JP2008037858A - Controlled release agent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a controlled release agent having excellent controlled release ability while having biodegradability. <P>SOLUTION: The controlled release agent is obtained by impregnating a base material comprising a polylactic acid copolymer obtained by polymerizing a prescribed proportion of L-lactide with a component of the subject of the controlled release. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a sustained release agent that gradually releases a sustained release target component, and particularly to a sustained release agent that uses a biodegradable polymer as a holding material for the sustained release target component.

  Conventionally, for example, pest / animal control in farms and parks has required a great deal of labor, such as spraying of agricultural chemicals and repellents. As one means for solving these problems, there can be mentioned, for example, a sustained release agent capable of gradually releasing a repellent component and maintaining its effect over a long period of time.

  Patent Document 1 describes a technique in which a sex pheromone agent is impregnated into a resin molded body or a molten resin using a supercritical fluid, and further describes that a biodegradable resin is used for a substrate from the environmental aspect. ing.

JP 2002-356403 A

  However, when a biodegradable polymer is used as the base material to be impregnated with the sustained release target component, effective sustained release ability may not be obtained due to degradation of the biodegradable polymer. Moreover, the sustained release target component cannot be impregnated in a large amount, and effective sustained release ability may not be obtained.

  The present invention has been proposed in view of such conventional circumstances, and an object of the present invention is to provide a sustained-release agent having excellent degradability while having biodegradability.

  As a result of intensive studies, the present inventors have made a significant leap in the amount of impregnation of the sustained release target component by using a copolymer of L-lactide and ε-caprolactone as the biodegradable polymer impregnated with the sustained release target component. The present invention has been found out that it can be increased.

  Further, the inventors have found that the amount of impregnation of the sustained release target component can be dramatically increased by using a polylactic acid copolymer obtained by polymerizing L-lactide at a predetermined ratio, and the present invention has been achieved.

  That is, the sustained release agent according to the present invention is obtained by impregnating a base material composed of a copolymer having a molar ratio of L-lactide and ε-caprolactone of 65:35 to 98: 2 with a component to be sustainedly released. It is characterized by.

  The sustained-release agent according to the present invention is a sustained-release agent obtained by impregnating a base material composed of a polylactic acid copolymer with a component to be sustained-released, and the polylactic acid copolymer contains L-lactide. It is characterized by being polymerized in a proportion of 65 to 98 mol%.

  According to the present invention, by using a copolymer of L-lactide and ε-caprolactone for the base material impregnated with the sustained release target component, the amount of the sustained release target component impregnated can be improved. A high concentration sustained release target component can be released within a period.

  Embodiments of the present invention will be described below. The sustained-release agent shown as a specific example of the present invention is a copolymer of L-lactide (hereinafter abbreviated as LLA) and ε-caprolactone (hereinafter abbreviated as CL) (hereinafter abbreviated as PLLACL). The base material thus formed is impregnated with the sustained release target component. Further, a sustained release target component is impregnated into a base material made of a polylactic acid copolymer obtained by polymerizing L-lactide at a predetermined ratio.

  A copolymer of LLA and CL can be obtained by ring-opening polymerization of LLA and CL. Specifically, a predetermined amount of LLA and CL are charged into a Schlenk tube as monomers, a catalyst is added, deaeration and argon gas replacement are performed, and then ring-opening polymerization is performed in an oil bath at a predetermined temperature for synthesis.

  Here, as for PLLACL, it is preferable that the molar ratio of LLA and CL is 65: 35-98: 2. Thereby, the injection amount of the sustained release target component can be increased. That is, it becomes possible to release a high concentration sustained release target component within the sustained release period.

  The polylactic acid copolymer is preferably one in which L-lactide is polymerized in a proportion of 65 to 98 mol%. Examples of the polylactic acid copolymer include a polyester copolymer, a polyester carbonate copolymer, a polyester amide copolymer, and a polyester ether copolymer. Polylactic acid copolymers include L-lactide, glycolide, D, L-lactide, β-propiolactone, γ-butyrolactone, δ-valerolactone, β-methyl-δ-valerolacto, ε-caprolactone, DL -Mavalonolactone, ethylene carbonate, trimethylene carbonate, 1-methyltrimethylene carbonate, 2,2-dimethyltrimethylene carbonate, tetramethylene carbonate, 1,5-dioxepan-2-one, morpholine-2,5-dione, 3 , 6-Dimethylmorpholine-2,5-dione, (R) -or (S) -3-methyl-4-oxa-6-hexanolide (MOHEL), ethylene oxide, 5-methyl-5-benzyloxycarbonyl-1 , 3-dioxane-2-one or one or more selected from Configuration are preferably.

  The shape of the substrate is preferably molded according to the purpose, but in order to increase the injection amount, it is preferably a film.

  As the sustained release target component, a repellent component, an insecticidal component, a scent component, and the like can be used. Specifically, d-limonene, menthone, menthol, plegon, carvone, nerolidol, terpineol, cedrol, pyrethrin, allethrin, hydramethylnon, permethrin, phthalthrin, nicotine sulfate, coumarin, eucalyptus extract, lavender extract, herbal extract, An example is wood vinegar. Examples of antibacterial components include hinokitiol, wasaol, trans-2-hexenal, trans-3-hexenal, cis-3-hexenal, catechin, bamboool, castor oil, 10-undecenoic acid, allyl mustard oil, allyl isothiocyanate, capsaicin, etc. be able to.

  As a method for injecting the sustained release target component into PLLACL, a general kneading method or a solvent dissolution method can be used, but a supercritical injection method using a supercritical fluid is preferably used. Thereby, a low boiling point compound can be inject | poured. In addition, unlike the solvent dissolution method, volatilization of the residual organic solvent and the sustained release target component at the time of solvent removal does not become a problem.

  Specifically, in the supercritical injection method using a supercritical fluid, the base material and the sustained release target component are enclosed in a high pressure cell, set to a predetermined temperature and pressure, and, for example, carbon dioxide is supplied to the high pressure cell. After that, the state of supercritical carbon dioxide is set, and this state is left for a predetermined time to carry the sustained release target component. Then, after supporting the sustained release target component, the supercritical carbon dioxide is returned to the gaseous state by releasing the back pressure valve and reducing the pressure, and the base material on which the sustained release target component is supported is obtained. . The supercritical fluid is carbon dioxide (critical temperature: 304.1 K, critical pressure: 7.38 MPa), ethane (critical) depending on the boiling point of the sustained release target component, the melting point of the copolymer of LLA and CL, and the like. Temperature (305.45 K, critical pressure: 18.7 MPa), nitrogen (critical temperature: 126 K, critical pressure: 3.4 MPa), or the like can be used.

