Biofilm formation inhibitor, biofilm formation inhibiting method, resin composition, molded article, and coating agent

Abstract

Provided are a biofilm formation inhibitor, a biofilm formation inhibition method, a resin composition, a molded article, and a coating agent which are capable of inhibiting the formation of a biofilm even at a low concentration that does not exhibit antibacterial properties. A biofilm formation inhibitor comprising a diterpenoid (A) having an octanol / water partition coefficient (logP) of 6 or more.

Description

Technical Field

[0001] This invention relates to a biofilm formation inhibitor, a method for inhibiting biofilm formation, a resin composition, a molded article, and a coating agent. Background Technology

[0002] Biofilms, biological aggregates encased in a sticky substance formed by bacteria, pose a problem in various industries, including medical fields related to oral diseases and infectious diseases, and water treatment fields related to water supply and drainage. Bacteria are protected by antibacterial agents or disinfectants due to biofilms, making disinfection and sterilization difficult. Furthermore, the adhesive nature of biofilms allows them to adhere firmly, making removal difficult. Therefore, once biofilms form, they cause environmental sanitation deterioration and, in medical settings, exacerbate infectious diseases. Inhibiting biofilm formation significantly contributes to improving environmental sanitation and the quality of medical care.

[0003] In the medical field, since Gram-positive cocci such as Enterococcus sometimes form biofilms on the surfaces of medical devices, oral compositions comprising a carrier such as water and glycerol, and a terpenoid compound dispersed in said carrier have been proposed to inhibit biofilm formation by Enterococcus (for example, see Patent Document 1). Furthermore, in the medical field, since Gram-positive cocci such as Staphylococcus aureus sometimes also form biofilms on the surfaces of medical devices, biofilm formation inhibitors comprising abietic acid or dehydroabietic acid have been proposed to inhibit biofilm formation by Staphylococcus aureus (for example, see Patent Document 2).

[0004] Existing technical documents

[0005] Patent documents

[0006] Patent Document 1: Japanese Patent Publication No. 2004-521880

[0007] Patent Document 2: International Publication No. 2010 / 119638 Summary of the Invention

[0008] However, the compositions described in Patent Documents 1 to 2 are not sufficiently effective in inhibiting the formation of biofilms.

[0009] The present invention was made in view of the existing problems, and its object is to provide a biofilm formation inhibitor that can inhibit the formation of biofilms, a method for inhibiting the formation of biofilms, a resin composition, a molded article, and a coating agent.

[0010] The biofilm formation inhibitor of the present invention, which solves the aforementioned problem, is a biofilm formation inhibitor comprising a diterpenoid (A) having an octanol / water partition coefficient (logP) of 6 or more.

[0011] In addition, one aspect of the present invention is a biofilm formation inhibition method in which the biofilm formation inhibitor comes into contact with at least one of the object or the object location.

[0012] Furthermore, one aspect of the resin composition of the present invention is a resin composition comprising the diterpenoid (A) and the resin.

[0013] Alternatively, one aspect of the molded body of the present invention is a molded body formed by molding the resin composition.

[0014] In addition, one aspect of the coating agent of the present invention is a coating agent containing the diterpenoid (A). Attached Figure Description

[0015] none Detailed Implementation

[0016] <Biofilm formation inhibitors>

[0017] One embodiment of the biofilm formation inhibitor of the present invention comprises a diterpenoid (A) with an octanol / water partition coefficient (logP) of 6 or more.

[0018] The octanol / water partition coefficient (logP) is preferably 6 or higher. In this embodiment, the details regarding the inhibition of biofilm formation by including a diterpenoid (A) with an octanol / water partition coefficient (logP) of 6 or higher are unclear, but the following conjectures can be considered. In this embodiment, since the diterpenoid (A) has an octanol / water partition coefficient (logP) of 6 or higher, it is conjectured that the biofilm formation inhibitor has a high affinity for bacterial cells or biofilms. Therefore, it is conjectured that among biofilm formation inhibitors, diterpenoid (A) readily acts on bacterial cells or biofilms and readily inhibits biofilm formation. Furthermore, the biofilm formation inhibitor of this embodiment has the following characteristic: even at low concentrations (e.g., concentrations of 1 / 8 of the minimum inhibitory concentration (MIC) that do not exhibit antibacterial activity), biofilm formation can be inhibited.

[0019] This effect is obtained by containing diterpenoids (A) with an octanol / water partition coefficient (logP) of 6 or higher, which cannot be obtained in abietic acid (AA, logP: 5.75) or dehydroabietic acid (DAA, logP: 5.66) with an octanol / water partition coefficient (logP) of less than 6.

[0020] Furthermore, the octanol / water partition coefficient (logP) is "the ratio of the concentration of a substance in octanol to the concentration of a substance in water when the substance is dissolved in a mixture of octanol and water," and is an indicator of the hydrophobicity (or hydrophilicity) of a substance. The larger the value, the higher the tendency for hydrophobicity (lipophilicity). The octanol / water partition coefficient (logP) can be calculated by software based on the structure of the substance (for example, referring to Japanese Patent Application Publication No. 2018-188420, Japanese Patent Application Publication No. 2019-043985, Japanese Patent Application Publication No. 2021-522873, and International Publication No. 2020 / 045514), or it can be calculated based on the structure of diterpenoids (A) using the software "Molecular Operating Environment (MOE) 2022.02 (MOLSIS)". In this embodiment, the value is calculated based on the structure of diterpenoid (A) using the software "MOE (Molecular Operating Environment) 2022.02 (MOLSIS)".

[0021] There is no particular limitation as long as the diterpenoid (A) is an octanol / water partition coefficient (logP) of 6 or higher. For example, diterpenoid (A) includes hemispheranes, pinanes, rosinanes, and various derivatives of these diterpenoids. One diterpenoid (A) may be used alone or in combination with two or more. Among these, diterpenoid (A) is preferably a diterpenoid having the structure represented by the following general formula (1). Therefore, biofilm formation inhibitors more easily inhibit biofilm formation, and even low concentrations that do not exhibit antibacterial activity can inhibit biofilm formation.

[0022] [Chemistry 1]

[0023]

[0024] (In formula (1), * indicates the bonding site with other substituents; in addition, the dashed part indicates that a carbon-carbon bond may be present at this point; when a carbon-carbon bond is present in the dashed part, a carbon-carbon bond may be present at any point in all the dashed parts)

[0025] Diterpenoids having the structure represented by general formula (1) are, for example, compounds that can be extracted from plants of the Pinaceae family, such as pine or fir, or plants of the Perilla family. There is no particular limitation on diterpenoids having the structure represented by general formula (1). If given as an example, diterpenoids having the structure represented by general formula (1) are diterpenoids having the structure represented by general formula (2) below, diterpenoids having the structure represented by general formula (3) below, etc.

[0026] [Chemistry 2]

[0027]

[0028] (In formula (2), * indicates the bonding site with other substituents)

[0029] [Chemistry 3]

[0030]

[0031] (In formula (3), * indicates the bonding site with other substituents; in addition, the dashed part indicates that there is a carbon-carbon bond at any point, and a carbon-carbon bond exists at any point in all the dashed parts.)

[0032] Diterpenes having the structure represented by general formula (2) are diterpenes having a skeleton derived from tetrahydroabietic acid. There is no particular limitation on diterpenes having a skeleton derived from tetrahydroabietic acid. For example, diterpenes having a skeleton derived from tetrahydroabietic acid include tetrahydroabietic acid (logP: 6.65), various derivatives of tetrahydroabietic acid (esters, salts, amides (primary amides, secondary amides, tertiary amides, etc.), alcohols, amines (primary amines, secondary amines, tertiary amines, etc.)). Diterpenes having the structure represented by general formula (3) are not particularly limited. For example, diterpenes having the structure represented by general formula (3) may include diterpenes having a skeleton derived from dihydroabietic acid. There are no particular limitations on diterpenoids with a skeleton derived from dihydroabietic acid. If one were to be listed, it would be dihydroabietic acid (logP: 6.12), various derivatives of dihydroabietic acid (esters, salts, amides (primary amides, secondary amides, tertiary amides, etc.), alcohols, amines (primary amines, secondary amines, tertiary amines, etc.)).

[0033] There is no particular limitation on the alcohols that form esters in various derivatives of tetrahydroabietic acid and dihydroabietic acid. If given as an example, such alcohols include diols such as ethylene glycol, diethylene glycol, triethylene glycol, propylene glycol, neopentyl glycol, dimerols, bisphenol A, and bisphenol F; triols such as glycerol, trimethylolethane, and trimethylolpropane; tetraols such as pentaerythritol and diglycerol; and hexaols such as dipentaerythritol. The alcohol may be used alone or in combination with two or more.

[0034] There are no particular limitations on the salts of various derivatives of tetrahydroabietic acid and dihydroabietic acid. If one example is given, such a salt is an alkali metal salt, alkaline earth metal salt, amine salt, or ammonium salt. There are no particular limitations on the alkali metals contained in alkali metal salts. If one example is given, such alkali metals are sodium, potassium, etc., and these alkali metals can be used alone or in combination with two or more. There are no particular limitations on the alkaline earth metals contained in alkaline earth metal salts. If one example is given, such alkaline earth metals are beryllium, magnesium, calcium, strontium, barium, etc., and these alkaline earth metals can be used alone or in combination with two or more.

