JP5040083B2 - Method for producing core-shell type polymer particles - Google Patents

Description

  The present invention relates to a method for producing monodisperse core-shell polymer particles having a sharp particle distribution expected to be used for DDS carriers, integrated material materials, pharmaceutical diagnostics, powder paints, cosmetics and the like.

  Conventionally, it is known that hydrophilic shell-hydrophobic core type polymer fine particles can be obtained by radical copolymerization of a hydrophilic macromonomer and a hydrophobic vinyl monomer. For example, Non-Patent Documents 1 and 2 report that when a water-soluble macromonomer and styrene are radically copolymerized in a water / ethanol mixed solvent, polymer fine particles having a spherical core-shell structure are generated. ing. However, in the methods described in these documents, in order to obtain a yield of 80% or more, the reaction must be performed for 12 hours or more, and core-shell type polymer fine particles having a sharp particle size distribution are produced. It was difficult.

On the other hand, Non-Patent Document 3 reports for the first time a method for synthesizing polystyrene fine particles by microwave irradiation using a styrene monomer. However, in this method using only a styrene monomer, the particle size distribution tends to widen when the monomer concentration is 3% by mass or more, and it is difficult to obtain monodisperse polystyrene fine particles, and high-quality polymer fine particles are obtained. Not.
Akashi Mitsuru, Ueno Shinji, Serizawa Takeshi, Baba Masanori, Chemical Industry, 52,705 (2001) M. Akashi, D. Chao, E. Yashima, N. Miyauchi, J. Appl. Polym. Sci., 39, 2027 (1990) W. Zhang, J. Gao, C. Wu, Macromolecules, 30, 6388 (1997)

  An object of the present invention is to provide a core-shell type polymer particle capable of obtaining monodisperse particles having a hydrophilic shell and a hydrophobic core structure in a simple and reproducible manner in a short time and with a high yield. It is to provide a manufacturing method.

  As a result of intensive studies to solve the above problems, the present inventors have selected a specific hydrophilic monomer and a hydrophobic monomer copolymerizable therewith as the polymerizable material, and have a specific concentration in the solvent. It was found that monodisperse core-shell type polymer particles having an average particle diameter of 0.05 to 10 μm can be produced efficiently in a short time by performing microwave irradiation on the polymerizable solution dissolved or dispersed in The invention has been completed.

That is, according to the present invention, a hydrophilic monomer having a polyethylene glycol chain or a phosphorylcholine group, and a hydrophobic monomer that is copolymerizable therewith and is composed of styrene, acrylic acid ester, methacrylic acid ester, or a mixture of two or more thereof. Water, methanol, ethanol, which can dissolve or disperse the hydrophilic monomer and the hydrophobic monomer and does not dissolve the core-shell type polymer particles produced in the next step (B). the solvent consisting of propanol, or ethylene glycol or water, methanol, ethanol, propanol or a mixed solvent composed of ethylene glycol dissolved or dispersed, preparing a concentration of 1 to 40% by weight of the polymerizable solution (a), the A step (B) of copolymerizing the polymerizable solution by irradiating with microwaves, and the obtained And a step (C) of purifying monodisperse core-shell type polymer particles having an average particle size of 0.05 to 10 μm from the copolymer, and a method for producing core-shell type polymer particles is provided. .

  The method for producing core-shell type polymer particles of the present invention uses a polymerizable material comprising a specific hydrophilic monomer having a polyethylene glycol chain or a phosphorylcholine group and a hydrophobic monomer copolymerizable therewith, and the polymerization. Since a polymerizable solution containing a functional material at a concentration of 1 to 40% by mass is irradiated with a high-energy microwave and copolymerized, the yield is high and the monodisperse with an average particle diameter of 0.05 to 10 μm Core-shell type polymer particles can be easily produced. Since the polymer particles obtained are fine particles having a hydrophilic shell and a hydrophobic core structure, they can be expected to be used for DDS carriers, integrated material materials, pharmaceutical diagnostics, powder coating materials, cosmetic materials, and the like.

