JPH02105827A - Preparation of hydrophilic polymer particle - Google Patents

Abstract

PURPOSE:To prepare the title fine particles with a controlled particle size substantially in the absence of any org. solvent by localizing a polymer precursor in an aq. soln. phase enclosed in a lipid membrane and polymerizing said precursor. CONSTITUTION:A lipid (e.g., dipalmitoylphosphatidylcholine) is pref. added to an aq. soln. contg. a polymer precursor (e.g., acrylamide or N,N- methylenebisacrylamide) and dispersed therein by ultrasonic treatment to form small bubbles of the lipid membrane in said aq. soln. The polymer precursor is localized in the aq. soln. phase enclosed in the lipid membrane by removing the polymer precursor present outside the small bubbles by, e.g., dialysis or gel filtration and said precursor is polymerized pref. by irradiation with a radiation.

Description

[Detailed description of the invention] (Industrial application field) The present invention relates to a method for producing polymer granules.

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

As the latter method of forming a polymer into particles, emulsion polymerization, suspension polymerization, and seed polymerization as variations thereof are known.

These methods have in common that two immiscible phases are made to coexist and a polymer is produced in one of the discontinuous phases. In these methods, the particle size of the polymer particles produced is determined by the volume ratio of the two phases and the width of the two-phase interface, which is determined by the volume of each of the two phases, viscosity, stirring conditions of the reaction tank, and the interface. It is sensitively affected by the concentration of additives such as activators.

Furthermore, since the interface between the two phases has positive energy, the selection of the surfactant is particularly important when producing a polymer material in the form of microscopic particles with a diameter of about 1 μm. In particular, when making granules of hydrophilic polymers, it is necessary to maintain a stable W2O-type reversed phase dispersion state, which requires a large amount of organic solvent and requires 0.1
There is a problem in that it is difficult to manufacture granular materials with a size of μm or less.

Accordingly, one of the objects of the present invention is to provide a method for producing granular polymers in which the particle size is not easily influenced by the reaction conditions during polymer production, thereby facilitating particle size control.

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 problems) The above objects are achieved by the present invention as described below.

That is, the present invention provides a hydrophilic polymer characterized by comprising a step of localizing a polymer precursor in an aqueous solution phase closed by a lipid membrane, and a step of polymerizing the polymer precursor. This is a method for producing granular materials.

(Function) With the structure of the present invention, it is possible to control the particle size produced without being affected by the reaction conditions during polymer production, and it is possible to easily produce polymer particles with a particle size of 1 μm or less without using a large amount of organic solvent. can be provided.

(Preferred Embodiments) Next, the present invention will be explained in more detail with reference to preferred embodiments.

The method for producing a polymer granule of the present invention includes (+) a step of sealing and localizing a polymer precursor in microvesicles closed with a lipid membrane; and (2) polymerizing the polymer precursor. It is characterized by consisting of a process.

The lipid membrane used in the present invention is a two-dimensional structure formed by association of lipids through intermolecular forces and hydrophobic interactions. The lipid used in the present invention is known as an amphipathic substance that can form such a two-dimensional structure, and any known lipid can be used, but specific examples include dipalmitoylphosphatidylcholine, Typical examples include dialkyl compounds such as simyristoylphosphatidylserine and distearyldimethylammonium bromide, and compounds having a hydrophobic group having a rigid portion and one or two parent groups. Further, substances such as those mentioned above in which the hydrogen atoms in the alkyl chains are partially or completely replaced with fluorine are also preferably used.

The above substances can be used alone, or two or more types can be used in combination. Furthermore, neutral lipids such as various higher fatty acids or their esters, amide derivatives, and cholesterol may be mixed to the extent that a two-dimensional structure can be formed in an aqueous solution. When these lipids are dispersed in an aqueous solution containing a polymeric precursor using an appropriate means, vesicles are formed and a portion of the aqueous solution is taken up inside.

The amount of lipid added to the aqueous solution is 0.2 as total lipid.
A concentration range from mM (millimol) to 100 mM is preferred. If an amount of lipid exceeding the above range is used, it becomes difficult to disperse the entire amount of lipid in an aqueous solution in an apparently uniform manner. On the other hand, if the amount is less than the above range, the proportion of the aqueous solution retained inside the lipid vesicles will be small, resulting in a small amount of polymer particles finally obtained, which is not practical.

The size of the aqueous phase inside the lipid vesicle can be adjusted within the range of 3 μm to 10 nm depending on the lipid used, dispersion means, etc.

The polymer precursors used in the present invention include monomers that can form polymers, oligomers that have reactive activity,
Any polymer that has reactive activity and can be substantially dissolved in an aqueous solution can be used. In particular, if a polymer precursor is used in which the polymer generated during the polymerization process is insoluble in water, polymer particles that remain stable in water even if the lipid membrane is removed from the resulting polymer particles. This method is preferable because product 6E can be obtained.

As mentioned above, the precursors that produce water-insoluble polymers include:
Among monomers and oligomers, the solubility in water becomes particularly low when polymerized, and in the case of polymers that have reactive activity, the solubility in water of the new polymer produced as a result of the reaction is particularly low. You can use something like this. Further, a polymerization reaction in which a polymer having a crosslinked structure is formed in the above-mentioned polymerization step is also an example of producing an insoluble polymer.