[0035] In this embodiment, the diterpenoid (A) may be a diterpenoid having a structure other than that represented by the general formula (1).

[0036] Diterpenes having structures other than those represented by general formula (1) are not particularly limited. If one example is given, diterpenes having structures other than those represented by general formula (1) include various derivatives of dehydroabietic acid (esters, salts, amides (primary amides, secondary amides, tertiary amides, etc.), alcohols, amines (primary amines, secondary amines, tertiary amines, etc.)), and various derivatives of abietic acid (esters, salts, amides (primary amides, secondary amides, tertiary amides, etc.), alcohols, amines (primary amines, secondary amines, tertiary amines, etc.)). Furthermore, the various derivatives of dehydroabietic acid and the alcohols that form esters among the various derivatives of abietic acid are not particularly limited; if one example is given, it is the alcohol mentioned above. Additionally, the various derivatives of dehydroabietic acid and the salts among the various derivatives of abietic acid are not particularly limited; if one example is given, it is the salt mentioned above.

[0037] The logP values ​​of representative examples of diterpenes having the structure represented by general formula (1) and diterpenes having structures other than those represented by general formula (1) are shown in Table 1 below. In addition, several diterpenes with logP less than 6 are also shown in Table 1 for reference.

[0038] [Table 1]

[0039] Table 1

[0040]

[0041] The details of the abbreviations in Table 1 are as follows.

[0042] DAA skeleton: derived from dehydroabietic acid skeleton; AA skeleton: derived from abietic acid skeleton; THAA skeleton: derived from tetrahydroabietic acid skeleton; DHAA skeleton: derived from dihydroabietic acid skeleton; Me: methyl; Na: sodium; K: potassium; Gly: glycerol; Gly diester: diester formed by esterification of 2 molecules of diterpene carboxylic acid and 1 molecule of glycerol; Gly triester: triester formed by esterification of 3 molecules of diterpene carboxylic acid and 1 molecule of glycerol; TEG monoester: monoester formed by esterification of 1 molecule of diterpene carboxylic acid and 1 molecule of triethylene glycol; TEG diester: diester formed by esterification of 2 molecules of diterpene carboxylic acid and 1 molecule of triethylene glycol.

[0043] Regarding the skeletons derived from pithiazolic acid in Table 1, the structures of the DAA skeleton, AA skeleton, THAA skeleton and DHAA skeleton are shown in the following general formulas (4) to (8).

[0044] [Chemistry 4]

[0045]

[0046] (In formula (4), * indicates the bonding site with other substituents)

[0047] [Chemistry 5]

[0048]

[0049] (In formula (5), * indicates the bonding site with other substituents)

[0050] [Chemistry 6]

[0051]

[0052] (In formula (6), * indicates the bonding site with other substituents)

[0053] [Chemistry 7]

[0054]

[0055] (In formula (7), * indicates the bonding site with other substituents)

[0056] [Chemistry 8]

[0057]

[0058] (In formula (8), * indicates the bonding site with other substituents; in addition, the dashed part indicates that there is a carbon-carbon bond at any point, and a carbon-carbon bond exists at any point in all the dashed parts.)

[0059] Of these, diterpenoid (A) is preferably at least one of the group consisting of diterpenoids having the structure represented by general formula (2), diterpenoids having the structure represented by general formula (3), and various derivatives of dehydroabietic acid; more preferably, it is at least one of the group consisting of tetrahydroabietic acid (THAA skeleton represented by general formula (7) bonded to COOH), various derivatives of tetrahydroabietic acid, dihydroabietic acid (DHAA skeleton represented by general formula (8) bonded to COOH), various derivatives of dihydroabietic acid, and various derivatives of dehydroabietic acid; and even more preferably, it is at least one of tetrahydroabietic acid or dihydroabietic acid. Thus, biofilm formation inhibitors more readily inhibit biofilm formation, and even low concentrations that do not exhibit antibacterial activity can inhibit biofilm formation.

[0060] Diterpenoids (A) may be rosin classes containing the diterpenoids mentioned above. There is no particular limitation on this type of rosin class; examples include hydrogenated rosin, disproportionated rosin, rosin esters, alkali metal salts of rosin, alkaline earth metal salts of rosin, rosin amines, rosin alcohols, rosin amides, etc. A single rosin class may be used, or two or more may be used in combination.

[0061] (Hydrogenated rosin)

[0062] Hydrogenated rosin can be obtained using various known methods. Specifically, for example, it can be obtained by hydrogenating natural rosin (gum rosin, tall oil rosin, wood rosin) or refined rosin (hereinafter, both natural and refined rosin are collectively referred to as unmodified rosin) derived from Pinus massoniana, Pinus elliottii, Pinus merkusii, Pinus caribaea, Pinus kesiya, Pinus taeda, and Pinus palustris, using known hydrogenation conditions. Examples of hydrogenation conditions include heating the unmodified rosin to approximately 100°C to 300°C in the presence of a hydrogenation catalyst at a hydrogen pressure of approximately 2 MPa to 20 MPa. Furthermore, the hydrogen pressure is preferably set to approximately 5 MPa to 20 MPa, and the reaction temperature is preferably set to approximately 150°C to 300°C. Various known hydrogenation catalysts, such as supported catalysts and metal powders, can be used as hydrogenation catalysts. Examples of supported catalysts include palladium-carbon, rhodium-carbon, ruthenium-carbon, and platinum-carbon. Examples of metal powders include nickel and platinum. Among these, palladium, rhodium, ruthenium, and platinum-based catalysts are preferred for increasing the hydrogenation rate and shortening the hydrogenation time of unmodified rosin. Furthermore, the amount of hydrogenation catalyst used is typically about 0.01 to 5 parts by weight relative to 100 parts by weight of unmodified rosin, preferably about 0.01 to 2 parts by weight.

[0063] Hydrogenation can be carried out as needed, with the unmodified rosin dissolved in a solvent. The solvent used is not particularly limited, as long as it is inert in the reaction and readily soluble in the reactants or products. Examples of solvents include cyclohexane, n-hexane, n-heptane, decahydronaphthalene, tetrahydrofuran, and dioxane; one or more of these can be used. The amount of solvent used is not particularly limited; generally, it is sufficient to have a solid content of 10% by mass or more, preferably around 10% to 70% by mass, relative to the unmodified rosin.

[0064] Furthermore, as hydrogenated rosin, the obtained hydrogenated rosin can be further refined, hydrogenated, or subjected to various treatments such as disproportionation (described later), either individually or in combination of two or more treatments. There are no particular limitations on the refining treatment. Examples include distillation, extraction, recrystallization, and adsorption.

[0065] Furthermore, to improve the color tone, the hydrogenated rosin can be further dehydrogenated. The dehydrogenation process is not particularly limited and can be performed under normal conditions. For example, the hydrogenated rosin can be subjected to dehydrogenation in a closed container in the presence of a dehydrogenation catalyst at an initial hydrogen pressure of less than 10 kg / cm².2 Preferably less than 5 kg / cm 2 The reaction is carried out at a temperature of approximately 100°C to 300°C, preferably within the lower limit of 200°C and the upper limit of 280°C. There are no particular limitations on the dehydrogenation catalyst; various known dehydrogenation catalysts can be used, preferably palladium-based, rhodium-based, or platinum-based catalysts, typically supported on silica, carbon, or other supports. Furthermore, the amount of catalyst used relative to hydrogenated rosin is typically set to approximately 0.01% to 5% by weight, preferably within the lower limit of 0.05% by weight and the upper limit of 3% by weight.

[0066] (Dismutated rosin)

[0067] Disproportionated rosin can be obtained using various known methods. Specifically, for example, it can be obtained by heating unmodified rosin in the presence of a disproportionation catalyst (disproportionation). As a disproportionation catalyst, various known disproportionation catalysts can be used, such as supported catalysts like palladium-carbon, rhodium-carbon, and platinum-carbon; metal powders like nickel and platinum; and iodides like iodine and iron iodide. The amount of catalyst used is typically about 0.01 to 5 parts by weight relative to 100 parts by weight of unmodified rosin, preferably about 0.01 to 1 part by weight. The reaction temperature is about 100°C to 300°C, preferably about 150°C to 290°C.

[0068] In addition, as disproportionated rosin, the obtained disproportionated rosin can be subjected to various treatments such as refining, disproportionation, and hydrogenation alone, or a combination of two or more treatments can be performed.

[0069] In addition, to improve the color tone, disproportionated rosin can also undergo the aforementioned dehydrogenation treatment, similar to that performed on hydrogenated rosin.

[0070] (Rosin esters)

[0071] Rosin esters are not specifically limited. If given as an example, rosin esters may be the reaction product of unmodified rosin and an alcohol (unmodified rosin ester), the reaction product of hydrogenated rosin and an alcohol (hydrogenated rosin ester), the reaction product of disproportionated rosin and an alcohol (disproportionated rosin ester), etc. The alcohols in rosin esters are not specifically limited; if given as an example, they may be the alcohols mentioned above.

[0072] In addition, to improve the color tone, the same dehydrogenation treatment can be performed on refined rosin, similar to that on hydrogenated rosin.

