JP6619592B2 - Vesicles containing 2-chain 2-hydrophilic surfactant and microcapsules using the same - Google Patents

Description

  The present invention relates to a vesicle containing a surfactant and a microcapsule using the same.

  Microcapsules usually have a diameter of several μm to several hundred μm. The microcapsules can provide various functions, such as sustained release of core material, environmental safety, isolation of reactive materials, reduced toxicity, liquid solidification, odor and taste masking, etc. .

  There are various production methods for nano-microcapsules, and many studies have been put into practical use (Non-patent Document 1). Among them, many amphipathic substances constituting vesicles have been studied. In particular, vesicles composed of phospholipids derived from living bodies are called liposomes, and various studies have been made from the viewpoint of safety to living bodies.

  For example, a cosmetic material in which a vesicle dispersion is formed by combining this phospholipid and a specific cationic surfactant has been proposed (Patent Document 1). There are also many reports on synthetic surfactants as another amphiphilic substance constituting vesicles.

  It has also been reported that vesicles are formed by mixing a gemini surfactant and a one-chain surfactant (Non-patent Document 2). And in recent years, examination of the vesicle composition using a polychain polyhydrophilic group type surfactant is performed (patent document 2).

  A conventional vesicle composition using a multi-chain, multi-hydrophilic type surfactant requires an auxiliary agent for formation and does not polymerize, so the film thickness is a bimolecular film, and the film strength is also there. Not expensive.

  Also, vesicles in which at least one block is hydrophobic and at least one block is hydrophilic amphiphilic diblock and multiblock copolymer amphiphiles are called “polymersomes”. It can be stably prepared by many techniques common to liposomes. In addition, there have been proposed polymersomes and the like that have no safety, feel in use, especially stickiness, good freshness, and excellent base stability due to film rehydration, sonication, and release. (Patent Document 3).

  On the other hand, polymersomes have high stability and thickness, but it is necessary to choose the chemical structure of block copolymer, number average molecular weight, hydrophilic to hydrophobic integration rate, and various preparation methods. Poor nature.

  In addition, methods for producing hollow particles by forming vesicles using a single-chain polymerizable surfactant and a single-chain surfactant have been studied (Patent Document 4, Non-Patent Document 3). When a one-chain polymerizable surfactant is used, a cross-linking agent is required and a bimolecular film, so that the porosity is high, but the holding capacity of the hydrophobic substance is small, and the strength of the film is weak.

  In the conventional vesicle manufacturing method, the size often varies, and a method capable of preparing microcapsules having a uniform particle size has been desired.

  The inventors of the present invention have been studying the application to vesicles of a two-chain two-hydrophilic surfactant having a polymerizable group (Patent Documents 5 and 6) (Non-Patent Documents 4 and 5).

JP 2006-193461 A JP 2006-290894 A Special table 2011-066506 gazette JP 2006-257300 A JP 2007-146108 A JP 2006-249059 A

Application development of micro / nano capsules and fine particles (CMC Publishing) J. Phys. Chem. B 2013, 117, 433-440 J. Jpn. Soc. Color Mater., 79 (6), 237-242 (2006) Abstracts of Lecture of Freshman Summit TOKYO 2012 (November 28, 2012) 2012 Material Technology Discussion Meeting (December 7, 2012)

  In these studies, a combination of a two-chain two-hydrophilic surfactant having a polymerizable group and a surfactant having a symmetrical charge with this resulted in a white precipitate and no aggregate was formed. , A 2-chain 2-hydrophilic surfactant having a polymerizable group (2-Propenoic acid, 2-methyl-, 1,1 '-[1,2-ethanediylbis [[(3-sulfopropyl) imino] (12- oxo-12,1-dodecanediyl)]] amide, sodium salt (1: 2)) and the cationic surfactant 11-methacryloxyundecyltrimethylammonium bromide (PC-11) The formation of vesicles of about 200 to 500 nm was confirmed. Photopolymerization of this vesicle was attempted and it was confirmed that the polymerization had progressed, but detailed characteristics were not studied.

  That is, a large particle size capable of preparing microcapsules has not been obtained. In addition, knowledge about the film thickness of vesicles has not been obtained.

  The present invention has been made in view of the circumstances as described above, and an object thereof is to provide a novel vesicle capable of preparing microcapsules having a uniform size (particle diameter) and a microcapsule using the same.

  The present inventors have proposed 2-Propenoic acid, 2-methyl-, 1,1 ′-[1,2-ethanediylbis [[(3-sulfopropyl) imino as a 2-chain 2-hydrophilic surfactant having a polymerizable group. ] (11-oxo-11,1-undecanediyl)]] In a study using amide, sodium salt (1: 2) (PGA-1102), etc. Further, the present invention was completed from various findings based on the film structure of the vesicle and the experimental results of photopolymerization.

  That is, in the vesicle of the present invention, a two-chain two-hydrophilic surfactant (A) having a radical polymerizable group in each of two hydrophobic chains and the two-chain two-hydrophilic surfactant have a symmetrical charge. A hollow shape having an outer shell containing the surfactant (B) having an average particle size of 1 μm or more.

  The microcapsule of the present invention is obtained by polymerizing the vesicle's 2-chain 2-hydrophilic surfactant (A).

  According to the present invention, a simple vesicle and microcapsule having a uniform size (particle diameter), a large particle diameter that can be prepared by microcapsules, and capable of controlled release can be obtained simply by mixing two kinds of drugs. Can be obtained in a simple manner.

2 is an optical microscope image of a liquid sample prepared in Example 1. FIG. 2 is an optical microscope image of a liquid sample prepared in Example 2. FIG. 3 is an optical microscope image of a liquid sample prepared in Example 3. FIG. 6 is an optical microscope image of a liquid sample prepared in Example 4. 6 is an optical microscope image of a liquid sample prepared in Example 5. FIG. 6 is an optical microscope image of a liquid sample prepared in Example 6. 6 is an optical microscope image of a liquid sample prepared in Example 7. 10 is an optical microscope image of a liquid sample prepared in Example 8. 2 is a Cryo-SEM image of a liquid sample prepared in Example 1. FIG. 2 is a confocal laser microscope image of a sedimented solution containing an oil-soluble dye (Nile Red) prepared in Example 1. FIG. 2 is a confocal laser scanning microscope image of a sediment containing a water-soluble dye (rhodamine B) prepared in Example 1. FIG. 2 is an optical microscope image of a liquid sample prepared in Comparative Example 1. It is an optical microscope image of the aqueous solution sample after the photopolymerization prepared in Example 1 (polarized light). 2 is an SEM observation image of a freeze-dried sample after photopolymerization prepared in Example 1. 2 is an SEM observation image of a freeze-dried sample after photopolymerization prepared in Example 1. 2 is an SEM observation image of a freeze-dried sample after photopolymerization prepared in Example 1. It is an optical microscope image of the aqueous solution sample after the photopolymerization prepared in Example 2 (polarized light). 3 is a SEM observation image of a freeze-dried sample after photopolymerization prepared in Example 2. It is an optical microscope image of the aqueous solution sample after the photopolymerization prepared in Example 3 (polarized light). 4 is a SEM observation image of a freeze-dried sample after photopolymerization prepared in Example 3. It is an optical microscope image of the aqueous solution sample after the photopolymerization prepared in Example 4 (polarized light). 4 is a SEM observation image of a freeze-dried sample after photopolymerization prepared in Example 4. It is an optical microscope image of the aqueous solution sample after the photopolymerization prepared in Example 5 (polarized light). 6 is a SEM observation image of a freeze-dried sample after photopolymerization prepared in Example 5. It is an optical microscope image of the aqueous solution sample after the photopolymerization prepared in Example 6 (polarized light). 6 is a SEM observation image of a freeze-dried sample after photopolymerization prepared in Example 6. It is an optical microscope image of the aqueous solution sample after the photopolymerization prepared in Example 7 (polarized light). 6 is a SEM observation image of a freeze-dried sample after photopolymerization prepared in Example 7. It is an optical microscope image of the aqueous solution sample after the photopolymerization prepared in Example 8 (polarized light). 10 is a SEM observation image of a freeze-dried sample after photopolymerization prepared in Example 8. It is an optical microscope image of the aqueous solution sample after the photopolymerization prepared in Comparative Example 1 (polarized light). 2 is a SEM observation image of a freeze-dried sample after photopolymerization prepared in Comparative Example 1. 4 is a chart showing the results of measuring the particle size of vesicles in a liquid sample prepared in Example 1 by dynamic light scattering (DLS). 2 is an optical microscope image of a liquid sample prepared by adding soybean lecithin to Example 1. FIG. It is an optical microscope image (polarized light) of the liquid sample prepared by adding soybean lecithin to Example 1. It is an optical microscope image of the aqueous solution sample after photopolymerization prepared by adding soybean lecithin to Example 1 (polarized light). It is a SEM observation image of the freeze-dried sample after the photopolymerization prepared by adding soybean lecithin to Example 1.

