JPH1087751A - Ph responsive and heat-sensitive microbead and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject beads useful for microbeads for diagnose, sustained release preparation, adsorbent, cosmetic, etc., sensitive to both pH and heat, capable of changing particle diameters according to their change, comprising a crosslinked substance of a copolymer of a specific unsaturated amide monomer and an N-vinylimidazole monomer. SOLUTION: The beads comprises a crosslinked substance of a copolymer of 60-99mol% of an unsaturated amide monomer of formula I (R<1> is H or methyl; at least one of R<2> and R<3> is an alkyl or an alkoxyalkyl and the other is H) and 40-1mol% of an N-vinylimidazole monomer of formula II (R<4> to R<6> are each H or an alkyl).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel pH-sensitive and heat-sensitive microbead and a method for producing the same. More specifically, the present invention is sensitive to both pH and heat, and changes in particle size in response to those changes;
The present invention relates to a pH-sensitive and heat-sensitive microbead useful as a functional material, and a method for efficiently producing the microbead.

[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, "Bulletin of Research Institute of Polymer and Textiles (Bull. Res. Inst. Polymer)
& Textiles], Vol. 167, pp. 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. 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. The purpose of the present invention is to provide microbeads and a method for efficiently producing the microbeads.

[0006]

The inventors of the present invention have conducted various studies to develop microbeads having a particle size that changes according to various conditions, and as a result, have found that N-substituted acrylamide or methacrylamide and N-vinylimidazole It has been found that the particle size of microbeads comprising a crosslinked product of the above can be changed by changing pH conditions or temperature conditions, and based on this finding, the present invention has been accomplished.

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 60 to 99
Mol% and the general formula

Embedded image (Wherein R ⁴ , R ⁵ and R ⁶ are each a hydrogen atom or an alkyl group, which may be the same or different). At least one selected monomer 40
PH-sensitive consisting of ~ 1 mol% of cross-linked copolymers,
The present invention provides thermosensitive microbeads.

The pH-sensitive and heat-sensitive microbeads are, for example, at least one monomer selected from the unsaturated amides represented by the general formula (I) and the monomers represented by the general formula (II). A surfactant is added to an aqueous solution containing at least one monomer selected from N-vinylimidazoles and at least one crosslinking agent selected from compounds having two vinyl groups. It can be produced by adding at a concentration equal to or higher than the critical micelle concentration and performing copolymerization in the micelle while stirring at a temperature equal to or higher than the cloud point.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION The microbead of the present invention comprises an unsaturated amide represented by the above general formula (I) and a general formula (I)
A crosslinked product of a copolymer with N-vinylimidazole represented by I), wherein the ratio of unsaturated amide to N-vinylimidazole is 6
0-99 mol%, preferably in the range of 70-95 mol%,
N-vinylimidazole is in the range of 40-1 mol%, preferably 30-5 mol%. When the amount of N-vinylimidazole is less than 1 mol%, the pH sensitivity is not sufficiently exhibited, and when it exceeds 40 mol%, the heat sensitivity becomes insufficient.

A cross-linked product of a copolymer of unsaturated amide and N-vinylimidazole is defined as
It has a cross-linked structure via a compound having two vinyl groups.

[0011] The microbeads 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 alkaline to acidic, the particle size increases, and as the temperature is lowered, the particle size sharply increases below a certain temperature. Although the size of the microbeads of the present invention varies depending on the manufacturing conditions, the hydrodynamic diameter (Ds) determined by photon correlation spectroscopy is usually
About 70-1000 nm in swelling state, 30- in shrinking state
It is about 300 nm.