[0073] Rosin esters can be obtained using various known methods. Specifically, for example, unmodified rosin, hydrogenated rosin, disproportionated rosin, and alcohol can be reacted at a temperature of approximately 150°C to 300°C for approximately 1 hour to 24 hours. There are no particular limitations on the amounts of unmodified rosin, hydrogenated rosin, disproportionated rosin, and alcohol; generally, the ratio of the OH groups of the alcohol to the COOH groups of the rosin (equivalent ratio) is determined to be approximately 0.8 to 8, preferably approximately 1.1 to 1.3.

[0074] In the manufacturing method of rosin esters, the obtained rosin esters may be further subjected to various treatments such as refining, hydrogenation, and disproportionation. Furthermore, these treatments may be performed individually or in combination of two or more.

[0075] In addition, the manufacturing methods of hydrogenated rosin esters and disproportionated rosin esters can also be methods that modify the reaction products of unmodified rosin and alcohol based on hydrogenation and disproportionation, respectively.

[0076] (Alkali metal salts of rosin)

[0077] Alkali metal salts of rosin (hereinafter also referred to as alkali metal salts) are neutral salts of rosin based on metal compounds containing alkali metals (hereinafter also referred to as alkali metal compounds).

[0078] There are no particular limitations on the rosin in alkali metal salts, as long as it is a rosin-based resin with a carboxyl group. For example, rosin in alkali metal salts includes unmodified rosin, hydrogenated rosin, and disproportionated rosin.

[0079] There is no particular limitation on the alkali metal contained in alkali metal salts. For example, alkali metal salts may contain sodium, potassium, etc. Alkali metals can be used alone or in combination with two or more.

[0080] There are no particular restrictions on alkali metal compounds, as long as they form salts with rosin. For example, alkali metal compounds include hydroxides, oxides, chlorides, nitrates, acetates, sulfates, and carbonates of alkali metals. Alkali metal compounds can be used alone or in combination with two or more.

[0081] The preferred alkali metal compounds are sodium hydroxide and potassium hydroxide. Furthermore, the form of the alkali metal compounds is not particularly limited, but aqueous solutions are preferred.

[0082] Alkali metal salts are obtained by reacting (neutralizing) rosin with alkali metal compounds.

[0083] Methods for reacting rosin with alkali metal compounds include, for example, the direct method (where rosin reacts directly with the alkali metal compound in the presence or absence of a solvent), and the double displacement method (where a metal salt other than an alkali metal in rosin reacts with an alkali metal compound in the presence of a solvent to achieve salt exchange). There are no particular limitations on the reaction temperature, which is usually in the range of room temperature to the boiling point of the solvent. The reaction time varies depending on the reaction temperature, but is typically from 10 minutes to about 24 hours. Alternatively, the solvent can be removed by distillation after the reaction is complete.

[0084] There are no particular limitations on the solvent. If given as an example, the solvent could be water; alcohol solvents such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, ethylene glycol, and propylene glycol; ether alcohol solvents such as diethylene glycol, triethylene glycol, and 2-methoxyethanol; aromatic hydrocarbon solvents such as toluene and xylene; ester solvents such as ethyl acetate and butyl acetate; and ketone solvents such as methyl ethyl ketone and methyl isobutyl ketone. Water is preferred as the solvent.

[0085] The reaction of rosin with alkali metal compounds is carried out in such a manner that the amount of alkali metal introduced relative to the COOH group of rosin is typically 5 equivalents to 100 equivalents, preferably 10 equivalents to 100 equivalents.

[0086] (Alkali earth metal salts of rosin)

[0087] Alkaline earth metal salts of rosin (hereinafter also referred to as alkaline earth metal salts) are neutralized salts of rosin based on metal compounds containing alkaline earth metals (hereinafter also referred to as alkaline earth metal compounds).

[0088] There are no particular limitations on the rosin in alkaline earth metal salts, as long as it is a rosin-based resin with a carboxyl group. For example, the rosin in alkaline earth metal salts could be unmodified rosin, hydrogenated rosin, or disproportionated rosin.

[0089] There are no particular limitations on the alkaline earth metals contained in alkaline earth metal salts. Examples include beryllium, magnesium, calcium, strontium, and barium. Alkaline earth metals can be used alone or in combination with two or more.

[0090] Alkaline earth metals are preferably selected from at least one of the groups consisting of magnesium and calcium.

[0091] There are no particular restrictions on alkaline earth metal compounds, as long as they form salts with rosin. For example, alkaline earth metal compounds include hydroxides, oxides, chlorides, nitrates, acetates, sulfates, and carbonates of alkaline earth metals. Alkaline earth metal compounds can be used alone or in combination with two or more.

[0092] The preferred alkaline earth metal compounds are magnesium hydroxide, magnesium oxide, calcium hydroxide, and calcium oxide.

[0093] Alkaline earth metal salts are obtained by reacting (neutralizing) rosin with alkaline earth metal compounds.

[0094] Methods for reacting rosin with alkaline earth metal compounds include, for example, the direct method, in the presence or absence of an organic solvent; and the double displacement method, in the presence of water and / or an organic solvent, reacting a metal salt of rosin other than an alkaline earth metal with an alkaline earth metal compound to achieve salt exchange. There are no particular limitations on the reaction temperature; in the direct method, it is typically around 150°C to 270°C, while in the double displacement method, it is typically the range from room temperature to the boiling point of the solvent. The reaction time varies depending on the reaction temperature, typically ranging from 10 minutes to 24 hours. Alternatively, the solvent can be removed by distillation after the reaction is complete.

[0095] There are no particular limitations on organic solvents. If we were to give an example, it would be aromatic hydrocarbon solvents such as toluene and xylene; ester solvents such as ethyl acetate and butyl acetate; ketone solvents such as methyl ethyl ketone and methyl isobutyl ketone, etc.

[0096] The reaction of rosin with alkaline earth metal compounds is carried out in such a manner that the amount of alkaline earth metal introduced relative to the COOH group of rosin is typically 5 equivalents to 100 equivalents, preferably 10 equivalents to 100 equivalents.

[0097] (Rosin amines)

[0098] There is no particular limitation on rosin amines. If given as an example, rosin amines are amines obtained by hydrogenation following a reaction of rosin with ammonia (as described in U.S. Patent No. 2,534,297), or amines obtained by reducing the amide group (hydride reduction, hydrogenation) of the rosin amide to produce the rosin amides described later from rosin and amines. There is no particular limitation on the rosin in rosin amines, as long as it is a rosin-based resin containing a carboxyl group. If given as an example, the rosin in rosin amines are unmodified rosin, hydrogenated rosin, disproportionated rosin, etc. Furthermore, amines obtained from unmodified rosin are referred to as unmodified rosin amines, amines obtained from hydrogenated rosin are referred to as hydrogenated rosin amines, and amines obtained from disproportionated rosin are referred to as disproportionated rosin amines.

[0099] (Rosin alcohols)

[0100] There is no particular limitation on rosin alcohols. If given as an example, rosin alcohols are alcohols obtained by hydrogenating and reducing the carboxyl groups in rosin (Japanese Patent Application Publication No. 2014-133866). There is no particular limitation on the type of rosin alcohol as long as it is a rosin-based resin containing carboxyl groups. If given as an example, the type of rosin alcohol includes unmodified rosin, hydrogenated rosin, disproportionated rosin, etc. Furthermore, alcohols obtained from unmodified rosin are referred to as unmodified rosin alcohols, alcohols obtained from hydrogenated rosin are referred to as hydrogenated rosin alcohols, and alcohols obtained from disproportionated rosin are referred to as disproportionated rosin alcohols.

[0101] (Rosin amides)

[0102] There are no particular limitations on rosin amides. If given as an example, rosin amides are amides obtained by reacting rosin with ammonia or amines (amidation). There are no particular limitations on the rosin in rosin amides, as long as it is a rosin-based resin containing a carboxyl group. If given as an example, the rosin in rosin amides can be unmodified rosin, hydrogenated rosin, disproportionated rosin, etc. Furthermore, amides obtained from unmodified rosin are also referred to as unmodified rosin amides, amides obtained from hydrogenated rosin are referred to as hydrogenated rosin amides, and amides obtained from disproportionated rosin are referred to as disproportionated rosin amides.

[0103] The amines in rosin amides are not particularly limited as long as they contain at least one amino group within the molecule. For example, amines in rosin amides could be aliphatic monoamines, aliphatic polyamines, alicyclic monoamines, alicyclic polyamines, aromatic monoamines, aromatic polyamines, etc. Furthermore, the amino group in the amines is also not particularly limited. For example, the amino group in the amines could be primary amino, secondary amino, tertiary amino, etc.

[0104] There are no particular limitations on the method for reacting rosin with amines, and various known methods can be used. Specifically, for example, the following methods can be listed: converting rosin into an acyl chloride via the thionyl chloride method, and then reacting it with amines in the presence or absence of an organic solvent (amidation).

[0105] The organic solvent is not particularly limited as long as it is inert to the reactants. For example, organic solvents include benzene, toluene, xylene, dimethyl ether, diisobutyl ether, tetrahydrofuran, acetone, methyl ethyl ketone, methyl isobutyl ketone, etc.