Various methods have been known for forming vesicles by dispersing lipids in an aqueous solution, and it is necessary to select an appropriate method among them to form vesicles of the desired size. Dispersion using ultrasonic waves is particularly effective for obtaining microscopic polymer particles.On the other hand, for obtaining relatively large particles, lipids are dissolved in an organic solvent that is insoluble in water. , after adding this to the aqueous solution of the polymer precursor, '17
An effective method is to remove the organic solvent by evaporation.

When the above-mentioned lipid vesicles are formed, polymer precursors are usually present in both the outer and inner aqueous phases of the vesicles, so next, only the polymer precursors in the outer aqueous phase are removed. do. Removal can be achieved, for example, by either of the following two methods.

The first method involves interacting within the aqueous phase with a polymeric precursor;
This is a method in which a processing agent that selectively adsorbs and removes this or a processing agent that reacts with the polymer precursor and loses its ability to form a polymer is added to the outer aqueous phase. The processing agent used must of course not penetrate into the inside of the lipid membrane, but it is selected in consideration of the combination with the polymer precursor used. These processing agents include, for example, when the polymer precursor is an acidic monomer such as styrene sulfonic acid, acrylic acid, or methacrylic acid, dimethylamine ethyl methacrylate, 2-
For basic monomers such as hydroxy-3-methacryloxypropyltrimethylammonium chloride,
They can be removed using an anion exchange resin and a cation exchange resin, respectively. Even if the polymer precursor is an oligomer or polymer, ion exchange resins are similarly effective when they have dissociative polar groups in the molecule, but multivalent ions with an opposite charge to the dissociative groups (e.g. 1ff+,
It is also possible to precipitate and remove the polymeric precursor by using a compound (e.g., Ca'', PO43-, etc.).

A second method for removing macromolecular precursors in the outer aqueous phase of lipid vesicles is to replace the outer aqueous phase with an aqueous solution free of macromolecular precursors. The purpose of this method can be easily achieved by using known means for separating lipid vesicles, such as dialysis and gel filtration.

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

The polymer precursor within the lipid vesicles is polymerized by the polymerization reaction, and polymer particles are obtained in a state dispersed in an aqueous solution. If the lipid remains around the particles, the dispersion state is stable. If it is necessary to remove lipids, it can be done by adding a surfactant to the resulting dispersion to destroy the lipid membrane and washing the particles.

The method for producing particulate polymers described above is similar to reverse-phase suspension polymerization and reverse-phase emulsion polymerization in that an amphiphilic substance is used to disperse an aqueous phase containing a polymer precursor. However, a feature of this method is that both of the two layers that are in contact with each other via the amphiphilic substance layer are aqueous phases. Once formed, such an amphiphilic material layer, that is, a lipid membrane, is stable and is not easily destroyed even by operations such as polymerization of a polymer precursor, and therefore, it is difficult to produce the polymer granules of the present invention. This effectively contributes to the purpose of controlling the particle size of the polymer in the method.

In addition, in general suspension polymerization and emulsion polymerization methods, the surfactant molecules used are rapidly exchanged between the state existing at the interface and the state dissolved in the liquid phase, and the dispersion system of the present invention is Since it is more sensitive to environmental conditions, it is difficult to obtain effects equivalent to those of the present invention (Examples).Hereinafter, the method for producing the hydrophilic polymer granules of the present invention will be explained using specific examples.

Example 1 Acrylic acid and 4g of droxyethyl, acrylamide t6
Dissolve 1.8 g of sodium chloride in 200 mf of water. 6 g of egg yolk lecithin is dissolved in 20 mJ2 of chloroform, and the chloroform is removed under reduced pressure in a stainless steel container with a capacity of 500 ml while rotating the container. The above aqueous solution was placed in this container, and while being cooled from the outside to 5°C, it was heated for 20 minutes using a globe-type ultrasonic oscillator (28 to flz, 2001).
Process for minutes. The resulting aqueous solution is centrifuged at 3,000 rpm for 20 minutes to remove the precipitate, frozen in a dry ice/acetone bath, and then thawed in a 15° C. water bath. This liquid is first filtered under pressure using a polycarbonate membrane with a pore size of 2.0 μm, and then filtered under pressure using a polycarbonate membrane with a pore size of 0.4 μm.

The filtrate was charged to a cross-linked dextranchel (Pharmacia ■, Sephadex G-50) column equilibrated with a 5% aqueous sodium chloride solution and subjected to gel filtration. The filtrate flowing out of the column is monitored with a turbidity meter, and the first highly turbid fraction that appears is collected. It was determined by a light scattering method whether particles with an average diameter of 350 nm were dispersed.

