Hollow particle in which (POLY)glycerol ester compounds are used, and method for producing said hollow particle

Abstract

The purpose of the present invention is to: use a relatively simple preparation method to provide a hollow particle of which the decomposition product is a component contained in a plant or a derivative thereof; and provide a method for producing said hollow particle. This purpose can be achieved by means of, inter alia, a hollow particle containing a plurality of (poly)glycerol ester compounds which are reaction products of a cinnamic acid and / or cinnamic acid derivative represented by general formula (1) (wherein each among R1-R5 independently represents any of a hydrogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, a nitro group, an amino group, an alkylamino group, or a hydroxyl group, and X represents any of a hydroxyl group, fluorine, chlorine, bromine, or iodine) and a (poly)glycerol having an average degree of polymerization of 1-40, wherein at least some of the cinnamoyl groups that are included in (poly)glycerol ester compounds and derived from the cinnamic acid or from the cinnamic acid derivative are photodimerized.

Description

Hollow particles using (poly)glycerin ester compounds and methods for producing the same

[0001] The present invention relates to hollow particles containing a (poly)glycerin ester compound which is a reaction product of at least one of cinnamic acid or a cinnamic acid derivative with (poly)glycerin, in which at least a portion of the cinnamoyl groups derived from cinnamic acid or modified cinnamoyl groups derived from a cinnamic acid derivative are photodimerized, and a method for producing the same.

[0002] Hollow particles formed using polymeric materials and the like have a predetermined amount of void space inside the particle and have properties such as low density, a high specific surface area, and a low refractive index. Therefore, they have been researched and put into practical use for various applications such as cosmetic pigments, resin fillers, ultraviolet absorbers, fragrances, and drug delivery systems (DDS) that deliver drugs encapsulated therein to affected areas.

[0003] Known examples of such hollow particles include those produced by a sacrificial template method (Non-Patent Document 1), those produced by a block copolymer self-assembly method (Non-Patent Document 2), those produced by a phase separation self-assembly method (Non-Patent Document 3), and those produced by a photointerfacial reaction method (Non-Patent Documents 4-6). Among these, hollow particles produced using a photointerfacial reaction method are produced much more easily than those produced using methods such as the sacrificial template method, the block copolymer self-assembly method, and the phase separation self-assembly method. Specifically, hollow particles produced by a photointerfacial reaction are produced through a process in which a (meth)acrylic acid ester monomer having a cinnamoyl group derived from cinnamic acid in its side chain is synthesized, the monomer is polymerized by radical polymerization, the cinnamoyl groups undergo a [2+2] cycloaddition reaction with each other under ultraviolet light, and the uncrosslinked polymer is removed under ultraviolet light.

[0004] However, the production method using the photointerfacial reaction method has the problem of low productivity because, as described above, at least four steps are required to form hollow particles. Furthermore, in recent years, there has been a demand for reduced environmental impact and high safety. If such hollow particles are released into rivers or the ocean using non-biodegradable polymers, there is concern about the adverse impact on the marine ecosystem, known as the marine microplastics problem. Therefore, there is also a demand for hollow particles that can be decomposed in nature using biomass-derived raw materials.

[0005] Ohno K., Tsujii Y., Fukuda T. etal., Macromolecules, 40, 1159 (2007).Kataoka K. et al., J. Am. Chem. Soc., 128, 5988 (2006).Minami H., Okubo M.et al, Langmuir, 21, 5655 (2005).Kitayama Y., Yoshikawa K., Takeuchi T., Langmuir, 32, 9245 (2016).Kitayama Y., Yoshikawa K., Takeuchi T., Macromolcules, 50, 7526 (2017).Kitayama Y., Takeuchi T., J. Colloid Interface Sci., 530, 99 (2018).

[0006] In view of the above problems, an object of the present invention is to provide hollow particles whose degradation products are components contained in plants or derivatives thereof, and a method for producing the same, using a relatively simple production method.

[0007] [1] That is, the present invention provides a compound represented by general formula (1): (In the formula, R 1 ~R 5are each independently any of a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a nitro group, an amino group, an alkylamino group, or a hydroxyl group, and X is any of a hydroxyl group, fluorine, chlorine, bromine, or iodine.) with (poly)glycerin having an average degree of polymerization of 1 to 40, and the hollow particles are characterized in that at least a portion of the cinnamoyl groups derived from the cinnamic acid or the modified cinnamoyl groups derived from the cinnamic acid derivatives contained in the (poly)glycerin ester compounds are photodimerized.

[0008] [2] The hollow particles according to [1], wherein some of the (poly)glycerin ester compounds have a plurality of the cinnamoyl groups or the modified cinnamoyl groups in one molecule.

[0009] [3] The hollow particles according to [1] or [2], wherein the (poly)glycerin ester compound is an ester compound obtained by reacting (poly)glycerin having an average degree of polymerization of 1 to 40 with cinnamic acid.

[0010] [4] The hollow particles according to [1] or [2] above, which contain a glycol ester which is a reaction product of at least one of the cinnamic acid or the cinnamic acid derivative with a glycol having 1 to 20 carbon atoms, are characterized in that at least a portion of the cinnamoyl groups derived from the cinnamic acid or the modified cinnamoyl groups derived from the cinnamic acid derivative contained in the (poly)glycerin ester compound, or the cinnamoyl groups derived from the cinnamic acid or the modified cinnamoyl groups derived from the cinnamic acid derivative contained in the glycol ester, are photodimerized.