[0106] In the reaction (amidation), a basic substance or a tertiary amine can be used as a catalyst as needed. The basic substance is not particularly limited; examples include sodium hydroxide, potassium hydroxide, sodium bicarbonate, and sodium carbonate. The tertiary amine is not particularly limited; examples include trimethylamine, triethylamine, tributylamine, and pyridine. Furthermore, the tertiary amine can also be used as a reaction solvent if the aromatic monoamine is soluble in it.

[0107] Additionally, diterpenoid (A) may also be a rosin containing a diterpenoid having the structure represented by general formula (1). There is no particular limitation on such a rosin, but if we give an example, a rosin containing a diterpenoid having the structure represented by general formula (1) is a rosin containing at least one of a diterpenoid having the structure represented by said general formula (2) or a diterpenoid having the structure represented by said general formula (3).

[0108] The term "rosin" is not particularly limited to rosins containing at least one of the diterpenoids having the structure represented by general formula (2) or the diterpenoids having the structure represented by general formula (3), but by way of example, it includes the hydrogenated rosin containing at least one of tetrahydroabsic acid or dihydroabsic acid, various derivatives of such hydrogenated rosin (hydrogenated rosin esters), various salts of hydrogenated rosin (alkali metal salts of hydrogenated rosin, alkaline earth metal salts of hydrogenated rosin, hydrogenated rosin...). The disproportionated rosin includes amine salts, hydrogenated rosin ammonium salts, hydrogenated rosin amides, hydrogenated rosin alcohols, hydrogenated rosin amines, and disproportionated rosin containing at least one of tetrahydroabsic acid or dihydroabsic acid, as well as various derivatives of such disproportionated rosin (disproportionated rosin esters, various salts of disproportionated rosin (alkali metal salts of disproportionated rosin, alkaline earth metal salts of disproportionated rosin, amine salts of disproportionated rosin, and hydrogenated rosin ammonium salts), disproportionated rosin amides, disproportionated rosin alcohols, and disproportionated rosin amines), etc.

[0109] Diterpenoids (A) can also be rosins containing diterpenoids having structures other than those represented by general formula (1). As an example, rosins containing diterpenoids having structures other than those represented by general formula (1) include various derivatives of the disproportionated rosin containing dehydroabsic acid (disproportionated rosin esters, various salts of disproportionated rosin (alkali metal salts of disproportionated rosin, alkaline earth metal salts of disproportionated rosin, amine salts of disproportionated rosin, ammonium salts of disproportionated rosin), disproportionated rosin amides, disproportionated rosin alcohols, disproportionated rosin amines), and various derivatives of the unmodified rosin containing abietic acid (alkali metal salts of unmodified rosin, alkaline earth metal salts of unmodified rosin, amine salts of unmodified rosin, ammonium salts of unmodified rosin, unmodified rosin amides, unmodified rosin alcohols, unmodified rosin amines), etc.

[0110] Of these, the diterpenoid (A) is preferably selected from at least one of the group consisting of diterpenoids having the structure represented by general formula (2), rosin derivatives having the structure represented by general formula (3), and various derivatives of disproportionated rosin containing dehydroabietic acid; more preferably, it is selected from at least one of the group consisting of hydrogenated rosin containing at least one of tetrahydroabietic acid or dihydroabietic acid, various derivatives of said hydrogenated rosin, disproportionated rosin containing at least one of tetrahydroabietic acid or dihydroabietic acid, various derivatives of said disproportionated rosin, and various derivatives of disproportionated rosin containing dehydroabietic acid; and even more preferably, it is selected from at least one of the group consisting of hydrogenated rosin containing at least one of tetrahydroabietic acid or dihydroabietic acid and esters of said hydrogenated rosin (hydrogenated rosin esters). Thus, biofilm formation inhibitors more readily inhibit biofilm formation, and even low concentrations that do not exhibit antibacterial activity can inhibit biofilm formation.

[0111] In the case where the diterpenoid (A) in this embodiment is the rosin, the content of the diterpenoid having the structure represented by general formula (1) in the rosin is not particularly limited. As an example, the content of the diterpenoid having the structure represented by general formula (1) relative to 100% by mass of the rosin is preferably 5% by mass or more, more preferably 10% by mass or more, more preferably 15% by mass or more, more preferably 20% by mass or more, more preferably 30% by mass or more, more preferably 40% by mass or more, more preferably 50% by mass or more, more preferably 60% by mass or more, more preferably 70% by mass or more, more preferably 80% by mass or more, and particularly preferably 90% by mass or more. Furthermore, the content of the diterpenoid having the structure represented by general formula (1) relative to 100% by mass of the rosin is preferably 100% by mass or less. With the content of the diterpenoid having the structure represented by general formula (1) within the aforementioned range, the biofilm formation inhibitor more easily inhibits biofilm formation; furthermore, even at low concentrations that do not exhibit antibacterial activity, biofilm formation can be inhibited.

[0112] In the case where the diterpenoid (A) in this embodiment is the rosin, the content of the diterpenoid having the structure represented by general formula (2) in the rosin is not particularly limited. As an example, the content of the diterpenoid having the structure represented by general formula (2) relative to 100% by mass of the rosin is preferably 5% by mass or more, more preferably 10% by mass or more, more preferably 15% by mass or more, more preferably 20% by mass or more, more preferably 30% by mass or more, more preferably 40% by mass or more, more preferably 50% by mass or more, more preferably 60% by mass or more, more preferably 70% by mass or more, more preferably 80% by mass or more, and particularly preferably 90% by mass or more. Furthermore, the content of the diterpenoid having the structure represented by general formula (2) relative to 100% by mass of the rosin is preferably 100% by mass or less. With the content of the diterpenoid having the structure represented by general formula (2) within the aforementioned range, the biofilm formation inhibitor more easily inhibits biofilm formation; furthermore, even at low concentrations that do not exhibit antibacterial activity, biofilm formation can be inhibited.

[0113] In the case where the diterpenoid (A) in this embodiment is the rosin, the content of the diterpenoid having the structure represented by general formula (3) in the rosin is not particularly limited. As an example, the content of the diterpenoid having the structure represented by general formula (3) relative to 100% by mass of the rosin is preferably 5% by mass or more, more preferably 10% by mass or more, more preferably 15% by mass or more, more preferably 20% by mass or more, more preferably 30% by mass or more, more preferably 40% by mass or more, more preferably 50% by mass or more, more preferably 60% by mass or more, and particularly preferably 70% by mass or more. Furthermore, the content of the diterpenoid having the structure represented by general formula (3) relative to 100% by mass of the rosin is preferably 100% by mass or less. With the content of the diterpenoid having the structure represented by general formula (3) within the aforementioned range, the biofilm formation inhibitor more easily inhibits biofilm formation; furthermore, even at low concentrations that do not exhibit antibacterial activity, biofilm formation can be inhibited.

[0114] When the diterpenoid (A) in this embodiment is the rosin, the content of tetrahydroabietic acid in the hydrogenated rosin is not particularly limited. As an example, the content of tetrahydroabietic acid relative to 100% by mass of the hydrogenated rosin is preferably 10% by mass or more, more preferably 15% by mass or more, more preferably 20% by mass or more, more preferably 30% by mass or more, more preferably 40% by mass or more, more preferably 50% by mass or more, more preferably 60% by mass or more, more preferably 70% by mass or more, more preferably 80% by mass or more, and particularly preferably 90% by mass or more. Furthermore, the content of tetrahydroabietic acid relative to 100% by mass of the hydrogenated rosin is preferably 100% by mass or less. With the tetrahydroabietic acid content within the aforementioned range, biofilm formation inhibitors more easily inhibit biofilm formation; furthermore, even low concentrations that do not exhibit antibacterial activity can inhibit biofilm formation.

[0115] When the diterpenoid (A) in this embodiment is the rosin, the content of dihydroabietic acid in the hydrogenated rosin is not particularly limited. As an example, the content of dihydroabietic acid relative to 100% by mass of the hydrogenated rosin is preferably 1% by mass or more, more preferably 5% by mass or more, more preferably 10% by mass or more, more preferably 15% by mass or more, more preferably 20% by mass or more, more preferably 30% by mass or more, more preferably 40% by mass or more, more preferably 50% by mass or more, more preferably 60% by mass or more, and particularly preferably 70% by mass or more. Furthermore, the content of dihydroabietic acid relative to 100% by mass of the hydrogenated rosin is preferably 100% by mass or less. With the dihydroabietic acid content within the aforementioned range, biofilm formation inhibitors more easily inhibit biofilm formation; moreover, even low concentrations that do not exhibit antibacterial activity can inhibit biofilm formation.

[0116] When the diterpenoid (A) in this embodiment is the rosin, the content of tetrahydroabietic acid in the disproportionated rosin is not particularly limited. As an example, the content of tetrahydroabietic acid relative to 100% by mass of the disproportionated rosin is preferably 10% by mass or more, more preferably 15% by mass or more, more preferably 20% by mass or more, more preferably 30% by mass or more, and particularly preferably 40% by mass or more. Furthermore, the content of tetrahydroabietic acid relative to 100% by mass of the disproportionated rosin is preferably less than 50% by mass. With the tetrahydroabietic acid content within the aforementioned range, biofilm formation inhibitors more easily inhibit biofilm formation; furthermore, even low concentrations that do not exhibit antibacterial activity can inhibit biofilm formation.

