Biodegradable polymer, hollow particles containing biodegradable polymer, and method for producing the same

Abstract

To provide a hollow particle including a biodegradable polymer that can be produced using a simple and safe method.SOLUTION: A hollow particle according to one embodiment includes a biodegradable polymer with a polyester main chain including a ε-caprolactone-derived repeating structure and photodimerization groups in side chains, wherein at least some of the photodimerization groups are dimerized.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] The present disclosure relates to a biodegradable polymer, hollow particles containing the biodegradable polymer, and a method for producing the same.

Background Art

[0002] Polymer hollow particles have high light scattering properties and a high specific surface area, and since substances can be encapsulated in the voids inside the particles, they are useful for applications such as organic white pigments, heat insulating materials, microreactors, drug delivery systems (DDS), and the like.

[0003] From the viewpoints of the outflow and accumulation of microplastics into the natural environment and biological applications such as DDS, it is desirable that the polymer hollow particles have degradability, particularly biodegradability.

[0004] Non-Patent Document 1 (Macromol. Rapid Commun. 2006, 27, 1265-1270) describes that poly(ε-caprolactone) is synthesized on silica template particles to form a shell layer, and the silica template particles are removed using hydrogen fluoride, whereby hollow particles having a poly(ε-caprolactone) main chain can be obtained.

[0005] Non-Patent Document 2 (Pharmaceutics 2019, 11, 528) describes that ring-shaped poly(ε-caprolactone) is prepared using a poly(dimethylsiloxane) (PDMS) mold, and by performing solvent treatment, hollow particles having pores on the surface can be obtained.

[0006] On the other hand, it is known that hollow particles are formed by irradiating a dispersion containing particles of a polymer having a photocrosslinkable site with ultraviolet light to crosslink the polymer contained in the particles near the interface between the particles and the dispersion medium (interface photocrosslinking method), and removing the uncrosslinked polymer inside the particles.

[0007] Non-patent document 3 (Langmuir 2016, 32, 9245-9253) describes the formation of hollow particles from particles containing a copolymer of methyl methacrylate and cinnamoyloxymethacrylate.

[0008] Non-patent document 4 (ACS Appl. Mater. Interfaces 2021, 13, 34973-34983) describes the formation of pH-responsive capsule polymer particles having a poly(acrylate) main chain by interfacial photocrosslinking.

[0009] Non-patent document 5 (ACS Appl. Mater. Interfaces 2021, 13, 10359-10375) describes the formation of capsule polymer particles having a poly(acrylate) main chain and controllable pH-responsive release capability by interfacial photocrosslinking. [Prior art documents] [Non-patent literature]

[0010] [Non-Patent Document 1] Macromol. Rapid Commun. 2006, 27, 1265-1270 [Non-Patent Document 2] Pharmaceutics 2019, 11, 528 [Non-Patent Document 3] Langmuir 2016, 32, 9245-9253 [Non-Patent Document 4] ACS Appl. Mater. Interfaces 2021, 13, 34973-34983 [Non-Patent Document 5] ACS Appl. Mater. Interfaces 2021, 13, 10359-10375 [Overview of the project] [Problems that the invention aims to solve]

[0011] The method described in Non-Patent Document 1 is a sacrificial template method and requires hydrogen fluoride to remove the silica template particles. The hollow particles obtained by the method described in Non-Patent Document 2 have voids on their surface due to the manufacturing method, and therefore their applications are limited. Non-Patent Documents 3 to 5 use acrylic copolymers as materials for hollow particles or encapsulated polymer particles, but there is no mention of biodegradable polymers.

[0012] This disclosure aims to provide hollow particles containing a biodegradable polymer that can be manufactured using a simple and safe method. [Means for solving the problem]

[0013] The inventors have discovered that biodegradable hollow particles can be formed by irradiating particles of a photoreactive polymer, which has a repeating structure derived from biodegradable ε-caprolactone in its main chain and a photodimerizing group such as a cinnamoyl group in its side chain, with light to crosslink the photoreactive polymer near its surface, thereby eluting and removing the unreacted photoreactive polymer inside the particles.

[0014] The present invention encompasses the following aspects.