[0011] [5] And, general formula (1) (In the formula, R 1 ~R 5each independently represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a nitro group, an amino group, an alkylamino group, or a hydroxyl group, and X represents a hydroxyl group, fluorine, chlorine, bromine, or iodine. ), and (poly)glycerin having an average degree of polymerization of 1 to 40; and a solution containing an organic solvent; emulsifying a mixture containing the solution, water, and optionally an emulsifier to prepare an oil-in-water emulsion containing droplets of the (poly)glycerin ester compound; volatilizing the organic solvent from the emulsion to form particles containing the (poly)glycerin ester compound; irradiating the particles with ultraviolet light to photodimerize cinnamoyl groups derived from the cinnamic acid or modified cinnamoyl groups derived from the cinnamic acid derivative contained in the (poly)glycerin ester compound, thereby crosslinking the (poly)glycerin ester compound present near the surface of the particles; and removing uncrosslinked (poly)glycerin ester compounds from the interiors of the particles to form hollow particles in which at least a portion of the cinnamoyl groups or modified cinnamoyl groups are dimerized.

[0012] According to the present invention, hollow particles whose degradation products are components contained in plants or derivatives thereof, and a method for producing the same can be provided using a relatively simple production method.

[0013] Glycerol cinnamic acid triester (Synthesis Example 1) 1 1 is a H NMR chart of 1,5-pentanediol cinnamic acid diester (Synthesis Example 2). 1 1H NMR chart of glycerin and glycerin 4-nitrocinnamic acid triester (Synthesis Example 3). 1 1 is a H NMR chart of glycerin 4-nitrocinnamic acid triester (Synthesis Example 3). 13 1 is a C NMR chart of 1,5-pentanediol and 1,5-pentanediol 4-nitrocinnamic acid diester (Synthesis Example 4). 1 1H NMR chart of 1,5-pentanediol 4-nitrocinnamic acid diester (Synthesis Example 4).13 1 is a C NMR chart of glycerin and glycerin 4-methoxycinnamic acid triester (Synthesis Example 5). 1 1 is a H NMR chart of glycerin 4-methoxycinnamic acid triester (Synthesis Example 5). 13 1 is a C NMR chart of 1,5-pentanediol and 1,5-pentanediol 4-methoxycinnamic acid diester (Synthesis Example 6). 1 1 is a H NMR chart of 1,5-pentanediol 4-methoxycinnamic acid diester (Synthesis Example 6). 13 1 is a C NMR chart of glycerin and glycerin p-dimethylaminocinnamic acid triester (Synthesis Example 7). 1 1 is a H NMR chart of glycerin p-dimethylaminocinnamic acid triester (Synthesis Example 7). 13 1 is a C NMR chart of 1,5-pentanediol and 1,5-pentanediol p-dimethylaminocinnamic acid diester (Synthesis Example 8). 1 1 is a H NMR chart of 1,5-pentanediol p-dimethylaminocinnamic acid diester (Synthesis Example 8). 13 1 is a C NMR chart of decaglycerol cinnamic acid triester (Synthesis Example 9). 11 is a H NMR chart. FIG. 1 is a microscope image of hollow particles of Example 1. FIG. 2 is a scanning electron microscope (SEM) image of hollow particles of Example 1 (shell partially destroyed). FIG. 3 is a microscope image of hollow particles of Example 2. FIG. 4 is a scanning electron microscope (SEM) image of hollow particles of Example 2 (shell partially destroyed). FIG. 5 is a microscope image of hollow particles of Example 3. FIG. 6 is a scanning electron microscope (SEM) image of hollow particles of Example 3 (shell partially destroyed). FIG. 7 is a microscope image of hollow particles of Example 4. FIG. 8 is a scanning electron microscope (SEM) image of hollow particles of Example 4 (shell partially destroyed). FIG. 9 is a microscope image of hollow particles of Example 5. FIG. 10 is a scanning electron microscope (SEM) image of hollow particles of Example 5 (shell partially destroyed). FIG. 11 is a microscope image of hollow particles of Example 6. FIG. 12 is a scanning electron microscope (SEM) image of hollow particles of Example 6 (shell partially destroyed). FIG. 13 is an appearance of hollow particles of Example 2 after irradiation with light at predetermined time intervals. 1 is a graph showing the transmittance of hollow particles of Example 2 after irradiation with light at predetermined time intervals; FIG. 2 is a graph showing the absorbance of hollow particles of Example 2 after irradiation with light at predetermined time intervals; FIG. 3 is a graph showing the appearance of hollow particles of Example 2 after hydrolysis at predetermined time intervals; FIG. 4 is a graph showing the transmittance of hollow particles of Example 2 after hydrolysis at predetermined time intervals; FIG. 5 is a graph showing the appearance of hollow particles of Example 2 after irradiation with light at predetermined time intervals.

[0014] The present invention will be described below based on the embodiments, but the scope of the present invention is not limited to these embodiments, and modifications made within the scope of the present invention also fall within the scope of the present invention. Note that the range "to" includes the upper and lower limits.

[0015] [Hollow Particles] The hollow particles of the present invention contain a plurality of (poly)glycerin ester compounds which are reaction products of at least one of cinnamic acid or a cinnamic acid derivative represented by the above general formula (1) with (poly)glycerin having an average degree of polymerization of 1 to 40, and at least a portion of the cinnamoyl groups derived from the cinnamic acid or modified cinnamoyl groups derived from the cinnamic acid derivative contained in the (poly)glycerin ester compounds are photodimerized. The dimerization of the cinnamoyl groups or modified cinnamoyl groups crosslinks the plurality of (poly)glycerin ester compounds, resulting in a high molecular weight, and as a result, forms the shell of the hollow particle.

[0016] [(Poly)glycerin Ester Compound] As described above, the (poly)glycerin ester compound of the present invention is a reaction product of at least one of cinnamic acid or a cinnamic acid derivative represented by the above general formula (1) with a (poly)glycerin having an average degree of polymerization of 1 to 40. Glycerin is a compound obtained from fats and oils such as coconut oil, and polyglycerin is a compound obtained by condensation of glycerin. Cinnamic acid and cinnamic acid derivatives are compounds contained in the bark of Cinnamomum chinensis, which is used as a herbal medicine and spice. Therefore, when hollow particles containing the (poly)glycerin ester compound of the present invention are released into rivers or the sea, the photodimerized crosslinked structure is cleaved by ultraviolet light, or the hollow particles are decomposed into the cinnamic acid or the cinnamic acid derivative and the (poly)glycerin by hydrolysis, both of which are decomposed into plant-derived components. Therefore, the hollow particles of the present invention decompose over time in the natural environment, thereby significantly reducing adverse effects on the marine environment, including ecosystems.