[0117] When the diterpenoid (A) in this embodiment is the rosin, the content of dihydroabietic acid in the disproportionated rosin is not particularly limited. As an example, the content of dihydroabietic acid relative to 100% by mass of the disproportionated rosin is preferably 5% by mass or more, more preferably 10% by mass or more, more preferably 15% by mass or more, more preferably 20% by mass or more, more preferably 30% by mass or more, and particularly preferably 40% by mass or more. Furthermore, the content of dihydroabietic acid relative to 100% by mass of the disproportionated rosin is preferably less than 50% by mass. With the dihydroabietic acid content within the aforementioned range, biofilm formation inhibitors more easily inhibit biofilm formation; furthermore, even low concentrations that do not exhibit antibacterial activity can inhibit biofilm formation.

[0118] Furthermore, the diterpenoid (A) of this embodiment may be derived from natural products extracted from the plant or may be a synthetic compound. Additionally, the diterpenoid (A) of this embodiment includes all its stereoisomers (non-mirror image isomers, epiisomers, mirror image isomers, etc.) or racemic mixtures.

[0119] The physical properties of the diterpenoid (A) in this embodiment are not particularly limited except for the octanol / water partition coefficient (logP). The solubility of the diterpenoid (A) in water at 20°C is not particularly limited, but is preferably 1% by mass or less, more preferably 0.1% by mass or less. By having a solubility in water within the aforementioned range, when the biofilm formation inhibitor is applied (e.g., by coating) to an object or site where a biofilm can form, it can inhibit the breakdown of the coating caused by environmental moisture or human sweat, or the exudation of the diterpenoid (A) from the coating. Therefore, the coating of the biofilm formation inhibitor exhibits excellent durability. Diterpenoids with a solubility in water exceeding 1% by mass at 20°C are not particularly limited; examples include alkali metal salts of tetrahydroabietic acid, alkali metal salts of dihydroabietic acid, alkali metal salts of dehydroabietic acid, alkali metal salts of abietic acid, and alkali metal salts of rosin.

[0120] The biofilm formation inhibitor of this embodiment may contain additives as needed. There are no particular limitations on the additives. For example, additives may include solvents, abrasives, gelling agents, wetting agents, corrosion inhibitors, flavoring agents, sweeteners, analgesics, anti-calcification agents, whitening agents, surfactants, binders, preservatives, opacifying agents, coloring agents, pH buffers, disinfectants, etc. These may be used alone or in combination of two or more. Furthermore, the proportion of additives should be appropriately set according to the purpose and application.

[0121] The types of bacteria from which the biofilm formation inhibitor can be used as the target biofilm source are not particularly limited. If given an example, the types of bacteria include Gram-positive bacteria, Gram-negative bacteria, etc.

[0122] There is no particular limitation on Gram-positive bacteria. If given as an example, Gram-positive bacteria include Staphylococcus (e.g., Staphylococcus aureus, Staphylococcus epidermidis), Enterococcus, Streptococcus (e.g., diplococci, tetradococci, octadococci, etc., Streptococcus pneumoniae, hemolytic streptococci, Streptococcus mutans), Bacillus (e.g., Bacillus anthracis, Bacillus subtilis), and Clostridium (e.g., Clostridium spp.). Tetanus bacteria, Clostridium botulinum, Micrococcus (e.g., Micrococcus luteus), Corynebacterium (e.g., Corynebacterium xerosis, Corynebacterium diphtheriae), Propionibacterium (e.g., Propionibacterium acnes), Mycobacterium (e.g., Mycobacterium tuberculosis), Actinomyces (e.g., Actinomyces israelii), etc.

[0123] There is no particular limitation on Gram-negative bacteria. If given an example, Gram-negative bacteria include Escherichia (e.g., *Escherichia coli*), Salmonella, Pseudomonas (e.g., *Pseudomonas aeruginosa*), Helicobacter, Neisseria (e.g., *Neisseria gonorrhoeae*, *Neisseria meningitidis*), Burkholderia (e.g., *Acinetobacter cephalosporin*), Klebsiella (e.g., *Klebsiella pneumoniae*), Vibrio (*Vibrio*; *Vibrio enteritidis*), Rickettsia, and Spirochaetes, among others.

[0124] Of these, the biofilm formation inhibitor of this embodiment is preferably one that inhibits the formation of biofilms originating from Gram-positive bacteria. Therefore, the biofilm formation inhibitor is particularly effective in inhibiting the formation of biofilms originating from Gram-positive bacteria.

[0125] In particular, the Gram-positive bacteria are preferably selected from at least one species in the group consisting of Staphylococcus, Enterococcus, and Streptococcus. Therefore, biofilm formation inhibitors are particularly effective at inhibiting the formation of biofilms originating from Staphylococcus, Enterococcus, and Streptococcus.

[0126] Furthermore, the Gram-positive bacteria are preferably selected from at least one species in the group consisting of Staphylococcus aureus, Staphylococcus epidermidis, and Streptococcus mutans. Therefore, biofilm formation inhibitors are particularly effective at inhibiting the formation of biofilms originating from Staphylococcus aureus, Staphylococcus epidermidis, and Streptococcus mutans.

[0127] The diterpenoid (A) content in the biofilm formation inhibitor of this embodiment has the following characteristics: it can be any concentration that inhibits biofilm formation, but even at concentrations below the MIC, excellent biofilm formation inhibition effects can be obtained. Furthermore, MIC refers to the minimum inhibitory concentration, which represents the minimum concentration of the agent that can prevent bacterial growth when performing agent susceptibility tests based on agar plate dilution or microliquid dilution methods.

[0128] Regarding the content of diterpenoid (A) in the biofilm formation inhibitor of this embodiment, excellent biofilm formation inhibition effects can be obtained even at concentrations less than the MIC, even at concentrations less than half the MIC, even at concentrations less than one-quarter the MIC, and even at concentrations less than one-eighth the MIC. That is, the biofilm formation inhibitor of this embodiment does not exhibit antibacterial activity but can inhibit biofilm formation. Therefore, the biofilm formation inhibitor can inhibit the emergence of drug-resistant bacteria. Furthermore, regarding obtaining excellent biofilm formation inhibition effects, the content of diterpenoid (A) in the biofilm formation inhibitor of this embodiment is preferably at a concentration of 1 / 100 or more of the MIC, more preferably at a concentration of 1 / 64 or more of the MIC.

[0129] <Methods for Inhibiting Biofilm Formation>

[0130] One embodiment of the present invention is a method for inhibiting biofilm formation by contacting the biofilm formation inhibitor with at least one of the object or the object location.

[0131] The object or location is not particularly limited as long as it is an object or location where microorganisms can easily proliferate and form biofilms. For example, the object or location could be water-related equipment such as kitchens, bathrooms, washrooms, and toilets; equipment, machines, and parts related to such water-related equipment; drainage / water supply / treatment equipment in general households or other establishments; machines and parts related to such drainage / water supply / treatment equipment; and the oral cavity (e.g., teeth, dentures, gums, tongue, oral mucosa, etc.). Additionally, the object or location could also be a hospital, medical equipment, or medical machine. Medical machines are not particularly limited. For example, medical machines could be respiratory endoscopes, gastroscopes, hematological catheters, dialyzer equipment, respiratory pathway maintenance devices, ion-selective electrodes (ISE), high-performance liquid chromatography (HPLC), and catheters used in these applications. Furthermore, medical machines could also be artificial hearts, stents, artificial joints, and dental implant materials.

[0132] The biofilm formation inhibition method of this embodiment inhibits biofilm formation by contacting a biofilm formation inhibitor with at least any of the objects or object sites. As described above, even at low concentrations that do not exhibit antibacterial activity, the biofilm formation inhibitor can inhibit biofilm formation. Therefore, the biofilm formation inhibition method of this embodiment preferably and readily inhibits biofilm formation on the objects or object sites, even when using low concentrations of the biofilm formation inhibitor that do not exhibit antibacterial activity, and furthermore, it can inhibit the emergence of drug-resistant bacteria.

[0133] When implementing methods to inhibit biofilm formation, there are no particular limitations on the form in which the biofilm formation inhibitor comes into contact with the target material or site. For example, the forms of contact between the biofilm formation inhibitor and the target material or site include dispersing, coating, spraying, layering, impregnation, washing, and kneading into the resin. These are chosen appropriately based on the form of the biofilm formation inhibitor.

[0134] <Resin Compositions and Molded Articles>

[0135] An embodiment of the resin composition of the present invention comprises the diterpenoid (A) and a resin.

[0136] There are no particular limitations on the resin. If given as an example, the resin may be a vinyl chloride resin, a styrene resin, a polyamide, a polyamide-imide, a polyimide, a polyester, a polycarbonate, a polyacetal, an acrylonitrile-butadiene-styrene (ABS) resin, a phenoxy resin, a polymethyl methacrylate resin, a polyphenylene ether, a polyphenylene sulfide, a polyetherimide, a liquid crystal polymer, a polyetherketone, a polyethersulfone, a polysulfone, a fluoropolymer, or a polyolefin resin (e.g., polyethylene, polypropylene).