  Hereinafter, the present invention will be further described with reference to examples. The present invention is not limited to these examples.

Injection substrate L-lactide (hereinafter abbreviated as LLA) and ε-prolactone (hereinafter abbreviated as CL) copolymer (hereinafter referred to as PLLACL) base material, poly L-lactide (hereinafter abbreviated as PLLA) , And a substrate made of polybutylene succinate adipate (hereinafter abbreviated as PBSA), were each impregnated with commercially available d-limonene as a sustained release target component. d-Limonene is a terpene hydrocarbon that is contained in citrus peels and cedar trees, and generally has a repellent effect on insects and the like.

(Example 1) A pellet-shaped substrate made of PLLACL having a diameter of about 4 mm was impregnated with d-limonene (first grade, manufactured by Wako Pure Chemical Industries, Ltd.). PLLACL consists of a predetermined amount of LLA ((3S) -cis-3,6-Dimethyl-1,4-dioxane-2,5-dione: Sigma-Aldrich) and CL (special grade, Wako Pure Chemical Industries, Ltd.) Was added to a Schlenk tube (φ16 mm × 110 mm: manufactured by Futaba Rika Seisakusho Co., Ltd.) as a monomer, Stannous 2-Ethyl-Hexanoate (manufactured by Sigma-Aldrich) was added as a catalyst, and deaeration and argon gas replacement were performed. Thereafter, ring-opening polymerization was performed in an oil bath at 120 ° C. for 24 hours to synthesize. The composition ratio (LLA / CL) of this copolymer was 73/27 as measured by ¹ H NMR (nuclear magnetic resonance apparatus: JNM-ECP400, manufactured by JEOL Ltd.).

The injection of d-limonene into PLLACL was performed using a supercritical carbon dioxide fluid device (manufactured by AKICO). In a stainless steel pressure vessel (0.5 L), PLLACL 10 g and d-limonene are set so that the concentration in the pressure vessel becomes 4.0 g / L, and in a supercritical carbon dioxide (scCO ₂ ) atmosphere (temperature 40 to 100). The mixture was stirred (100 rpm) at 3 ° C. for 3 hours. Thereafter, the pressure was gradually reduced over 3 hours, the sample was taken out from the pressure vessel, and the weight was measured. Since the sample after the injection treatment contains carbon dioxide in addition to d-limonene, the injection amount of d-limonene is ¹ H NMR (nuclear magnetic resonance apparatus: JNM-ECP400, manufactured by JEOL Ltd.) ).

  (Comparative Example 1) d-Limonene was injected in the same manner as in Example 1 except that PLLA (manufactured by Mitsui Chemicals, Inc.) was used as the base material.

  (Comparative Example 2) d-Limonene was injected in the same manner as in Example 1 except that PBSA (manufactured by Showa Polymer Co., Ltd.) was used as the substrate.

  The experimental results of Example 1 and Comparative Examples 1 and 2 are shown in Table 1.

  When PLLA and PBSA were used as the base material, the injection amounts were 1.03% and 0.51%, respectively, whereas when PLLACL was used, the injection amount was 3.07%. Compared to the case of using, the injection amount was about 3 times under the same conditions.

  Table 2 shows the thermal characteristics of PLLACL, PLLA and PBSA. These thermal characteristics were measured by DSC (Differential Scanning Calorimeter: Thermo plus2 / DSC8230, manufactured by Rigaku Corporation).

PLLACL has the lowest heat of fusion representing the crystallinity of the polymer (21.1 J / g) and the glass transition point is 23.9 ° C., which is lower than the processing temperature. In addition to the treatment conditions in the scCO ₂ atmosphere, it was confirmed that the crystallinity, melting point, and glass transition point of the polymer greatly affected the injection amount. The reason why the injection amount into PBSA is the lowest is that the melting point and glass transition point of PBSA are the lowest among the three types of polymers and the heat of fusion representing the crystallinity of the polymer is the highest. Conceivable. Note that the melting point (167.1 ° C.) and the glass transition point (55.9 degrees) of PLLA are the highest among these, and both are higher than the injection processing temperature.

Influence of injection amount on d-limonene concentration, treatment time and temperature Factors related to injection amount were investigated. Here, the test was performed using PLLA as a base material.

  (Reference Example 1) A base material made of PLLA (made by Mitsui Chemicals, Inc.) was formed into a pellet having a diameter of about 4 mm and impregnated with d-limonene (first grade, manufactured by Wako Pure Chemical Industries, Ltd.). .

The injection of d-limonene into PLLA was performed with a supercritical carbon dioxide fluid device (manufactured by AKICO). In a stainless steel pressure vessel (0.5 L), PLLA 10 g and d-limonene are set so that the concentration in the pressure vessel is 1.0 g / L, and the atmosphere is supercritical carbon dioxide (scCO ₂ ) (temperature 40 ° C., The mixture was stirred (100 rpm) for 3 hours at a pressure of 20 MPa. Thereafter, the pressure was gradually reduced over 3 hours, the sample was taken out from the pressure vessel, and the weight was measured. Since the sample after the injection treatment contains carbon dioxide in addition to d-limonene, the injection amount of d-limonene is ¹ H NMR (nuclear magnetic resonance apparatus: JNM-ECP400, manufactured by JEOL Ltd.) ).

  (Reference Example 2) d-limonene was injected in the same manner as in Reference Example 1 except that d-limonene was set so that the concentration in the stainless steel pressure vessel (0.5 L) was 2.0 g / L.

  (Reference Example 3) d-Limonene was injected in the same manner as in Reference Example 1 except that d-limonene was set so that the concentration in the stainless steel pressure vessel (0.5 L) was 4.0 g / L.

  (Reference Example 4) d in the same manner as Reference Example 1 except that 25 g of PLLA and d-limonene were set so that the concentration in the pressure vessel became 5.0 g / L in a stainless steel pressure vessel (0.5 L). -Limonene was injected.

  (Reference Example 5) PLLA 20 g and d-limonene are set in a pressure vessel of stainless steel (0.5 L) so that the concentration in the pressure vessel becomes 4.0 g / L, and injection treatment (40 ° C., 20 MPa, 3 hours) ) Was carried out in the same manner as in Reference Example 1 except that d-limonene was injected.

Reference Example 6 d-Limonene is set so that the concentration in the stainless steel pressure vessel (0.5 L) is 1.7 g / L, and the treatment is performed in a supercritical carbon dioxide (scCO ₂ ) atmosphere at a temperature of 75 ° C. Except that, d-limonene was injected in the same manner as in Reference Example 1.

