hydrodynamic diameter (Ds) of the microbead at each temperature was determined. Table 1 shows the results.

Comparative Example In the same manner as in Example 1 except that the amount of N-isopropylacrylamide was changed to 8.96 g, polyacrylic acid was not used, and the reaction temperature was changed to 50 ° C. Thus, a polymer microbead dispersion having a pH of 6.5 was obtained. Using the microbead dispersion liquid, three kinds of microbead dispersion liquids having different pH values obtained in the same manner as in Example 1 were changed in temperature in the range of 20 to 50 ° C., and the microbeads at each temperature were changed. The hydrodynamic diameter (Ds) was determined. Table 1 shows the results.

[0025]

[Table 1]

[Note] The molar ratio of the N-isopropylacrylamide unit to the acrylic acid unit in the polymer was as follows: Comparative Example = 100: 0, Example 1 = 90: 10, Example 2 =
70:30.

As can be seen from Table 1, the microbeads obtained by the method of the present invention are sensitive to both pH and heat, whereas the microbeads of the comparative example are sensitive to heat, but are sensitive to pH. Almost insensitive.

Claims (3)

[Claims] 1 to 40 mol% of at least one polymer selected from polyacrylic acid and polymethacrylic acid
And 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 remainder is a hydrogen atom). At least one monomer 99 to 60
Mol% of the mixture and the aqueous solution containing the cross-linking agent, a cationic surfactant or an anionic surfactant is further added at a concentration higher than the critical micelle concentration. A method for producing pH-sensitive and heat-sensitive microbeads, which is performed. 2. The method according to claim 1, wherein the weight average molecular weight of at least one polymer selected from polyacrylic acid and polymethacrylic acid is in the range of 1,000 to 10,000,000. 3. The cross-linking agent is at least one selected from compounds having two vinyl groups in a molecule.
Or the production method according to 2.