JP2739967B2 - Method for producing hydrophilic polymer particles - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a method for producing a polymer particle.

(Prior art and its problems) Conventionally, as a method of obtaining a granular polymer material, for example, a method of converting a polymer material synthesized into a shape other than a granular material into a granular material by means such as pulverization or from the beginning. There is a method of generating a polymer in a granular shape. Both methods are industrially practiced, but the latter is particularly characterized in that the obtained polymer material can be made uniform in particle size, particle shape and the like.

Emulsion polymerization, suspension polymerization and seed polymerization and the like are known as the latter method for producing a polymer in a granular form.

These methods are common in that two phases that are not mixed with each other coexist, and the formation of a polymer occurs in one of the discontinuous phases. In these methods, the particle size of the produced polymer particles is determined by the volume ratio of the two phases and the width of the two-phase interface, and these are determined by the respective volumes and viscosities of the two phases, the stirring conditions of the reaction tank, and the interface. Sensitively affected by the concentration of additives such as activators. In addition, since the interface between the two phases has a positive energy, the selection of a surfactant is important particularly when a fine granular polymer material having a diameter of about 1 μm is produced. In particular, when preparing hydrophilic polymer particles, it is necessary to stably maintain the W / O-type reversed-phase dispersion state, which requires a large amount of an organic solvent, and also requires a large amount of 0.
There is a problem that it is difficult to produce a granular material of 1 μm or less.

Therefore, one of the objects of the present invention is to provide a production method in which the particle size is not easily affected by the reaction conditions during the production of the polymer in the production of the polymer particles, and to facilitate the control of the particle size.

Another object of the present invention is to provide a method for easily preparing polymer particles having a particle size of 1 μm or less.

(Means for Solving the Problems) The above object is achieved by the present invention described below.

That is, the present invention provides a step of adding a lipid to an aqueous solution in which a polymer precursor is dissolved to form a vesicle closed by the lipid and containing the aqueous solution therein; And a step of polymerizing the precursor.

(Function) According to the constitution of the present invention, the particle size to be produced can be controlled without being affected by the reaction conditions at the time of producing the polymer, and polymer particles having a particle size of 1 μm or less can be easily provided.

 Next, the present invention will be described in detail.

The method for producing a polymer particulate according to the present invention comprises the steps of: (1) adding lipid to an aqueous solution in which a polymer precursor is dissolved, and forming vesicles closed by the lipid and containing the aqueous solution therein; And (2) a step of polymerizing the polymer precursor in the vesicle.

The lipid membrane used in the present invention is a two-dimensional structure formed by associating lipids by mutual molecular force and hydrophobic interaction. The lipid used in the present invention is known as an amphipathic substance capable of forming such a two-dimensional structure, and any of known lipids can be used. Specific examples thereof include dipalmitoylphosphatidylcholine, Dimyristoyl phosphatidylserine, dialkyl compounds such as distearyl dimethyl ammonium bromide, And a hydrophobic chain having a rigid part such as yolk lecithin
A typical example is a compound having one or two hydrophilic groups. In addition, a substance in which hydrogen atoms in the alkyl chain of the above substances are partially or entirely substituted with fluorine is also preferably used.

The above substances can be used alone or in combination of two or more. Furthermore, neutral lipids such as various higher fatty acids or their esters, amide derivatives, and cholesterol may be mixed within a range where a two-dimensional structure can be formed in an aqueous solution. When these lipids are dispersed in an aqueous solution containing a polymer precursor by an appropriate means, vesicles are formed and a part of the aqueous solution is taken in.

The amount of lipid added to the aqueous solution is 0.2 m
A concentration range from M (mmol) to 100 mM is preferred. If an amount of lipid exceeding the above range is used, it will be difficult to apparently and uniformly disperse the entire amount of lipid in the aqueous solution. On the other hand, if the amount is less than the above range, the ratio of the aqueous solution retained inside the lipid vesicles is small, and the amount of the finally obtained polymer particulates is small, which is not practical.

The size of the aqueous phase inside the lipid vesicles can be adjusted in the range of 3 μm to 10 nm depending on the lipid used, dispersion means and the like.

The polymer precursor used in the present invention is a monomer capable of forming a polymer, an oligomer having a reaction activity, a polymer having a reaction activity, and the like, which can be substantially dissolved in an aqueous solution. Any can be used. In particular, when a polymer precursor is used that makes the polymer produced in the polymerization process insoluble in water, polymer particles that are stably present in water even if the lipid membrane is removed from the obtained polymer particles It is preferable because a product is obtained.