[0015] [Aspect 1] Hollow particles comprising a biodegradable polymer having a polyester main chain containing a repeating structure derived from ε-caprolactone and a side chain with a photodimerizing group, wherein at least a portion of the photodimerizing group is dimerized. [Aspect 2] The hollow particle according to embodiment 1, wherein the photodimerizing group is selected from the group consisting of a cinnamoyl group, a coumarinyl group, a thymine group, a uracil group, a quinone group, a maleimide group, and a chalcone group. [Aspect 3] The hollow particle according to embodiment 1 or 2, wherein the photodimerizing group is bonded to the polyester main chain via a triazole ring linking group. [Aspect 4] The hollow particles according to any one of Aspects 1 to 3, wherein the ratio of the structural unit having the photo-dimerizable group is 20 mol% to 80 mol% based on all the structural units of the biodegradable polymer. [Aspect 5] Prepare a solution containing a biodegradable polymer having a polyester main chain containing a repeating structure derived from ε-caprolactone and a photo-dimerizable group in the side chain, and an organic solvent. Emulsify a mixture containing the solution, water, and optionally an emulsifier to prepare an oil-in-water emulsion containing droplets of the biodegradable polymer. Volatilize the organic solvent from the emulsion to form particles containing the biodegradable polymer. React the photo-dimerizable group by irradiating the particles with ultraviolet light to crosslink the biodegradable polymer present near the surface of the particles, and Remove the uncrosslinked biodegradable polymer from the inside of the particles to form hollow particles in which at least a part of the photo-dimerizable group is dimerized. A method for producing hollow particles containing a biodegradable polymer, comprising: [Aspect 6] A biodegradable polymer having a polyester main chain containing a repeating structure derived from ε-caprolactone and a photo-dimerizable group in the side chain, wherein the photo-dimerizable group is bonded to the polyester main chain via a triazole ring linking group. [Advantages of the Invention]

[0016] According to the present invention, hollow particles containing a biodegradable polymer can be provided using a simple and safe method.

[0017] The above description should not be regarded as disclosing all embodiments of the present invention and all advantages related to the present invention. [Brief Description of the Drawings]

[0018] [Figure 1] It is a schematic diagram showing a production scheme of hollow particles. [Figure 2]These are the 1H NMR (CDCl3) spectra of α-chloro-ε-caprolactone and 2-chlorocyclohexanone. [Figure 3] These are the 1H NMR (CDCl3) spectra of cinnamoyl-alkyne, cinnamoyl chloride, and 3-buty-1-ol. [Figure 4] These are the 1H NMR (CDCl3) spectra of P(ClεCl-co-εCl), ε-caprolactone, and α-chloro-ε-caprolactone. [Figure 5] These are the 1H NMR (CDCl3) spectra of P(N3εCL-co-εCL) and P(ClεCL-co-εCL). [Figure 6] These are the 1H NMR (CDCl3) spectra of P(cinnamoyl εCl-co-εCl) and P(N3εCl-co-εCl). [Figure 7] These are the UV-vis spectra of P(ClεCL-co-εCL), P(N3εCL-co-εCL), and P(cinnamoylεCL-co-εCL). [Figure 8] These are the UV-vis spectra of P (cinnamoyl εCL-co-εCL) for irradiation times of 0 minutes (no irradiation), 1 minute, 3 minutes, 5 minutes, 10 minutes, 30 minutes, 60 minutes, and 100 minutes. [Figure 9] These are optical microscope images of particles before UV irradiation (a), particles after UV irradiation (b), and hollow particles (c). [Figure 10] This is a scanning electron microscope image of a hollow particle with a partially destroyed shell. [Figure 11] This graph shows the hydrolysis properties of particles before and after UV irradiation, with hydrolysis time (seconds) on the horizontal axis and transmittance (%T) at a wavelength of 500 nm on the vertical axis. [Figure 12] These are optical microscope images of the hollow particles (a) from Example 2 and (b) from Example 3. [Figure 13] These are the UV-vis spectra of the supernatant obtained by washing the particles from Example 1 before UV irradiation and the particles from Examples 1 to 3 after UV irradiation with THF. [Figure 14] This graph shows the measurement results of the shell thickness of hollow particles in Examples 1 to 3. [Modes for carrying out the invention]

[0019] The following describes representative embodiments of the present invention in more detail, but the present invention is not limited to these embodiments.

[0020] [Hollow particles] One embodiment of the hollow particles comprises a biodegradable polymer having a polyester main chain containing a repeating structure derived from ε-caprolactone and photodimerizing groups in the side chains, wherein at least a portion of the photodimerizing groups are dimerized. Dimerization of the photodimerizing groups introduces a crosslinked structure into the shell of the hollow particle, maintaining the shape of the hollow particle.

[0021] <Biodegradable polymers> The biodegradable polymer is not particularly limited as long as it has a polyester main chain containing a repeating structure derived from ε-caprolactone and has photodimerizing groups in its side chains.