Hereinafter, the present invention will be described in more detail.
The production method of the present invention comprises dissolving or dispersing a polymerizable material composed of a hydrophilic monomer having a polyethylene glycol chain or a phosphorylcholine group and a specific hydrophobic monomer copolymerizable therewith in a specific solvent, and having a specific concentration. The step (A) for preparing the polymerizable solution is performed.
The hydrophilic monomer used in the step (A) is not particularly limited as long as it is a polymerizable monomer having a polyethylene glycol chain or a phosphorylcholine group. For example, 2-methacryloyloxyethyl phosphorylcholine, polyethylene glycol monomethacrylate, polyethylene glycol monostyrene, etc. Can be mentioned. In particular, in the case of a monomer having a polyethylene glycol chain, the number average molecular weight of the polyethylene glycol chain is preferably 300 to 5000 from the viewpoint of enhancing the dispersion stability of the obtained core-shell type polymer particles.

Hydrophobic monomers used in step (A), the hydrophilic monomer and a radical copolymerization possible scan styrene, acrylic acid ester, methacrylic acid ester le also consist of two or more of these mixtures, particularly preferably obtained From the viewpoint of properties, styrene and methyl methacrylate are exemplified.

  In step (A), the composition of the polymerizable material is not particularly limited as long as it is composed of the hydrophilic monomer and the hydrophobic monomer, but the particle size distribution of the obtained polymer is limited to a narrower range, that is, a sharp particle size distribution. For this purpose, it is preferably composed of 1 to 95 mol% of a hydrophilic monomer and 5 to 99 mol% of a hydrophobic monomer.

In step (A), the solvent for preparing the polymerizable solution by dissolving or dispersing the polymerizable material is a core-shell that dissolves or disperses the hydrophilic monomer and the hydrophobic monomer, and is formed after copolymerization. a solvent that does not dissolve the mold polymer particles, one lifting the property of easily being heated by microwave irradiation in a step which will be described later (B), water; selected from the alcohols, methanol, ethanol, propanol, alcohols such as ethylene glycol Preferred is a mixed solvent of one kind of water and water, and most preferably, water alone or a mixed solvent of water and ethanol is used because of the dispersibility of the produced polymer particles and the ease of removing unreacted monomers. Can be mentioned.

In the step (A), the concentration of the polymerizable material comprising a mixture of hydrophilic monomer and hydrophobic monomer in the polymerizable solution suppresses aggregation of the generated polymer particles and increases the dispersion stability of the fine particles. 1 to 40% by mass, preferably 1 to 30% by mass, and most preferably 1 to 20% by mass for the reason of improving the yield.
The polymerizable solution may contain a radical polymerization initiator in addition to the solvent and the polymerizable material. Examples of radical polymerization initiators include 2,2′-azobisisobutyronitrile, 2,2′-azobis (2,4-dimethylvaleronitrile), and 2,2′-azobis-2-amidinopropane hydrochloride. Azo compounds such as sodium salt of 4,4′-azobis-4-cyanovaleric acid; peroxides such as benzoyl peroxide, lauryl peroxide, t-butyl hydroperoxide, and the like. From the viewpoint of the decomposition temperature of the radical polymerization initiator, 2,2′-azobis-2-amidinopropane hydrochloride is most preferred.
The mixing ratio in the case of containing a radical polymerization initiator can be appropriately determined, but is usually about 0.1 to 5.0 parts by mass with respect to 100 parts by mass of the polymerizable material in the polymerizable solution.

In the production method of the present invention, the step (B) is carried out by irradiating the polymerizable solution prepared in the step (A) with microwaves for copolymerization.
Microwave irradiation can be performed using a commercially available microwave generator. For example, it can be carried out by placing the polymerizable solution in a container such as a flask or test tube and irradiating with microwaves.
The irradiation intensity of the microwave is not particularly limited as long as the radical polymerization initiator in the polymerizable solution can generate radicals. For example, to limit the particle size distribution of the obtained polymer particles to a narrower range. For this, it is preferable to control the microwave intensity to 0.001 to 30 W / cm ³ . In order to generate radicals from the radical polymerization initiator in a short time, it is preferable to set the irradiation intensity to 0.05 W / cm ³ or more.