[0137] The content of diterpenoid (A) is not particularly limited. As an example, the content of diterpenoid (A) in the resin composition is preferably 0.01% by mass or more, more preferably 0.1% by mass or more, and even more preferably 5% by mass or more. Furthermore, the content of diterpenoid (A) in the resin composition is preferably 50% by mass or less, more preferably 30% by mass or less. By maintaining the diterpenoid (A) content within the aforementioned range, the resin composition can inhibit biofilm formation even when containing low concentrations of diterpenoid (A) that do not exhibit antibacterial activity.

[0138] One embodiment of the present invention is a molded body formed by molding the resin composition. The shape of the molded body is not particularly limited. By way of example, the shape of the molded body can be appropriately selected according to its use and purpose. By way of example, the shape of the molded body may be plate-shaped, flat plate-shaped, rod-shaped, sheet-shaped, film-shaped, cylindrical, ring-shaped, circular, elliptical, polygonal, irregularly shaped, hollow, frame-shaped, box-shaped, panel-shaped, etc.

[0139] Alternatively, the molded body of this embodiment may also be various molded bodies that constitute the object and the object site in association with the method for inhibiting the formation of biofilms.

[0140] There are no particular limitations on the forming method of the molded body. If we were to give an example, the forming methods of the molded body would be injection molding, injection compression molding, extrusion molding, profile extrusion, compression molding, sheet forming, film forming, transfer molding, gas-assisted molding, hollow forming, gas-assisted hollow forming, blow molding, extrusion blow molding, IMC (in-mold coating) molding, rotational molding, multilayer molding, two-color molding, insert molding, sandwich molding, foam molding, and pressure molding, etc.

[0141] The applications of the resulting molded articles are not particularly limited. For example, the applications of the molded articles include packaging materials, agricultural materials, civil engineering materials, fibers, building materials, automotive parts, household appliance parts, sanitary and medical materials, and other industrial materials.

[0142] Even when the molded body of this embodiment contains a low concentration of diterpenoids (A) that do not exhibit antibacterial properties, the formation of biofilms can be inhibited in the molded body.

[0143] <Coating Agent>

[0144] One embodiment of the coating agent of the present invention comprises the diterpenoid (A). The coating agent is not particularly limited. By way of example, the coating agent may be various thermosetting coating agents, photosetting coating agents, etc.

[0145] The content of diterpenoid (A) is not particularly limited. As an example, the content of diterpenoid (A) in the coating agent is preferably 0.01% by mass or more, more preferably 0.1% by mass or more. Furthermore, the content of diterpenoid (A) in the coating agent is preferably 50% by mass or less, more preferably 30% by mass or less. By using the diterpenoid (A) content within the aforementioned range, the coating agent, when applied to the object or object location, can inhibit biofilm formation even when containing low concentrations of diterpenoid (A) that do not exhibit antibacterial activity.

[0146] There are no particular limitations on the components other than the diterpenoid (A) constituting the coating agent. For example, other components of the coating agent can be any components formulated in existing known thermosetting or photocuring coating agents, such as adhesive resins (acrylic resins, urethane resins, polyester resins, epoxy resins, alkyd resins, phenolic resins, melamine resins, silicone resins, etc.) and polymerization initiators (free radical polymerization initiators, cationic polymerization initiators, anionic polymerization initiators, free radical photopolymerization initiators, cationic photopolymerization initiators, anionic photopolymerization initiators). Ingredients include: hair-setting agents, solvents (ketone solvents, aromatic solvents, alcohol solvents, glycol solvents, glycol ether solvents, ester solvents, petroleum-based solvents, haloalkane solvents, amide solvents, etc.), silicone oils, silane coupling agents and other bonding agents, fillers, leveling agents, rheology modifiers, diluents, surfactants, dispersants, defoamers, dehydrating agents, anti-aging agents, antioxidants, antistatic agents, infrared absorbers, ultraviolet absorbers, light stabilizers, fluorescent agents, dyes, pigments, fragrances, abrasives, rust inhibitors, thixotropic agents, etc.

[0147] There is no particular limitation on the object or location to which the coating agent is applied. However, if given as an example, the object or location may be the object and location associated with the method for inhibiting biofilm formation.

[0148] By applying the coating agent of this embodiment to objects or object sites, the surfaces of these objects and symmetrical sites can be endowed with excellent biofilm formation inhibition effects.

[0149] <Oral Compositions>

[0150] An embodiment of the oral composition of the present invention comprises the diterpenoid (A).

[0151] There are no particular limitations on the form of oral compositions. For example, oral compositions may be in the form of toothpaste, gel, powder, solution (oral cleanser, dental rinse), suspension, emulsion, lozenges (candy), liquid, tablets, chewing gum, etc. Furthermore, there are no particular limitations on the method of preparing oral compositions; known methods may be used depending on the form of the oral composition.

[0152] There are no particular limitations on the method of using the oral composition, and known methods can be used depending on the form of the oral composition. For example, when the oral composition is toothpaste, the oral composition can be used to treat the oral cavity (e.g., teeth, dentures, gums, tongue, oral mucosa, etc.) at any frequency.

[0153] There are no particular limitations on the components other than diterpenoids (A) constituting the oral composition. If one were to cite an example, other components of the oral composition could be any components formulated in existing, known oral compositions, such as water, surfactants, abrasives, humectants, monohydric alcohols, binders, flavorings, sweeteners, pH adjusters, preservatives, colorings, bactericides, natural polymers (e.g., gelatin, collagen, konjac mannan, polyglucan, chitosan, starch, etc.), synthetic polymers (e.g., polyethylene glycol, carboxyvinyl polymers, etc.), polysaccharides (e.g., dextran, polyacrylic acid dextran, etc.), lecithin (soy lecithin, egg yolk lecithin, etc.), polylactic acid, polyglycolic acid, albumin, cyclodextrin, etc.

[0154] There are no particular limitations on the method of using the oral composition, and known methods can be used depending on the form of the oral composition. For example, when the oral composition is toothpaste, the oral cavity (e.g., teeth, dentures, gums, tongue, oral mucosa, etc.) can be treated with the oral composition at any frequency.

[0155] The present invention has been described above as one embodiment. The present invention is not particularly limited to this embodiment. Furthermore, the embodiment described primarily refers to an invention having the following structure.

[0156] (1) A biofilm formation inhibitor comprising a diterpenoid (A) having an octanol / water partition coefficient (logP) of 6 or more.

[0157] Based on this structure, biofilm formation inhibitors can suppress biofilm formation.

[0158] (2) The biofilm formation inhibitor according to (1), wherein the diterpenoid (A) has the structure represented by the following general formula (1).

[0159] [Chemistry 9]

[0160]

[0161] (In formula (1), * indicates the bonding site with other substituents; in addition, the dashed part indicates that a carbon-carbon bond may be present at this point; when a carbon-carbon bond is present in the dashed part, a carbon-carbon bond may be present at any point in all the dashed parts)

[0162] Based on this structure, biofilm formation inhibitors are more likely to suppress biofilm formation.

[0163] (3) The biofilm formation inhibitor according to (1) or (2), wherein the diterpenoid (A) comprises at least one of tetrahydroabsic acid or dihydroabsic acid.

[0164] Based on this structure, biofilm formation inhibitors are more likely to suppress biofilm formation.

[0165] (4) The biofilm formation inhibitor according to (1) or (2), wherein the diterpenoid (A) is a hydrogenated rosin containing at least one of tetrahydroabsic acid or dihydroabsic acid.

[0166] Based on this structure, biofilm formation inhibitors are more likely to suppress biofilm formation.

[0167] (5) The biofilm formation inhibitor according to (1) or (2), wherein the diterpenoid (A) is a rosin ester, and the rosin ester is a reaction product of hydrogenated rosin containing at least one of tetrahydroabsic acid or dihydroabsic acid and an alcohol.

[0168] Based on this structure, biofilm formation inhibitors are more likely to suppress biofilm formation.

[0169] (6) A biofilm formation inhibitor according to any one of (1) to (5), wherein the solubility of the diterpenoid (A) in water at 20°C is less than 1% by mass.

[0170] Based on this structure, when biofilm formation inhibitors are applied (e.g., by coating) to objects or sites where biofilms can form, they can inhibit the breakdown of the coating caused by environmental moisture or human sweat, or the exudation of diterpenoids (A) from the coating. Therefore, biofilm formation inhibitor coatings exhibit excellent durability.

[0171] (7) A biofilm formation inhibitor according to any one of (1) to (6) that inhibits the formation of biofilms derived from Gram-positive bacteria.

[0172] Based on this structure, biofilm formation inhibitors, especially in applications involving the formation of biofilms derived from Gram-positive bacteria, preferably readily inhibit biofilm formation.

[0173] (8) The biofilm formation inhibitor according to (7), wherein the Gram-positive bacteria is selected from at least one species of the group consisting of Staphylococcus, Enterococcus and Streptococcus.

[0174] Based on this structure, biofilm formation inhibitors are particularly effective at inhibiting the formation of biofilms originating from Staphylococcus, Enterococcus, and Streptococcus.