(Reference Example 7) d-limonene is set so that the concentration in the stainless steel pressure vessel (0.5 L) is 2.0 g / L, and the treatment is performed in a supercritical carbon dioxide (scCO ₂ ) atmosphere at a temperature of 100 ° C. Except that, d-limonene was injected in the same manner as in Reference Example 1.

  The experimental results of these reference examples 1 to 7 are shown in Table 3.

  The injection amount of d-limonene in Reference Example 1 was 0.25%, but when the d-limonene concentration was doubled and the treatment was performed under the same conditions, the injection amount was doubled (Reference Example 2). ). Furthermore, when the experiment was carried out by increasing the polymer amount and d-limonene concentration of Reference Example 2 by 2.5 times, the injection amount was 3.3 times (Reference Example 4). From this, it was confirmed that the injection amount was further increased by increasing the polymer amount and the d-limonene amount.

  Further, the amount of d-limonene injected when the number of treatments was increased was examined. As in Reference Example 4, when the treatment was performed at a polymer amount of 25 g and a d-limonene concentration of 5.0 g / L (40 ° C., 20 MPa, 3 h), the injection amount was 1.68%. Furthermore, when the treatment was performed twice under the conditions of a polymer amount of 20 g and a d-limonene concentration of 4.0 g / L, the injection amount reached 1.99% even though the polymer amount and d-limonene amount were lowered. It increased (Reference Example 5). Thereby, it was confirmed that the injection amount increased by extending the processing time.

  Further, when the influence of temperature was examined, when the treatment was performed at a polymer amount of 10 g and a d-limonene concentration of 2.0 g / L (40 ° C., 20 MPa, 3 h), the injection amount was 0.51% (Reference Example 2 ) By increasing the temperature to 75 ° C. and 100 ° C., the injection amounts increased to 1.05% (Reference Example 6) and 1.59% (Reference Example 7), respectively. It has been confirmed that it has a great influence on

The influence of the injection amount on the polymer shape and the influence of the polymer shape on the injection amount of d-limonene were also examined. In the above Reference Examples 1 to 7, the shape was a substantially cylindrical pellet having a diameter of about 4 mm. In Reference Examples 8 to 11, an injection test was performed using film-like PLLA as a base material.

  (Reference Example 8) A base material made of PLLA (Mitsui Chemicals Co., Ltd.) was formed into a film having a thickness of 50 μm and impregnated with d-limonene (first grade, manufactured by Wako Pure Chemical Industries, Ltd.). .

The injection of d-limonene into PLLA was performed with a supercritical carbon dioxide fluid device (manufactured by AKICO Corporation). In a stainless pressure vessel (0.5 L), PLLA 10 g and d-limonene are set so that the concentration in the pressure vessel is 7.3 g / L, and the atmosphere is supercritical carbon dioxide (scCO ₂ ) (temperature 40 ° C., The mixture was stirred (100 rpm) for 3 hours at a pressure of 20 MPa. Thereafter, the pressure was gradually reduced over 3 hours, the sample was taken out from the pressure vessel, and the weight was measured. Since the sample after the injection treatment contains carbon dioxide in addition to d-limonene, the injection amount of d-limonene is ¹ H NMR (nuclear magnetic resonance apparatus: JNM-ECP400, manufactured by JEOL Ltd.) ).

  Reference Example 9 d-Limonene was injected in the same manner as in Reference Example 8 except that PLLA having a film thickness of 100 μm was used as the base material.

  Reference Example 10 d-Limonene was injected in the same manner as in Reference Example 8 except that PLLA having a film thickness of 300 μm was used as the substrate.

  Reference Example 11 d-Limonene was injected in the same manner as in Reference Example 8 except that PLLA having a film thickness of 500 μm was used as the base material.

  Table 4 shows the experimental results of the injection amount with respect to the film thickness.

  The amount of d-limonene injected into PLLA having a film thickness of 50 μm was 2.13% (Reference Example 8). The amount injected into the pellet-like PLLA under the same conditions is calculated to be about 1.9% when calculated based on the results shown in Table 3, and the film-like injection amount is about 0.2% more than the pellet shape. It is conceivable that it will increase (about 10% increase). Moreover, it has also confirmed that the injection quantity increased with the increase in film thickness (Reference Examples 9-10). However, when the base material having a film thickness of 500 μm in Reference Example 11 was used, the injection amount was reduced, which was almost the same result as the pellet-like PLLA obtained by calculation. From the above results, it was confirmed that the target injection was difficult to enter inside as the film thickness increased.

Effect of injection amount on PLLACL composition ratio As shown in Table 1, the injection amount into PLLACL (composition ratio 73/27) was about three times the injection amount into PLLA. Therefore, in order to examine the influence of the injection amount on the composition ratio of PLLACL, an injection test was performed using copolymers having different composition ratios as base materials.

(Example 2) A predetermined amount of LLA ((3S) -cis-3,6-Dimethyl-1,4-dioxane-2,5-dione: Sigma-Aldrich) and CL (special grade, Wako Pure Chemical Industries ( Is made into a Schlenk tube (φ16mm × 110mm: Futaba Rika Seisakusho Co., Ltd.) as a monomer, Stannous 2-Ethyl-Hexanoate (Sigma-Aldrich) is added as a catalyst, and deaeration and argon gas replacement are performed. Then, polymerization was performed in an oil bath at 120 ° C. for 24 hours to synthesize PLLACL. The composition ratio (LLA / CL) of the copolymer was 66/34 as measured by ¹ H NMR (nuclear magnetic resonance apparatus: JNM-ECP400, manufactured by JEOL Ltd.). Further, this sample was formed into a film having a film thickness of 100 μm.

The injection of d-limonene into PLLACL was performed using a supercritical carbon dioxide fluid device (manufactured by AKICO). In a stainless steel pressure vessel (0.5 L), PLLA 10 g and d-limonene are set so that the concentration in the pressure vessel is 1.0 g / L, and the atmosphere is supercritical carbon dioxide (scCO ₂ ) (temperature 40 ° C., The mixture was stirred (100 rpm) for 3 hours at a pressure of 20 MPa. Thereafter, the pressure was gradually reduced over 3 hours, the sample was taken out from the pressure vessel, and the weight was measured. Since the sample after the injection treatment contains carbon dioxide in addition to d-limonene, the injection amount of d-limonene is ¹ H NMR (nuclear magnetic resonance apparatus: JNM-ECP400, manufactured by JEOL Ltd.) ).