[0017] The cinnamic acid or cinnamic acid derivative represented by the general formula (1) includes either or both of (E)-cinnamic acid or its cinnamic acid derivative, which is the E-form represented by the general formula (2), or allocinnamic acid or its allocinnamic acid derivative, which is the Z-form represented by the general formula (3). That is, the cinnamic acid or cinnamic acid derivative represented by the general formula (1) may be only the E-form, only the Z-form, or a mixture of the E-form and the Z-form. Note that the R 1 ~R 5When at least one of the groups is an alkylamino group, it is preferably a secondary alkylamino group having 1 to 6 carbon atoms, such as a methylamino group, or a tertiary alkylamino group having 1 to 6 carbon atoms, such as a dimethylamino group. (In the formula, R 1 ~R 5 each independently represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a nitro group, an amino group, an alkylamino group, or a hydroxyl group, and X represents a hydroxyl group, fluorine, chlorine, bromine, or iodine. (In the formula, R 1 ~R 5 each independently represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a nitro group, an amino group, an alkylamino group, or a hydroxyl group, and X represents a hydroxyl group, fluorine, chlorine, bromine, or iodine.

[0018] The average degree of polymerization of the (poly)glycerin used in the (poly)glycerin ester compound of the present invention is preferably 1 to 40, more preferably 1 to 20, and most preferably 1 to 10. When the average degree of polymerization of (poly)glycerin is within this range, it is more likely to be decomposed into glycerin more quickly than high-molecular-weight polyglycerins. Since the average degree of polymerization n is a repeating unit of the glycerin skeleton, an average degree of polymerization n of 1 indicates glycerin as a monomer, while an average degree of polymerization n of 2 to 40 indicates polyglycerin as a polymer. Here, the average degree of polymerization n is calculated from the hydroxyl value determined by terminal analysis using the following formulas (4) and (5). The hydroxyl value in formula (5) is a numerical value that serves as an index of the number of hydroxyl groups contained in the (poly)glycerin and refers to the number of milligrams of potassium hydroxide required to neutralize the acetic acid required to acetylate the free hydroxyl groups contained in 1 g of (poly)glycerin. The number of milligrams of potassium hydroxide is calculated in accordance with "Standard Test Methods for Analysis of Fats, Oils and Related Materials, 2013 Edition, Established by the Japan Oil Chemists' Society" edited by the Japan Oil Chemists' Society. Molecular weight = 74n + 18 (4) Hydroxyl value = 56110 (n + 2) / molecular weight (5)

[0019] From the viewpoint of carbon neutrality, it is preferable that both the cinnamic acid or cinnamic acid derivative represented by the above general formula (1) and the (poly)glycerin are derived from natural products, but at least one or both may be chemically synthesized products. Moreover, the cinnamic acid or cinnamic acid derivative represented by the above general formula (1) may be used alone or in combination of two or more kinds.

[0020] The (poly)glycerin ester compound of the present invention is synthesized by a reaction of forming an ester bond using at least one of cinnamic acid or a cinnamic acid derivative represented by the above general formula (1) and (poly)glycerin as raw materials, using a basic catalyst or an acid catalyst. In the synthesis, the raw materials may be heated or dissolved in an organic solvent, as necessary. An example of the (poly)glycerin ester compound of the present invention is a compound of the general formula (6) obtained by a dehydration condensation reaction of (E)-cinnamic acid and (poly)glycerin: It is a compound represented by the formula: Preferably, one molecule of the (poly)glycerin ester compound has a plurality of cinnamoyl groups derived from cinnamic acid. Specifically, it is preferable that the number of cinnamoyl groups is 3 to 42, more preferably 3 to 22, and even more preferably 3 to 12. Furthermore, in one molecule of the (poly)glycerin ester compound, the esterification rate, which is the ratio of the number of cinnamoyl groups derived from cinnamic acid to the number of hydroxyl groups in (poly)glycerin, is preferably {3 / (n+2)}×100 to 100%. Here, n represents the average degree of polymerization described above, and (n+2) represents the number of hydroxyl groups in (poly)glycerin. For example, if one molecule of a glycerin ester compound has an average degree of polymerization of 1 and has three cinnamoyl groups, the esterification rate is 100%. Furthermore, if one molecule of a polyglycerin ester compound has an average degree of polymerization of 6 and has six cinnamoyl groups, the esterification rate is 75%. By having the above number of cinnamoyl groups in one molecule of the (poly)glycerin ester compound, or by having the above esterification rate, the cinnamoyl groups are dimerized between multiple (poly)glycerin ester compounds, making it easier to form the basic skeleton of the shell of the hollow particle. Furthermore, even if one molecule of the (poly)glycerin ester compound has only one or two cinnamoyl groups, it is possible to impart water solubility to the hollow particle by photodimerization with a cinnamoyl group derived from cinnamic acid or a modified cinnamoyl group derived from a cinnamic acid derivative in another polyhydric alcohol ester compound, and therefore this is not excluded from the present invention. The same applies to the case where the cinnamic acid derivative is used.

[0021] [Glycol Ester Compound] A glycol ester compound can be used in combination with the (poly)glycerin ester compound of the present invention. The glycol ester compound is a reaction product of at least one of cinnamic acid or a cinnamic acid derivative represented by the above general formula (1) with a glycol having 1 to 20 carbon atoms. Preferred examples of the glycol having 1 to 20 carbon atoms include methanediol, ethylene glycol, propylene glycol, 1,4-butanediol, 1,5-pentanediol, 1,6-hexanediol, diethylene glycol, and triethylene glycol. The glycol ester compound is synthesized in the same manner as the above-mentioned (poly)glycerin ester compound.