[0175] (9) The biofilm formation inhibitor according to (7) or (8), wherein the Gram-positive bacteria is selected from at least one of the group consisting of Staphylococcus aureus, Staphylococcus epidermidis and Streptococcus mutans.

[0176] Based on this structure, biofilm formation inhibitors are particularly effective at inhibiting the formation of biofilms originating from Staphylococcus aureus, Staphylococcus epidermidis, and Streptococcus mutans.

[0177] (10) A method for inhibiting the formation of a biofilm, wherein the biofilm formation inhibitor according to any one of (1) to (9) is brought into contact with at least one of the object or the object site.

[0178] Based on this structure, biofilm formation inhibition methods can easily suppress biofilm formation on objects (such as medical catheters) or locations (especially bathrooms or washbasins).

[0179] (11) A resin composition comprising the diterpenoid (A) according to any one of (1) to (9) and a resin.

[0180] Based on this structure, the resin composition can inhibit the formation of biofilms.

[0181] (12) A molded body formed from the resin composition according to (11).

[0182] According to this structure, the formation of biofilm can be suppressed in the shaped body.

[0183] (13) A coating agent comprising the diterpenoid (A) according to any one of (1) to (9).

[0184] Based on this structure, the coating agent can inhibit the formation of biofilms by being applied to the object or object site.

[0185] In addition, the following items are provided in this disclosure.

[0186] (Project A1)

[0187] A biofilm formation inhibitor comprising a diterpenoid (A) with an octanol / water partition coefficient (logP) of 6 or higher.

[0188] (Project A2)

[0189] According to the biofilm formation inhibitor of the project, the diterpenoid (A) has the structure represented by the following general formula (1).

[0190] [Chemistry 10]

[0191]

[0192] (In formula (1), * indicates the bonding site with other substituents; in addition, the dashed part indicates that a carbon-carbon bond may be present at this point; when a carbon-carbon bond is present in the dashed part, a carbon-carbon bond may be present at any point in all the dashed parts)

[0193] (Project A3)

[0194] The biofilm formation inhibitor according to any one of the items, wherein the diterpenoid (A) has the structure represented by the following general formula (2).

[0195] [Chemistry 11]

[0196]

[0197] (In formula (2), * indicates the bonding site with other substituents)

[0198] (Project A4)

[0199] The biofilm formation inhibitor according to any one of the items, wherein the diterpenoid (A) has the structure represented by the following general formula (3).

[0200] [Chemistry 12]

[0201]

[0202] (In formula (3), * indicates the bonding site with other substituents; in addition, the dashed part indicates that there is a carbon-carbon bond at any point, and a carbon-carbon bond exists at any point in all the dashed parts.)

[0203] (Project A5)

[0204] The biofilm formation inhibitor according to any one of the items, wherein the diterpenoid (A) comprises at least one selected from the group consisting of diterpenoids having the structure represented by the general formula (2), diterpenoids having the structure represented by the general formula (3), and derivatives of dehydroabsic acid.

[0205] (Project A6)

[0206] Biofilm formation inhibitor according to any one of the items, wherein the diterpenoid (A) comprises at least one selected from the group consisting of tetrahydroabsic acid, derivatives of tetrahydroabsic acid, dihydroabsic acid, derivatives of dihydroabsic acid, and derivatives of dehydroabsic acid.

[0207] (Project A7)

[0208] The biofilm formation inhibitor according to any one of the items, wherein the diterpenoid (A) comprises at least one of tetrahydroabsic acid or dihydroabsic acid.

[0209] (Project A8)

[0210] The biofilm formation inhibitor according to any one of the items, wherein the diterpenoid (A) is a rosin class comprising a diterpenoid having the structure represented by the general formula (1).

[0211] (Project A9)

[0212] The biofilm formation inhibitor according to any one of the items, wherein the diterpenoid (A) is a rosin class comprising a diterpenoid having the structure represented by the general formula (2).

[0213] (Project A10)

[0214] The biofilm formation inhibitor according to any one of the items, wherein the diterpenoid (A) is a rosin class comprising a diterpenoid having the structure represented by the general formula (3).

[0215] (Project A11)

[0216] According to any one of the biofilm formation inhibitors, wherein the diterpenoid (A) is a rosin class comprising at least one of the group consisting of diterpenoids having the structure represented by the general formula (2), diterpenoids having the structure represented by the general formula (3), and derivatives of dehydroabsic acid.

[0217] (Project A12)

[0218] The biofilm formation inhibitor according to any one of the items, wherein the diterpenoid (A) is a rosin class comprising at least one selected from the group consisting of tetrahydroabsic acid, derivatives of tetrahydroabsic acid, dihydroabsic acid, derivatives of dihydroabsic acid, and derivatives of dehydroabsic acid.

[0219] (Project A13)

[0220] The biofilm formation inhibitor according to any one of the items, wherein the diterpenoid (A) is a rosin class comprising at least one of tetrahydroabsic acid or dihydroabsic acid.

[0221] (Project A14)

[0222] According to any one of the biofilm formation inhibitors of the project, wherein the diterpenoid (A) is a rosin comprising at least one of the group consisting of disproportionated rosin containing at least one of tetrahydroabsic acid or dihydroabsic acid, derivatives of said disproportionated rosin, hydrogenated rosin containing at least one of tetrahydroabsic acid or dihydroabsic acid, and derivatives of said hydrogenated rosin.

[0223] (Project A15)

[0224] The biofilm formation inhibitor according to any one of the items, wherein the diterpenoid (A) is a disproportionated rosin containing at least one of tetrahydroabsic acid or dihydroabsic acid.

[0225] (Project A16)

[0226] The biofilm formation inhibitor according to any one of the items, wherein the diterpenoid (A) is a derivative of disproportionated rosin containing at least one of tetrahydroabsic acid or dihydroabsic acid.

[0227] (Project A17)

[0228] Biofilm formation inhibitor according to any one of the items, wherein the diterpenoid (A) is a hydrogenated rosin containing at least one of tetrahydroabsic acid or dihydroabsic acid.

[0229] (Project A18)

[0230] The biofilm formation inhibitor according to any one of the items, wherein the diterpenoid (A) is a derivative of hydrogenated rosin containing at least one of tetrahydroabsic acid or dihydroabsic acid.

[0231] (Project A19)

[0232] Biofilm formation inhibitor according to any one of the items, wherein the diterpenoid (A) is a rosin ester, the rosin ester being a reaction product of hydrogenated rosin containing at least one of tetrahydroabsicoic acid or dihydroabsicoic acid and an alcohol.

[0233] (Project A20)

[0234] The biofilm formation inhibitor according to any one of the items, wherein the diterpenoid (A) is a rosin class comprising a diterpenoid having the structure represented by the general formula (1),

[0235] The content of diterpenoids having the structure represented by the general formula (1) is 20% by mass or more and 100% by mass or less, relative to 100% by mass of rosin.

[0236] (Project A21)

[0237] The biofilm formation inhibitor according to any one of the items, wherein the diterpenoid (A) is a rosin class comprising a diterpenoid having the structure represented by the general formula (2),

[0238] The content of diterpenoids having the structure represented by the general formula (2) is 10% by mass or more and 100% by mass or less, relative to 100% by mass of rosin.

[0239] (Project A22)

[0240] The biofilm formation inhibitor according to any one of the items, wherein the diterpenoid (A) is a rosin class comprising a diterpenoid having the structure represented by the general formula (3),

[0241] The content of diterpenoids having the structure represented by the general formula (3) is more than 5% by mass and less than 100% by mass relative to 100% by mass of rosin.

[0242] (Project A23)

[0243] The biofilm formation inhibitor according to any one of the items, wherein the diterpenoid (A) is a hydrogenated rosin containing tetrahydroabscisic acid,

[0244] The content of tetrahydroabsic acid is more than 10% by mass and less than 100% by mass relative to 100% by mass of hydrogenated rosin.

[0245] (Project A24)

[0246] The biofilm formation inhibitor according to any one of the items, wherein the diterpenoid (A) is a hydrogenated rosin containing dihydroabsic acid.

[0247] The content of dihydroabietic acid is more than 1% by mass and less than 100% by mass relative to 100% by mass of hydrogenated rosin.

[0248] (Project A25)

[0249] The biofilm formation inhibitor according to any one of the items, wherein the diterpenoid (A) is an ester of hydrogenated rosin containing tetrahydroabsicoic acid,

[0250] The content of tetrahydroabsic acid is more than 10% by mass and less than 100% by mass relative to 100% by mass of hydrogenated rosin.

[0251] (Project A26)

[0252] The biofilm formation inhibitor according to any one of the items, wherein the diterpenoid (A) is an ester of hydrogenated rosin containing dihydroabsic acid.

[0253] The content of dihydroabietic acid is more than 1% by mass and less than 100% by mass relative to 100% by mass of hydrogenated rosin.

[0254] (Project A27)

[0255] The biofilm formation inhibitor according to any one of the items, wherein the diterpenoid (A) is a disproportionated rosin containing tetrahydroabscisic acid.

[0256] The content of tetrahydroabsic acid is 10% to 100% by mass relative to 100% by mass of disproportionated rosin.

