JP5246675B2 - Shell cross-linked micelle and method for producing the same - Google Patents

Description

  The present invention relates to a shell cross-linked micelle and a method for producing the same. More specifically, the present invention relates to a shell cross-linked micelle having a space in which hydrophilicity and hydrophobicity can be changed by stimulation inside the micelle and a method for producing the same.

Micelles, which are aggregates of surfactants, are widely used as dispersants and solubilizers in various solvents. Conventionally, micelles having various structures composed of high molecular weight polymers have been reported, and micelles composed of polyalkenyl ethers have also been reported.
On the other hand, there is a polymer called “stimulus responsive polymer” as a part of polyalkenyl ether, which changes its physical properties in response to environmental changes such as temperature, pH, chemical substance addition, and the like. For example, it is known that an aqueous poly (4-hydroxybutyl vinyl ether) solution changes hydrophilicity and hydrophobicity depending on temperature (see Non-Patent Document 1). In addition, it is known that a block copolymer in which a stimulus-responsive polymer and a hydrophilic polymer are linked in a block shape changes from a molecular dispersion state (dissolution) to a micelle or from a micelle to a molecular dispersion state (dissolution) by stimulation. (See Non-Patent Document 2).
However, a stable micelle in which the environment inside the micelle is changed by an external stimulus without being affected by the solution concentration has not yet been reported.
Journal of Polymer Science, Part A: Polymer Chemistry, 41, 3300-3212 (2003) Macromolecules, 37, 1711-1719 (2004)

  An object of the present invention is to provide a shell-crosslinked micelle having high stability in which micelles have stimulus responsiveness and the internal environment changes in response to external stimuli.

  As a result of various investigations on the above problems, the present inventors have made a block copolymerization of a stimulus-responsive alkenyl ether monomer, a soluble alkenyl ether monomer that dissolves in a solvent to be used, and an alkenyl ether monomer having a crosslinkable group, and a shell portion. By using a block copolymer that has been photocrosslinked, shell-crosslinked micelles that exist stably regardless of the solution concentration and have a space in which the hydrophilicity and hydrophobicity can be changed by stimulation inside the micelle can be obtained. As a result, the present invention has been completed.

That is, the present invention relates to the general formula (1)
CHR ¹ = CH (OR ² ) (1)
(In the formula, R ¹ represents a hydrogen atom or a methyl group, and R ² represents a linear or branched alkyl group having 1 to 6 carbon atoms which may be substituted with a hydroxyl group, C ₁ -C ₆ alkoxy C _1. -C shows a ₆ alkyl group.)
A responsive alkenyl ether monomer represented by the following general formula (2):
CHR ³ = CH (OR ⁴ ) (2)
(In the formula, R ³ represents a hydrogen atom or a methyl group, R ⁴ represents a linear or branched alkyl group having 1 to 6 carbon atoms which may be substituted with a hydroxyl group, C ₁ -C ₆ alkoxy C ₁ -C shows a ₆ alkyl group.)
And a soluble alkenyl ether monomer that is soluble in the solvent used (however, different from the aforementioned stimulus-responsive monomer), and general formula (3)
^{CHR 5 = CH (O-R} 6 -OCO-CR 7 = CHR 8) (3)
(Wherein R ⁵ and R ⁷ represent a hydrogen atom or a methyl group, R ⁶ represents a linear, branched or cyclic alkylene group having 1 to 18 carbon atoms, an ethoxyethyl group or an ethoxyethoxyethyl group, R ⁸ represents a hydrogen atom or a phenyl group.)
The present invention provides a shell-crosslinked micelle containing a block copolymer obtained by block copolymerization of an alkenyl ether monomer having a crosslinkable group represented by formula (I) and photocrosslinking of a shell part.
In addition, the present invention provides a general formula (1)
CHR ¹ = CH (OR ² ) (1)
(In the formula, R ¹ represents a hydrogen atom or a methyl group, and R ² represents a linear or branched alkyl group having 1 to 6 carbon atoms which may be substituted with a hydroxyl group, C ₁ -C ₆ alkoxy C _1. -C shows a ₆ alkyl group.)
A responsive alkenyl ether monomer represented by the following general formula (2):
CHR ³ = CH (OR ⁴ ) (2)
(In the formula, R ³ represents a hydrogen atom or a methyl group, R ⁴ represents a linear or branched alkyl group having 1 to 6 carbon atoms which may be substituted with a hydroxyl group, C ₁ -C ₆ alkoxy C ₁ -C shows a ₆ alkyl group.)
And a soluble alkenyl ether monomer that is soluble in the solvent used (however, different from the aforementioned stimulus-responsive monomer) , and general formula (3)
^{CHR 5 = CH (O-R} 6 -OCO-CR 7 = CHR 8) (3)
(Wherein R ⁵ and R ⁷ represent a hydrogen atom or a methyl group, R ⁶ represents a linear, branched or cyclic alkylene group having 1 to 18 carbon atoms, an ethoxyethyl group or an ethoxyethoxyethyl group, R ⁸ represents a hydrogen atom or a phenyl group.)
A shell-crosslinking type in which the alkenyl ether monomer having a crosslinkable group represented by the above formula is block-copolymerized by living cationic polymerization, the resulting copolymer is micellized in a solvent, and then the shell portion of the micelle is photocrosslinked A method for producing micelles is provided.