[0022] [Method for Producing Hollow Particles] Hollow particles containing a (poly)glycerin ester compound are produced by the following steps. First, in the first step, microparticles containing a (poly)glycerin ester compound are formed. Then, in the second step, the microparticles are irradiated with ultraviolet light, causing two cinnamoyl groups or modified cinnamoyl groups to undergo a [2+2] cycloaddition reaction, thereby crosslinking the (poly)glycerin ester compound present near the surface of the microparticles. Finally, in the third step, uncrosslinked (poly)glycerin ester compounds are removed from the interior of the microparticles, thereby producing the hollow particles of the present invention. The glycol ester compound described above may also be blended with the (poly)glycerin ester compound at a predetermined ratio before use.

[0023] In the first step, microparticles containing a (poly)glycerin ester compound are further prepared through steps 1-1 to 1-3. For example, a solution containing a (poly)glycerin ester compound and an organic solvent is prepared (step 1-1), the resulting solution, water, and an optional emulsifier are emulsified to prepare an oil-in-water emulsion containing droplets of the (poly)glycerin ester compound (step 1-2), and the organic solvent is then evaporated from the emulsion (step 1-3). The organic solvent is not particularly limited as long as it is a good solvent for the (poly)glycerin ester compound. For example, halogenated solvents such as methyl chloride and chloroform, aromatic solvents such as toluene and xylene, and ketone solvents such as acetone, methyl ethyl ketone, and methyl isobutyl ketone are preferred. The organic solvent may be used alone, or two or more of these may be used in combination. The concentration of the (poly)glycerin ester compound in the solution may be, for example, 5% to 50% by mass.

[0024] In the above-mentioned step 1-2, the solution is emulsified by adding water, and an emulsifier may be used at this time. Examples of preferred emulsifiers include polymer dispersion stabilizers such as polyvinyl alcohol and polyvinylpyrrolidone, anionic surfactants such as sodium dodecyl sulfate, cationic surfactants such as tetradecyltrimethylammonium bromide, and nonionic surfactants such as polyoxyethylene oleyl ether. When the (poly)glycerin ester compound of the present invention retains hydroxyl groups derived from (poly)glycerin and has self-emulsifying properties, an emulsifier need not be used. Emulsification conditions are not particularly limited. Emulsification can be carried out, for example, at room temperature using a homogenizer.

[0025] The average diameter of the droplets of the (poly)glycerin ester compound in the emulsion can be appropriately determined depending on the desired size of the hollow particles, and can be, for example, 0.1 μm to 2 mm. The average particle size of the droplets of the (poly)glycerin ester compound is measured by a method such as dynamic light scattering (DLS).

[0026] The hollow particles are prepared at a temperature between the freezing point and the boiling point of the organic solvent used, but are preferably prepared at room temperature, for example, 20 to 30°C.

[0027] In the second step, the obtained microparticles are irradiated with ultraviolet light in a wavelength range in which the cinnamoyl group or the modified cinnamoyl group contained in the (poly)glycerin ester compound reacts. For example, since the cinnamoyl group absorbs light in the vicinity of 270 nm, the microparticles are irradiated with ultraviolet light using a deep ultraviolet LED with a wavelength of 265 nm. As a result, the microparticles are irradiated with ultraviolet light represented by the general formula (7) As shown in the figure, in a (poly)glycerin ester compound and another adjacent (poly)glycerin ester compound, two adjacent cinnamoyl groups form a crosslink by a [2+2] cycloaddition reaction. The irradiation intensity and irradiation time of ultraviolet light can be appropriately determined depending on the reactivity of the cinnamoyl group or the modified cinnamoyl group, the desired size and shell thickness of the hollow particles, etc. When the cinnamic acid or cinnamic acid derivative represented by the above general formula (1) is in the Z form, the cinnamoyl group derived from cinnamic acid or the modified cinnamoyl group derived from the cinnamic acid derivative can be photoisomerized to the E form upon irradiation with ultraviolet light, thereby undergoing a [2+2] cycloaddition reaction.

[0028] Two cinnamoyl groups or modified cinnamoyl groups must be close to each other to form crosslinks by a [2+2] cycloaddition reaction. In the (poly)glycerin ester compound of the present invention, the cinnamoyl groups or modified cinnamoyl groups are arranged as side chains on the (poly)glycerin main chain, and therefore are likely to come into close proximity with cinnamoyl groups or modified cinnamoyl groups in other adjacent (poly)glycerin ester compounds. Because the UV intensity is high near the surface of the microparticles where UV light first strikes, the reaction of the cinnamoyl groups or modified cinnamoyl groups proceeds effectively to form crosslinks. Meanwhile, cinnamoyl groups or modified cinnamoyl groups that remain unreacted near the surface of the particles due to the absence of other nearby cinnamoyl groups or modified cinnamoyl groups simply absorb UV light and do not contribute to crosslinking. Due to the crosslinking and UV absorption near the surface of the microparticles, the UV intensity inside the microparticles rapidly decreases, making it difficult for crosslinking by the cinnamoyl groups or modified cinnamoyl groups inside the microparticles to proceed. Therefore, as will be described later, the uncrosslinked (poly)glycerin ester compound can be easily removed from the inside of the particles after ultraviolet irradiation.

[0029] In the third step, the uncrosslinked (poly)glycerin ester compound can be removed by eluting the uncrosslinked (poly)glycerin ester compound in an organic solvent. This allows hollow particles to be formed. Preferred organic solvents that can be used for elution include halogenated solvents such as methyl chloride and chloroform, aromatic solvents such as toluene and xylene, ketone solvents such as acetone, methyl ethyl ketone, and methyl isobutyl ketone, ester solvents such as ethyl acetate and butyl acetate, ether solvents such as diethyl ether and tetrahydrofuran, sulfoxide solvents such as dimethyl sulfoxide, and amide solvents such as dimethylformamide and dimethylacetamide. The organic solvents may be used alone or in combination. In this way, through the first to third steps, hollow particles can be directly produced from fine particles with the simplest structure without using template particles.