As described above, as a precursor that produces a polymer insoluble in water, those that become particularly low in solubility in water when polymerized in a monomer or oligomer, in the case of a polymer having a reaction activity, A new polymer resulting from the reaction can be used which has particularly low solubility in water. In addition, a polymer precursor that forms a polymer having a cross-linked structure in the above-mentioned polymerization step is one of examples in which an insoluble polymer is also generated.

Various methods for forming vesicles by dispersing lipids in an aqueous solution have been conventionally known, and it is necessary to select an appropriate method from among them to form vesicles having a desired size. I can do it. In particular, for the purpose of obtaining fine polymer particles, dispersion using ultrasonic waves is effective. On the other hand, for the purpose of obtaining relatively large particles, it is effective to dissolve lipid in an organic solvent insoluble in water, add the lipid to an aqueous solution of a polymer precursor, and then evaporate and remove the organic solvent.

After the lipid vesicles are formed, a retarder or inhibitor of the polymerization reaction is added to the outer aqueous phase in order to prevent the polymer precursor present in the outer aqueous phase of the vesicles from being polymerized. These additives must of course not migrate across the lipid vesicle interface to the inner aqueous phase. The additive that can be used must be selected according to the type of the polymer precursor to be used.For example, when the polymerization reaction of the polymer precursor is radical polymerization, hydroquinonesulfonic acid is used as the additive. Sodium, sodium ascorbate, 2,2,5,5-tetramethylpyrrolidine-1-
Sodium oxyl-3-carboxylate, sodium 2,2,5,5-tetramethylpyrroline-1-oxyl-3-carboxylate, 2,2,5,5-tetramethylpyrroline-N-oxide-3-carboxylic acid A water-soluble substance having a radical reaction inhibiting action represented by sodium, thionine, iron chloride, copper chloride, zinc chloride, potassium ferrocyanide and the like can be used.

Preferably, the additives are present in a concentration ranging from 1 mM to 3M relative to the outer aqueous phase of the lipid vesicles. Depending on the types of additives and polymer precursors used, generally, use at a concentration lower than this is not sufficient to stop the polymerization reaction outside the lipid vesicles, and use at a concentration higher than this. The stability of the lipid vesicle once formed may be impaired, which is not preferable.

When the above-mentioned additive for suppressing the polymerization reaction is added to the outer aqueous phase of the lipid vesicle, aggregation or fusion of the lipid vesicle may occur depending on the conditions, or part of the additive may be contained in the lipid membrane of the vesicle. Or reach the inner aqueous phase. It is necessary to prevent such a phenomenon because the produced polymer particles have a nonuniform particle size or inhibit the generation of the particles themselves. If a material exhibiting a gel-liquid crystal phase transition is used as a lipid, the above problem is partially solved. That is, the lipid vesicle formation step is performed as described above at a temperature higher than the phase transition temperature of the lipid (that is, in a liquid crystal state in which the lipid has fluidity). If an additive that suppresses the polymerization reaction is added to the aqueous phase outside the vesicle (in the gel state in which the vesicle has been lost), vesicle fusion and permeation of the additive through the lipid membrane can be prevented. In this case, the temperature should be kept below the phase transition temperature of the lipid in the subsequent polymerization step.

After the vesicles are formed stably as described above, the polymer precursor is polymerized by means depending on the precursor used. As this means, it is possible to use the addition of a substance having a catalytic activity for initiating the polymerization reaction, but more preferably, irradiation with visible light, ultraviolet light, X-ray, or radiation such as γ-ray is used. I can do it. When using these radiations, a compound having a sensitizing effect on the radiations may be allowed to coexist with the polymer precursor in order to promote the polymerization reaction.

The polymer precursor in the lipid vesicles is polymerized by the polymerization reaction, and the polymer precursor is obtained in a state where the polymer particles are dispersed in the aqueous solution. If lipids remain around the granules, the dispersion is stable. When it is necessary to remove lipids, a surfactant can be added to the obtained dispersion to break the lipid membrane, and the particles can be removed by washing.

The above-described method for producing a granular polymer is similar to the reversed-phase suspension polymerization method and the reversed-phase emulsion polymerization method in that an aqueous phase containing a polymer precursor is dispersed using an amphiphilic substance. However, it is a feature of the present method that both layers in contact with each other via the amphiphilic substance layer are aqueous phases. Since such an amphiphilic substance layer, that is, a lipid film, is stable once formed and is not easily destroyed by the operation of polymerizing a polymer precursor, etc., the production of the polymer particulate material of the present invention The method effectively contributes to the purpose of regulating the particle size of the polymer.

