JP3069633B2 - Method for producing pH-sensitive and heat-sensitive microbeads - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION The present invention relates to novel pH-sensitive, to a method of manufacturing a heat-sensitive micro-beads. More particularly, the present invention is sensitive to both pH and heat, particle size varies according to their variation, useful pH-sensitive as functional material, a heat-sensitive micro-beads effect <br/> It relates to a method for efficient production.

[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] As such heat-sensitive microbeads, for example, microgel beads obtained by polymerizing N-isopropylacrylamide in the presence of a crosslinkable monomer, N, N'-methylenebisacrylamide, and the like are known. ing. Then, the microgel beads are prepared, for example, by a reverse phase suspension polymerization method (“Macromolecules (Macromol)”) performed in the presence of (1) an organic solvent and a surfactant.
ecules) ", Vol. 20, p. 1342 (198
7 years)], (2) Precipitation polymerization method in water [“Colloid & Polym”
270, p. 53 (1992)] and (3) a method of performing polymerization in an aqueous surfactant solution having a concentration equal to or higher than the critical micelle concentration [Japanese Patent Publication No. 7-3]
No. 5402, "Bull. Res. Inst. Po.
lymer & Textiles ”Vol. 167, No. 6
7-80 (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. p
If microbeads that respond to both H and heat can be developed, further expansion of applications as functional materials can be expected.

[0005]

SUMMARY OF THE INVENTION Under such circumstances, the present invention is sensitive to both pH and heat, and has a pH-sensitive property and a heat-sensitive property in which the particle size changes according to the change. It has been made for the purpose of providing a method of fabricating a micro beads efficiently.

[0006]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies on pH-sensitive and heat-sensitive microbeads and have found that a specific ratio of N-substituted (meth) acrylamide derivative and (meth) acrylic acid That microbeads consisting of cross-linked copolymers are sensitive to both pH and heat, and that the microbeads have a certain proportion of N-substituted (meth) acrylamide derivative and (meth) acrylic acid , A surfactant is added to the aqueous solution containing these at a concentration higher than the critical micelle concentration, and copolymerization in micelles is performed at a temperature higher than the cloud point , and then 5 μm the Rukoto passed through a filter, found that the efficiency is often obtained, and have completed the present invention based on this finding.

That is, the present invention provides a compound represented by the general formula

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 70 to 95
Weight percent and the general formula

Embedded image (Wherein R ⁴ is a hydrogen atom or a methyl group) in a mixture with 30 to 5% by weight of at least one monomer selected from unsaturated carboxylic acids represented by the following formula: At least one cross-linking agent selected from compounds having the same, and further adding a cationic surfactant or an anionic surfactant to the aqueous solution containing them at a concentration higher than the critical micelle concentration, and the cloud point or higher. After the copolymerization in the micelles at a temperature of 5 ° C., the solution is allowed to pass through a 5 μm filter to obtain a neutral hydrodynamic diameter at 20 to 30 ° C. (D
s) is in the range from 150 to 700 nm in the swollen state;
It is intended to provide a method for producing pH-sensitive and heat-sensitive microbeads.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION The microbead obtained by the method of the present invention is a copolymer of an unsaturated amide represented by the above general formula (I) and an unsaturated carboxylic acid represented by the general formula (II). The unsaturated amide and the unsaturated carboxylic acid are in a ratio of 70 to 95% by weight of the unsaturated amide and 30 to 5% by weight of the unsaturated carboxylic acid. . If the amount of the unsaturated carboxylic acid is less than 5 % by weight, the pH sensitivity is not sufficiently exhibited, and if it exceeds 30 % by weight, the heat sensitivity becomes insufficient.

In order to crosslink a copolymer of an unsaturated amide and an unsaturated carboxylic acid, for example, an unsaturated amide and an unsaturated carboxylic acid are mixed in the presence of a crosslinking agent comprising a polyfunctional monomer. Is preferably used.