  The present invention is described in detail below.

  The vesicle of the present invention includes, on its outer shell, a two-chain two-hydrophilic surfactant (A) having a radical polymerizable group in each of two hydrophobic chains, and the two-chain two-hydrophilic surfactant. And a surfactant (B) having a symmetric charge.

  As the two-chain two-hydrophilic surfactant (A) having a polymerizable group, a two-chain two-hydrophilic group-containing anionic surfactant (A1) can be used.

  As the two-chain two-hydrophilic group-containing anionic surfactant (A1), a compound represented by the following formula (I) can be used.

(In the formula, R ¹ represents a hydrogen atom or a methyl group, X represents an oxygen atom, an amino group (NH), or an aminomethyl group (NCH ₃ ), m represents an integer of 2 to 8, and n represents 8 -20, preferably an integer of 8-10, and p is an integer of 2-6.
The two-chain two-hydrophilic group-containing anionic surfactant (A1) represented by the formula (I) is a hydroxyalkyl carboxylic acid or aminoalkyl carboxylic acid and a halide of (meth) acrylic acid, as in the examples described later. Can be synthesized by reacting a precursor compound synthesized from the above and Vistaurine · 2Na in the presence of a dehydration condensing agent. Moreover, it is compoundable with reference to patent document 5.

  As the two-chain two-hydrophilic group-containing anionic surfactant (A1), a compound represented by the following formula (I ′) can also be used.

(In the formula, R ¹¹ represents an unsaturated fatty acid residue, m represents an integer of 2 to 8, and p represents an integer of 2 to 6).
The two-chain two-hydrophilic group-containing anionic surfactant (A1) represented by the formula (I ′) contains an unsaturated fatty acid and Vistaurine · 2Na in the presence of a dehydration condensing agent as in the examples described later. It can be synthesized by reacting.

Examples of the residue of the unsaturated fatty acid represented by R ¹¹ include an alkenyl group having preferably 8 to 18 carbon atoms, more preferably 10 to 17 straight chain, and 1 to 2 double bond sites. It is done.

  As surfactant (B) used with 2 chain | strand 2 hydrophilic group containing anionic surfactant (A1), it is C8-C14 which may be substituted by the acryloxy group or methacryloxy group which is a polymeric group. Examples thereof include alkyl ammonium salts having a linear alkyl group and alkenyl ammonium salts having a linear alkenyl group having 8 to 14 carbon atoms. In these alkylammonium salts and alkenylammonium salts, the other three groups bonded to the nitrogen atom are closely packed in a mixed state in the molecular assembly with the 2-chain 2-hydrophilic group-containing anionic surfactant (A1). Although it may be appropriate in consideration of formation, etc., one having 1 to 3 carbon atoms, for example, an alkyl group having 1 to 3 carbon atoms such as a methyl group, a glyceryl group, or the like is considered.

  Examples of the alkyl ammonium salt having a linear alkyl group having 8 to 14 carbon atoms which may be substituted with a polymerizable acryloxy group or methacryloxy group include an alkyl trialkyl ammonium salt, an alkyl monoglyceryl dialkyl ammonium salt, Examples include acryloxy or methacryloxyalkyltrialkylammonium salts. More specifically, for example, dodecyltrimethylammonium bromide (DTAB), decyltrimethylammonium chloride (DTAC), octyltrimethylammonium bromide (OTAB), dodecylmonoglyceryldimethylammonium chloride (DMGDAC), 11-methacryloxyundecyltrimethylammonium Examples thereof include bromide (PC-11).

  Examples of the alkenyl ammonium salt having a linear alkenyl group having 8 to 14 carbon atoms include alkenyl trialkyl ammonium salts. More specifically, for example, myristol trimethyl ammonium chloride and the like can be mentioned.

  Moreover, as a 2 chain | strand 2 hydrophilic group type surfactant (A) which has a polymeric group, 2 chain | strand 2 hydrophilic group containing cationic surfactant (A2) can be used.

  As the two-chain two-hydrophilic group-containing cationic surfactant (A2), a compound represented by the following formula (II) can be used.

(In the formula, R ² represents a hydrogen atom or a methyl group, q represents an integer of 2 to 12, r represents an integer of 8 to 20, and Y represents a halogen ion.)
The 2-chain 2-hydrophilic group-containing anionic surfactant (A2) represented by the formula (II) can be synthesized with reference to Patent Document 6. For example, it is synthesized by reacting a halide of a higher alcohol and a halide of (meth) acrylic acid to obtain a halide of a (meth) acrylic acid higher alcohol ester, and then reacting with a diamine to form a quaternary chloride.

  Examples of the surfactant (B) used together with the two-chain two-hydrophilic group-containing cationic surfactant (A2) include alkyl sulfates having a linear alkyl group having 8 to 14 carbon atoms, and straight chain having 8 to 14 carbon atoms. Examples thereof include alkenyl sulfates having a chain alkenyl group and polyoxyalkylene alkenyl ether sulfates having a linear alkenyl group having 8 to 14 carbon atoms.

  Examples of the alkyl sulfate having a linear alkyl group having 8 to 14 carbon atoms include sodium octyl sulfate (SOS) and sodium dodecyl sulfate (SDS).

  Examples of the alkenyl sulfate having a straight chain alkenyl group having 8 to 14 carbon atoms include sodium myristyl sulfate.

  Examples of the polyoxyalkylene alkenyl ether sulfate having a linear alkenyl group having 8 to 14 carbon atoms include polyoxyalkylene alkenyl ether ammonium sulfate.

  As described above, the two-chain two-hydrophilic surfactant (A) having a radical polymerizable group in each of two hydrophobic chains and the two-chain two-hydrophilic surfactant have symmetrical charges. The vesicle is prepared in an aqueous solution using the surfactant (B) having the same.