  (Example 3) d-limonene was injected in the same manner as in Example 2 except that PLLACL having a composition ratio (LLA / CL) of 76/24 was used as a base material.

  (Example 4) d-limonene was injected in the same manner as in Example 2 except that PLLACL having a composition ratio (LLA / CL) of 85/15 was used as a base material.

  (Example 5) d-limonene was injected in the same manner as in Example 2 except that PLLACL having a composition ratio (LLA / CL) of 92/8 was used as a base material.

  (Example 6) d-limonene was injected in the same manner as in Example 2 except that PLLACL having a composition ratio (LLA / CL) of 95/5 was used as a base material.

  (Comparative Example 3) d-Limonene was injected in the same manner as in Example 2 except that PLLACL having a composition ratio (LLA / CL) of 12/88 was used as the base material.

  (Comparative Example 4) d-Limonene was injected in the same manner as in Example 2 except that PLLACL having a composition ratio (LLA / CL) of 24/76 was used as a base material.

  Comparative Example 5 d-Limonene was injected in the same manner as in Example 2 except that PLLACL having a composition ratio (LLA / CL) of 34/66 was used as the base material.

  Comparative Example 6 d-Limonene was injected in the same manner as in Example 2 except that the composition ratio (LLA / CL) was 100/0, that is, PLLA was used as the base material.

  Table 5 shows the experimental results of Examples 2 to 6 and Comparative Examples 3 to 6. Table 6 shows the thermal characteristics of PLLACL.

Since the melting point of the copolymer (copolymer) having an LLA / CL composition ratio of 12/88, 24/76, 34/66 is as low as about 50 ° C. or less as shown in Table 6, the scCO ₂ fluid at 40 ° C. and 20 MPa Below, melting occurred. For this reason, the injection amount of d-limonene was 1% or less and lower than using PLLA (LLA / CL composition ratio 100/0) as a base material (Comparative Examples 3 to 5). A copolymer having a sufficiently high melting point and an LLA content of 66% or more by molar ratio did not cause melting, and the amount of d-limonene injected was sufficiently larger than that of PLLA (Examples 2 to 6). Furthermore, when the LLA / CL composition ratio was 85/15, the injection amount was the highest and was 3.19% (Example 4). In addition, the copolymers with LLA / CL composition ratios of 66/34 and 76/24 had injection amounts of 2.42% and 2.80%, respectively, and it was confirmed that the injection amount was twice or more that of PLLA.

  FIG. 1 is a graph showing the injection amount with respect to the LLA content of PLLACL. From the graph shown in FIG. 1, by using PLLACL having a LLA content of 65% or more and 98% or less as a base material as a base material, the injection amount of d-limonene is 2 under the same conditions as compared with the case where PLLA is used as the base material. It was found to increase by 2.7 times.

Influence of injection amount on d-limonene concentration and temperature Further, an injection test was conducted by changing the d-limonene concentration and temperature.

(Example 7) A predetermined amount of LLA ((3S) -cis-3,6-Dimethyl-1,4-dioxane-2,5-dione: manufactured by Sigma-Aldrich) and CL (special grade, Wako Pure Chemical Industries ( Is made into a Schlenk tube (φ16mm × 110mm: Futaba Rika Seisakusho Co., Ltd.) as a monomer, Stannous 2-Ethyl-Hexanoate (Sigma-Aldrich) is added as a catalyst, and deaeration and argon gas replacement are performed. Then, polymerization was performed in an oil bath at 120 ° C. for 24 hours to synthesize PLLACL. The composition ratio (LLA / CL) of this copolymer was 76/24 as measured by ¹ H NMR (nuclear magnetic resonance apparatus: JNM-ECP400, manufactured by JEOL Ltd.). Further, this sample was formed into a film having a film thickness of 100 μm.

The injection of d-limonene into PLLACL was performed using a supercritical carbon dioxide fluid device (manufactured by AKICO). In a stainless steel pressure vessel (0.5 L), PLLA 0.3 g and d-limonene are set so as to have a concentration of 4.0 g / L, and in a supercritical carbon dioxide (scCO ₂ ) atmosphere (temperature 40 ° C., pressure 20 MPa). ) For 3 hours (100 rpm). Thereafter, the pressure was gradually reduced over 3 hours, the sample was taken out from the pressure vessel, and the weight was measured. Since the sample after the injection treatment contains carbon dioxide in addition to d-limonene, the injection amount of d-limonene is ¹ H NMR (nuclear magnetic resonance apparatus: JNM-ECP400, manufactured by JEOL Ltd.) ).

  (Example 8) d-limonene was injected in the same manner as in Example 7 except that d-limonene was set so that the concentration in the stainless steel pressure vessel (0.5 L) was 20.0 g / L.

(Example 9) d-limonene is set so that the concentration in a stainless steel pressure vessel (0.5 L) is 20.0 g / L, and the treatment is performed in a supercritical carbon dioxide (scCO ₂ ) atmosphere at a temperature of 75 ° C. Except that, d-limonene was injected in the same manner as in Example 7.

  Table 7 shows the experimental results of Examples 7-9.

  In the case of Example 7 in which the d-limonene concentration was 4.0 g / L and treated at 40 ° C. and 20 MPa for 3 hours, the injection amount was 2.80%, but the d-limonene concentration was increased to 20.0 g / L. In the case of Example 8, the injection amount was 6.19%, an increase of about 2 times. In the case of Example 9 treated at 75 ° C. and 20 MPa for 3 hours, the injection amount was 5.81% since the copolymer was melted. From the above results, it was found that when the d-limonene concentration was increased, the injection amount was significantly increased.

Degradation test An experiment was also conducted on the degradability of the copolymer.

  (Example 10) PLLACL having a composition ratio of 66/34 was hydrolyzed with a tricine buffer solution (pH 8.0) at 37 ° C.

  (Example 11) PLLACL having a composition ratio of 73/27 was hydrolyzed with a tricine buffer solution (pH 8.0) at 37 ° C.

  (Example 12) PLLACL having a composition ratio of 85/15 was hydrolyzed with a tricine buffer solution (pH 8.0) at 37 ° C.

  Comparative Example 7 PLLA was hydrolyzed with a 37 ° C. tricine buffer solution (pH 8.0).

  The experimental results of Examples 10 to 12 and Comparative Example 7 are shown in Table 8.