[0022] The biodegradable polymer may be a monopolymer or a copolymer. The polyester main chain may consist only of repeating structures derived from ε-caprolactone, or it may consist of repeating structures derived from ε-caprolactone and one or more other repeating structures.

[0023] Examples of polyester backbone include poly(ε-caprolactone). Other examples of polyester backbone include copolymers of ε-caprolactone with at least one selected from the group consisting of lactic acid, glycolic acid, β-propiolactone, γ-butyrolactone, and δ-valerolactone. Examples of such copolymers include poly(ε-caprolactone-co-lactic acid) and poly(ε-caprolactone-co-glycolic acid).

[0024] The photodimerizing group is preferably selected from the group consisting of cinnamoyl group, coumarinyl group, thymine group, uracil group, quinone group, maleimide group, and chalcone group. In one embodiment, the photodimerizing group is a cinnamoyl group. The photodimerizing group may be directly bonded to the polyester main chain or bonded to the polyester main chain via a linking group.

[0025] In one embodiment of the biodegradable polymer, the photodimerizing group is bonded to the polyester main chain via a triazole ring linking group. Although not bound by any particular theory, since ε-caprolactone constitutes an aliphatic chain in biodegradable polymers, biodegradable polymers having a polyester main chain containing repeating structures derived from ε-caprolactone are relatively flexible. It is thought that by introducing a triazole ring structure into the biodegradable polymer, rigidity can be imparted to the biodegradable polymer, and as a result, the shape retention of hollow particles can be improved.

[0026] The biodegradable polymer may be a copolymer containing structural units having photodimerizing groups and structural units not having photodimerizing groups. The proportion of structural units having photodimerizing groups in the biodegradable polymer can be appropriately determined according to the required strength and shell thickness of the hollow particles, taking into account the molecular weight of the biodegradable polymer. For example, when expressed as a molar ratio based on the total structural units of the biodegradable polymer, the proportion of structural units having photodimerizing groups can be 20 mol% to 80 mol%, and preferably 25 mol% to 75 mol%. By setting the proportion of structural units having photodimerizing groups within the above range, hollow particles with the desired strength and shell thickness can be formed.

[0027] The number-average molecular weight of the biodegradable polymer is preferably 500 to 500,000, more preferably 1,000 to 200,000, and even more preferably 2,000 to 100,000. The weight-average molecular weight of the biodegradable polymer is preferably 500 to 1,000,000, more preferably 1,000 to 500,000, and even more preferably 2,000 to 100,000. In this disclosure, "number-average molecular weight" and "weight-average molecular weight" refer to the molecular weight calculated using standard polyethylene glycol (PEG) by gel permeation chromatography (GPC).

[0028] <Method for producing biodegradable polymers> Biodegradable polymers can be obtained by ring-opening polymerization of an ε-caprolactone derivative having a functional group and, optionally, other ring-opening polymerizable monomers, and by converting at least a portion of the functional groups of the resulting (co)polymer into a photodimerizing group or a group containing a photodimerizing group.

[0029] Examples of ε-caprolactone derivatives include α-chloro-ε-caprolactone, which has a chloro group as a functional group. α-chloro-ε-caprolactone can be synthesized by Baeyer-Villiger oxidation of 2-chlorocyclohexanone. For example, m-chloroperbenzoic acid can be used as the oxidizing agent for Baeyer-Villiger oxidation. ε-caprolactone derivatives may be used alone or in combination of two or more.

[0030] Other ring-opening polymerizable monomers include, for example, ε-caprolactone, dilactide, glycolide, β-propiolactone, γ-butyrolactone, and δ-valerolactone. These other ring-opening polymerizable monomers may be used individually or in combination of two or more.

[0031] In embodiments using other ring-opening polymerizable monomers, the molar ratio of the ε-caprolactone derivative can be 10 mol% to 99 mol%, preferably 20 mol% to 90 mol%, and more preferably 30 to 80 mol%, based on the total amount of the ε-caprolactone derivative and the other ring-opening polymerizable monomers.

[0032] The conditions for ring-opening polymerization are not particularly limited. Ring-opening polymerization can be carried out in a solvent such as benzyl alcohol or toluene using organometallic initiators such as tin compounds, zinc compounds, aluminum compounds, or molybdenum compounds. The organometallic initiator and the solvent may be used individually or in combination of two or more. The polymerization temperature can be, for example, 20°C to 200°C. The polymerization time can be appropriately determined according to the desired molecular weight, and can be, for example, 10 minutes to 120 hours.