[0010] The microbeads obtained by the method of the present invention have the property that the particle size changes in response 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. The size of the microbeads was 20 to 20 determined by photon correlation spectroscopy.
Neutral hydrodynamic diameter (Ds) at 30 ° C. is in the range of 150-700 nm in the swollen state and 20 in the contracted state.
範 囲 100 nm.

In the unsaturated amide represented by the general formula (I), the alkyl group of R ² and R ³ is preferably a linear, branched or cyclic alkyl group having 1 to 10 carbon atoms. No. Such compounds include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, octyl, cyclo Examples thereof include a propyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. Further, as the alkoxyalkyl group of R ² and R ^3, a linear, branched or cyclic alkoxyalkyl having 2 to 10 carbon atoms is preferably exemplified. Such compounds include, for example, methoxymethyl group, methoxyethyl group, methoxypropyl group, ethoxymethyl group, ethoxyethyl group, ethoxypropyl group, isopropoxymethyl group, isopropoxyethyl group, isopropoxypropyl group, cyclopropoxymethyl Groups, 2,2-dimethoxyethyl, 1-methyl-2-methoxyethyl, 1-methoxymethylpropyl, methoxyethoxypropyl and the like. R ² and R ³ 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 the unsaturated amide 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-NNn-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.

On the other hand, the unsaturated carboxylic acids represented by the general formula (II) are acrylic acid and methacrylic acid,
These may be used alone or in combination of two or more.

As the cross-linking agent comprising a polyfunctional monomer, a compound having two vinyl groups is preferably used. Preferred examples of such a compound include N, N'-methylenebisacrylamide and divinylbenzene. These may be used alone or in combination of two or more.

By using the method of the present invention described below, desired microbeads can be efficiently produced. First, a mixture of 70 to 95% by weight of the unsaturated amide represented by the general formula (I) and 30 to 5% by weight of the unsaturated carboxylic acid represented by the general formula (II) has two vinyl groups. A crosslinking agent comprising a compound is added, preferably in a ratio of 0.01 to 10% by weight, to prepare an aqueous solution containing these. At this time, water used as a reaction medium may be any of ion-exchanged water, distilled water, tap water and the like.

Next, a cationic surfactant or an anionic surfactant is added to the aqueous solution at a concentration higher than the critical micelle concentration to prepare a uniform aqueous solution. As the cationic surfactant, for example, those having a long chain having 12 or more carbon atoms as a hydrophobic group, such as trimethyl stearyl ammonium chloride, trimethyl cetyl ammonium chloride, trimethyl cetyl ammonium bromide, and trimethyl n-tetradecyl ammonium chloride, are preferred. Can be 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 those having a hydrophobic group having 12 or more carbon atoms, such as sodium dioctylsulfosuccinate and sodium dodecyl sulfate, are preferred.
These anionic surfactants may be used alone or in combination of two or more.

As a method for initiating the 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; 2,2'-azobis-2 , 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 of the radical polymerization initiator is usually 0.01 to 10% 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 to be 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 the polymerization.

In such a polymerization mode, the copolymerization reaction occurs in the micelle, and a copolymer emulsion having a crosslinked structure can be obtained efficiently. After the polymerization, 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 , and then passed through a 5 μm filter.
By that, it is possible to obtain the desired pH-sensitive, heat-sensitive microbeads.

[0019]

The microbeads obtained according to the present invention are sensitive to both pH and heat, and have a property that the particle size changes in accordance with those changes. It is useful for microbeads, sustained release preparations, adsorbents, cosmetics, etc. Further, according to the method of the present invention, the pH-sensitive and heat-sensitive microbeads can be efficiently produced.

[0020]

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 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 g of distilled water, 8.51 g of N-isopropylacrylamide, 0.28 g of acrylic acid, N, N'-
0.12 g of methylenebisacrylamide and 0.70 g of sodium softdodecylbenzenesulfonate (60% by weight aqueous solution) were added, and nitrogen gas was passed vigorously for 30 minutes. Next, 0.05 g of ammonium persulfate was added, and the mixture was heated to 50 ° C. while stirring under a nitrogen stream to initiate polymerization. After polymerization was carried out at 50 ° C. for 2 hours, air was blown in to stop the polymerization, and a copolymer emulsion was formed.