  The vesicle is prepared by mixing the 2-chain 2-hydrophilic surfactant (A) and the surfactant (B) in water. The two-chain two-hydrophilic surfactant (A) and the surfactant (B) are preferably added so that the molar ratio is about 1: 2. In addition to these, other components such as a forming aid, a stabilizer, and a binder may be included as long as the structure is not broken. Moreover, a stronger film can be obtained by using a surfactant having a polymerizable group in (B).

  The forming aid has an affinity with the 2-chain 2-hydrophilic surfactant (A) and / or the surfactant (B), and is contained in the vesicle by electrostatic interaction or hydrophobic interaction. It is considered that the charge of the formed vesicle is controlled by adding a forming aid and contributes to the improvement of the stability of the vesicle. Furthermore, the inclusion rate and sustained release property of the obtained microcapsules can be improved by containing a forming aid.

  The formation aid is not particularly limited, but is phospholipid, monoglyceride, diglyceride, polyglycerin fatty acid ester, sterol, polyoxyalkylene sterol, fatty acid ester of sterol, fatty acid, polyoxyalkylene hydrogenated castor oil, polyoxyalkylene A castor oil etc. are mentioned.

  The phospholipid may be a natural phospholipid or a modified phospholipid. For example, natural phospholipids include soybean lecithin, rapeseed lecithin, egg yolk lecithin and the like. Examples of the modified phospholipid include lecithin such as lysolecithin and fractionated lecithin obtained from natural systems, synthetic lecithin, and PEG-modified lecithin further improved in stability by PEG modification. Examples of the monoglyceride include stearic acid monoglyceride, oleic acid monoglyceride, palmitic acid monoglyceride, lauric acid monoglyceride and the like. Examples of diglycerides include 1,2-diglycerides and 1,3-diglycerides, and the fatty acids at positions 1, 2 or 1, 3 are based on various oil compositions such as stearic acid, oleic acid, linoleic acid, and palmitic acid. The thing formed with the fatty acid is mentioned. Examples of polyglycerol fatty acid esters include diglycerol monostearate, diglycerol monooleate, diglycerol dioleate, diglycerol monoisostearate, tetraglycerol monostearate, tetraglycerol tristearate, hexa Examples thereof include glycerin monolaurate and decaglycerate distearate. Examples of sterols include cholesterol, stigmasterol, lanosterol, ergosterol, and phytosterol. As polyoxyalkylene sterols, polyoxyethylene (10) cholesteryl ether, polyoxyethylene (20) cholesteryl ether, polyoxyethylene (20) cholesteryl ether, polyoxyethylene (30) cholesteryl ether, polyoxyethylene (10 ) Phytosterol ether, polyoxyethylene (20) phytosterol ether, polyoxyethylene (20) phytosterol ether, polyoxyethylene (30) phytosterol ether, and the like. Examples of fatty acid esters of sterols include cholesterol laurate, cholesterol palmitate, cholesterol stearate, cholesterol oleate, phytosterol laurate, phytosterol palmitate, phytosterol stearate, and phytosterol oleate. Examples of fatty acids include those having a saturated or unsaturated linear or branched chain, such as lauric acid, palmitic acid, stearic acid, oleic acid, and isostearic acid. Examples of the polyoxyalkylene hardened castor oil include polyoxyethylene (10) hardened castor oil, polyoxyethylene (20) hardened castor oil, and polyoxyethylene (30) hardened castor oil. Examples of the polyoxyalkylene castor oil include polyoxyethylene (4) castor oil, polyoxyethylene (10) castor oil, polyoxyethylene (20) castor oil, polyoxyethylene (30) castor oil, and the like.

These formation aids can be used alone or in admixture of two or more.
The content of the formation auxiliary agent is a mass ratio with respect to the total mass of the two-chain two-hydrophilic surfactant (A) and the surfactant (B), and the total mass of (A) and (B): Mass = 1: 0.01 to 1: 100, preferably 1: 0.1 to 1:10, more preferably 1: 1 to 1: 5.

  Examples of the stabilizer include acrylic polymers, vinyl polymers, synthetic polymers such as polyoxyalkylene, semi-synthetic polymers such as cellulose derivatives, modified starches, and lignin derivatives, natural polymers, and the like. Stabilizers are mainly added to water and have an effect of improving the storage stability of vesicles and microcapsules in a dispersion medium by increasing viscosity and the like.

These stabilizers can be used alone or in admixture of two or more.
The content of the stabilizer is a mass ratio with respect to the total mass of the 2-chain 2-hydrophilic surfactant (A) and the surfactant (B), and the total mass of (A) and (B): Mass = 1: 0.01 to 1: 100, preferably 1: 0.1 to 1:10, more preferably 1: 1 to 1: 5.

  Examples of the acrylic polymer include sodium polyacrylate and sodium polymethacrylate, examples of the vinyl polymer include polyvinyl alcohol, polyvinyl pyrrolidone, and vinyl acetate copolymer. Examples of the polyoxyalkylene include Examples include cellulose derivatives such as polyoxyethylene and polyoxypropylene. Examples of cellulose derivatives include sodium carboxymethylcellulose, dextrin, hydroxypropylmethylcellulose, methylcellulose, methylethylcellulose, and hydroxypropylcellulose. Modified starch and carboxymethyl are examples of processed starch. Examples include starch and soluble starch. Examples of lignin derivatives include sodium lignin sulfonate. Examples of natural polymers include agar, gum arabic, and xanthan. Arm, tragacanth, guar gum, carrageenan, alginic acid, polysaccharides such as sodium alginate, casein, casein lime, gelatin, proteins such as collagen and the like.

  These formation aids can be used alone or in admixture of two or more.

  The content of the formation auxiliary agent is a mass ratio with respect to the total mass of the two-chain two-hydrophilic surfactant (A) and the surfactant (B), and the total mass of (A) and (B): Mass = 1: 0.01 to 1: 100, preferably 1: 0.1 to 1:10, more preferably 1: 1 to 1: 5.

  Thereafter, the concentrated vesicles can be separated and formed by centrifuging. The size of these vesicle solutions or concentrated vesicles can be controlled by high-speed stirring dispersion processing using an ultrasonic homogenizer or stirring homogenizer, dispersion processing using a jet mill, dispersion processing using high shear stirring, and the like.

  The vesicles thus obtained have an average particle size of 1 μm or more, and microcapsules can be obtained using this. Here, the average particle diameter is calculated based on the average particle diameter (weight (volume)) from the measured value of the particle size distribution by the laser diffraction / dynamic light scattering method using a commercially available laser diffraction / dynamic light scattering particle size distribution measuring device (Average diameter of the standard distribution).

  When polymerizing the vesicle film, a water-soluble polymerization initiator is added to the aqueous solution containing the vesicle, and the two-chain two-hydrophilic surfactant (A) is polymerized by heating or ultraviolet irradiation. it can. When placed under conditions effective for the polymerization initiator, the polymerization reaction proceeds easily. You may deaerate by inert gas, such as nitrogen and argon, as needed. When the polymerization reaction ends, microcapsules that are hollow polymer particles can be obtained.

  The water-soluble polymerization initiator is not particularly limited, and a known radical photopolymerization initiator such as an alkylphenone series can be used. When performing thermal polymerization, potassium persulfate, ammonium persulfate, or an azo-based water-soluble thermal polymerization initiator can be used.