[0033] The conversion to a photodimerizing group is not particularly limited, but for example, it can be carried out by converting the chloro group of the (co)polymer to an azide group, and then adding a compound having an alkynyl group and a photodimerizing group to the azide group of the (co)polymer by a hysgen cycloaddition reaction. This makes it possible to obtain a biodegradable polymer having a polyester main chain containing a repeating structure derived from ε-caprolactone and a photodimerizing group in the side chain.

[0034] The conversion of chloro groups to azide groups can be carried out using an azidating agent such as sodium azide (NaN3). The conditions for azidation are not particularly limited. Azidation can be carried out, for example, in a solvent such as N,N-dimethylformamide (DMF), under an argon gas atmosphere, at a reaction temperature of 10°C to 50°C, and for a reaction time of 10 minutes to 240 hours.

[0035] Compounds having an alkynyl group and a photodimerizing group are not particularly limited, but examples include 3-buty-1-yl cinnamate, 3-buty-1-yl coumarin-3-acetate, and 3-buty-1-yl coumarin-4-acetate. For example, 3-buty-1-yl cinnamate can be obtained by reacting cinnamoyl chloride with 3-buty-1-ol.

[0036] A catalyst may be used in the Huisgen cycloaddition reaction. Examples of catalysts include copper catalysts, ruthenium catalysts, and silver catalysts. Copper(II) sulfate (CuSO4) may be used, and a reducing agent such as sodium ascorbate may be added to generate a copper(I) catalyst in the reaction system.

[0037] The conditions for the hysgene cycloaddition reaction are not particularly limited. For example, the hysgene cycloaddition reaction can be carried out in a solvent such as N,N-dimethylformamide (DMF), under an argon gas atmosphere, at a reaction temperature of 20°C to 100°C, and for a reaction time of 10 minutes to 48 hours. The hysgene cycloaddition reaction may also be carried out in the presence of an amine compound such as N,N,N',N”,N”-pentamethyldiethylenetriamine.

[0038] [Method for producing hollow particles] Hollow particles containing biodegradable polymers can be formed by creating particles containing biodegradable polymers; irradiating these particles with ultraviolet light to react with photodimerizing groups, thereby crosslinking the biodegradable polymers near the surface of the particles; and removing uncrosslinked biodegradable polymers from within the particles. Figure 1 schematically shows the manufacturing scheme for hollow particles.

[0039] Particles containing biodegradable polymers can be formed, for example, by (1) preparing a solution containing a biodegradable polymer and an organic solvent, (2) emulsifying the resulting solution, water, and optionally an emulsifier to prepare an oil-in-water emulsion containing droplets of the biodegradable polymer, and (3) volatilizing the organic solvent from the emulsion.

[0040] The organic solvent is not particularly limited as long as it is a good solvent for the biodegradable polymer, and examples include halogenated solvents such as methyl chloride, methylene chloride, and chloroform; aromatic solvents such as toluene and xylene; ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone; and esters such as ethyl acetate and butyl acetate. The organic solvent may be used alone or in combination of two or more. The concentration of the biodegradable polymer in the solution can be, for example, 5% to 50% by mass.

[0041] Next, water is added to the solution to emulsify the resulting mixture. An emulsifier may also be used to emulsify the mixture. Examples of emulsifiers include polymeric 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. If the biodegradable polymer is self-emulsifying, an emulsifier may not be necessary. The emulsification conditions are not particularly limited. Emulsification can be carried out, for example, at room temperature using a homogenizer.

[0042] The average diameter of the biodegradable polymer droplets in the emulsion can be appropriately determined according to the desired size of the hollow particles, for example, from 0.1 μm to 2 mm. In this disclosure, the average diameter of the biodegradable polymer droplets is determined by dynamic light scattering (DLS).

[0043] It is preferable to volatilize the organic solvent from the emulsion gradually at low temperatures. For example, the volatilization of the organic solvent can be carried out at 0°C to 10°C.

[0044] The resulting particles are irradiated with ultraviolet light using ultraviolet light in the wavelength range in which the photodimerizing group reacts. For example, if the photodimerizing group is a cinnamoyl group that absorbs around 270 nm, ultraviolet irradiation can be performed using a deep ultraviolet LED with a wavelength of 265 nm. The irradiation intensity and duration of the ultraviolet light can be appropriately determined according to the reactivity of the photodimerizing group, the desired size of the hollow particles, and the shell thickness.