  ADVANTAGE OF THE INVENTION According to this invention, a highly stable shell bridge | crosslinking type micelle which has a stimulus responsiveness inside a micelle and has the space which can change the internal environment in response to an external stimulus can be obtained. In addition, the shell-crosslinked micelle of the present invention can be encapsulated with pharmaceuticals and the like inside the micelle, and is released as a result of stimulation such as temperature change. Therefore, it is extremely useful as a material for drug carriers and the like.

  In the present invention, the “shell-crosslinked micelle” is a micelle having a nano-order size, and is a nanogel in which a shell that is an outer portion of the micelle is photocrosslinked. The size of the shell cross-linked micelle of the present invention is preferably 10 to 600 nm, particularly preferably 40 to 200 nm.

  In the present invention, “stimulus responsiveness” means that the physical state changes in response to at least one stimulus such as temperature change, pH change, light change, concentration change, and the like. The polymer is a “stimulus responsive polymer”, and the constituent unit (monomer) of the stimulus responsive polymer is a “stimulus responsive monomer”.

The stimulus-responsive alkenyl ether monomer used in the present invention is not particularly limited as long as it is a monomer that can make the polyalkenyl ether stimuli-responsive, and examples thereof include a vinyl group, a propenyl group, a 2-butenyl group, and a 3-butenyl group. And ether monomers having a linear or branched alkenyl group having 2 to 8 carbon atoms such as a group, 1-methylallyl group, 2-pentenyl group, and 2-hexenyl group. The alkenyl ether monomer may be one compound or two or more compounds.
As the alkenyl ether monomer exhibiting stimulus responsiveness in water, a compound represented by the following general formula (1) is preferably used.

(In the formula, R ¹ represents a hydrogen atom or a methyl group, and R ² represents a monovalent organic group.)
In the formula (1), the monovalent organic group represented by R ² is a linear or branched alkyl group having 1 to 6 carbon atoms which may be substituted with a hydroxyl group, C ₁ -C ₆ alkoxy C such as ₁ -C ₆ alkyl group. Specifically, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, n-pentyl group, isopentyl group, n-hexyl group, isohexyl group; Methoxyethyl group, 2-ethoxyethyl group, 2-butoxyethyl group, 2-phenoxyethyl group, 4-ethoxybutyl group, 4-butoxybutyl group, 2- (2-methoxyethoxy) ethyl group, 2- (2- Ethoxyethoxy) ethyl group, 2- [2- (2-methoxyethoxy) ethoxy] ethyl group, 2- [2- (2-ethoxyethoxy) ethoxy] ethyl group; 2-hydroxyethyl group, 3-hydroxypropyl group, 4-hydroxybutyl group, 3-hydroxy-2-methylpropyl group, 2- (2-hydroxyethoxy) ethyl group, 2- (2-hydroxy Tokishietokishi) and ethyl group and the like, in particular 2-ethoxyethyl group, 2- (2-ethoxyethoxy) ethyl group is preferred.