In the step (B), in order to carry out the copolymerization by irradiating the microwave, it is preferable that the temperature of the polymerizable solution is usually maintained in the range of 0 to 150 ° C, particularly in the range of 40 to 100 ° C. . At this time, the copolymerization time can be shortened by setting the temperature to 40 ° C. or higher.
The microwave irradiation time for copolymerization is not limited as long as the object of the present invention is not impaired, but is usually 10 to 120 minutes, preferably 20 to 120 minutes. If the irradiation time is shorter than 10 minutes, the copolymerization reaction does not proceed sufficiently, the degree of dispersion of the resulting polymer particles increases, and it may be difficult to control the particle size of the particles, and the reaction conversion rate may be low. Causes to decrease. In addition, the copolymerization can usually be performed with stirring.

In the production method of the present invention, the step (C) for purifying monodisperse core-shell polymer particles having an average particle diameter of 0.5 to 10 μm from the copolymer obtained in the step (B) is desired. The polymer particles can be obtained.
Purification in the step (C) can be performed by a method of removing unreacted monomers from the solution containing the copolymer obtained in the step (B) by dialysis or the like and freeze-drying.
As the polymer particles obtained, for example, when polyethylene glycol monomethacrylate is used as a hydrophilic monomer, styrene is used as a hydrophobic monomer, and water is used as a solvent, a styrene core-polyethylene glycol monomethacrylate shell type polymer particle is obtained. When polyethylene glycol monomethacrylate is used as the hydrophilic monomer, methyl methacrylate is used as the hydrophobic monomer, and water is used as the solvent, methyl methacrylate core-polyethylene glycol monomethacrylate shell type polymer particles are obtained, When 2-methacryloyloxyethyl phosphorylcholine is used as the hydrophilic monomer and styrene is used as the hydrophobic monomer, styrene core-methacryloyloxyethyl phosphorylcholine shell-type polymer particles are obtained. .

  In the present invention, the average particle diameter is a value measured by a dynamic light scattering measurement device, and being monodispersed means that the uniformity of the particle diameter of the synthesized core-shell type polymer particles is high, It means that the particle size distribution shows a sharp particle size distribution of 10% or less when measured using a dynamic light scattering measuring apparatus.

EXAMPLES Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited thereto.
Examples 1-6
A monomer and initiator having the composition shown in Table 1 and 10 ml of water were placed in a 30 ml glass tube to prepare a polymerizable solution. The resulting polymerizable solution was irradiated with 300 W of microwave until the polymerizable solution reached a reaction temperature of 70 ° C. using a microwave irradiation device (Green Motif I, manufactured by Tokyo Denshi Co., Ltd.). Then, a 20 W microwave was irradiated for 1 hour to cause a copolymerization reaction. After cooling the resulting solution, unreacted monomers were removed by dialysis, and the resulting polymer was prepared by lyophilization.
The particle size distribution and particle size of the obtained polymer were measured by a dynamic light scattering measuring device (NICOMP 380ZLS Particle Sizer, manufactured by Particle Sizing System), and the yield was measured. The results are shown in Table 1 and FIGS.
Furthermore, when the structure of the obtained polymer particles was measured by an X-ray photoelectron analyzer (ESCA-3300, manufactured by Shimadzu Corporation), the hydrophobic monomer unit became the core and the hydrophilic monomer unit became the shell. It was found to be shell type polymer particles.
In Table 1, MA-PEG350 represents polyethylene glycol monomethacrylate (Nippon Yushi Co., Ltd., trade name: Blemmer PE-350, number average molecular weight 439), St represents styrene, V-50 represents 2, 2'-Azobis-2-amidinopropane hydrochloride is shown.

Examples 7-9
In Examples 1 to 6, polymer particles were prepared in the same manner as in Example 1 except that the monomer and initiator compositions were changed to the monomer and initiator compositions shown in Table 2. In short, Examples 7 to 9 are examples in which 2-methacryloyloxyethyl phosphorylcholine was used as a hydrophilic monomer instead of the polyethylene glycol monomethacrylate as the hydrophilic monomer of Examples 1 to 6. The yield and particle size were measured as in Example 1. The results are shown in Table 2 and FIG.
In Table 2, MPC represents 2-methacryloyloxyethyl phosphorylcholine, and other abbreviations have the same meaning as in Table 1.