[0045] Uncrosslinked biodegradable polymers can be removed by eluting them into an organic solvent. This allows for the formation of hollow particles. Examples of organic solvents that can be used for elution include halogenated solvents such as methyl chloride, methylene chloride, and chloroform; aromatic solvents such as toluene and xylene; ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone; esters such as ethyl acetate and butyl acetate; ethers such as diethyl ether and tetrahydrofuran; sulfoxides such as dimethyl sulfoxide; and amides such as dimethylformamide and dimethylacetamide. Organic solvents may be used individually or in combination of two or more.

[0046] Photodimerizing groups will not form crosslinks by dimerization unless they are in close proximity to each other. In the biodegradable polymer of this disclosure, since the photodimerizing groups are pendanted to the polyester main chain as side chains, the movement of the photodimerizing groups is restricted compared to crosslinking using a separate low-molecular-weight crosslinking agent. Near the surface of the particle where ultraviolet light first enters, the ultraviolet intensity is high, so the reaction of the photodimerizing groups proceeds effectively and crosslinks are formed. On the other hand, photodimerizing groups that remain unreacted near the surface of the particle because there are no other nearby photodimerizing groups only absorb ultraviolet light and do not contribute to crosslinking. Due to this crosslinking and ultraviolet absorption near the particle surface, the ultraviolet intensity decreases rapidly inside the particle, so crosslinking by photodimerizing groups inside the particle is difficult to proceed. Therefore, uncrosslinked biodegradable polymer can be easily removed from inside the particle after ultraviolet irradiation, and as a result, hollow particles can be directly produced from particles with the simplest structure without using template particles.

[0047] <Physical properties of hollow particles> The average particle size of the hollow particles can be appropriately determined depending on the application and is not particularly limited. For example, the average particle size of the hollow particles can be 0.1 μm to 1 mm. In this disclosure, the average particle size of the hollow particles is the volume cumulative particle size D determined using laser diffraction / scattering particle size distribution measurement. 50 That is the case.

[0048] The porosity of hollow particles can be appropriately determined depending on the application and is not particularly limited. The porosity (percentage of internal space volume) of hollow particles can be, for example, 20% to 85%.

[0049] The shell thickness of the hollow particles can be determined appropriately depending on the application and is not particularly limited. For example, the shell thickness of the hollow particles can be 50 nm to 100 μm.

[0050] <Applications of hollow particles> The hollow particles containing the biodegradable polymers of this disclosure can be suitably used in applications such as organic white pigments, thermal insulation materials, microreactors, and drug delivery systems (DDS). [Examples]

[0051] The present invention will be described more specifically below based on examples, but the present invention is not limited to these examples.

[0052] In this example, the following reagents, as shown in Table 1, were used.

[0053] [Table 1]

[0054] ε-Caprolactone and benzyl alcohol were used after distillation in a glass tube oven, model GTO-2000 (Shibata Scientific Co., Ltd.). In the formation of hollow particles, poly(vinyl alcohol) (PVA) 3500 was used in the form of a 0.0067% by mass aqueous PVA solution.

[0055] Example 1 1. Synthesis of α-chloro-ε-caprolactone (ClεCl) [ka]

[0056] 19.9 g, 0.150 mol of 2-chlorocyclohexanone, 9.97 g, 0.0578 mol of m-chloroperbenzoic acid, and 100 mL of dichloromethane (DCM) were added to a round-bottom flask and stirred at room temperature for 4 days. The mixture was then cooled to -20°C for 3 hours and filtered by suction. After removing the white solid impurities by filtration, the resulting liquid was separated three times with saturated Na2SO3 aqueous solution, three times with saturated NaHCO3 aqueous solution, once with saturated NaHSO3 aqueous solution, and once with saturated NaCl aqueous solution. After separation, magnesium sulfate was added to the organic layer to remove water. The DCM was then evaporated to obtain an oily liquid. The resulting liquid was subjected to silica gel chromatography (ethyl acetate:hexane = 1:9, vol / vol), vacuum dried, and the liquid containing the product α-chloro-ε-caprolactone (ClεCl) was separated (yield 4.90 g, yield 43%).

[0057] Figure 2 shows the relationship between α-chloro-ε-caprolactone and 2-chlorocyclohexanone. 1 The 1H NMR (CDCl3) spectrum is shown.