  By carrying out the polymerization, it is possible to prepare a stable microcapsule having a large particle size and a uniform particle size and capable of controlled release.

  The prepared microcapsules of hollow polymer particles can be used as an aqueous solution, but can also be used as a solid by filtration or drying. Further, the solidified hollow polymer can be used again dispersed in a solvent.

  Since the microcapsules of the present invention can contain a large amount of drug in both the hydrophobic part and the hydrophilic part, they can be applied to fragrances, agricultural chemicals, drug delivery, cosmetics, pharmaceuticals, inks and the like.

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.
<Synthesis of 2-chain 2-hydrophilic surfactant (A)>
(Synthesis Example 1) 2-Propenoic acid, 2-methyl-, 1,1 '-[1,2-ethanediylbis [[(3-sulfopropyl) imino] (11-oxo-11,1-undecanediyl)]] amide, Synthesis of sodium salt (1: 2) (PGA-1102) (R ¹ = CH ₃ , X = NH, m = 2, n = 10, p = 3 represented by formula (I))
Synthesis of 11-Methacrylamidoundecanic acid (PA-11) PA-11, which is a reaction intermediate of PGA1102, was synthesized. First, 11-Aminoundecanoic acid (32.0 g, 0.16 mol), acetone (super-dehydrated) (300 mL), sodium hydrogen carbonate (16.0 g, 0.19 mol), and a polymerization inhibitor 2,5 were added to a 500 mL three-necked flask. -Bis (1,1,3,3-tetfamethylbutyI) hydroquinone (0.27 g, 0.0008 mol) was added and stirred with a stirrer. Methacryloyl chloride (24.0 g, 0.23 mol) was gradually added dropwise thereto and refluxed (45 ° C., 4 h) under a nitrogen atmosphere. After refluxing, the reaction solution was poured into ice-cooled water (400 mL) and stirred for 20 minutes. Then, it cooled in the refrigerator for 12 hours or more, and the precipitated crystal | crystallization was filtered. The crystals were washed again with water (stirring) and then recrystallized twice with ethyl acetate to obtain white crystals of PA-11. The yield was 60.7%. ^The structure was confirmed by ¹ H-NMR.

Synthesis of 3,3 '-(ethane-1,2-diylbis (azanediyl)) dipropane-1-sulfonic acid (vistaurine (m = 2)) Vistaurine (m = 2) which is a reaction intermediate of PGA1102 Was synthesized. First, Ethylenediamine (6.0 g, 0.10 mol) and methanol (150 mL) were added to a 1 L eggplant flask, and 1,3-Propanesultone (25.0 g, 0.20 mol) was gradually added dropwise under ice cooling. After stirring for 1 hour, the ice bath was removed, and the mixture was further stirred for 1.5 hours at room temperature. Subsequently, water (25 mL) and ethanol (40 mL) were added, and when cooled in a refrigerator for 12 hours or more, white crystals were precipitated. This crystal was recrystallized with water, and further the solvent was distilled off by drying under reduced pressure, whereby white crystals of Vistaurin (m = 2) were obtained. The yield was 55.6%.

When actually used for the synthesis of PGA-1102, sodium 3,3 '-(ethane-1,2-diylbis (azanediyl)) dipropane-1-sulfonate (hereinafter referred to as Vistaurine (m = 2) · 2Na) is used. First, Vistaurine (m = 2) (10.0 g, 0.03 mol) was dispersed in methanol (50 mL), sodium hydroxide (3.0 g, 0.08 mol) was added, and the mixture was stirred for 30 minutes. Subsequently, when ethanol (100 mL) was added, crystals began to precipitate, and after cooling in the refrigerator for 12 hours or more, the crystals were filtered. Finally, the solvent was distilled off by drying under reduced pressure to obtain the desired white crystals.
Synthesis of PGA-1102 A 2-chain 2-hydrophilic group-containing anionic surfactant PGA-1102 having a polymerizable group was synthesized. First, PA-11 (25.0 g, 0.09 mol) synthesized above was added to a 500 mL three-necked flask and dissolved in THF (400 mL). Subsequently, DIPC (12.3 g, 0.10 mol) as a dehydrating condensing agent, HOBt (13.2 g, 0.10 mol) and 2,5-Bis (1,1,3,3-tetramethylbutyl) as a polymerization inhibitor. ) Hydroquinone (0.15 g, 0.00045 mol) was added, respectively, and refluxed for 1 hour in a nitrogen atmosphere. Thereto was added Vistaurine (m = 2) · 2Na (9.7 g, 0.028 mol) synthesized above, and the mixture was further refluxed at 45 ° C. for 12 hours. After completion of the reaction, when cooled for 12 hours or more, sherbet-like crystals were obtained. The crystals were washed twice with 130 mL acetone (10 min each), twice with 125 mL methanol (10 min each), and once with 100 mL water (30 min) (filtered after stirring with a stirrer). At this time, the residue was recovered with acetone, and the flow-through was recovered with methanol / water, and the solvent was distilled off with an evaporator in the case of methanol and freeze-drying in the case of water.

The crystals obtained here were washed again with 30 mL of acetone six times (each 30 min), and the filtered residue was collected to obtain the desired white crystals. The yield was 29.4%. Structure and purity were confirmed by ¹ H-NMR, FAB-MASS, and elemental analysis.

(Synthesis Example 2) 2-Propenoic acid, 2-methyl-, 1,1 '-[1,4-buthanediylbis [[(3-sulfopropyl) imino] (11-oxo-11,1-undecanediyl)]] amide, Synthesis of sodium salt (1: 2) (PGA-1104) (R ¹ = CH ₃ , X = NH, m = 4, n = 10, p = 3 represented by formula (I))
PA-11 was synthesized in the same manner as in Synthesis Example 1.
Synthesis of 3,3 '-(buthane-1,2-diylbis (azanediyl)) dipropane-1-sulfonic acid (vistaurine (m = 4)) Vistaurine (m = 4) as a reaction intermediate of PGA-1104 Was synthesized. First, 1,4-diaminobutane (11.1 g, 0.126 mol) and 150 mL of methanol are added to a 500 mL four-necked flask, and 1,3-Propanesultone (25.0 g, 0.20 mol) is added at 0 to 5 ° C. It was added dropwise over time. After removing the ice bath and reacting at room temperature for 3 hours, the temperature was further raised to 35 ° C. and stirred for 15 hours. After confirming disappearance of the spot of the raw material amine by TLC, the crystals were filtered at room temperature, and further the solvent was distilled off by drying under reduced pressure to obtain 35 g of white crystals of Vistaurine (m = 4). The yield was 87.5%.