[0030] [Average particle size, porosity, etc. of hollow particles] The average particle size of hollow particles can be appropriately determined depending on the application and is not particularly limited. The average particle size of hollow particles is preferably, for example, 0.1 μm to 1 mm. In the present invention, the average particle size of hollow particles can be determined as the average value obtained by measuring several tens of hollow particles using an optical microscope, or as the volume cumulative particle size D determined using laser diffraction / scattering particle size distribution measurement. 50 The porosity of the hollow particles can be determined appropriately depending on the application and is not particularly limited. The porosity of the hollow particles (the ratio of the internal void volume of the hollow particles to the total volume of the hollow particles) is calculated by measuring the diameters and film thicknesses of several tens of hollow particles using an optical microscope, and is preferably, for example, 20% to 85%. The shell thickness of the hollow particles can be determined appropriately depending on the application and is not particularly limited. The shell thickness of the hollow particles is preferably, for example, 50 nm to 100 μm.

[0031] [Uses of Hollow Particles] The hollow particles containing the (poly)glycerin ester compound of the present invention can be suitably used for applications such as cosmetic pigments, resin fillers, heat insulating materials, ultraviolet absorbers, fragrances, and drug delivery systems (DDS).

[0032] The present invention will be described in more detail below based on examples, but the present invention is not limited to these examples.

[0033] Synthesis Example 1 Synthesis of Glycerin Cinnamic Acid Triester Glycerin (2.00 g, 0.022 mol) and triethylamine (10 mL, 0.075 mol) were added to chloroform (20 mL), and the mixture was cooled and stirred under an argon atmosphere. A solution of (E)-cinnamoyl chloride (12.57 g, 0.075 mol) in chloroform (20 mL) was added dropwise thereto, and the mixture was removed from the ice bath and stirred overnight at room temperature. A separation operation was performed three times using a saturated saline solution, and the mixture was dried over anhydrous magnesium sulfate, after which the solvent was again removed. The product was dissolved in a small amount of ethyl acetate and recrystallized to recover the target product. The resulting product was 1The product was identified as glycerin cinnamic acid triester by H NMR (yield: 1.78 g, yield: 27.7%). 1 The H NMR chart is shown below. 1 H and 13 The C NMR measurement was carried out using a nuclear magnetic resonance apparatus (manufactured by JEOL, model: JNM-ECX400), and the same applies to the following synthesis examples.

[0034] Synthesis Example 2 Synthesis of 1,5-pentanediol cinnamic acid diester 1,5-Pentanediol (2.006 g, 0.019 mol) and triethylamine (4.264 g, 0.042 mol) were added to tetrahydrofuran (20 mL), cooled, and stirred. A solution of (E)-cinnamoyl chloride (7.092 g, 0.043 mol) in tetrahydrofuran (10 mL) was added dropwise thereto, and the mixture was removed from the ice bath and stirred overnight at room temperature. The precipitate was removed by filtration, and the filtrate was evaporated under reduced pressure. The product was then redissolved in ethyl acetate, and a separation operation was performed three times using distilled water. After drying over anhydrous magnesium sulfate, the solvent was removed. Further, recrystallization was performed twice using ethyl acetate. The obtained crystals were then washed with hexane and dried under vacuum. The obtained product was 1 The product was identified as 1,5-pentanediol cinnamic acid diester by H NMR (yield: 2.34 g, yield: 33.3%). 1 The H NMR chart is shown.

[0035] Synthesis Example 3 Synthesis of Glycerin 4-Nitrocinnamic Acid Triester 4-Nitrocinnamic acid (3.95 g, 20.5 mmol), glycerin (0.574 g, 6.23 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (4.31 g, 22.5 mmol), and 4-dimethylaminopyridine (0.400 g, 3.27 mmol) were dissolved in N,N-dimethylformamide (80 mL) and stirred at room temperature for 2 days. After removing the solvent by distillation under reduced pressure, the residue was dissolved in chloroform and subjected to a separation operation using saturated saline three times. After drying over anhydrous magnesium sulfate, the solvent was removed. The residue was further dissolved in ethyl acetate and recrystallized to purify the target product. The resulting product was 1 H NMR and 13 The product was identified as glycerin 4-nitrocinnamic acid triester by C NMR (yield: 24.5%). 1 H NMR and 13 The C NMR chart is shown.

[0036] Synthesis Example 4 Synthesis of 1,5-pentanediol 4-nitrocinnamic acid diester 4-Nitrocinnamic acid (4.26 g, 22.0 mmol), 1,5-pentanediol (1.05 g, 10.0 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (4.80 g, 25.0 mmol), and 4-dimethylaminopyridine (0.610 g, 4.50 mmol) were dissolved in N,N-dimethylformamide (80 mL) and stirred at room temperature for 4 days. After removing the solvent by distillation under reduced pressure, the residue was dissolved in chloroform and subjected to a separation operation using saturated saline three times. After drying over anhydrous magnesium sulfate, the solvent was removed. The residue was further dissolved in ethyl acetate and recrystallized to purify the target product. The resulting product was 1 H NMR and 13 The product was identified as 1,5-pentanediol 4-nitrocinnamic acid diester by C NMR (yield: 51.8%). 1 H NMR and 13 The C NMR chart is shown.

[0037] Synthesis Example 5 Synthesis of glycerin 4-methoxycinnamic acid triester 4-Methoxycinnamic acid (2.69 g, 15.1 mmol), glycerin (0.397 g, 4.31 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (2.98 g, 15.5 mmol), and 4-dimethylaminopyridine (1.04 g, 8.49 mmol) were dissolved in dichloromethane (80 mL) and stirred overnight at room temperature. A separation operation was performed three times using saturated saline, and the mixture was dried over anhydrous magnesium sulfate, after which the solvent was removed. The mixture was further dissolved in ethyl acetate and recrystallized. The precipitate was redissolved in dichloromethane and washed three times with distilled water to purify the target product. The resulting product was 1 H NMR and 13 The product was identified as glycerin 4-methoxycinnamic acid triester by C NMR (yield: 34.2%). 1 H NMR and 13 The C NMR chart is shown.