Since the copolymer thus obtained exists in micelles, dialysis against pure water using a dialysis membrane is carried out for 4 hours.
This was carried out for one day to obtain a copolymer microbead dispersion having a pH of about 7.0 from which the surfactant and unreacted monomers were completely removed. The content of the copolymer microbeads in this dispersion was 4.3% by weight, and the weight ratio of N-isopropylacrylamide units to acrylic acid units in the copolymer was 95: 5.

Next, a part of the microbead dispersion liquid was taken, and 0.1 M hydrochloric acid was added thereto. Then, an aqueous solution of pH 2.5 and 0.1 M sodium hydroxide in which the side chain COOH was not dissociated was added. After changing the chain COOH to COONa,
The pH was adjusted to 9.0 by diluting with distilled water to obtain three kinds of acidic, neutral and alkaline microbead dispersions. For these three types of microbead dispersions, 20 to 50 ° C.
, And the hydrodynamic diameter (Ds) of the microbeads at each temperature was determined. Table 1 shows the results.

Example 2 The procedure of Example 1 was repeated, except that the amount of N-isopropylacrylamide was changed to 8.07 g and the amount of acrylic acid was changed to 0.57 g. A polymer microbead dispersion was obtained. The weight ratio of N-isopropylacrylamide units to acrylic acid units in this copolymer was 90:10.

Using the microbead dispersion liquid, three kinds of acidic, neutral and alkaline microbead dispersion liquids obtained in the same manner as in Example 1 were changed in the temperature range of 20 to 50 ° C. The hydrodynamic diameter (Ds) of the microbeads at temperature was determined. Table 1 shows the results.

Example 3 The procedure of Example 1 was repeated, except that the amount of N-isopropylacrylamide was changed to 6.27 g and the amount of acrylic acid was changed to 1.71 g. A polymer microbead dispersion was obtained. The weight ratio of N-isopropylacrylamide units to acrylic acid units in this copolymer was 70:30.

Using the microbead dispersion liquid, three kinds of acidic, neutral and alkaline microbead dispersion liquids obtained in the same manner as in Example 1 were changed in the temperature range of 20 to 50 ° C. The hydrodynamic diameter (Ds) of the microbeads at 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 and that acrylic acid was not used, polymer microbeads having a pH of 7.0 were obtained. A dispersion was obtained. Using the microbead dispersion liquid, three kinds of acidic, neutral, and alkaline microbead dispersion liquids obtained in the same manner as in Example 1 were used, and the temperature was changed in the range of 20 to 50 ° C. The hydrodynamic diameter (Ds) of the beads was determined. Table 1 shows the results.

[0030]

[Table 1]

[Note] The weight ratio of N-isopropylacrylamide unit to acrylic acid unit in the polymer was 100% in Comparative Example, 95: 5 in Example 1 and 9 in Example 2
0:10 and Example 3 = 70: 30.

As can be seen from Table 1, the results obtained according to the invention are:
The resulting microbeads are sensitive to both pH and heat, whereas the microbeads of the comparative example are sensitive to heat but hardly sensitive to pH.

Claims (1)

(57) [Claims] 1. A compound of 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 70 to 95
% By weight and the general formula (Wherein R ⁴ is a hydrogen atom or a methyl group) in a mixture with 30 to 5% by weight of at least one monomer selected from unsaturated carboxylic acids represented by the following formula: At least one cross-linking agent selected from compounds having the same, and further adding a cationic surfactant or an anionic surfactant to the aqueous solution containing them at a concentration higher than the critical micelle concentration, and the cloud point or higher. The copolymer has a hydrodynamic diameter (Ds) at 20 to 30 ° C. at neutral temperature of from 150 to 700 nm in a swollen state, after being subjected to intra-micellar copolymerization at a temperature of 5 μm. A method for producing pH-sensitive and heat-sensitive microbeads within the range.