Sodium 3,3 ′-(buthane-1,2-diylbis (azanediyl)) dipropane-1-sulfonate (hereinafter referred to as Vistaurine (m = 4), which was previously converted to Na salt with sodium hydroxide for use in the synthesis of PGA-1104. 2Na) is used. First, Vistaurine (m = 4) (35 g, 0.11 mol) was dispersed in 100 mL of methanol, sodium hydroxide (9.2 g, 0.23 mol) was added, and the mixture was stirred at room temperature for 3 hours. Subsequently, when ethanol (100 mL) was added, crystals began to precipitate, and after cooling in the refrigerator for 12 hours or more, the crystals were filtered. Finally, the solvent was distilled off under reduced pressure to obtain 28.5 g (yield 65.8%) of the target white crystal.
Synthesis of PGA-1104 A 2-chain 2-hydrophilic group-containing anionic surfactant PGA-1104 having a polymerizable group was synthesized. First, PA-11 (22.9 g, 0.085 mol) synthesized in Synthesis Example 1 was added to a 500 mL four-necked flask and dissolved in 450 mL of MEK. Subsequently, DCC (18.4 g, 0.089 mol) as a dehydrating condensing agent, HOBt (12.0 g, 0.089 mol) and 2,5-Bis (1,1,3,3-tetramethylbutyl) as a polymerization inhibitor. ) Hydroquinone (0.4 g, 0.000119 mol) was added, and the mixture was refluxed for 1 hour in a nitrogen atmosphere. Vistaurine (m = 4) 2Na (13.4 g, 0.034 mol) synthesized above was added thereto, and the mixture was further refluxed for 4 hours to react. After completion of the reaction, the mixture was cooled and filtered to obtain crystals. The crystals were washed twice with cold methanol, the filtrate was concentrated by an evaporator, purified by column chromatography with chloroform: methanol = 7: 3, purified with MP-Carbonate resin, and then methanol: acetone (2: 5). And 1.8 g of the desired white crystal was obtained. The yield was 6.0%. ^The structure and purity were confirmed by ¹ H-NMR and elemental analysis.

(Synthesis Example 3) 2-Propenoic acid, 2-methyl-, 1,1 ′-[1,2-ethanediylbis [[(3-sulfopropyl) imino] (12-oxo-12,1-dodecanediyl)]] ester, Synthesis of sodium salt (1: 2) (PG-1202) (R ¹ = CH ₃ , X = O, m = 2, n = 11, p = 3 represented by formula (I))
Synthesis of Vistaurine (m = 2) was carried out in the same manner as in Synthesis Example 1.

Synthesis of 12-Methacryloxy dodecanoic acid (PE-12) In a 200 mL three-necked flask, 12-hydroxylauric acid (25 g, 0.11 mol), pyridine (10.1 g, 0.13 mol), and a polymerization inhibitor 2,5 -Bis (1,1,3,3-tetfamethylbutyI) hydroquinone (0.16 g, 0.00048 mol) was added and dissolved in 100 mL of THF. Under ice cooling, Methacryloyl chloride (13.3 g, 0.13 mol) was slowly added dropwise, and the reaction was allowed to proceed at room temperature for 5 hours after completion of the addition. Pyridine was used to remove hydrogen chloride generated in the reaction process into hydrochloride.

After the reaction, the produced pyridine hydrochloride was removed by filtration, and THF was distilled off by an evaporator. In order to completely remove pyridine, a 5% hydrochloric acid solution and diethyl ether were added, and a liquid separation operation was performed to obtain an organic layer. Diethyl ether was distilled off with an evaporator, and the resulting solution was purified by column chromatography. Silica gel (C-100) was used as a packing material for column chromatography, and a mixed solvent of hexane: ethyl acetate (2: 1) was used as an eluent. After purification, the solvent was distilled off to obtain a white yellow viscous solution. The yield was 70%.
Synthesis of 12-Methacryloxy dodecanoic chloride (PECl-12) In order to use for the synthesis of PG-1202, PE-12 was converted to acid chloride with oxalyl chloride in advance. First, PE-12 (23.5 g, 0.083 mol) synthesized above was added to a 200 mL eggplant-shaped flask, and oxalyl chloride (41.2 g, 0.33 mol) was slowly dropped with a dropping funnel under ice cooling. . After completion of dropping, the reaction was allowed to proceed at room temperature for 3 hours. In order to remove unreacted oxalyl chloride, it was distilled off under reduced pressure with an evaporator. The yield was 70%.
Synthesis of PG-1202 A 2-chain 2-hydrophilic group-containing anionic surfactant PG-1202 having a polymerizable group was synthesized.

  First, in a 300 mL three-necked flask, Vistaurine (m = 2) (10 g, 0.033 mol) and a polymerization inhibitor 2,5-Bis (1,1,3,3-tetfamethylbutyI) hydroquinone (0.16 g, 0.00048 mol) was added and dissolved in 200 mL of a mixed solvent of water: acetone (7: 3). An aqueous sodium hydroxide solution was added dropwise with a dropping funnel to adjust the pH of the solution to 9 to 10 and then adjusted to 0 ° C. or lower in an ice bath. Next, PECl-12 (22.1 g, 0.066 mol) synthesized above was slowly dropped with a dropping funnel. At this time, sodium hydroxide was added dropwise at any time to keep the solution at pH 7.5 to 10 for reaction. After completion of the dropwise addition, the mixture was reacted for 24 hours, and the solvent was removed by lyophilization to obtain yellowish white crystals. The obtained crystals were purified by column chromatography. Silica gel (C-100) was used as a packing material for column chromatography, and a mixed solvent of hexane: ethyl acetate (2: 1) and a mixed solvent of chloroform: methanol (5: 2) were used as an eluent. After purification, the solvent was distilled off to obtain white crystals. The yield was 15%.

Synthesis Example 4 1-Propanesulfonic acid, 3,3 ′-[1,2-ethanediylbis [(1-oxo (ω-Hendecenoyl)) imino]] bis-, sodium salt (1: 2) ( PU 02) (R ¹¹ = C ₁₀ H ₁₉ , m = 2, p = 3 represented by formula (I ′))
Synthesis of Vistaurine (m = 2) (Vistaurin (m = 2) · 2Na) was carried out in the same manner as in Synthesis Example 1.
Synthesis of PU -02 A 2-chain 2-hydrophilic group-containing anionic surfactant PU -02 having a polymerizable group was synthesized. First, undecenoic acid (25.0 g, 0.14 mol) was added to a 500 mL four-necked flask and dissolved in THF (420 mL). Subsequently, DIPC (17.9 g, 0.14 mol) as a dehydrating condensing agent, HOBt (19.2 g, 0.14 mol) and 2,5-Bis (1,1,3,3-tetramethylbutyl) as a polymerization inhibitor. ) hydroquinone (0.60 g, 0.0018 mol) was added, and the mixture was refluxed for 1 hour in a nitrogen atmosphere. Vistaurine (m = 2) · 2Na (14.9 g, 0.043 mol) synthesized above was added thereto, and the mixture was further refluxed at 65 ° C. for 4 hours. After completion of the reaction, when cooled for 12 hours or more, sherbet-like crystals were obtained. The crystals were washed with 140 mL of acetone twice (each for 10 min) (filtered after stirring with a stirrer). The obtained residue was washed twice with cold methanol, the filtrate was concentrated by an evaporator, purified by column chromatography with a mixed solvent of chloroform: methanol (7: 3), and the resulting crystals were washed twice with water (50 ml each). The target white crystals were obtained by distilling off the solvent from the filtrate with an evaporator. The yield was 9.4%. ^The structure and purity were confirmed by ¹ H-NMR and elemental analysis.