[0038] Synthesis Example 6 Synthesis of 1,5-pentanediol 4-methoxycinnamic acid diester 4-Methoxycinnamic acid (2.06 g, 11.6 mmol), 1,5-pentanediol (0.501 g, 4.81 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (2.30 g, 12.0 mmol), and 4-dimethylaminopyridine (1.05 g, 8.59 mmol) were dissolved in dichloromethane (80 mL) and stirred overnight at room temperature. A separation operation was performed three times using saturated saline, and the mixture was dried over anhydrous magnesium sulfate, after which the solvent was removed. The mixture was further dissolved in ethyl acetate and recrystallized. The precipitate was redissolved in dichloromethane and washed three times with distilled water to purify the target product. The resulting product was 1 H NMR and 13 The product was identified as 1,5-pentanediol 4-methoxycinnamic acid diester by C NMR (yield: 23.3%). 1 H NMR and 13 The C NMR chart is shown.

[0039] Synthesis Example 7 Synthesis of glycerin p-dimethylaminocinnamic acid triester p-(dimethylamino)cinnamic acid (1.51 g, 7.89 mmol), glycerin (0.220 g, 2.39 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.66 g, 8.64 mmol), and 4-dimethylaminopyridine (0.152 g, 1.24 mmol) were dissolved in N,N-dimethylformamide (60 mL) and stirred at room temperature for 2 days. After removing the solvent by distillation under reduced pressure, the residue was dissolved in chloroform and subjected to a separation operation three times using a saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was removed. Methanol was further added, and the target product was purified by reprecipitation. The resulting product was 1 H NMR and 13 The product was identified as glycerin p-dimethylaminocinnamic acid triester by C NMR (yield: 9.2%). 1 H NMR and 13 The C NMR chart is shown.

[0040] Synthesis Example 8 Synthesis of 1,5-pentanediol p-dimethylaminocinnamic acid diester p-(dimethylamino)cinnamic acid (1.03 g, 5.39 mmol), 1,5-pentanediol (0.255 g, 2.45 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.18 g, 6.13 mmol), and 4-dimethylaminopyridine (0.151 g, 1.23 mmol) were dissolved in dichloromethane (40 mL) and stirred overnight at room temperature. After removing the solvent by evaporation under reduced pressure, the residue was dissolved in chloroform and subjected to a separation operation three times using a saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was removed. The residue was further dissolved in methanol and recrystallized to purify the target product. The resulting product was 1 H NMR and 13 The product was identified as 1,5-pentanediol p-dimethylaminocinnamic acid diester by C NMR (yield: 27.6%). 1 H NMR and 13The C NMR chart is shown.

[0041] Synthesis Example 9 Synthesis of Decaglycerol Cinnamic Acid Triester Decaglycerol (1.008 g, 1.33 mmol), a glycerol decamer, and sodium hydroxide (2.519 g, 24.9 mmol) were dissolved in water (25 mL), and (E)-cinnamoyl chloride (3.963 g, 23.8 mmol) was dissolved in methyl ethyl ketone (25 mL). The resulting aqueous solution and methyl ethyl ketone solution were mixed and stirred at room temperature for 3 days under an argon atmosphere. The methyl ethyl ketone layer was then dried over anhydrous magnesium sulfate, and the solvent was removed by evaporation under reduced pressure. The solution was then dissolved in chloroform (100 mL), and the separation procedure was repeated twice using distilled water (100 mL). The chloroform layer was dehydrated, and the solvent was removed by evaporation under reduced pressure to obtain a viscous component. The viscous component was again dissolved in chloroform (10 mL), reprecipitated in hexane (300 mL), and the precipitate was collected. The resulting product is 1 The product was identified as decaglycerol cinnamic acid triester by H NMR (yield: 1.31 g, yield: 42.4%). 1 The H NMR chart is shown.

[0042] Example 1: The glycerol cinnamic acid triester (50.0 mg, 0.1036 mmol) obtained in Synthesis Example 1 was dissolved in chloroform (1 mL), and 25 mL of an aqueous polyvinyl alcohol solution (0.067 wt%) was added. Homogenization was performed (12,000 rpm, 1 min), followed by overnight stirring to volatilize the chloroform. This dispersion (1 mL) was mixed with 2 mL of an aqueous polyvinyl alcohol solution and irradiated with UV-LED light (wavelength λ = 265 nm) for 16 hours. The solvent was then replaced by centrifugation (10,000 rpm, 5 min), and the uncrosslinked monomer inside the particles was washed three times with dimethyl sulfoxide. The solvent was then replaced with an aqueous polyvinyl alcohol solution by centrifugation (10,000 rpm, 5 min). In this manner, hollow particles composed of photocrosslinked glycerol cinnamic acid triester were prepared.

[0043] The hollow particles obtained in Example 1 were observed with an optical microscope. Figure 16 shows an image taken with the microscope. Figure 17 shows an image taken with a scanning electron microscope (SEM) of hollow particles with partially destroyed shells. Furthermore, as a result of observing 50 randomly selected hollow particles with an optical microscope, the average particle size of the hollow particles obtained in Example 1 was 4.7 µm, and the average porosity was 38%.