[0058] 2. Synthesis of photoreactive molecules with alkyne termini (cinnamoyl-alkynes) [ka]

[0059] 3-Butyn-1-ol (1.51 mL, 0.02 mol), triethylamine (TEA) (3.35 mL, 0.024 mol), and chloroform (20 mL) were placed in a round-bottom flask and stirred while cooled in an ice bath. A solution obtained by dissolving cinnamoyl chloride (4.0 g, 0.024 mol) in chloroform (10 mL) was gradually added dropwise to the stirring solution. After the addition was complete, the ice bath was removed and the mixture was stirred at room temperature for 3 days. After stirring, the mixture was separated twice with saturated NaCl aqueous solution, three times with saturated Na2CO3 aqueous solution, and once with saturated NaCl aqueous solution. After separation, magnesium sulfate was added to the organic layer to remove water, and the liquid phase was vacuum dried. The liquid obtained by vacuum drying was subjected to silica gel chromatography (ethyl acetate:hexane = 3:7, vol / vol), and the liquid containing the product 3-butyn-1-yl cinnamate (cinnamoyl-alkyne) was separated (yield 6.45 g, yield 67%).

[0060] Figure 3 shows cinnamoyl-alkynes, cinnamoyl chloride, and 3-buty-1-ol. 1 The 1H NMR (CDCl3) spectrum is shown.

[0061] 3. Synthesis of a biodegradable polymer (P(cinnamoylεCL-co-εCL)) having a cinnamoyl group in its side chain.

[0062] (1) Synthesis of a copolymer of α-chloro-ε-caprolactone (ClεCl) and ε-caprolactone (εCl) (P(ClεCl-co-εCl)) [ka]

[0063] ε-caprolactone (0.285 g, 2.5 mmol), α-chloro-ε-caprolactone (1.15 g, 7.5 mmol), benzyl alcohol (0.0108 g, 0.10 mmol), tin(II) 2-ethylhexanoate (0.0114 g, 0.028 mmol), and toluene (super-dehydrated, 2 mL) were placed in a Schlenk tube while being purged with argon. The Schlenk tube was then evacuated and immersed in an oil bath at 110°C for 24 hours. The reaction mixture was then removed from the Schlenk tube, and the copolymer was collected by reprecipitation using hexane and filtration, and then vacuum-dried. This yielded a copolymer of α-chloro-ε-caprolactone (ClεCl) and ε-caprolactone (εCl) (P(ClεCl-co-εCl)) (yield 1.70 g, yield 85%).

[0064] Figure 4 shows P(ClεCL-co-εCL), ε-caprolactone, and α-chloro-ε-caprolactone. 1 The 1H NMR (CDCl3) spectrum is shown. From Figure 4, it can be seen that the proton (a) on the carbon atom to which the chloro group of α-chloro-ε-caprolactone is attached, which is around 4.8 ppm, is shifted to around 2.0 ppm (a) due to ring-opening copolymerization. The peak (a) around 2.0 ppm is derived from α-chloro-ε-caprolactone, and the peak (a') around 2.4 ppm is derived from ε-caprolactone. Calculating from the integral ratio of these peaks, the proportion of structural units derived from α-chloro-ε-caprolactone in the copolymer was approximately 71 mol% relative to the total structural units.

[0065] (2) Conversion of chloro groups in copolymer side chains to azide groups [ka]

[0066] P(ClεCl-co-εCl) (0.8 g, 5.8 mmol), sodium azide (0.384 g, 5.9 mmol), and N,N-dimethylformamide (DMF) (2.5 mL) were placed in a round-bottom flask under argon purging and stirred for 6 days. After stirring, the reaction mixture was vacuum-dried for 3 hours while heating in a 50°C water bath. Toluene was added to the solution containing the copolymer obtained after vacuum drying to precipitate the salt, and the solution was centrifuged. The supernatant was collected and vacuum-dried. This yielded a copolymer (P(N3εCl-co-εCl)) in which the chloro groups of the side chains were converted to azide groups (yield 0.80 g, yield 60%).

[0067] Figure 5 shows P(N3εCL-co-εCL) and P(ClεCL-co-εCL). 1 The 1H NMR (CDCl3) spectrum is shown. From Figure 5, it can be seen that the proton (a') on the carbon atom to which the chloro group of P(ClεCl-co-εCl) is attached, which is around 2.0 ppm, is converted to an azide group and shifts to around 3.8 ppm (a). The peak (a) around 3.8 ppm is derived from the proton on the carbon atom to which the azide group of P(N3εCl-co-εCl) is attached, and the peak (b) around 2.4 ppm is derived from ε-caprolactone. Calculating from the integral ratio of these peaks, the proportion of structural units containing azide groups in the copolymer was 44 mol% relative to the total structural units.