Synthesis Example 5 1-Propanesulfonic acid, 3,3 ′-[1,2-ethanediylbis [(1-oxo (9-cis, 12-cis-Octadecenoyl)) imino]] bis-, sodium salt (1: 2 ) Synthesis of (PL-02) (R ¹¹ = C ₁₇ H ₃₁ , m = 2, p = 3 represented by Formula (I ′))
Synthesis of Vistaurine (m = 2) (Vistaurin (m = 2) · 2Na) was carried out in the same manner as in Synthesis Example 1.
Synthesis of P-L-02 A 2-chain 2-hydrophilic group-containing anionic surfactant P-L-02 having a polymerizable group was synthesized. First, linoleic acid (25.0 g, 0.08 mol) was added to a 500 mL four-necked flask and dissolved in THF (570 mL). Subsequently, DIPC (11.5 g, 0.09 mol) as a dehydrating condensing agent, HOBt (12.3 g, 0.09 mol) and 2,5-Bis (1,1,3,3-tetramethylbutyl) as a polymerization inhibitor. ) Hydroquinone (0.50 g, 0.0015 mol) was added, and the mixture was refluxed for 1 hour in a nitrogen atmosphere. Vistaurine (m = 2) · 2Na (14.9 g, 4.3 × 10 ⁻² mol) synthesized above was added thereto, and the mixture was further refluxed at 65 ° C. for 5 hours. After completion of the reaction, the mixture was cooled and filtered to obtain crystals. The crystals were washed twice with 250 mL of acetone (10 min each), and the residue obtained by filtration was dissolved by heating to 30 ° C. with 60 mL of methanol. 200 ml of acetone was added to this solution and refrigerated for 3 hours, and the precipitated crystals were separated by filtration. The filtrate was concentrated with an evaporator, purified by column chromatography with a mixed solvent of chloroform: methanol (7: 3), and the solvent was distilled off with an evaporator to obtain the desired white crystals. The yield was 17.7%. ^The structure and purity were confirmed by ¹ H-NMR and elemental analysis.

Synthesis Example 6 Synthesis of Hexanediyl-1,6-bis (dimethyl (11-methacryloyloxy) undecylammonium bromide) (PC11-6-11) (R ² = CH ₃ , q = 6, r represented by Formula (II) = 11, Y = Br)
Synthesis of Bromoundecyl methacrylate 11-Bromo-1-undecanol (80 g, 0.32 mol), pyridine (29.2 g, 0.37 mol), 4-methoxyphenol (0.28 g) were added to a 1000 ml three-necked flask, and THF (300 ml) was added. Dissolved. Methacryloyl chloride (38 g, 0.36 mol) was added little by little by a dropping funnel at room temperature under a nitrogen atmosphere, and reacted with 11-Bromo-1-undecanol for 5 hours. In the course of the reaction, pyridine was used to remove the hydrogen chloride generated in the form of hydrochloride, and 4-methoxyphenol was used to prevent polymerization during the reaction. After the reaction, the produced pyridine hydrochloride was removed by filtration, and THF was removed by an evaporator. The resulting solution was then purified by column chromatography. Silica gel (C-100) was used as a packing material for column chromatography, and a mixed solvent of hexane: ethyl acetate (2: 1) was used as an eluent. When the solvent was removed after purification, a clear solution with a light yellowish color was obtained. The obtained 11-Bromoundecyl methacrylate was unstable at room temperature and was stored at 4 ° C. ^The target product was confirmed by ¹ H-NMR.

Synthesis of PC11-6-11 A polymerizable 2-chain 2-hydrophilic group-containing cationic surfactant PC11-6-11 was synthesized. First, 11-Bromoundecyl methacrylate (25 g, 0.076 mol), N, N, N ′, N′-Tetramethyl-1,6-hexanediamine (6.5 g, 0.042 mol), 4-methoxyphenol ( 0.21 g) was added and dissolved with 150 ml of dehydrated ethanol. The reaction was carried out at 80 ° C. for 48 hours. After the reaction, the obtained product was recrystallized with an acetone / methanol mixed solvent. Recrystallization was repeated 5 times, and the desired crystals were obtained by drying under reduced pressure. The yield was 72%. The structure and purity of the target product were confirmed by ¹ H-NMR, FAB-MASS, and elemental analysis.

<Experiment and evaluation>
1. Vesicle formation confirmation (visual, optical microscope, DLS, Cryo-SEM, dye method)
Example 3 and Example 8 were prepared using a 1% by weight aqueous solution of a polymerizable 2-chain 2-hydrophilic surfactant: 1-chain surfactant (molar ratio 1: 2) using the compounds of Synthesis Examples 1-6. Prepared by heating and stirring at 0 ° C., and others were prepared by stirring at room temperature. Visual observation of a clouded liquid, optical microscope observation (manufactured by Carl Zeiss, Axio Imager. A2m), Cryo-SEM (manufactured by Hitachi High-Technology, S -3400N) and observed to confirm the formation of vesicles.

  Comparative Example 1 was based on Non-Patent Document 3. Specifically, VBTAC (Vinylbenzyltrimethylammonium chloride, Aldrich) 0.1280 g, SDS (Sodium dodecyl Sufate, Nacalai Tesque) 0.1154 g, DVB (divinylbenzene, Tokyo Kasei) 0.0436 g (molar ratio VBTAC: SDS: DVB = 60) : 40: 30) was placed in a 10 ml volumetric flask, diluted to 10 ml with ultrapure water, an aqueous solution was prepared, and formation of vesicles was confirmed by the same method as described above.

  As a result of visual observation, it was confirmed that the aqueous solutions of Examples 1 to 8 were clouded, settled with time or by centrifugation, and were separated into two layers. Moreover, it redispersed by performing processes, such as a vortex mixer and ultrasonic dispersion | distribution, and the spherical aggregate considered to be a vesicle was observed by optical microscope observation (100-400 times) (FIGS. 1-8). The aqueous solutions of Examples 1 to 8 were subjected to particle size measurement by dynamic light scattering (DLS, zeta potential particle size measurement system, manufactured by Otsuka Electronics, ELS-Z2 or particle size measurement system, manufactured by Particle Sizing System, NICOMP380-ZLS). In addition, particles having a uniform particle diameter of 1 μm or more were observed (FIG. 33, Table 1). Furthermore, the aqueous solution of Example 1 was confirmed to be a spherical aggregate of about several μm by observation with Cryo-SEM (FIG. 9).

Comparative Example 1 was a homogeneous cloudy liquid by visual observation, and was observed to be a spherical aggregate of 1 μm or less by optical microscope observation (FIG. 12) and particle size measurement by dynamic light scattering (Table 2). .
Fluorescent dye method In order to confirm that the aggregate obtained in Example 1 is a vesicle, Nile red (oil-soluble fluorescent dye: fluorescence wavelength 580 nm) or rhodamine B (water-soluble fluorescence) was added to the aqueous solution obtained in Example 1, respectively. (Dye: Fluorescence wavelength 637 nm) was added to 0.01 mg / L, stirred, centrifuged (3500 rpm, 20 min), and the sediment was observed at each wavelength using a confocal laser microscope (OLYMPUS, FV1000IX81) Went. The results are shown in FIGS.

  From the results of FIGS. 10 and 11, it was found that Nile red, which is an oil-soluble dye, penetrates into the inside of the film, and rhodamine B, which is a water-soluble fluorescent dye, exists inside and outside the film. The aqueous solution was confirmed to be a vesicle together with the results observed by visual observation, optical microscope, DLS, and Cryo-SEM observation.

In Examples 2 to 8, vesicles were confirmed by the dye method as an alternative to the fluorescent dye method.
Dye method Oil-soluble dye confirmation: 0.5 mg of Oil Orange SS is dissolved in 5 ml of a 1% by mass aqueous solution and stirred. If the vesicles gather over time and the precipitated vesicles are red, it is considered that the oil-soluble dye is retained in the film.