[0044] Example 2: Glycerol cinnamic acid triester (21.7 mg, 0.0596 mmol) obtained in Synthesis Example 1 and 1,5-pentanediol cinnamic acid diester (28.6 mg, 0.0593 mmol) obtained in Synthesis Example 2 were dissolved in chloroform (1 mL), and an aqueous polyvinyl alcohol solution (0.067 wt %) (25 mL) was added. Homogenization was performed (12,000 rpm, 1 min) and the mixture was stirred overnight to volatilize the chloroform. This dispersion (1 mL) was mixed with an aqueous polyvinyl alcohol solution (2 mL) and subjected to UV-LED light irradiation (λ = 265 nm) for 16 hours. The solvent was then replaced by centrifugation (10,000 rpm, 5 min). The uncrosslinked monomer inside the particles was washed three times with dimethyl sulfoxide, and the solvent was replaced by an aqueous polyvinyl alcohol solution by centrifugation again (10,000 rpm, 5 min). In this way, hollow particles were prepared by photocrosslinking glycerin cinnamic acid triester and 1,5-pentanediol cinnamic acid diester.

[0045] The hollow particles obtained in Example 2 were observed with an optical microscope. Figure 18 shows an image taken with the microscope. Figure 19 shows an image taken with a scanning electron microscope (SEM) of hollow particles with partially destroyed shells. Furthermore, as a result of observing 50 randomly selected hollow particles with an optical microscope, the particle diameter of the hollow particles obtained in Example 2 was found to be 4.6 µm on average, and the porosity was also found to be 45% on average.

[0046] Example 3 Using the glycerin 4-nitrocinnamic acid triester obtained in Synthesis Example 3 and the 1,5-pentanediol 4-nitrocinnamic acid diester obtained in Synthesis Example 4, hollow particles were prepared by photocrosslinking the glycerin 4-nitrocinnamic acid triester and the 1,5-pentanediol 4-nitrocinnamic acid diester in the same manner as in Examples 1 and 2.

[0047] The hollow particles obtained in Example 3 were observed with an optical microscope. Figure 20 shows an image taken with the microscope. Figure 21 shows an image taken with a scanning electron microscope (SEM) of hollow particles with partially destroyed shells. Furthermore, as a result of observing 200 randomly selected hollow particles with an optical microscope, the particle diameter of the hollow particles obtained in Example 3 was found to be 8.6 μm on average, and the porosity was also found to be 33% on average.

[0048] Example 4 Using the glycerin 4-methoxycinnamic acid triester obtained in Synthesis Example 5 and the 1,5-pentanediol 4-methoxycinnamic acid obtained in Synthesis Example 6, hollow particles were prepared by photocrosslinking the glycerin 4-methoxycinnamic acid triester and the 1,5-pentanediol 4-methoxycinnamic acid diester in the same manner as in Examples 1 and 2.

[0049] The hollow particles obtained in Example 4 were observed with an optical microscope. Figure 22 shows an image taken with the microscope. Figure 23 shows an image taken with a scanning electron microscope (SEM) of hollow particles with partially destroyed shells. Furthermore, as a result of observing 200 randomly selected hollow particles with an optical microscope, the particle diameter of the hollow particles obtained in Example 4 was found to be 7.3 μm on average, and the porosity was also found to be 36% on average.

[0050] Example 5 Using the glycerin p-dimethylaminocinnamic acid triester obtained in Synthesis Example 7 and the 1,5-pentanediol p-dimethylaminocinnamic acid diester obtained in Synthesis Example 8, hollow particles were prepared by photocrosslinking the glycerin p-dimethylaminocinnamic acid triester and the 1,5-pentanediol p-dimethylaminocinnamic acid diester in the same manner as in Examples 1 and 2.

[0051] The hollow particles obtained in Example 5 were observed with an optical microscope. Figure 24 shows an image taken with the microscope. Figure 25 shows an image taken with a scanning electron microscope (SEM) of hollow particles with a partially recessed shell. Furthermore, as a result of observing 200 randomly selected hollow particles with an optical microscope, the particle diameter of the hollow particles obtained in Example 5 was found to be 5.7 μm on average, and the porosity was also found to be 34% on average.

[0052] Example 6: Decaglycerol cinnamic acid triester (49.4 mg) obtained in Synthesis Example 9 was dissolved in chloroform (1 mL), and 25 mL of aqueous polyvinyl alcohol solution (0.067 wt%) was added. Homogenization (16,000 rpm, 5 min) was performed, followed by overnight stirring to volatilize the chloroform. This dispersion (1 mL) was mixed with aqueous polyvinyl alcohol solution (2 mL) and subjected to UV-LED light irradiation (λ = 265 nm) for 2 hours. The solvent was then replaced by centrifugation (10,000 rpm, 5 min), and the uncrosslinked monomer inside the particles was washed three times with dimethyl sulfoxide. The solvent was then replaced with aqueous polyvinyl alcohol solution by centrifugation (10,000 rpm, 5 min). In this manner, hollow particles composed of photocrosslinked decaglycerol cinnamic acid triester were prepared.

[0053] The hollow particles obtained in Example 6 were observed with an optical microscope. Figure 26 shows an image taken with the microscope. Figure 27 shows an image taken with a scanning electron microscope (SEM) of hollow particles with a partially recessed shell. Furthermore, as a result of observing 200 randomly selected hollow particles with an optical microscope, the particle diameter of the hollow particles obtained in Example 6 was found to be 4.5 μm on average, and the porosity was also found to be 24% on average.

[0054] As shown in Examples 1 to 6, hollow particles containing a (poly)glycerin ester compound, which is a reaction product of cinnamic acid or a cinnamic acid derivative, which is a component contained in plants, with glycerin or polyglycerin, and in which a portion of the cinnamoyl groups derived from cinnamic acid or modified cinnamoyl groups derived from cinnamic acid derivatives have been photodimerized, were obtained.

[0055] Furthermore, two types of decomposition properties, namely photodecomposition and hydrolysis, of the hollow particles obtained in Example 2 were confirmed.