  When PLLA was hydrolyzed with a 37 ° C. tricine buffer solution (pH 8.0), the remaining weight ratio was about 97% until 350 days, and almost no degradation progressed. There was a decrease and it completely degraded in 500 days. On the other hand, when a similar experiment was performed on PLLACL, PLLACL having a composition ratio of 73/27 had a higher hydrolysis rate than PLLA and completely decomposed in 100 days. Further, as the LLA content increased, the hydrolysis rate tended to be slow, and the 85/15 copolymer took about 5 months to completely decompose. The copolymer with a composition ratio of 66/34 had a lower crystallinity (heat of fusion) than that of the 73/27 copolymer, and the hydrolysis rate seemed to be faster. Due to the increase in content, the hydrolysis rate was almost the same as 73/27.

  That is, it was found that PLLACL having a LLA content of 65% or more and 98% or less in terms of molar ratio has a sustained release period of at least 3 months, and the sustained release period is extended by increasing the LLA content.

  In addition, since such a hydrolysis test requires a long time to decompose the polymer, a degradation test (enzymatic degradation test) was performed using an enzyme in order to quickly confirm the sustained release property. As the PLLACL for the degradation test, a film having a thickness of 100 μm was used.

  FIG. 2 is a graph showing the results of an enzymatic degradation test of PLLACL with lipase PS. The experiment was performed at 37 ° C. by immersing lipase PS and copolymer in a phosphate buffer solution (pH 7). Lipase PS is an enzyme having a high degradation activity against PCL.

  PCL completely decomposed in 20 hours. The copolymer having an LLA / CL composition ratio of 12/88 was completely degraded in 100 hours, and the degradation rate became slower as the LLA content increased. Further, PLLA was hardly decomposed, and the residual weight ratio at 240 hours was about 95%.

  FIG. 3 is a graph showing the results of the enzymatic degradation test of PLLACL with proteinase K. The experiment was performed at 37 ° C. by immersing proteinase K and the copolymer in a tricinate buffer solution (pH 8). Proteinase K is an enzyme that has different substrate characteristics from lipase PS and exhibits high degradation activity against PLLA.

  PLLA had a residual weight percentage reduced to about 8% in 240 hours. A copolymer having an LLA content of 66% or more has a faster degradation rate than PLLA, and a copolymer having an LLA / CL composition ratio of 76/24 was completely degraded in 80 hours. The reason why the decomposition rate was faster than PLLA is that the inclusion of CL decreased the crystallinity compared to PLLA, making it easier for the enzyme to adhere and decompose. In addition, the degradation rate was slowed by decreasing the unit (LLA) content easily degraded by proteinase K, and the copolymer having a composition ratio of 34/66 had a residual weight ratio of about 86% after 240 hours.

  As described above, according to the sustained release agent according to the present invention, by using PLLACL having a LLA content of 65% or more and 98% or less as a base material as a base material, at least twice the amount of the sustained release target component as compared with LLA is impregnated. Can be made. Therefore, a high concentration sustained release target component can be released within the sustained release period. Further, since it has a sustained release period of at least 3 months, it can be used for pest control and the like.

  Hereinafter, polyester-based polylactic acid (PLLA) and its copolymer L-lactide / trimethylene carbonate copolymer (PLLATMC), L-lactide / 2,2- Dimethyltrimethylene carbonate copolymer (PLLA22DTMC), L-lactide / tetramethylene carbonate copolymer (PLLATEMC), L-lactide / glycolide copolymer (PLLAGL), L-lactide / D, L-lactide copolymer ( (PLLADLLA), D, L-lactide / ε-caprolactone copolymer (PDLLACL) and the like were used for experiments.

Influence of injection amount on composition ratio of PLLA22DTMC An injection test of d-limonene into PLLA and its polymer PLLA22DTMC was conducted. d-Limonene is a terpene hydrocarbon that has repellent effects on insects contained in citrus peels and cedar trees.

(Example 13) A predetermined amount of LLA ((3S) -cis-3,6-Dimethyl-1,4-dioxane-2,5-dione: Sigma-Aldrich) and 22DTMC (Ube Industries, Ltd.) Is added to a Schlenk tube (φ16 mm × 110 mm: manufactured by Futaba Rika Seisakusho Co., Ltd.) as a monomer, Stannous 2-Ethyl-Hexanoate (manufactured by Sigma-Aldrich) is added as a catalyst, and after deaeration and argon gas replacement, Polymerization was performed in an oil bath at 120 ° C. for 24 hours to synthesize PLLA22DTMC. The composition ratio (LLA / 22DTMC) of this copolymer was measured by ¹ H NMR (nuclear magnetic resonance apparatus: JNM-ECP400, manufactured by JEOL Ltd.) and found to be 76/24. Further, this sample was formed into a film having a film thickness of 100 μm.

The injection of d-limonene into PLLA22DTMC was performed with a supercritical carbon dioxide fluid device (manufactured by AKICO). In a stainless steel pressure vessel (0.5 L), PLLA22DTMC 0.3 g and d-limonene are set so that the concentration in the pressure vessel is 4.0 g / L, and the atmosphere is supercritical carbon dioxide (scCO ₂ ) (temperature 40 The mixture was stirred (100 rpm) at 3 ° C. for 3 hours. Thereafter, the pressure was gradually reduced over 3 hours, the sample was taken out from the pressure vessel, and the weight was measured. Since the sample after the injection treatment contains carbon dioxide in addition to d-limonene, the injection amount of d-limonene is ¹ H NMR (nuclear magnetic resonance apparatus: JNM-ECP400, manufactured by JEOL Ltd.) ).

  (Example 14) d-Limonene was injected in the same manner as in Example 13 except that PLLA22DTMC having a composition ratio (LLA / 22DTMC) of 90/10 was used as a base material.

  (Comparative Example 8) d-Limonene was injected in the same manner as in Example 13 except that the composition ratio (LLA / 22DTMC) was 0/100, that is, 22DTMC was used as the base material.

  (Comparative Example 9) d-Limonene was injected in the same manner as in Example 13 except that PLLA22DTMC having a composition ratio (LLA / 22DTMC) of 10/90 was used as a base material.

  (Comparative Example 10) d-Limonene was injected in the same manner as in Example 13 except that PLLA22DTMC having a composition ratio (LLA / 22DTMC) of 36/64 was used as a base material.

  (Comparative Example 11) d-Limonene was injected in the same manner as in Example 13 except that PLLA22DTMC having a composition ratio (LLA / 22DTMC) of 58/42 was used as the base material.

  Table 9 shows the experimental results of Examples 13 and 14 and Comparative Examples 6 and 8-11.