  Confirmation of water-soluble dye: 0.5 mg of methylene blue is dissolved in 5 ml of a 1% by mass aqueous solution and stirred. If the vesicles gather over time and the precipitated vesicles appear blue, it is considered that the water-soluble pigment is retained in the inner aqueous phase of the vesicles. That is, if it is confirmed that the oil-soluble dye penetrates into the membrane and the water-soluble dye is retained in the inner aqueous phase, it can be concluded that vesicles are formed.

In Examples 2 to 8, since the vesicles gathered over time and the precipitated sediment was colored, the results of visual observation, optical microscope, and DLS were also confirmed to be vesicles. Since Example 5 and Comparative Example 1 were homogeneous solutions, there was no sedimentation, but both dyes were solubilized neatly, so it is considered that vesicles were formed.
These results are summarized in Tables 1 and 2 and shown.

2. Polymerization (visual, NMR, polarization microscope, SEM)
In Example 1, in a quartz cell with a screw cap, DTAB (2.90 × 10 ⁻² g), PGA-1102 (2.10 × 10 ⁻² g), IRGACURE2959 (radical photopolymerization initiator: 1- [ 4- (2-hydroxyethoxy) -phenyl] -2-hydroxy-2-methyl-1-propan-1-one) (5.0 × 10 ⁻⁴ g), degassed water (4.95 mL) was added, The mixture was stirred with a vortex mixer to obtain an aqueous vesicle solution. The water used as the solvent was deaerated water that was subjected to nitrogen bubbling and ultrasonic deaeration.

In this vesicle aqueous solution, under a nitrogen atmosphere, an Hg-Xe lamp (Minami Electric Manufacturing UVF-204S) was used as a light source so that the wavelength of transmitted light was converted to 365 nm, and the UV illuminance was adjusted to 5 mW / cm ² for 15 min. UV irradiation was performed under the following conditions. For Examples 2 to 8, IRGACURE2959 (3.0 × 10 ⁻⁴ g) was added using 3 ml of the vesicle aqueous solution prepared in Item 1, and the mixture was dispersed with ultrasound for 1 minute, and the resulting polymerization vesicle aqueous solution was lyophilized. Then, this vesicle aqueous solution was prepared using an LED lamp (manufactured by LUMEN DYNAMICS, OminiCure LX400, 365 nm LED head) as a light source so that the UV illuminance and the ultraviolet irradiation time were adjusted to the values shown in Table 3, and then irradiated with ultraviolet rays.

The polymerization was confirmed by freeze-drying the obtained aqueous vesicle solution after polymerization and by reducing or eliminating the ¹ H-NMR peak due to protons derived from the polymerization group. Moreover, the sample after lyophilization was redispersed in ethanol and observed with polarized light using an optical microscope. Similarly, a small sample dispersed in ethanol was placed on a grid, vacuum-deposited after vacuum drying, and SEM observation was performed using a scanning electron microscope (SEM) (Hitachi S-510 or Hitachi TM3000). The polymerization conditions and the confirmation results of the polymerization are shown in Tables 3 and 4.

As a result, it was confirmed by visual observation that polymerization proceeds. Moreover, the disappearance of the peak due to the proton derived from the polymerization group was confirmed by ¹ H-NMR, and it was observed that the polymerization was in progress. Further, when the lyophilized sample was redispersed in ethanol and observed with polarized light with an optical microscope, the polarized light in the film portion was confirmed, and it was found that the sample was polymerized (FIGS. 13, 17, 19, and 21). 23, 25, 27, 29, 31). Moreover, the production | generation of the microcapsule was confirmed from SEM observation (FIGS. 14-16, 18, 20, 22, 24, 26, 28, 30, 32). As shown in FIG. 20, it was found that a strong film can be obtained by using a surfactant having a polymerizable group as the surfactant (B).
3. Inclusion rate and sustained release (dye method)
Add 0.3 mg of Oil Orange SS to 3 ml of 1% by weight aqueous solution of the microcapsules obtained in Example 1 of Item 1 and filter with a 0.8 μm filter to remove the remaining oil orange SS. Photopolymerization was performed in 30 minutes. After polymerization, the mixture was centrifuged at 13500 rpm for 20 minutes to remove the supernatant aqueous solution in which the oil orange SS was solubilized. Further, 3 ml of water was added and centrifuged again to remove the supernatant, and then a sample was obtained by lyophilization. . Thereafter, 6 ml of EtOH was added to extract the oil orange SS, and the absorbance at 480 nm of the extract immediately after measurement was measured with a UV-Vis absorptiometer (VA-055 manufactured by JASCO). In order to confirm the sustained release, the absorbance of the extract after applying ultrasonic waves for 1 minute (absorbance after treatment for 24 hours at 25 ° C., 20 rpm with a shaker (BT-100 manufactured by Yamato Scientific)) The concentration of Oil Orange SS was measured.

  As a comparative example, VBTAC 0.4517g (2.13mmol), SDS 0.4108g (1.42mmol), DVB 0.1383g (1.06mmol), VA-044 so that a density | concentration might be 1 mass% similarly to an Example. (Low-temperature water-soluble azo polymerization initiator, 2,2′-Azobis [2- (2-imidazolin-2-yl) propane] dihydrochloride) 0.0608 g and Oil Orange SS 10.0 mg are put into a 100 ml volumetric flask. Measure up with ultrapure water and stir well. Of these, 10 ml was filtered through a 0.8 μm filter in order to remove the remaining undissolved oil orange SS, and thermal polymerization was carried out while stirring the filtrate at 50 ° C. for 1 hour. Among them, 3 ml of the polymerization vesicle solution was collected, and then the absorbance was measured and compared in the same manner as the post-polymerization operation in Example 1. The results are shown in Tables 5 and 6.

As a result, the particles after polymerization in Example 1 and Comparative Example 1 were both orange particles, but the concentration calculated from the absorbance of the EtOH extract of Example 1 was 2.0 ppm (extraction The concentration of the EtOH extract of Comparative Example 1 was 13.95 ppm (extraction rate 27.9%). From this, the polymerization capsule of Comparative Example 1 had small particles and had many agglomerates, so that it eluted immediately, whereas the polymerization capsule of Example 1 polymerized by taking in Oil Orange SS. It was conceivable that they were not easily eluted and retained in the capsule, and the extraction rate was low, in other words, the inclusion rate was high. In addition, the concentration of the EtOH extract of Example 1 after 1 minute of the ultrasonic wave increased to 3.18 ppm (extraction rate 6.4%), and sustained release was confirmed by applying energy, whereas comparison was made. In Example 1, it was considered that the oil orange SS was extracted almost at the beginning, with only a slight increase of 14.16 ppm (extraction rate: 28.3%), and it is considered that there is almost no sustained release property.