[0056] Regarding photodegradability, a predetermined amount of hollow particles obtained in Example 2 was dispersed in 2 ml of dimethyl sulfoxide, and the dispersion was irradiated with short wavelength light (wavelength λ=254 nm, 2 mW / cm) from a UV-LED while stirring. 2 ) was performed. The transmittance at a wavelength of 600 nm after irradiation for 0, 6, 12, 24, 48, and 72 hours was measured using an ultraviolet-visible spectrophotometer (manufactured by JASCO Corporation, model: V-560). The appearance of each of the resulting solutions is shown in FIG. 28, and the transmittance at each irradiation time is shown in FIG. 29. The light irradiation time and transmittance values ​​in FIG. 29 are shown in Table 1. Note that the average values ​​in Table 1 are plotted for transmittance in FIG. 29.

[0057] Furthermore, each time-dependent solution was centrifuged (10,000 rpm, 5 min), and the resulting supernatant was diluted 10-fold. The UV spectrum was measured using an ultraviolet-visible spectrophotometer (manufactured by JASCO, model: V-670) to confirm the change in absorbance at a wavelength of 280 nm over time. The absorbance at each light irradiation time is shown in Figure 30. The light irradiation time and absorbance values ​​in Figure 30 are shown in Table 1.

[0058]

[0059] These results suggest that the hollow particles obtained in Example 2 undergo photodecomposition over time at the [2+2] cycloaddition site upon light irradiation, and are decomposed into the raw materials, glycerin ester compounds having cinnamoyl groups, 1,5-pentanediol ester compounds having cinnamoyl groups, and their oligomers, as shown in formula (8).

[0060] Regarding hydrolysis, a predetermined amount of hollow particles obtained in Example 2 was dispersed in a mixing vessel containing 6 mL of 10 mM aqueous sodium hydroxide solution and 6 mL of dimethyl sulfoxide, and the dispersion was heated and stirred at 80°C. 2 mL samples were collected at reaction times of 0, 0.5, 1, and 3 hours, and the transmittance at a wavelength of 600 nm for each sample was measured using a UV-Visible spectrophotometer (manufactured by JASCO Corporation, Model: V-560). The appearance of each resulting solution is shown in Figure 31, and the transmittance at each reaction time is shown in Figure 32. The reaction times and transmittance values ​​in Figure 32 are shown in Table 2.

[0061]

[0062] These results suggest that the hollow particles obtained in Example 2 are reacted under alkaline conditions, and as a result, the ester moieties are hydrolyzed over time, and decomposed into a cinnamate ion dimer, glycerin, and 1,5-pentanediol, as shown in formula (9).

[0063] Furthermore, the photodegradability of the hollow particles obtained in Example 5 was confirmed in the same manner as in Example 2. The transmittance at a wavelength of 600 nm after 0 and 24 hours of light irradiation was measured using an ultraviolet-visible spectrophotometer (JASCO, Model: V-560). The resulting appearances of the solutions obtained are shown in FIG. 33 . The transmittance after 0 hours of light irradiation was 31%, and the transmittance after 24 hours of light irradiation was 98%. These results suggest that the hollow particles obtained in Example 5 undergo photodegradation over time at the [2+2] cycloaddition site upon light irradiation, and decompose into the raw materials, the glycerin ester compound having a modified cinnamoyl group, the 1,5-pentanediol ester compound having a modified cinnamoyl group, and their oligomers, as in formula (8).

[0064] As described above, it is suggested that the crosslinked structure of the hollow particles of the present invention, which has been photodimerized by ultraviolet light, is cleaved, or the hollow particles are decomposed into cinnamate ion dimers, glycerin, etc. by hydrolysis, and it is presumed that the hollow particles are decomposed into plant-derived components.

Claims

1. General formula (1) (In the formula, R 1 ~R 5 each independently represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a nitro group, an amino group, an alkylamino group, or a hydroxyl group, and X represents a hydroxyl group, fluorine, chlorine, bromine, or iodine.) with (poly)glycerin having an average degree of polymerization of 1 to 40, and the (poly)glycerin ester compound is characterized in that at least a portion of the cinnamoyl groups derived from the cinnamic acid or the modified cinnamoyl groups derived from the cinnamic acid derivative contained in the (poly)glycerin ester compound are photodimerized.

2. The hollow particles according to claim 1, characterized in that some of the (poly)glycerin ester compounds have a plurality of the cinnamoyl groups or the modified cinnamoyl groups in one molecule.

3. The hollow particles according to claim 1 or 2, characterized in that the (poly)glycerin ester compound is an ester compound obtained by reacting (poly)glycerin having an average degree of polymerization of 1 to 40 with cinnamic acid.

4. The hollow particle according to claim 1 or 2, characterized in that it contains a glycol ester which is a reaction product of at least one of the cinnamic acid or the cinnamic acid derivative with a glycol having 1 to 20 carbon atoms, and at least a portion of the cinnamoyl groups contained in the (poly)glycerin ester compound and derived from the cinnamic acid or the modified cinnamoyl groups contained in the glycol ester and derived from the cinnamic acid or the modified cinnamoyl groups contained in the glycol ester and derived from the cinnamic acid or the modified cinnamoyl groups contained in the glycol ester and derived from the cinnamic acid is photodimerized.

5. General formula (1) (In the formula, R 1 ~R 5 each independently represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a nitro group, an amino group, an alkylamino group, or a hydroxyl group, and X represents a hydroxyl group, fluorine, chlorine, bromine, or iodine. ), and (poly)glycerin having an average degree of polymerization of 1 to 40; and a solution containing an organic solvent; emulsifying a mixture containing the solution, water, and optionally an emulsifier to prepare an oil-in-water emulsion containing droplets of the (poly)glycerin ester compound; volatilizing the organic solvent from the emulsion to form particles containing the (poly)glycerin ester compound; irradiating the particles with ultraviolet light to photodimerize cinnamoyl groups derived from the cinnamic acid or modified cinnamoyl groups derived from the cinnamic acid derivative contained in the (poly)glycerin ester compound, thereby crosslinking the (poly)glycerin ester compound present near the surface of the particles; and removing uncrosslinked (poly)glycerin ester compounds from the interiors of the particles to form hollow particles in which at least a portion of the cinnamoyl groups or modified cinnamoyl groups are dimerized.

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