  The amounts of d-limonene injected into the homopolymers of PLLA (Comparative Example 6) and 22DTMC (Comparative Example 8) were 1.20% and 2.10%, respectively. As the LLA increased, the amount of d-limonene injected into the copolymer tended to increase. When the LLA / 22DTMC composition ratio was 76/24, the amount injected was the highest, 5.02%. In the injection test into the copolymers having a composition ratio of 36/64 (Comparative Example 10) and 58/42 (Comparative Example 11), melting of the copolymer was observed. Moreover, in PLLACL, the copolymer with a composition ratio of 85/15 (Example 4) had the highest injection amount of 3.19%, but as a result of the injection experiment into PLLA 22DTMC, Example 13 Compared to Example 4, the amount of d-limonene injected was increased 1.6 times.

PLLA22DTMC has a lower melting point and glass transition temperature than PLLA, and also has a low heat of fusion representing the degree of crystallinity, and it is considered that the injection amount increased due to the progress of plasticization with scCO ₂ . Furthermore, 22DTMC is a compound having a carbonate bond, this bond is because it is the same chemical structure as CO _2, the solubility in the copolymer of CO ₂ limonene d- is dissolved is also contemplated that increased. Due to the above factors, it can be inferred that PLLA22DTMC increased the amount of d-limonene injected over PLLA.

Injection test to other polylactic acid copolymers The same injection experiment was conducted for other polylactic acid copolymers other than PLLA22DTMC. As the polylactic acid copolymer, PLLAGL, PLLLADLLA, and PDLLACL were used, and the injection experiment was performed under the same conditions as PLLACL and PLLA22DTMC.

  (Example 15) d-Limonene was injected in the same manner as in Example 13 except that PLLAGL having a composition ratio (LLA / GL) of 80/20 was used as a base material.

  (Example 16) d-Limonene was injected in the same manner as in Example 13 except that PLLADLLA having a composition ratio (LLA / DLLA) of 80/20 was used as a base material.

  (Comparative Example 12) d-Limonene was injected in the same manner as in Example 13 except that PLLAGL having a composition ratio (LLA / GL) of 49/51 was used as the base material.

  Comparative Example 13 d-Limonene was injected in the same manner as in Example 13 except that PLLADLLA having a composition ratio (LLA / DLLA) of 20/80 was used as the base material.

  (Comparative Example 14) d-Limonene was injected in the same manner as in Example 13 except that PLLADLLA having a composition ratio (LLA / DLLA) of 50/50 was used as the base material.

  (Comparative Example 15) d-Limonene was injected in the same manner as in Example 13 except that PDLLACL having a composition ratio (DLLA / CL) of 19/81 was used as a base material.

  (Comparative Example 16) d-Limonene was injected in the same manner as in Example 13 except that PDLLACL having a composition ratio (DLLA / CL) of 51/49 was used as a base material.

  (Comparative Example 17) d-Limonene was injected in the same manner as in Example 13 except that PDLLACL having a composition ratio (DLLA / CL) of 83/17 was used as the base material.

  (Comparative Example 18) d-Limonene was injected in the same manner as in Example 13 except that PDLLACL having a composition ratio (DLLA / CL) of 91/9 was used as the base material.

  Table 10 shows the experimental results of Examples 15 and 16 and Comparative Examples 12 to 18.

  When an experiment was conducted with composition ratios (LLA / GL) of 49/51 (Comparative Example 12) and 80/20 (Example 15), the injection amounts of d-limonene were 1.30% and 1.67%, respectively. Met. GL is generally known as a highly hydrophilic compound like LLA, and this copolymer is not very compatible with d-limonene, but this Example 15 is more than Comparative Example 12. The injection volume was large.

  As for PLLLADLLA, when the composition ratio was 50/50 (Comparative Example 14), the injection amount was the highest and was 7.35%, but the composition ratio was 20/80 (Comparative Example 13) and 50/50 ( The copolymer of Comparative Example 14) was melted. DLLA is an amorphous compound and appears to have accelerated the melting of the copolymer. In the copolymer (Example 16) containing about 20 mol% of amorphous DLLA, no melting was observed, and the injection amount was 4.01%. This was a 3.3-fold increase compared to 1.20%, which is the amount injected into PLLA.

As a result of the injection test into PDLLACL, since amorphous DLLA was used as a monomer, melting was observed in all copolymers. ^{In the} measurement by ¹ H NMR, the injection amount was the highest at 5.73% in the composition ratio 91/9 (Comparative Example 18), and as the CL content increased, the injection of d-limonene was similar to LLACL. The amount tended to decrease.

Comparison of injection amount of polylactic acid copolymer having an LLA content of about 80% Table 11 shows the result of comparison of the injection amount of d-limonene into the polylactic acid copolymer having an LLA content of about 80%. Table 12 shows the thermal characteristics of the polylactic acid copolymer.

  Examples 17 and 18 were the same as Example 13 except that a copolymer of LLA and trimethylene carbonate (TMC) and a copolymer of LLA and tetramethylene carbonate (TEMC) were used. Then, d-limonene was injected.

In a polyester copolymer (PLLAGL, PLLLADLLA, PLLACL), a polylactic acid copolymer containing 20% GL (C ₁ ) having a short methylene chain length between ester bonds has an injection amount of d-limonene of 1.67. % Showed a slight increase from the polylactic acid result (1.20%). On the other hand, in the polylactic acid copolymer containing 15% CL (C ₅ ) having a long methylene chain length, the injection amount of d-limonene is 3.19%, which is 2.4 times higher than PLLAGL. It was. This indicates that CL is more hydrophobic than GL and increases the hydrophobicity of the polylactic acid copolymer, making it easier to become familiar with scCO ₂ having lipophilic properties and increasing the injection amount. ing.

The injection amount into PLLLADLLA was 4.01%. Both LLA and DLLA have a structure in which a methyl group is bonded to GL, and are more hydrophobic than GL. Furthermore, LLA is an optically active compound, whereas DLLA is not an optically active compound. This DLLA decreases the optical activity of polylactic acid copolymerization, and the decrease in optical activity causes the crystallinity or melting point of the polymer structure to decrease. The decrease in crystallinity and melting point increases the solubility in scCO ₂ and is considered to be a factor that increased the amount of d-limonene injection compared to polylactic acid composed of LLA alone. Therefore, it is considered that the injection amount of the target compound can be increased by increasing the hydrophobicity of the polymer or decreasing the crystallinity or melting point, and lactones such as γ-butyrolactone and δ-valerolactone have the same effect. Can be expected.