Among these, particularly preferable stimulus-responsive alkenyl ether monomers are the following monomers.
_{CH 2 = CH (OCH 2 -CH} 2 -CH 2 -CH 2 -OH),
_{CH 2 = CH (OCH 2 -CH} 2 (CH 3) -CH 2 -OH),
_{CH 2 = CH (OCH 2 -CH} 2 -O-CH 3),
_{CH 2 = CH (OCH 2 -CH} 2 -O-CH 2 -CH 2 -O-CH 3),
_{CH 2 = CH (OCH 2 -CH} 2 -O-CH 2 -CH 2 -O-CH 2 -CH 2 -O-CH 3),
_{CH 2 = CH (OCH 2 -CH} 2 -O-CH 2 -CH 3),
_{CH 2 = CH (OCH 2 -CH} 2 -O-CH 2 -CH 2 -O-CH 2 -CH 3),
_{CH 2 = CH (OCH 2 -CH} 2 -O-CH 2 -CH 2 -O-CH 2 -CH 2 -O-CH 2 CH 3).

Polymers of these alkenyl ether monomers have the property of being dissolved in water at a low temperature and becoming insoluble at a certain critical temperature as the temperature rises.
The OH group of the stimulus-responsive alkenyl ether monomer having an OH group is protected with a protective group such as a trialkylsilyl group, trialkylsilyloxy group, acetoxy group, or benzoxy group before polymerization. Here, as the protecting group, a trimethylsilyl group, a triethylsilyl group, and a tert-butyldimethylsilyl group are preferable, and a tert-butyldimethylsilyl group is particularly preferable. Subsequently, after the polymerization reaction, a structural unit having an OH group is obtained by removing the protecting group with an acid or an alkali.

The soluble alkenyl ether monomer dissolves in the solvent to use in the present invention, such as water or an organic solvent is not particularly limited as long as the monomer dissolves in the solvent used. Here, examples of the alkenyl ether monomer include ether monomers having a linear or branched alkenyl group having 2 to 8 carbon atoms as described above. The alkenyl ether monomer may be one compound or two or more compounds.
As the alkenyl ether monomer that is soluble in water, a compound represented by the following general formula (2) is preferably used.

(Wherein R ³ represents a hydrogen atom or a methyl group, and R ⁴ represents a monovalent organic group)
In the formula (2), as the monovalent organic group represented by R ⁴ , as in R ² , a linear or branched alkyl group having 1 to 6 carbon atoms which may be substituted with a hydroxyl group, C such as ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl group, and in particular 2-hydroxyethyl group, 2- (2-hydroxyethoxy) ethyl group is preferred. In addition, the monomer which melt | dissolves in water uses a monomer different from the stimulus responsive monomer mentioned above.

Among these, particularly preferred soluble alkenyl ether monomers are the following monomers.
_{CH 2 = CH (OCH 2 -CH} 2 -OH),
_{CH 2 = CH (OCH 2 -CH} 2 -CH 2- -OH),
_{CH 2 = CH (OCH 2 -CH} 2 -O-CH 2 -CH 2 -OH) or _{CH 2 = CH (OCH 2 -CH} 2 -O-CH 2 -CH 2 -O-CH 2 -CH 2 -OH ),

  Polymers of these alkenyl ether monomers also dissolve in water and do not form aggregates. The OH group of the soluble alkenyl ether monomer having an OH group is protected with a protective group before polymerization in the same manner as described above, and then, after the polymerization reaction, the protective group is removed with an acid or an alkali to remove the OH group. A structural unit having is obtained.