[0068] (3) Introduction of photodimerizing groups into copolymer side chains [ka]

[0069] P(N3εCl-co-εCl) (481 mg, 3.64 mmol), cinnamoyl alkyne (272 mg, 1.38 mmol), copper(II) sulfate (23.6 mg, 0.143 mmol), N,N,N',N”,N”-pentamethyldiethylenetriamine (41.5 mg, 0.24 mmol), and DMF (4.8 mL) were placed in a Schlenk tube. Then, while purging with nitrogen, sodium L-ascorbate (49.3 mg, 0.247 mmol) was added to the Schlenk tube, and the Schlenk tube was heated in an oil bath at 40°C for 4 hours. After heating, the resulting solution was vacuum-dried, and the copolymer was dissolved in toluene. The copolymer was collected by reprecipitation using cold hexane and filtration, and then vacuum-dried. This yielded a biodegradable polymer (P(cinnamoylεCL-co-εCL)) having a poly(ε-caprolactone) main chain and cinnamoyl groups as photodimerizing groups in the side chains (yield 0.68g, yield 82%).

[0070] Figure 6 shows P(cinnamoyl εCL-co-εCL) and P(N3εCL-co-εCL). 1 The 1H NMR (CDCl3) spectrum is shown. From Figure 6, it can be seen that the proton (a') on the carbon atom to which the azide group of P(N3εCl-co-εCl) is attached, around 3.8 ppm, is shifted to around 5.4 ppm (a) due to conversion to a triazole group. The peak (a) around 5.4 ppm originates from the proton on the carbon atom to which the triazole group of P(cinnamoylεCl-co-εCl) is attached, and the peak (a') around 3.8 ppm originates from the proton on the carbon atom to which the unreacted azide group is attached. Calculating from the integral ratio of these two peaks, the conversion efficiency of the azide group to the triazole group was 75%. The proportion of structural units containing the azide group in the copolymer was 44 mol% relative to all structural units. Therefore, the proportion of structural units containing the cinnamoyl group in the copolymer was calculated to be 33 mol% (= 44 mol% × 0.75) relative to all structural units.

[0071] 4. Physical property evaluation GPC measurements (standard polymer: PEG, solvent: THF) and UV-vis measurements were performed on P(ClεCL-co-εCL), P(N3εCL-co-εCL), and P(cinnamoylεCL-co-εCL). The number-average molecular weight (Mn), weight-average molecular weight (Mw), and dispersion (Mw / Mn) of these copolymers are shown in Table 2, and the UV-vis spectra are shown in Figure 7.

[0072] [Table 2]

[0073] The absence of significant molecular weight changes during the synthesis of P(cinnamoylεCL-co-εCL) suggests that the side-chain transformation operation did not decompose the copolymer main chain. P(cinnamoylεCL-co-εCL) showed absorption around 270 nm, originating from the cinnamoyl group, which was not present in P(ClεCL-co-εCL) and P(N3εCL-co-εCL).

[0074] 5. Photodimerization reactivity The photodimerization reactivity of the cinnamoyl group in P(cinnamoyl εCL-co-εCL) was confirmed by UV-vis measurement. A solution of P(cinnamoyl εCL-co-εCL) dissolved in chloroform was applied to a glass substrate, and a film approximately 1 μm thick was formed on the glass substrate by drying to remove the solvent. The film was irradiated with ultraviolet light at a wavelength of 265 nm, and the change in absorbance with respect to irradiation time was measured. Figure 8 shows the UV-vis spectra of P(cinnamoyl εCL-co-εCL) when the irradiation time was 0 minutes (no irradiation), 1 minute, 3 minutes, 5 minutes, 10 minutes, 30 minutes, 60 minutes, and 100 minutes. As the irradiation time increased, the UV absorption originating from the cinnamoyl group around 270 nm decreased, confirming that the photodimerization reaction of the cinnamoyl group, indicated by the right arrow in the following reaction equation, proceeded. [ka]

[0075] 6. Preparation of hollow particles P(cinnamoyl εCl-co-εCl) (30 mg) was dissolved in chloroform (600 μL), and 0.0067 mass% PVA aqueous solution (15 mL) was added. The mixture was emulsified for 2 minutes using a homogenizer (10,000 rpm). The resulting emulsion was stirred while cooling at 4°C to volatilize the chloroform and obtain a dispersion containing P(cinnamoyl εCl-co-εCl) particles. The resulting dispersion was then exposed to ultraviolet light (265 nm, 4 mW / cm²). 2 The particles were irradiated with UV light at 4°C for 2 hours. This caused a photodimerization reaction of the cinnamoyl groups, crosslinking the P(cinnamoyl εCl-co-εCl) near the surface of the particles. After UV irradiation, the particles were washed with THF and DMSO to elute and remove the uncrosslinked P(cinnamoyl εCl-co-εCl) from the inside, and the liquid phase was replaced with a 0.0067 mass% PVA aqueous solution. This yielded hollow particles dispersed in the PVA aqueous solution.