The above-mentioned fraction was placed in a glass container, kept at 20° C., stirred, and irradiated with γ-rays (radiation source: C660) at a radiation rate of 2×10′R/hr for 4 hours under a nitrogen atmosphere. Next, 2% of the liquid volume of Triton X100 (Rohm and Haas) is added to disrupt lipid vesicles. This liquid was shown to contain particles with an average diameter of 450 nm by light scattering at 25°C. By centrifuging this at 20,000 rpm+ for 1 hour, fine polymer particles precipitated in the form of a translucent paste were obtained. The water content as a paste was 98% or more (by drying method).

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 rifoflavin were added to 20 g of water.
Add to 0 mu and stir. Thereafter, lipid vesicles having an average particle size of 350 nm are formed in the same manner as in Example 1. The dissolved aqueous solution was kept at 10℃ and stirred gently while bubbling nitrogen.
Irradiate for 0 minutes. Thereafter, the same treatment as in Example 1 was performed to obtain particles with an average particle size of 360 nm (light scattering method).

Example 3 Polymer particles with an average particle size of 220 μm were obtained by carrying out the same operation as in Example 1, except that the pore size of the polycarbonate membrane used for the second pressure filtration was 0.2 μm.

Example 4 10 g of acrylamide, 2.5 g of N,N-methylenebisacrylamide and 0.9 g of sodium chloride were added to 100 g of water.
Dissolve in mIL. Add 2.6 g of dipalmitoylphosphatidylcholine and 0.2 g of cholesterol to 2.2 g of ethanol.
Dissolve in 0 ml 1 and dry in a glass container with a gentle stream of air. The aqueous solution was added to this container, heated to 50°C, and a globe-type ultrasonic oscillator (28 KHz, 1
20W) for 30 minutes. The obtained aqueous solution was
Cool to 0.degree. C. and centrifuge at 3,000 rpm for 20 minutes to remove the precipitate. This solution is gel-filtered through a cross-linked dextran gel column equilibrated with a 6% aqueous sodium chloride solution, and the highly turbid fraction is collected in the same manner as in Example 1.

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

Example 5 Dissolve 0.2 g of sodium acrylate in 2 ml of water.

7 mg of simyristoylphosphatidylglycerol, 36 mg of simyristoylphosphatidylcholine, and 24 mg of cholesterol are dissolved in 7 mJ2 of diethyl ether, and the above aqueous solution is added and treated with ultrasound to form an emulsion. The ether is distilled off under reduced pressure. During distillation, the liquid loses its fluidity and is shaken to continue distillation.

A 6.5% aqueous sodium chloride solution was added to the resulting solution, and D
Acrylic acid ions in the outer aqueous phase are removed by ion exchange using EAE Sepharose (Pharmacia ■).

The resulting liquid was cooled to 5°C and 2x106
An average of 0.6 after 2 hours of irradiation with R/hr of γ-rays (Co”)
Particles with a diameter of 2 μm were obtained.

Example 6 2 g of N-vinylpyrrolidone, 4 g of acrylamide, 0.3 g of ethylene glycol diacrylate and 0.6 g of sodium chloride are dissolved in 70 mk of water. egg yolk lecithin 4
5 mg is dissolved in 35 m2 of diethyl ether. The above aqueous solution is heated to 35°C, and the ether solution F is slowly injected while the pressure is slightly reduced. Thereafter, gel filtration and γ-ray irradiation were performed in the same manner as in Example 1 to obtain particles with an average particle size of 0.22 μm.

(effect) Following the method of the present invention as further described.

(1) The particle size of the hydrophilic polymer particles is determined in the lipid vesicle formation step independently of the reaction conditions of the polymer production step, so particle size control is easy.

(2) It is possible to produce minute hydrophilic polymer particles of 0.1 μm or less.

(3) Since the W10 type dispersion state is not utilized, hydrophilic polymer particles can be produced in an aqueous solution system with almost no organic solvent used.

Effects not found in conventional methods were obtained in these respects.

[Brief explanation of drawings]

Figure 1 is a schematic diagram showing the state in which a small chamber consisting of a lipid membrane is formed in an aqueous solution in which a polymer precursor is dispersed.
The figure is a schematic diagram showing the state in which the polymer @ precursor is localized inside a vesicle made of a lipid membrane, and Figure 3 is a schematic diagram showing the state in which the polymer precursor in Figure 2 has been polymerized. It is. ! , 3: Aqueous solution containing dispersed polymer precursor 2; Lipid membrane 4: Aqueous solution not containing polymer precursor 5: Hydrophilic polymer particles

Claims (3)

[Claims] (1) Production of hydrophilic polymer granules characterized by comprising a step of localizing a polymer precursor in an aqueous solution phase closed by a lipid membrane, and a step of polymerizing the polymer precursor. Method. (2) The step of localizing the polymer precursor in the aqueous solution phase closed by a lipid membrane includes the step of forming a vesicle made of a lipid membrane in the aqueous solution of the polymer precursor, and the subsequent step of forming a vesicle made of a lipid membrane in the aqueous solution of the polymer precursor, and then 2. The method for producing a hydrophilic polymer granule according to claim 1, comprising the step of removing a polymer precursor present in the hydrophilic polymer granules. (3) The method for producing hydrophilic polymer particles according to claims 1 and 2, wherein the polymerization step involves irradiation with radiation.