The alkenyl ether monomer having a crosslinkable group used in the present invention is not particularly limited as long as it is a monomer having a crosslinkable group such as a vinyl group, an allyl group, an acetylene group, a (meth) acryloyl group, or an isocyanate group. Here, examples of the alkenyl ether monomer include ether monomers having a linear or branched alkenyl group having 2 to 8 carbon atoms as described above. The alkenyl ether monomer may be one compound or two or more compounds.
As the alkenyl ether monomer having a crosslinkable group, a compound represented by the following general formula (3) is preferably used.

(Wherein R ⁵ and R ⁷ represent a hydrogen atom or a methyl group, R ⁶ represents a linear, branched or cyclic alkylene group having 1 to 18 carbon atoms, an ethoxyethyl group or an ethoxyethoxyethyl group, R ⁸ represents a hydrogen atom or a phenyl group.)
In formula (3), examples of the linear, branched or cyclic alkylene group having 1 to 18 carbon atoms represented by R ⁶ include methylene, ethylene, propylene, butylene, pentylene, hexylene, peptylene, octylene, nonylene and decylene. , Undecylene, dodecylene, tridecylene, tetradecylene, pentadecylene, hexadecylene, heptadecylene, octadecylene, 1-methylethylene, 1-methylpropylene, 1-ethylpropylene, etc., preferably an alkylene group having 1 to 8 carbon atoms, especially An ethylene group is preferred.

Among these, particularly preferred alkenyl ether monomers having a crosslinkable group are the following monomers.
_{CH 2 = CH (OCH 2 -CH} 2 -OCO-C (CH 3) = CH 2),
_{CH 2 = CH (OCH 2 -CH} 2 -OCH 2 -CH 2 -OCO-C (CH 3) = CH 2),
_{CH 2 = CH (OCH 2 -CH} 2 -OCO-CH = CH (C 6 H 5)),
_{CH 2 = CH (OCH 2 -CH} 2 -OCO-CH = CH 2).

  In addition to the alkenyl ether monomer, for example, a styrene derivative monomer can be used as appropriate for the shell-crosslinked micelle of the present invention.

As a method for block copolymerization of a stimuli-responsive alkenyl ether monomer, a soluble alkenyl ether monomer that dissolves in the solvent used, and an alkenyl ether monomer having a crosslinkable group, a living polymerization method is preferable, and a living cationic polymerization method is particularly preferable. . In the living cationic polymerization method, the molecular weight of the resulting copolymer is almost uniquely determined by the molar ratio between the monomer and the polymerization initiator. Therefore, the molecular weight can be changed over a wide range by changing the amount of monomer and polymerization initiator used. Can be controlled.
In the present invention, “living polymerization” is a polymerization system in which there is almost no chain termination reaction or chain transfer reaction, and the polymerization terminal activity is maintained for a long time. In this case, when all the monomers enter the polymer and the monomers are added at the end of the polymerization, a block copolymer is formed. This continues without the terminal active species being deactivated at the end of the polymerization. In particular, the “active cation polymerization” means that the active species is “cation”.

Examples of the cationic polymerization initiator used in the present invention include sulfuric acid, phosphoric acid, hydrochloric acid, odorous acid, hydrogen iodide, acetic acid, trifluoroacetic acid and other proton acids; phosphorus oxide, titanium oxide, aluminum oxide and other metal oxides; Other solid acids; halogens such as chlorine, bromine, iodine, iodine chloride, bromine chloride and iodine bromide; chlorides such as magnesium, zinc, aluminum, titanium, iron and boron; metal halides such as bromide and fluoride; Examples thereof include alkyl compounds such as aluminum or zinc; organometallic compounds such as magnesium alkylated products called Grignard reagents; and stable carbonium ions such as triphenylmethylcarbonium ion. Among these initiators, metal-containing initiators include compounds that generate protons such as water, alcohols, and protonic acids, or compounds that generate carbonium ions such as alkyl halides, if necessary. It is added as a cocatalyst.
Among these, as living cationic polymerization initiators, HI / I ₂ type initiators reported in JP-A-60-228509, JP-A-62-257910, JP-A-1-108202 are disclosed. An initiator that is a combination of an organoaluminum compound and an additive such as ether or ester reported in JP-A-1-108203 and JP-A-4-318004 is preferably used.