[0076] Figure 9 shows optical microscope images of particles before UV irradiation (a), particles after UV irradiation (b), and hollow particles (c). Figure 10 shows a scanning electron microscope image of a hollow particle with a partially destroyed shell.

[0077] The hydrolysis properties of particles before and after UV irradiation were evaluated. For particles before UV irradiation, 0.2 mL of 1 M NaOH aqueous solution was added to the dispersion (1.8 mL) before UV irradiation, and the transmittance was measured while heating and stirring at 70°C. For particles after UV irradiation, UV light (265 nm, 4 mW / cm²) was applied to the dispersion (1.8 mL) before UV irradiation. 2 After irradiating with ) at 4°C for 2 hours, 0.2 mL of 1 M NaOH aqueous solution was added to the resulting dispersion, and the transmittance was measured while heating and stirring at 70°C. Figure 11 shows a graph with hydrolysis time (seconds) on the horizontal axis and transmittance (%T) at a wavelength of 500 nm on the vertical axis.

[0078] In both the particles before and after UV irradiation, the transmittance increased with increasing hydrolysis time. The increase in the transmittance of the dispersion is thought to be due to the hydrolysis of the polyester main chain of P (cinnamoyl εCl-co-εCl) contained in the particles, resulting in the decomposition of the particles and their dissolution in the PVA aqueous solution. Therefore, this evaluation of hydrolysis suggests that crosslinking near the particle surface due to UV irradiation does not adversely affect the hydrolysis properties of the biodegradable polymer, and that hydrolysis properties are maintained even in hollow particles.

[0079] Examples 2 and 3 Hollow particles were prepared using the same procedure as in Example 1, except that the UV irradiation time was changed to 4 hours (Example 2) or 6 hours (Example 3). Figure 12 shows optical microscope images of the hollow particles from Example 2 (a) and Example 3 (b).

[0080] Figure 13 shows the UV-vis spectra of the particles before UV irradiation in Example 1, and the supernatant obtained by washing the particles after UV irradiation in Examples 1 to 3 with THF. From Figure 13, it was confirmed that as the irradiation time increased, the UV absorption originating from the cinnamoyl group around 270 nm decreased, indicating that the photodimerization reaction of the cinnamoyl group proceeded and the amount of uncrosslinked P (cinnamoyl εCl-co-εCl) eluted into THF decreased. This suggests that the shell thickness of the hollow particles can be controlled by changing the amount of UV irradiation.

[0081] The shell thickness of the hollow particles in Examples 1 to 3 was determined by analyzing images taken with an optical microscope using the image processing software ImageJ. The measurement results are shown graphically in Figure 14. It was observed that the shell thickness of the hollow particles increased as the irradiation time increased. [Industrial applicability]

[0082] The hollow particles containing the biodegradable polymers of this disclosure can be suitably used in applications such as organic white pigments, thermal insulation materials, microreactors, and drug delivery systems (DDS).

Claims

1. Hollow particles comprising a biodegradable polymer having a polyester main chain containing a repeating structure derived from ε-caprolactone and a side chain with a photodimerizing group, wherein at least a portion of the photodimerizing group is dimerized.

2. The hollow particle according to claim 1, wherein the photodimerizing group is selected from the group consisting of a cinnamoyl group, a coumarinyl group, a thymine group, a uracil group, a quinone group, a maleimide group, and a chalcone group.

3. The hollow particle according to claim 1 or 2, wherein the photodimerizing group is bonded to the polyester main chain via a triazole ring linking group.

4. The hollow particle according to claim 1 or 2, wherein the proportion of structural units having the photodimerizing group is 20 mol% to 80 mol%, based on the total structural units of the biodegradable polymer.

5. Prepare a solution containing a polyester main chain having a repeating structure derived from ε-caprolactone, a biodegradable polymer having a photodimerizing group in its side chain, and an organic solvent. Emulsifying the aforementioned solution, water, and optionally an emulsifier to prepare an oil-in-water emulsion containing droplets of the biodegradable polymer. The organic solvent is volatilized from the emulsion to form particles containing the biodegradable polymer. By irradiating the particles with ultraviolet light, the photodimerizing groups are reacted to crosslink the biodegradable polymer present near the surface of the particles, and The uncrosslinked biodegradable polymer is removed from the inside of the particles to form hollow particles in which at least a portion of the photodimerizing groups are dimerized. A method for producing hollow particles containing a biodegradable polymer.

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