* Extraction rate = 100 × (EtOH extract concentration) / (Concentration when oil orange SS charged before polymerization is dissolved in ethanol = 50 ppm)
4). Preparation of vesicles using soybean lecithin as a forming aid and preparation of microcapsules Degassed water obtained by ultrasonically degassing 10 ml of a 1% by mass aqueous solution of PGA-1102: DTAB (molar ratio 1: 2) of Example 1 Soy lecithin (Wako Reagent) with respect to the total mass of PGA-1102 (A) and DTAB (B) as a forming aid, and total mass of PGA-1102 and DTAB: soy lecithin The vesicle was prepared by stirring while heating at 50 ° C. The results of observing this vesicle with an optical microscope and polarized light of the optical microscope are shown in FIGS. Next, 2.5 ml of this vesicle solution was taken and IRGACURE2959 (radical photopolymerization initiator: 1- [4- (2-hydroxyethoxy) -phenyl] -2-hydroxy-2-methyl-1-propan-1-one ) (2.5 × 10 ⁻⁴ g) was added, and under a nitrogen atmosphere, UV light was applied to the aqueous vesicle solution for 15 minutes using an LED lamp (LUMEN DYNAMICS, OminiCure LX400, 365 nm LED head) as a light source at 100 mW / cm ² UV illumination Irradiated. After the polymerization, the supernatant was washed several times by centrifuging the polymerized vesicle aqueous solution, and the result of observation with polarized light using an optical microscope is shown in FIG. A small amount was lyophilized, ¹ H-NMR of the sample after lyophilization was measured, and polymerization was confirmed by the decrease or disappearance of the ¹ H-NMR peak attributed to the proton derived from the polymerization group. A small sample of the precipitated polymerized vesicles was placed on a grid, dried under reduced pressure, evaporated with gold, and observed with a scanning electron microscope (SEM) (Hitachi, Ltd. TM3000). The results are shown in FIG.

  In the total mass of PGA-1102 (A) and DTAB (B): mass of soybean lecithin = 1: 1, vesicle formation was confirmed from the result of optical microscope observation as shown in FIG. As shown in FIG. 35, a characteristic structure of a vesicle called maltase cross was also observed in a polarizing microscope.

As a result, when a microscopic observation of the microcapsule was performed by polymerization, it was found that the microcapsule was fixed after polymerization as shown in FIG. 36, and it was also confirmed that the polymerization was completed by NMR. . The SEM observation shown in FIG. 37 confirmed the microcapsule shape.
5). Oil orange SS encapsulation rate (uses soy lecithin)
0.25 mg of Oil Orange SS was added to 2.5 ml of an aqueous vesicle solution using soybean lecithin obtained in item 4 as a forming aid, and IRGACURE 2959 (radical photopolymerization initiator: 1- [4- (2-hydroxyethoxy) was added. ) -Phenyl] -2-hydroxy-2-methyl-1-propan-1-one) 2.5 × 10 ⁻⁴ g was added, and photopolymerization was performed at a UV illumination of 100 mW / cm ^{2 for} 15 minutes. After polymerization, 2 ml is taken out, centrifuged at 13500 rpm for 10 minutes, the supernatant aqueous solution in which the oil orange SS is solubilized is removed, 2 ml of water is further added, centrifugation is repeated, and the supernatant is removed twice. After that, a sample was obtained by lyophilization. Thereafter, 4 ml of EtOH was added to extract the oil orange, and the absorbance at 480 nm of the extract immediately after was measured with a UV-Vis absorptiometer (VASCO, VA-055). In order to confirm the encapsulation rate, the absorbance of the extract after applying ultrasonic waves for 1 minute (absorbance after treatment for 24 hours at 25 ° C, 40 rpm with a shaker (BT-100 manufactured by Yamato Kagaku)) was measured. The concentration of orange SS was measured.

  As a result, the polymerized particles were both orange particles regardless of the presence or absence of the forming aid. When the EtOH extract was observed, in Example 1, the microcapsules remained almost colored, whereas the microcapsules added with soy lecithin were decolorized. The concentration calculated from the absorbance was 50 ppm (extraction rate 100%), and the concentration of the EtOH extract of Example 1 was 3.18 ppm (extraction rate 6.4%). Thus, soy lecithin was formed. It was found that the inclusion rate was dramatically improved by using it as an auxiliary agent.

* Extraction rate = 100 × (EtOH extract concentration) / (Concentration when oil orange SS charged before polymerization is dissolved in ethanol = 50 ppm)
6). Methylene blue sustained release (uses soy lecithin)
0.25 mg of methylene blue was added to 2.5 ml of an aqueous vesicle solution using soybean lecithin obtained in item 4 as a forming aid, and IRGACURE2959 (radical photopolymerization initiator: 1- [4- (2-hydroxyethoxy)- Phenyl] -2-hydroxy-2-methyl-1-propan-1-one 2.5 × 10 ⁻⁴ g was added, and photopolymerization was performed at a UV illumination of 100 mW / cm ^{2 for} 15 minutes. Centrifuge at 13500 rpm for 10 minutes to remove the supernatant aqueous solution in which methylene blue was solubilized, add 2 ml of water, centrifuge again, and repeat the operation to remove the supernatant twice, and methylene blue not contained in the vesicle Was washed.

  Thereafter, 2 ml of water was added, and the mixture was vigorously stirred for 1 minute, centrifuged at 13500 rpm for 10 minutes, and the supernatant was collected three times to confirm the sustained release of methylene blue. The absorbance at 664 nm of the obtained first to third supernatants was measured with a UV-Vis absorptiometer (VASCO, VA-055). The concentration of methylene blue was calculated.

  As a result, the polymerized particles were blue particles. The concentration calculated from the absorbance of the supernatant is 1.09 μmol / L for the first time, 1.25 μmol / L for the second time, and 1.48 μmol / L for the third time, and is constant by applying external force. It was confirmed that methylene blue was released slowly. It is considered that this polymer capsule does not easily elute because it has taken in and polymerized soybean lecithin and is retained in the capsule.

Claims (5)

  A two-chain two-hydrophilic surfactant (A) having a radically polymerizable group in each of two hydrophobic chains, and a surfactant (B) having a symmetrical charge with respect to the two-chain two-hydrophilic surfactant A vesicle having a hollow shape and an average particle diameter of 1 μm or more. The two-chain two-hydrophilic surfactant (A) having a polymerizable group is represented by the following formula (I):
(In the formula, R ¹ represents a hydrogen atom or a methyl group, X represents an oxygen atom, an amino group (NH), or an aminomethyl group (NCH ₃ ), m represents an integer of 2 to 8, and n represents 8 10 represents an integer of 10 to 10 and p represents an integer of 2 to 6). The surfactant (B) is an acryloxy group which is a polymerizable group. Or an alkyl ammonium salt having a linear alkyl group having 8 to 14 carbon atoms which may be substituted with a methacryloxy group, or an alkenyl ammonium salt having a linear alkenyl group having 8 to 14 carbon atoms. Vesicles. The 2-chain 2-hydrophilic surfactant (A) has the following formula (II):
(Wherein R ² represents a hydrogen atom or a methyl group, q represents an integer of 2 to 12, r represents an integer of 8 to 20, and Y represents a halogen ion). The surfactant is a basic surfactant, and the surfactant (B) is an alkyl sulfate having a linear alkyl group having 8 to 14 carbon atoms, an alkenyl sulfate having a linear alkenyl group having 8 to 14 carbon atoms, or carbon The vesicle according to claim 1, which is a polyoxyalkylene alkenyl ether sulfate having a linear alkenyl group of formula 8-14.   The vesicle according to any one of claims 1 to 3, further comprising a forming aid.   A microcapsule obtained by polymerizing the two-chain two-hydrophilic surfactant (A) of the vesicle according to any one of claims 1 to 4.