  The amount of the cationic polymerization initiator used is preferably 0.001 to 20 mol%, more preferably 0.01 to 10 mol%, particularly preferably 1 mol% or less, based on the total amount of the raw material monomers.

  In the present invention, for example, it is preferable to use an initiator such as 1-isobutoxyethyl acetate in combination with a cationic polymerization initiator. The use ratio of the starting species is preferably 1/50 to 1/600 mol with respect to 1 mol of the monomer.

The polymerization is preferably performed by a sequential addition method. In the living cationic polymerization method, the monomers are sequentially polymerized, so that a block copolymer can be obtained by adding the next monomer after polymerization of one monomer.
In the present invention, first, at the end of the stimulus-responsive alkenyl ether monomer polymerization, a soluble alkenyl ether monomer that dissolves in the solvent used is added. Here, if the stimulus-responsive alkenyl ether monomer or the soluble alkenyl ether monomer has an OH group, it is masked in advance with a protective group. Next, when the polymerization rate reaches 50% or more of the whole, preferably 70% or more, an alkenyl ether monomer having a crosslinkable group is added.

  In the present invention, the polymerization solvent is not particularly limited, and examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran and dioxane; and ester solvents such as ethyl acetate. Of these, toluene and ethyl acetate are preferred.

  As polymerization conditions, the reaction temperature is -78 to 70 ° C, preferably -15 ° C to 30 ° C, and the reaction time is 5 to 50 hours, preferably 25 to 40 hours.

  After all the monomers are polymerized, the polymerization is stopped with a lower alcohol solution in which a lower alcohol such as methanol and, if necessary, a basic compound such as ammonia and amine are added in a very small amount. The product can be obtained as it is, or purified by reprecipitation method such as methanol, thin film evaporation method or the like to obtain a copolymer.

  Examples of the copolymer of the present invention include polyalkenyl ethers containing a structural unit represented by the following general formula (4).

(In the formula, n and m represent the degree of polymerization, each represents an integer of ¹ to 800, x is a molar ratio, and R ¹ to R ⁸ are as defined above.)
The degree of polymerization (n and m) is 1 to 800, respectively, preferably 50 to 600, and particularly preferably 50 to 400.

  The number average molecular weight (Mn) measured by the gel permeation chromatography method of the copolymer of the present invention is preferably 500 to 1,000,000 because it is necessary to generate micelles uniformly. It is preferable that it is 5,000-80,000. The ratio (Mw / Mn) of the number average molecular weight (Mn) and the weight average molecular weight (Mw) measured by gel permeation chromatography is preferably 1.0 to 1.5, In particular, it is preferably 1.0 to 1.2.

The obtained copolymer is dissolved in water or an organic solvent, and then micelles are formed by applying a stimulus such as temperature. 0-100 degreeC is preferable and, as for the solvent temperature at the time of micellization, 20-50 degreeC is especially preferable.
The micelle solution is put in a quartz test tube and chemically crosslinked with 254 nm light using a low-pressure mercury lamp or the like to obtain a shell-crosslinked micelle containing a block copolymer obtained by photocrosslinking the outer shell portion. It is done. The low pressure mercury lamp at the time of photocrosslinking is preferably 120 watts for 10 minutes or longer and 15 watts for 1 hour or longer.

  The copolymer concentration at the time of crosslinking may be not less than the critical micelle concentration, and is particularly preferably 0.001% by weight to 0.5% by weight. FIG. 1 schematically shows a series of steps.

A hydrophobic substance can be encapsulated inside the shell-crosslinked micelle of the present invention. Examples of the hydrophobic substance that can be encapsulated in the micelle include hydrophobic vitamins, hydrophobic dyes, pharmaceuticals, and inks.
The shell-crosslinked micelle of the present invention changes from a micelle to a molecularly dispersed state (dissolved) by a stimulus such as temperature, as will be apparent from the examples described later. Sexual substances can be released.

  EXAMPLES Next, the present invention will be specifically described with reference to examples, but the present invention is not limited to these examples.