In the unsaturated amide represented by the general formula (I), the alkyl group of R ² and R ³ is
A linear, branched or cyclic alkyl group having 1 to 10 carbon atoms is preferably exemplified. Examples of such a compound include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group,
Examples include a tert-butyl group, a pentyl group, a hexyl group, an octyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. Also, R
^As the alkoxyalkyl group of 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, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, isopropoxymethyl, isopropoxyethyl, isopropoxypropyl, cyclopropoxymethyl Groups, 2,2-dimethoxyethyl, 1-methyl-2-methoxyethyl, 1-methoxymethylpropyl, methoxyethoxypropyl and the like. R ² and R ³ may be the same,
They may be different from each other, or 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, N represented by the general formula (II)
As the alkyl group for R ⁴ , R ⁵ and R ⁶ in -vinylimidazole, a linear, branched or cyclic alkyl group having 1 to 3 carbon atoms is preferable. Examples of such a group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, and a cyclopropyl group. This R ⁴ ,
R ⁵ and R ⁶ may be the same or different. The N represented by the general formula (II)
Examples of -vinylimidazole include 1-vinylimidazole, 1-vinyl-2-methylimidazole, 1-vinyl-2,4-dimethylimidazole and the like. These may be used alone or in combination of two or more.

A compound having two vinyl groups is used as a cross-linking agent for forming a cross-link between copolymers. Examples of such a compound include N and N '.
-Methylenebisacrylamide, 1,4-diacloylpiperazine, divinylbenzene and the like. These may be used alone or in combination of two or more.

The microbeads of the present invention can be produced, for example, according to the following method. First, a predetermined amount of the unsaturated amide represented by the general formula (I) and the general formula (I)
A predetermined amount of N-vinylimidazole represented by I),
An aqueous solution containing a crosslinking agent consisting of a compound having two vinyl groups is prepared. At this time, water used as a reaction medium is ion-exchanged water, distilled water, tap water, or the like.

The proportion of the unsaturated amide and N-vinylimidazole used at this time is selected depending on the desired physical properties of the microbeads.
The latter is selected within the range of 30 to 5 mol%. The amount of the crosslinking agent is usually in the range of 0.01 to 50 mol% based on the total amount of the monomers.

Next, a surfactant is added to this aqueous solution at a concentration higher than the critical micelle concentration to prepare a uniform aqueous solution. The surfactant may be either cationic or anionic, and in some cases, other surfactants may be used. Examples of the cationic surfactant include trimethyl stearyl ammonium chloride, trimethyl cetyl ammonium chloride, trimethyl cetyl ammonium bromide, trimethyl-n-tetradecyl ammonium chloride, and the like.
Those having two or more long chains are mentioned. These cationic surfactants may be used alone or in combination of two or more. Examples of the anionic surfactant include sodium hard dodecylbenzenesulfonate, sodium softdodecylbenzenesulfonate, alkylbenzene sulfonates such as sodium 4-n-octylbenzenesulfonate, and sulfuric acid such as sodium nonylphenol sulfate. Examples thereof include ester salts and those having a hydrophobic group having 12 or more carbon atoms, such as sodium dioctyl sulfosuccinate and sodium dodecyl sulfate. These anionic surfactants may be used alone or in combination of two or more.

The polymerization may be initiated by a conventionally known method, for example, irradiation with radiation or an electron beam, heating in the presence of a radical polymerization initiator, or irradiation with 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, bisulfite, ceric ammonium nitrate, 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. Also,
The amount used is usually 0.01 to the total amount of the monomers.
The range is from 10 to 10% by weight, preferably from 0.05 to 8% by weight. The polymerization temperature varies depending on the type of the monomer and the initiator used, but it is usually required to be in the range of 0 to 100 ° C. and a temperature equal to or higher than the cloud point of the aqueous polymer solution produced by the polymerization. . It is necessary to carry out this polymerization reaction while stirring.

In this case, the copolymerization reaction occurs in the dispersed micelles, and a copolymer emulsion having a crosslinked structure can be obtained efficiently. After completion of the polymerization, the surfactant and the unreacted monomer are removed by ultrafiltration or dialysis, whereby desired pH-sensitive and heat-sensitive microbeads can be obtained.

[0021]

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

[0022]

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. In addition, about the particle diameter of the obtained microbead, the hydrodynamic diameter (Ds) was calculated | required by the photon correlation spectroscopy shown below.