In addition, surfactant molecules used in a general suspension polymerization method or emulsion polymerization method have a fast exchange between a state existing at the interface and a state dissolved in the liquid phase, and the dispersion system according to the present invention. Since it is more sensitive to environmental conditions, it is difficult to obtain the same effect as the present invention.

(Examples) Hereinafter, a method for producing the hydrophilic polymer granules of the present invention will be described with reference to specific examples.

Example 1 Hydroxyethyl acrylate 4 g, acrylamide 16 g
And 1.8 g of sodium chloride are dissolved in 200 ml of water. 6 g of egg yolk lecithin is dissolved in 20 ml of chloroform, and chloroform is removed under reduced pressure while rotating the container in a stainless steel container having a capacity of 500 ml. Put the above aqueous solution in this container and
Probe type ultrasonic oscillator (28KHz, 2K
00W) for 20 minutes. 3,000 rp of the obtained aqueous solution
centrifuge at 20 m for 20 minutes to remove the precipitate, and dry ice /
Freeze in an acetone bath, then thaw in a 15 ° C water bath. This solution is first pressure-filtered using a polycarbonate membrane having a pore size of 2.0 μm, and further filtered under pressure using a polycarbonate membrane having a pore size of 0.4 μm to form lipid vesicles. To this filtrate
Add the same volume of an 18% by weight aqueous sodium ascorbate solution, hold at 20 ° C., and in a nitrogen atmosphere, use Co ⁶⁰ as a radiation source.
The line is irradiated at 1.2 × 10 ⁶ R / hr for 8 hours. Next, Triton X1
00 (Rohm and Haas) was added, 5% of the liquid volume was added, diluted by adding 2 volumes of water, and centrifuged at 20,000 rpm for 1 hour to obtain polymer fine particles precipitated in a translucent paste form. Was. This product was dispersed in pure water, and the particle size was measured by a light scattering method. The average particle size was 420 nm.

Example 2 4 g of hydroxyethyl acrylate, 1.5 g of N, N-methylenebisacrylamide, 20 g of acrylamide, 1.8 g of potassium chloride and 70 mg of riboflavin were added to 200 ml of water and stirred. Thereafter, lipid vesicles are formed in the same manner as in Example 1.
An 18% by weight aqueous solution of sodium ascorbate is added to the dissolved aqueous solution in the same volume, and while maintaining the temperature at 10 ° C., the light of a white fluorescent lamp (6w × 4) is irradiated from a distance of 5 cm for 60 minutes in an atmosphere. Thereafter, the same treatment as in Example 1 was performed to obtain particles having an average particle diameter of 350 nm.

Example 3 Polymer particles having an average particle size of 210 μm were obtained by performing the same operation as in Example 1 except that the pore size of the polycarbonate membrane used for the second pressure filtration was changed to 0.2 μm.

Example 4 10 g of acrylamide, 2.5 g of N, N-methylenebisacrylamide and 0.9 g of sodium chloride are dissolved in 100 ml of water.
2.6 g of dipalmitoyl phosphatidylcholine and 0.2 g of cholesterol are dissolved in 20 ml of ethanol and dried in a glass container by gentle airflow. The aqueous solution was added to this container, heated to 50 ° C., and a probe-type ultrasonic oscillator (28
(KHz, 120W) for 30 minutes. The resulting aqueous solution is cooled to 5 ° C. and centrifuged at 3,000 rpm for 20 minutes to remove a precipitate. The solution is cooled to 5 ° C. and mixed with a 16% by weight aqueous solution of potassium ferrocyanide.

The solution was cooled and stirred at 5 ° C., and irradiated with γ rays under the same conditions as in Example 1 to obtain polymer particles having an average particle size of 18 nm.

Example 5 0.2 g of sodium acrylate is dissolved in 2 ml of water. Dimyristoyl phosphatidylglycerol 7 mg, dimyristoyl phosphatidylcholine 36 mg and cholesterol 24
mg was dissolved in 7 ml of diethyl ether, and the above aqueous solution was added thereto, followed by sonication to obtain an emulsion. The pressure is reduced and the ether is distilled off. If the fluidity of the liquid is lost during the distillation, the liquid is shaken and the distillation is continued.