In the following examples, each measurement method followed the following method.
(1) Weight average molecular weight, number average molecular weight, and ratio of weight average molecular weight to number average molecular weight (Mw / Mn) were measured by gel filtration chromatography (GPC) in terms of polystyrene gel [RI detector, column (Tosoh ( TSKgel column GMH _HR- M × 2), eluent is tetrahydrofuran].
(2) The shape change due to the structure and temperature of the polymer was observed by ¹ H-NMR using NMR (JEOL JNM-EX 500 Spectrometer).
(3) The particle diameter of the shell crosslinked micelle was analyzed by dynamic light scattering (DLS) (DLS7000 manufactured by Otsuka Electronics Co., Ltd.).

Example 1
A glass reaction vessel fitted with a three-way stopcock was heated under a nitrogen gas stream to sufficiently dry the inside of the vessel. Under a nitrogen atmosphere, 0.53 mL (0.8 M) of 2-ethoxyethyl vinyl ether, 0.5 mL (1.0 M) of ethyl acetate, 1-isobutoxyethyl acetate (4 mM) and toluene were placed in a container. After 5 mL and cooling to 0 ° C., 0.50 mL (20 mM) of a 200 mM hexane solution of (CH ₃ CH ₂ ) _1.5 AlCl _1.5 was added to initiate polymerization. After 4 hours, 2.15 mL of tert-butyldimethylsilyloxyethyl vinyl ether was added, and the mixture was vigorously stirred at 0 ° C. After 12 hours, 0.03 mL of vinyloxyethyl methacrylate was added (0.02M), and after 23 hours, ammoniacal methanol was added to terminate the polymerization. A sample at each stage was taken out, extracted with dichloromethane, and then the organic solvent was evaporated. The synthesized sample Chi was dissolved in tetrahydrofuran, and the mixture was stirred for 6 hours at 0.3N- HCl / ethanol, dialyzed sample was obtained prior to photocrosslinking.

The molecular weight and molecular weight distribution of the polymer before crosslinking were measured by gel filtration chromatography (GPC), and the molecular weight was constituted by a polystyrene standard sample. The number average molecular weight of the produced polymer was 56000, and the molecular weight distribution was 1.14. Further, when ¹ H-NMR measurement was performed at 10 ° C. in heavy water, it was confirmed that a radical polymerizable unit was present in each polymer, and a methacryl group was also unreacted. As a result, corresponding to FIG. 2, n = 200, x = 0.98, l = 300, and m = 400. These chain lengths could be changed by changing the polymerization time and the monomer charge.
FIG. 2 shows the results of ¹ H-NMR measurement of the polymer in each step, and FIG. 3 shows the results of GPC measurement of the polymer before crosslinking obtained.

^{When 1} H-NMR was carried out in heavy water at 40 ° C., the portion corresponding to the signal of the stimulus-responsive segment was changed to a broad peak, indicating that micelles were formed.
FIG. 4 shows the results of ¹ H-NMR measurement of the polymer before crosslinking obtained in heavy water (10 ° C.) and during micelle formation (40 ° C.).
From dynamic light scattering measurements, this sample was found to have a particle size of 100 nm. Also, when the temperature was lowered, micelles were not formed.
FIG. 5 shows the result of DLS measurement at the time of micelle formation (40 ° C.) of the polymer before crosslinking obtained.

Example 2
When the polymer obtained in the above example was transferred to a quartz glass test tube to prepare a 0.01 wt% aqueous solution and the temperature was raised to 40 ° C., the entire aqueous solution changed from transparent to a slightly cloudy color. This was irradiated with light of 254 nm for 10 minutes or 40 minutes with a 120 W low-pressure mercury lamp. As a result, the particle diameter of 100 nm was maintained by dynamic light scattering measurement.
The DLS measurement result in water (10 degreeC) of the obtained shell bridge | crosslinking type polymer micelle is shown in FIG.