Moreover, in the polyester carbonate copolymer (PLLATMC, PLLA22DTMC, PLLATEMC), the injection amount of d-limonene was 5% or more in any copolymer. Among them, TMC (C ₃ ) and TEMC (C ₄ ) having no substituent showed high values. The melting points and heats of fusion of PLLATMC (86/14), PLLA22DTMC (76/24) and PLLATEMC (81/19) are 48.9 ° C. and 29.0 J / g, 138.6 ° C. and 24.4 J / g, respectively. 97.9 ° C. · 5.1 J / g, and since the injection amount increases as the melting point decreases, it is considered that the injection amount is caused by the melting point rather than the length of the methylene chain length. In addition, since carbonates have carbonate bonds similar in structure to CO ₂ , it is presumed that the injection amount of the target component was increased as compared with copolymerization of lactones such as CL.

  From the above results, polyester amide copolymers, polyester ether copolymers, etc. that can increase hydrophobicity, decrease crystallinity or melting point, such as polyester copolymers and polyester carbonate copolymers, etc. This copolymer can also be used as a polymer material capable of increasing the injection amount of the target compound.

Injection test of antibacterial component into biodegradable polymer (film form) Next, an injection test of the antibacterial component into the above-described biodegradable polymer was performed. As the antibacterial component, hinokithiol, allyl isothiocyanate, trans-2-hexenal, trans-3-hexenal, cis-3-hexenal, and the like, which are contained in hinoki, wasabi, tea leaves, etc. are known. -2-hexenal or hinokitiol was used.

(Example 19) Trans-2-hexenal was injected into a copolymer having a composition ratio (LLA / CL) of 81/19 (film thickness: 100 μm) by a supercritical carbon dioxide fluid device (manufactured by AKICO Corporation). ). In a stainless steel pressure vessel (0.5 L), PLLACL 0.3 g and trans-2-hexenal were set so that the concentration in the pressure vessel would be 4.0 g / L, and in a supercritical carbon dioxide (scCO ₂ ) atmosphere ( The mixture was stirred (100 rpm) at a temperature of 40 ° C. and a pressure of 20 MPa for 3 hours. Thereafter, the pressure was gradually reduced over 3 hours, the sample was taken out from the pressure vessel, and the weight was measured. Since the sample after the injection treatment contains carbon dioxide in addition to trans-2-hexenal, the amount of trans-2-hexenal injected was determined by ¹ H NMR (nuclear magnetic resonance apparatus: JNM-ECP400, JEOL ( Measured by Co. Ltd.

  (Example 20) Trans-2-hexenal was injected in the same manner as in Example 19 except that PLLACL having a composition ratio (LLA / CL) of 91/9 was used as a base material.

  Example 21 trans-2-hexenal was injected in the same manner as in Example 19 except that PLLAGL having a composition ratio (LLA / GL) of 80/20 was used as a base material.

  (Comparative Example 19) Trans-2-hexenal was injected in the same manner as in Example 19 except that PLLACL having a composition ratio (LLA / CL) of 49/51 was used as a base material.

  Comparative Example 20 Trans-2-hexenal was injected in the same manner as in Example 19 except that PLLACL having a composition ratio (LLA / CL) of 60/40 was used as the base material.

  (Comparative Example 21) trans-2-hexenal was injected in the same manner as in Example 19 except that PDLACL having a composition ratio (DLLA / CL) of 59/41 was used as the base material.

  (Comparative Example 22) Trans-2-hexenal was injected in the same manner as in Example 19 except that PDLACL having a composition ratio (DLLA / CL) of 71/29 was used as a base material.

  (Comparative Example 23) Trans-2-hexenal was injected in the same manner as in Example 19 except that PLLA was used as the base material.

  Table 13 shows the result of trans-2-hexenal injection into PLLA and its copolymers PLLACL, PLLAGL, and PDLLACL.

The injection amount of trans-2-hexenal with respect to PLLACL was 0.86% when the composition ratio was 49/51 (Comparative Example 19), and the injection amount increased as the LLA content increased. The amount of trans-2-hexenal injected into PLLACL was lower than that of d-limonene. This is thought to be due to the low solubility of trans-2-hexenal in scCO ₂ compared to d-limonene. As shown in Example 20, in the copolymer having a high LLA content (composition ratio 91/9), the injection amount of trans-2-hexenal tended to increase to 2.56%. The amount of d-limonene injected into the copolymer having the same composition ratio (92/8) was 2.15%. From the above, it was found that in the copolymer having a high LLA content, the amount of trans-2-hexenal injected was increased. This is considered due to the high compatibility between LLA and trans-2-hexenal.

  In order to clarify the compatibility, trans-2-hexenal was injected into LLAGL. As shown in Example 21, the amount injected into LLAGL (composition ratio 80/20) was more than doubled. Since GL is structurally less hydrophobic than CL as in LLA, it is considered that GL is easily compatible with compounds such as trans-2-hexenal.

  As for DLLCL, although the copolymer containing DLLA was an amorphous polymer, melting of the polymer was observed under the reaction conditions, but the injection amount of trans-2-hexenal was 3 in a composition ratio of 71/29. It was 31%.

  Moreover, the injection | pouring test of hinokitiol was done by changing the composition ratio of PLLA22DTMC.

(Example 22) Injection of hinokitiol into a copolymer (film thickness: 100 µm) having (LLA / 22DTMC) of 79/21 was carried out with a supercritical carbon dioxide fluid device (manufactured by AKICO Corporation). Set stainless steel pressure vessel (0.5L) PLLA22DTMC 0.3g, and hinokitiol so that the concentration in the pressure vessel becomes 4.0g / L, under supercritical carbon dioxide (scCO ₂ ) atmosphere (temperature 40 ° C, The mixture was stirred (100 rpm) for 3 hours at a pressure of 20 MPa. Thereafter, the pressure was gradually reduced over 3 hours, the sample was taken out from the pressure vessel, and the weight was measured. Since the sample after the injection treatment contains carbon dioxide in addition to hinokitiol, the injection amount of hinokitiol was measured by ¹ H NMR (nuclear magnetic resonance apparatus: JNM-ECP400, manufactured by JEOL Ltd.). .

  (Example 23) Hinokitiol was injected in the same manner as in Example 22 except that PLLA22DTMC having a composition ratio (LLA / 22DTMC) of 86/14 was used as a base material.

  (Example 24) Hinokitiol was injected in the same manner as in Example 22 except that PLLA22DTMC having a composition ratio (LLA / 22DTMC) of 91/9 was used as a base material.

  (Example 25) Hinokitiol was injected in the same manner as in Example 22 except that PLLA22DTMC having a composition ratio (LLA / 22DTMC) of 98/2 was used as a base material.