Examples 10 and 11
In Examples 1 to 6, polymer particles were prepared in the same manner as in Example 1 except that the monomer and initiator compositions were changed to the monomers and initiators having the compositions shown in Table 3. In short, Examples 10 and 11 are examples using polyethylene glycol monomethacrylate having a number average molecular weight different from that of polyethylene glycol monomethacrylate as the hydrophilic monomer of Examples 1-6. The yield and particle size were measured as in Example 1. The results are shown in Table 3 and FIG.
In Table 1, MA-PEG2000 indicates polyethylene glycol monomethacrylate (manufactured by NOF Corporation, trade name: Blemmer PE-2000, number average molecular weight 2000), and other abbreviations have the same meaning as in Table 1.

Comparative Examples 1 and 2
In Examples 1 to 6, polymer particles were prepared in the same manner as in Example 1 except that the monomer and initiator compositions were changed to the monomer and initiator compositions shown in Table 2. In short, Comparative Examples 1 and 2 are examples in which methacrylic acid 2-hydroxyethyl ester was used as the hydrophilic monomer instead of polyethylene glycol monomethacrylate as the hydrophilic monomer of Examples 1 to 6. The yield and particle size were measured as in Example 1. The results are shown in Table 4 and FIG.
In Table 4, HEMA represents methacrylic acid 2-hydroxyethyl ester, and other abbreviations have the same meaning as in Table 1.

  It can be seen from Tables 1 to 4 and FIGS. 1 to 7 that in Examples 1 to 11, the target core-shell type polymer particles can be obtained with good yield by copolymerization by microwave irradiation for 1 hour. In addition, it can be seen that in the method according to the example, the particle size distribution of the obtained polymer is narrow and monodisperse particles are obtained as compared with the method of the comparative example.

3 is a graph showing the particle size distribution of core-shell type polymer particles obtained in Example 2. FIG. 4 is a graph showing the particle size distribution of core-shell type polymer particles obtained in Example 3. FIG. 6 is a graph showing the particle size distribution of core-shell type polymer particles obtained in Example 5. FIG. 7 is a graph showing the particle size distribution of core-shell type polymer particles obtained in Example 6. FIG. 6 is a graph showing the particle size distribution of core-shell type polymer particles obtained in Example 8. FIG. 3 is a graph showing the particle size distribution of core-shell type polymer particles obtained in Example 11. FIG. 3 is a graph showing the particle size distribution of core-shell type polymer particles obtained in Comparative Example 1. FIG.

Claims (5)

A polymerizable material comprising a hydrophilic monomer having a polyethylene glycol chain or a phosphorylcholine group, and a hydrophobic monomer that is copolymerizable therewith and is composed of styrene, acrylic acid ester, methacrylic acid ester, or a mixture of two or more thereof . A solvent composed of water, methanol, ethanol, propanol or ethylene glycol, which can dissolve or disperse the hydrophilic monomer and the hydrophobic monomer and does not dissolve the core-shell type polymer particles produced in the next step (B). Or a step (A) of preparing a polymerizable solution having a concentration of 1 to 40% by mass by dissolving or dispersing in a mixed solvent consisting of water and methanol, ethanol, propanol or ethylene glycol, and applying a microwave to the polymerizable solution Step (B) of copolymerization by irradiation, and average particles from the obtained copolymer Monodisperse core 0.05 to 10 [mu] m - core, characterized in that it comprises a step (C) to purify the shell polymer particles - method of manufacturing shell-type polymer particles.   The method according to claim 1, wherein the polyethylene glycol chain has a number average molecular weight of 300 to 5,000.   The production method according to claim 1, wherein the polymerizable material comprises 1 to 95 mol% of the hydrophilic monomer and 99 to 5 mol% of the hydrophobic monomer. The process according to any one of claims 1 to ³ , wherein in the step (B), the irradiation intensity of the microwave is 0.05 to 30 W / cm ³ .   The process according to any one of claims 1 to 4, wherein in the step (B), the microwave irradiation time is 10 to 120 minutes.

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