The obtained liquid is cooled to 4 ° C., and the same volume of a 16% by weight aqueous solution of potassium ferrocyanide is added. The solution was kept at 4 ° C. and irradiated with 2 × 10 ⁶ R / hr γ-rays (Co ⁶⁰ ) under a nitrogen atmosphere for 2 hours to obtain particles having an average diameter of 0.58 μm.

Example 6 2 g of N-vinylpyrrolidone, 4 g of acrylamide, 0.3 g of ethylene glycol diacrylate and 0.1 g of sodium chloride.
6 g are dissolved in 70 ml of water. Dissolve 45 mg of egg yolk lecithin in 35 ml of diethyl ether. Heat the above aqueous solution to 35 ° C,
The above ether solution is slowly injected while slightly reducing the pressure. To this aqueous solution, the same volume of an 18% by weight aqueous sodium ascorbate solution was added, and γ-ray irradiation was performed in the same manner as in Example 1 to obtain particles having an average particle size of 0.2 μm.

(Effects) As described above, according to the method of the present invention, (1) the particle size of the hydrophilic polymer particles can be controlled in the lipid vesicle formation step independently of the reaction conditions in the polymer generation step. I can do it.

(2) Fine hydrophilic polymer particles having a size of 0.1 μm or less can be produced.

(3) An organic solvent is hardly used, and hydrophilic molecular particles can be produced in an aqueous solution system.

In this respect, an effect not obtained by the conventional method was obtained.

[Brief description of the drawings]

FIG. 1 is a schematic view showing a state in which vesicles composed of a lipid membrane are formed in an aqueous solution in which a polymer precursor is dispersed.
The figure is a schematic diagram showing a state in which the polymer precursor is polymerized in the aqueous phase in the vesicle. 1: Aqueous solution in which polymer precursor and polymerization inhibitor are dispersed 2: Lipid membrane 3: Aqueous solution in which polymer precursor is dispersed 4: Hydrophilic polymer particles

Claims (11)

(57) [Claims] A step of adding lipid to an aqueous solution in which a polymer precursor is dissolved to form vesicles closed by the lipid and containing the aqueous solution therein; And a step of polymerizing the substance. 2. The method according to claim 1, wherein an additive for suppressing a polymerization reaction is present outside the vesicle after the formation of the vesicle. 3. The method for producing a hydrophilic polymer particulate according to claim 1, wherein the polymerizing step is performed by irradiation with radiation. 4. The method according to claim 1, wherein the lipid is dipalmitoylphosphatidylcholine, dimyristoylphosphatidylserine, distearyldimethylammonium bromide, The method for producing a hydrophilic polymer granule according to claim 1, wherein the granule is selected from the group consisting of egg yolk lecithin and egg yolk lecithin. 5. The amount of lipid is 0.2 mmol (m
The method for producing a hydrophilic polymer particulate according to claim 1, wherein the amount ranges from M) to 100 mmol (mM). 6. The method for producing a hydrophilic polymer particle according to claim 1, wherein the polymer precursor is water-soluble and, when polymerized, shows a water-insoluble property. 7. The method for producing a hydrophilic polymer particulate according to claim 6, wherein the polymer precursor is a monomer or an oligomer. 8. The hydrophilic polymer according to claim 2, wherein the polymer precursor is polymerized by radical polymerization, and the additive for suppressing the polymerization reaction is a water-soluble substance having a radical reaction inhibiting action. A method for producing a polymer particle. 9. The water-soluble substance having a radical reaction inhibiting action is sodium hydroquinone sulfonate, sodium ascorbate, 2,2,5,5-tetramethylpyrrolidine-1.
Sodium oxyl-3-carboxylate, sodium 2,2,5,5-tetramethylpyrroline-1-oxyl-3-carboxylate, 2,2,5,5-tetramethylpyrroline-N-oxide-3-carboxylic acid Sodium acid, thionine, iron chloride,
The method for producing a hydrophilic polymer particulate according to claim 8, which is selected from copper chloride, zinc chloride, and potassium ferrocyanide. 10. The production of the hydrophilic polymer particulate according to claim 8, wherein the amount of the water-soluble substance having a radical reaction inhibiting action is in the range of 1 mmol (mM) to 3 mol (M) with respect to the aqueous solution. Method. 11. The method according to claim 11, wherein vesicles are formed at a temperature higher than the phase transition temperature of the lipid and the temperature is lower than the phase transition temperature of the lipid, and then an additive for suppressing the polymerization reaction is added outside the vesicles. 3. The method for producing a hydrophilic polymer particulate according to item 2.