  Comparative Example 24 Hinokitiol was injected in the same manner as in Example 22 except that the composition ratio (LLA / 22DTMC) was 100/0, that is, PLLA was used as the base material.

  Table 14 shows the results of an injection test of hinokitiol into PLLA22DTMC, which is a copolymer with PLLA.

The injection amount of d-limonene into the PLLA copolymer (PLLACL, PLLAGL, PLLA22DLLA) was the highest injection amount of PLLA22DTMC (76/24) except for the melted copolymer. The injection into the copolymer was conducted using PLLA22DTMC. In the injection experiment of hinokitiol into PLLA (temperature 40 ° C., pressure 20 MPa, time 3 h), the injection amount into PLLA is 2.41%, which is an injection amount compared to the d-limonene injection amount 1.20%. Increased by a factor of two. This indicates that the solubility of hinokitiol in scCO ₂ is higher than that of d-limonene. When the experiment was performed under the same conditions for PLLA22DTMC, the amount injected into the copolymer (Example 25) with a composition ratio of 98/2 was 7.92%, and it was considered that the solubility in scCO ₂ was high. As the 22DTMC content increased, the amount injected into the copolymer increased. The injection amount into the copolymer (Example 24) with a composition ratio of 91/9 is 10.58%, while the injection amount of d-limonene into the same copolymer (composition ratio 90/10) is It was 4.59%, which was about ½ of the injection amount of hinokitiol.

From the above results, injection of a useful component into a polymer by scCO ₂ may be largely caused by the polymer as a base material, the solubility of the useful component in scCO ₂ and the compatibility of the polymer and the useful component. I understood.

Biodegradable polymer degradation test The sustained release properties of this sustained release agent depend on the hydrolyzability, and therefore the degradation property was evaluated. Regarding degradability, hydrolyzability and enzyme degradability were examined. About hydrolyzability, the degradation test at 37 degreeC in a tricine buffer solution (pH 8.0) was done. As a result, PLLA had a residual weight ratio of about 97% until 350 days and hardly decomposed, but gradually decreased in weight after 350 days and completely dissolved in 500 days. Regarding the hydrolyzability of the PLLA copolymer (PLLACL, PLLAGL, PLL22DTMC) used in the injection test, the hydrolysis rate was fast in the copolymer having an LLA content of about 80%, and it completely decomposed in about 100 days.

  FIG. 4 is a graph showing the results of an enzymatic degradation test of PLLA22DTMC with proteinase K. The experiment was performed at 37 ° C. by immersing proteinase K and the copolymer in a tricinate buffer solution (pH 8). Proteinase K is an enzyme that exhibits high degradation activity against PLLA.

  The residual weight percentage of PLLA decreased to about 8% in 240 hours. PLLA 22DTMC having a 22DTMC content of 18% or less had a faster decomposition rate than PLLA, and the copolymer with a composition ratio of 98/2 was completely decomposed in 160 hours. The reason why the degradation rate was higher than that of PLLA is that the inclusion of 22DTMC decreases the crystallinity as compared with PLLA, and the degradation rate becomes slower as LLA that is easily degraded by the enzyme decreases, resulting in a composition ratio of 34/66. This polymer had a slow decomposition rate and a residual weight ratio of about 93% after 240 hours. The same results were obtained for the other copolymers, and the copolymer having an LLA content of 80% or more had a faster decomposition rate than PLLA.

  From the above results, the sustained release agent according to the present invention can gradually release useful components incorporated into the polymer as the decomposition proceeds.

It is a graph which shows the injection amount with respect to the LLA content of PLLACL. It is a graph which shows the result of the enzymatic degradation test of PLLACL by lipase PS. It is a graph which shows the result of the enzymatic degradation test of PLLACL by proteinase K. It is a graph which shows the result of the enzymatic degradation test of PLLA22DTMC by proteinase K.

Claims (9)

  A sustained release agent comprising a base material made of a copolymer having a molar ratio of L-lactide and ε-caprolactone of 65:35 to 98: 2, impregnated with a sustained release target component.   The sustained-release agent according to claim 1, wherein the sustained-release target component is impregnated into the base material using a supercritical fluid injection method.   The amount of the sustained release target component injected into the substrate is at least twice the amount injected into the substrate made of poly-L-lactide under the conditions for injection into the substrate. The sustained release agent according to claim 1.   The above sustained release target ingredients are d-limonene, menthone, menthol, pregone, carvone, nerolidol, terpineol, cedrol, pyrethrin, allethrin, hydramethylnon, permethrin, phthalthrin, nicotine sulfate, coumarin, eucalyptus extract, lavender extract, herb The sustained-release agent according to claim 1, wherein the sustained-release agent is at least one selected from extracts.   The sustained-release agent according to claim 1, wherein the substrate is in the form of a film. A sustained release agent obtained by impregnating a base material composed of a polylactic acid copolymer with a component for sustained release,
The above-mentioned polylactic acid copolymer is a sustained release agent characterized in that L-lactide is polymerized in a proportion of 65 to 98 mol%.   The polylactic acid copolymer includes L-lactide, glycolide, D, L-lactide, β-propiolactone, γ-butyrolactone, δ-valerolactone, β-methyl-δ-valerolacto, ε-caprolactone, DL- Mavalonolactone, ethylene carbonate, trimethylene carbonate, 1-methyltrimethylene carbonate, 2,2-dimethyltrimethylene carbonate, tetramethylene carbonate, 1,5-dioxepan-2-one, morpholine-2,5-dione, 3, 6-dimethylmorpholine-2,5-dione, (R) -or (S) -3-methyl-4-oxa-6-hexanolide (MOHEL), ethylene oxide, 5-methyl-5-benzyloxycarbonyl-1, From one or more selected from 3-dioxan-2-one Sustained release agent according to claim 6, wherein the made.   The sustained-release agent according to claim 6, wherein the sustained-release target component is impregnated in the base material using a supercritical fluid injection method.   The sustained release target components are hinokitiol, wasaol, trans-2-hexenal, trans-3-hexenal, cis-3-hexenal, catechin, takeol, castor oil, 10-undecenoic acid, allyl mustard oil, allyl isothiocyanate, capsaicin, d -At least one selected from limonene, menthone, menthol, pregon, carvone, nerolidol, terpineol, cedrol, pyrethrin, allethrin, hydramethylnon, permethrin, phthalthrin, nicotine sulfate, coumarin, eucalyptus extract, lavender extract, herbal extract The sustained-release agent according to claim 6, wherein

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