  From the dynamic light scattering measurement, the angular dependence of the translational diffusion constant was measured. At 30, 60, 90, 120, and 150 degree angles, the 10 ° C. translational diffusion constant is 2.0, 2.26, 2.82, 2.25, 1.83, and the 40 ° C. translational diffusion constant is The values were 4.12, 4.64, 5.52, 6.15, and 6.00, which were almost unchanged at each temperature.

Example 3
A small amount of the hydrophobic dye 1,6-diphenyl 1,3,5-hexatriene (DPH) was added to the shell-crosslinked micelle aqueous solution produced in Example 2, and the mixture was stirred at room temperature for 30 minutes. The UV absorption of the resulting solution was measured to confirm dye capture. Although absorption could not be confirmed in water, absorption was confirmed at around 350 nm in the presence of shell-crosslinked micelles. Since no absorption was observed when the temperature was lowered, it was found that the product was released by temperature (stimulation).
FIG. 7 shows the state of DPH absorption in water of the obtained shell cross-linked polymer micelles.

FIG. 1 is a diagram showing a process of forming a shell cross-linked micelle. FIG. 2 is a diagram showing ¹ H-NMR measurement results of each polymer during block copolymerization. FIG. 3 is a diagram showing a GPC measurement result of a polymer before shell crosslinking. FIG. 4 is a diagram showing ¹ H-NMR measurement results during micelle formation of a polymer obtained by block copolymerization and ¹ H-NMR measurement results of the polymer before shell crosslinking. FIG. 5 is a diagram showing a DLS measurement result at the time of micelle formation of a polymer before shell crosslinking. FIG. 6 is a diagram showing a DLS measurement result of shell cross-linked micelles. FIG. 7 is a diagram showing the state of DPH absorption of shell-crosslinked micelles.

Claims (8)