That is, the microbead dispersion liquid is mixed with 2 to 5
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 1 200 g of distilled water, 8.51 g (0.0753 mol) of N-isopropylacrylamide, 0.37 g of 1-vinylimidazole (0.07 g) were placed in a 500 ml Erlenmeyer flask equipped with a U-tube fitted with a capillary stopper. 0041 mol), N, N '
0.12 g of methylenebisacrylamide (0.000
8 mol) and 0.70 g of sodium harddodecylbenzenesulfonate, and nitrogen gas was passed vigorously for 30 minutes. Next, 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. After polymerization was performed at 60 ° 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 micelles, dialysis against pure water using a dialysis membrane is performed.
This was carried out for one day to obtain a copolymer microbead dispersion having a pH of about 6.5 from which surfactants and unreacted monomers were completely removed. The content of the copolymer microbeads in this dispersion was 4.3% by weight, and the molar ratio of N-isopropylacrylamide units to 1-vinylimidazole units in the copolymer was 95: 5.

Next, a part of the microbead dispersion liquid is taken and adjusted to pH 2.9 with 0.1 mol hydrochloric acid to dissociate the side chain imidazolyl group. Was added to make the side chain imidazolyl group undissociated, and diluted with distilled water to adjust the pH to 8.9 to obtain three kinds of acidic, neutral and alkaline microbead dispersions. For these three types of microbead dispersions,
The temperature was changed in the range of 20 to 50 ° C., and the hydrodynamic diameter (Ds) of the microbead at each temperature was determined. Table 1 shows the results.

Example 2 In Example 1, except that the amount of N-isopropylacrylamide was changed to 8.45 g (0.0748 mol) and the amount of 1-vinylimidazole was changed to 0.75 g (0.008 mol). In the same manner as in Example 1, a copolymer microbead dispersion having a pH of 6.5 was obtained. The molar ratio between N-isopropylacrylamide units and 1-vinylimidazole 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 Example 1 was repeated except that the amount of N-isopropylacrylamide was changed to 8.12 g (0.0719 mol) and the amount of 1-vinylimidazole was changed to 2.28 g (0.0253 mol). In the same manner as in Example 1, a copolymer microbead dispersion having a pH of 6.5 was obtained. The molar ratio of N-isopropylacrylamide units to 1-vinylimidazole 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 subjected to temperature changes in the range of 20 to 50 ° C. The hydrodynamic diameter (Ds) of the microbeads at temperature was determined. Table 1 shows the results.

COMPARATIVE EXAMPLE The procedure of Example 1 was repeated except that the amount of N-isopropylacrylamide was changed to 8.96 g and that 1-vinylimidazole was not used.
A polymer microbead dispersion of 6.5 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. Hydrodynamic diameter of beads (Ds)
I asked. Table 1 shows the results.

[0032]

[Table 1]

[Note] The molar ratio of N-isopropylacrylamide unit to 1-vinylimidazole unit in the polymer was as follows: Comparative example = 100: 0, Example 1 = 95: 5,
Example 2 = 90: 10, Example 3 = 70: 30.

As can be seen from Table 1, the microbeads of the present invention are sensitive to both pH and heat, whereas
Although the microbeads of the comparative example are sensitive to heat,
It is almost insensitive to pH.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code FI // C08F 226/06 C08F 226/06

Claims (2)

[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 60 to 99
Mol% and the general formula (Wherein R ⁴ , R ⁵ and R ⁶ are each a hydrogen atom or an alkyl group, which may be the same or different). At least one selected monomer 40
PH-sensitive consisting of ~ 1 mol% of cross-linked copolymers,
Thermosensitive microbeads. 2. 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 having the general formula: (Wherein R ⁴ , R ⁵ and R ⁶ are each a hydrogen atom or an alkyl group, which may be the same or different). At least one selected monomer;
A surfactant is added to an aqueous solution containing at least one crosslinking agent selected from compounds having two vinyl groups in one molecule at a concentration higher than the critical micelle concentration, and the temperature is higher than the cloud point. A method for producing pH-sensitive and heat-sensitive microbeads, wherein copolymerization in micelles is carried out while stirring.