General formula (1)
CHR ¹ = CH (OR ² ) (1)
(In the formula, R ¹ represents a hydrogen atom or a methyl group, and R ² represents a linear or branched alkyl group having 1 to 6 carbon atoms which may be substituted with a hydroxyl group, C ₁ -C ₆ alkoxy C _1. -C shows a ₆ alkyl group.)
A responsive alkenyl ether monomer represented by the following general formula (2):
CHR ³ = CH (OR ⁴ ) (2)
(In the formula, R ³ represents a hydrogen atom or a methyl group, R ⁴ represents a linear or branched alkyl group having 1 to 6 carbon atoms which may be substituted with a hydroxyl group, C ₁ -C ₆ alkoxy C ₁ -C shows a ₆ alkyl group.)
And a soluble alkenyl ether monomer that is soluble in the solvent used (however, different from the aforementioned stimulus-responsive monomer), and general formula (3)
^{CHR 5 = CH (O-R} 6 -OCO-CR 7 = CHR 8) (3)
(Wherein R ⁵ and R ⁷ represent a hydrogen atom or a methyl group, R ⁶ represents a linear, branched or cyclic alkylene group having 1 to 18 carbon atoms, an ethoxyethyl group or an ethoxyethoxyethyl group, R ⁸ represents a hydrogen atom or a phenyl group.)
A cross-linked micelle containing a block copolymer obtained by block copolymerizing an alkenyl ether monomer having a crosslinkable group represented by formula (1) and photocrosslinking a shell part. The stimulus-responsive alkenyl ether monomer is
_{CH 2 = CH (OCH 2 -CH} 2 -CH 2 -CH 2 -OH),
_{CH 2 = CH (OCH 2 -CH} 2 (CH 3) -CH 2 -OH),
_{CH 2 = CH (OCH 2 -CH} 2 -O-CH 3),
_{CH 2 = CH (OCH 2 -CH} 2 -O-CH 2 -CH 2 -O-CH 3),
_{CH 2 = CH (OCH 2 -CH} 2 -O-CH 2 -CH 2 -O-CH 2 -CH 2 -O-CH 3),
_{CH 2 = CH (OCH 2 -CH} 2 -O-CH 2 -CH 3),
_{CH 2 = CH (OCH 2 -CH} 2 -O-CH 2 -CH 2 -O-CH 2 -CH 3) or _{CH 2 = CH (OCH 2 -CH} 2 -O-CH 2 -CH 2 -O-CH _{2 -CH 2 -O-CH 2 CH} 3)
A soluble alkenyl ether monomer that is soluble in the solvent used,
_{CH 2 = CH (OCH 2 -CH} 2 -OH),
_{CH 2 = CH (OCH 2 -CH} 2 -CH 2- -OH),
_{CH 2 = CH (OCH 2 -CH} 2 -O-CH 2 -CH 2 -OH) or _{CH 2 = CH (OCH 2 -CH} 2 -O-CH 2 -CH 2 -O-CH 2 -CH 2 -OH )
An alkenyl ether monomer having a crosslinkable group is
_{CH 2 = CH (OCH 2 -CH} 2 -OCO-C (CH 3) = CH 2),
_{CH 2 = CH (OCH 2 -CH} 2 -OCH 2 -CH 2 -OCO-C (CH 3) = CH 2),
_{CH 2 = CH (OCH 2 -CH} 2 -OCO-CH = CH (C 6 H 5)) or _{CH 2 = CH (OCH 2 -CH} 2 -OCO-CH = CH 2)
The shell cross-linked micelle according to claim 1. A block copolymer obtained by photocrosslinking the shell portion has the following general formula (4):
(In the formula, n and m each represent a degree of polymerization, each represents an integer of ¹ to 800, x is a molar ratio, and R ¹ to R ⁸ are as defined above.)
3. The shell-crosslinked micelle according to claim 1, wherein the polyalkenyl ether containing a group represented by the formula: is micellized in a solvent, and then the shell portion of the micelle is photocrosslinked.   The number average molecular weight measured by the gel permeation chromatography method of the block copolymer is 500 to 1,000,000, and the number average molecular weight (Mn) was measured by the gel permeation chromatography method. The shell cross-linked micelle according to any one of claims 1 to 3, wherein the ratio (Mw / Mn) to the weight average molecular weight (Mw) is 1.0 to 1.5.   The shell cross-linked micelle according to any one of claims 1 to 4, wherein the hydrophobic substance is encapsulated.   The shell-crosslinked micelle according to claim 5, wherein the hydrophobic substance is a substance selected from pharmaceuticals, cosmetics, dyes, pigments and fragrances.   The shell cross-linked micelle according to any one of claims 1 to 6, wherein the inside of the micelle is changed to hydrophilic or hydrophobic by an external stimulus. General formula (1)
CHR ¹ = CH (OR ² ) (1)
(In the formula, R ¹ represents a hydrogen atom or a methyl group, and R ² represents a linear or branched alkyl group having 1 to 6 carbon atoms which may be substituted with a hydroxyl group, C ₁ -C ₆ alkoxy C _1. -C shows a ₆ alkyl group.)
A responsive alkenyl ether monomer represented by the following general formula (2):
CHR ³ = CH (OR ⁴ ) (2)
(In the formula, R ³ represents a hydrogen atom or a methyl group, R ⁴ represents a linear or branched alkyl group having 1 to 6 carbon atoms which may be substituted with a hydroxyl group, C ₁ -C ₆ alkoxy C ₁ -C shows a ₆ alkyl group.)
And a soluble alkenyl ether monomer that is soluble in the solvent used (however, different from the aforementioned stimulus-responsive monomer) , and general formula (3)
^{CHR 5 = CH (O-R} 6 -OCO-CR 7 = CHR 8) (3)
(Wherein R ⁵ and R ⁷ represent a hydrogen atom or a methyl group, R ⁶ represents a linear, branched or cyclic alkylene group having 1 to 18 carbon atoms, an ethoxyethyl group or an ethoxyethoxyethyl group, R ⁸ represents a hydrogen atom or a phenyl group.)
A shell-crosslinking type in which the alkenyl ether monomer having a crosslinkable group represented by the above formula is block-copolymerized by living cationic polymerization, the resulting copolymer is micellized in a solvent, and then the shell portion of the micelle is photocrosslinked A method for manufacturing micelles.