[0257] (Project A28)

[0258] The biofilm formation inhibitor according to any one of the items, wherein the diterpenoid (A) is a disproportionated rosin containing dihydroabsicoic acid.

[0259] The content of dihydroabietic acid is between 5% and 100% by mass relative to 100% by mass of disproportionated rosin.

[0260] (Project A29)

[0261] The biofilm formation inhibitor according to any one of the items, wherein the solubility of the diterpenoid (A) in water at 20°C is less than 1% by mass.

[0262] (Project A30)

[0263] The biofilm formation inhibitor according to any one of the items, wherein the solubility of the diterpenoid (A) in water at 20°C is less than 0.1% by mass.

[0264] (Project A31)

[0265] The biofilm formation inhibitor according to any one of the items, wherein the diterpenoid (A) does not contain an alkali metal salt of tetrahydroabsic acid, an alkali metal salt of dihydroabsic acid, an alkali metal salt of dehydroabsic acid, an alkali metal salt of abietic acid, or an alkali metal salt of rosin.

[0266] (Project A32)

[0267] The biofilm formation inhibitor according to any one of the items inhibits the formation of biofilms originating from Gram-positive bacteria.

[0268] (Project A33)

[0269] According to the biofilm formation inhibitor described in Project A32, the Gram-positive bacteria are selected from at least one species in the group consisting of Staphylococcus, Enterococcus, and Streptococcus.

[0270] (Project A34)

[0271] According to the biofilm formation inhibitors described in Project A32 or Project A33, the Gram-positive bacteria are selected from at least one of the group consisting of Staphylococcus aureus, Staphylococcus epidermidis, and Streptococcus mutans.

[0272] (Project A35)

[0273] A method for inhibiting biofilm formation, comprising contacting the biofilm formation inhibitor according to any one of the items with at least one of the object or object location.

[0274] (Project A36)

[0275] A resin composition comprising the diterpenoid (A) according to any one of the items and a resin.

[0276] (Project A37)

[0277] A resin composition comprising the diterpenoid (A) according to any one of the items and a polyolefin resin.

[0278] (Project A38)

[0279] A molded body is formed from a resin composition according to item A37.

[0280] (Project A39)

[0281] A coating agent comprising the diterpenoid (A) according to any one of the items.

[0282] Example

[0283] The present invention will now be described in more detail by way of examples. The present invention is not limited to these examples. Furthermore, unless otherwise specified, “%” means “mass %” and “parts” means “parts by mass”. The materials used in the following examples and comparative examples are as follows. The units of the values ​​in the columns relating to each component and total in the tables are “mass %”.

[0284] The sample used in this embodiment is shown below. Furthermore, the octanol / water partition coefficient logP and the solubility in water at 20°C were calculated using the following method.

[0285] (Octanol / Water partition coefficient logP)

[0286] The calculation was performed using the software "MOE (Molecular Operating Environment) 2022.02 (MOLSIS)" based on the sample's structure.

[0287] (Solubility in water at 20℃)

[0288] The sample was pulverized into powder and added to deionized water at a mass ratio of 1:10. The mixture was then incubated at 20°C for 2 hours. The solution was filtered using a membrane filter (Advantech H050A047A) and the filtrate was collected. The collected filtrate was dried at 105°C for 5 hours. Based on the mass after drying, the solubility was calculated using the following formula.

[0289] (Sample concentration A)% = (Grinded sample) g / (Grinded sample + Deionized water) g × 100

[0290] (Non-volatile component B in aqueous solution)% = (Mass after drying) g / (Amount of filtrate collected) g × 100

[0291] Solubility in water % = (Non-volatile component B in aqueous solution) % / (Sample concentration A) %

[0292] In addition, the quantification of tetrahydroabsic acid and dihydroabsic acid in hydrogenated rosin 1, hydrogenated rosin 2, hydrogenated rosin K salt, and disproportionated rosin used in this embodiment was carried out by the following method.

[0293] 0.1 g of the sample was dissolved in 2.0 g of n-hexanol. 0.1 g of this solution was then mixed with 0.4 g of a methanol solution (0.2 mol / L, manufactured by GL Sciences, Inc.) of a column-mounted methylating agent. 1 μL of this mixture was injected into a commercially available gas chromatograph / mass spectrometer (GC / MS) for analysis. The total peak area of ​​the component with a mass number of 320 was set as the peak area representing the methyl ester of tetrahydroabietic acid, and the total peak area of ​​the component with a mass number of 318 was set as the peak area representing the methyl ester of dihydroabietic acid. The peak area ratios of each component relative to the total peak area representing the methylated resin acids (the total peak area of ​​components with mass numbers 314 to 320) were calculated to determine the content of tetrahydroabietic acid and dihydroabietic acid. The analytical apparatus and column are shown below.

[0294] • Gas chromatography-mass spectrometry equipment: “Agilent 6890”, “Agilent 5973N”; manufactured by Agilent Technologies.

[0295] • Pipeline: "Advance-DS", manufactured by Sinochem Chemicals (stock).

[0296] In addition, the quantification of tetrahydroabsic acid and dihydroabsic acid in the hydrogenated rosin ester used in this embodiment was carried out by the following method.

[0297] Hydrogenated rosin ester and potassium hydroxide were added to n-hexanol and refluxed (hydrolyzed) for 2 hours. The mixture was then neutralized by hydrochloric acid treatment to obtain resin acid. 0.1 g of the resin acid was dissolved in 2.0 g of n-hexanol. 0.1 g of this solution was mixed uniformly with 0.4 g of a column-mounted methylating agent (a methanol solution of phenyltrimethylammonium hydroxide (PTAH) (0.2 mol / L, manufactured by GLSciences, Inc.)). 1 μL of this mixture was injected into a commercially available gas chromatograph-mass analyzer (GC / MS) for determination. The total peak area of ​​the component with a mass number of 320 was set as the peak area representing the methyl ester of tetrahydroabietic acid, and the total peak area of ​​the component with a mass number of 318 was set as the peak area representing the methyl ester of dihydroabietic acid. The peak area ratios of each component relative to the total peak area representing the methylated resin acid (the total peak area of ​​components with mass numbers 314 to 320) were calculated to determine the content of tetrahydroabietic acid and dihydroabietic acid. The analytical apparatus and tubing are shown below.

[0298] • Gas chromatography-mass spectrometry equipment: “Agilent 6890”, “Agilent 5973N”; manufactured by Agilent Technologies.

[0299] • Pipeline: "Advance-DS", manufactured by Sinochem Chemicals (stock).

[0300] Furthermore, regarding the content of triethylene glycol (hereinafter also referred to as TEG) monoester and TEG diester in the hydrogenated rosin ester used in this embodiment, the content was determined by gel permeation chromatography (GPC) of the hydrogenated rosin ester, and calculated based on the area ratio of the peak value derived from TEG monoester to the total peak area, and the area ratio of the peak value derived from TEG diester to the total peak area. The determination conditions are described below.

[0301] (Measurement conditions)

[0302] Device: HLC-8320 GPC high-speed GPC device manufactured by Tosoh Corporation.

[0303] Guard column: TSKgel guard column (HXL-L / G2000HXL / G1000HXL) manufactured by Tosoh Co., Ltd.

[0304] Eluent: Tetrahydrofuran

[0305] Flow rate: 1.0 mL / min

[0306] Temperature: 40℃

[0307] Refractive index (RI) detector: Manufactured by Tosoh Corporation, Bryce type dual-pass, dual-current mode, red light emitting diode (LED) (wavelength: 630nm~670nm)

[0308] Test sample: The sample was diluted with the eluent to a rosin concentration of 0.1%.

[0309] (Sample manufacturing)

[0310] Manufacturing Example 1

[0311] 600 parts of hydrogenated rosin (manufactured by Guangxi Wuzhou Richeng Forestry Chemical Co., Ltd.) were placed in a 1-liter flask and distilled under reduced pressure of 400 Pa to obtain the component distilled at 195℃–250℃. 100 parts of the component distilled at 195℃–250℃ were added to a 1-liter autoclave along with 1.5 parts of 5% palladium alumina and 100 parts of cyclohexane. After fully purging the system with hydrogen, the initial hydrogen pressure was set to 6 MPa. The temperature was raised to 200℃, and the hydrogen pressure was then set to 10 MPa. The reaction was continued for 4 hours while gradually increasing the pressure to reduce the component. The catalyst was filtered and separated, and the cyclohexane was removed by reduced pressure distillation to obtain hydrogenated rosin. The obtained hydrogenated rosin was recrystallized twice in acetone and dried under reduced pressure to obtain tetrahydroabietic acid. The tetrahydroabietic acid had an octanol / water partition coefficient (logP) of 6.65 and a solubility in water at 20℃ of 0.01%.

[0312] Manufacturing Example 2

[0313] 100 parts of unrefined Chinese rosin and 100 parts of rosin oil, along with 5 parts of Reichländer nickel catalyst as a hydrogenation catalyst, were charged into an autoclave. After hydrogen replacement, the pressure was increased to 10 MPa, and the reaction was carried out at 110°C for 5 hours. The catalyst was filtered under nitrogen to obtain a rosin oil solution of semi-hydrogenated rosin. 0.2 parts of p-toluenesulfonic acid were added to 100 parts of the solution, and after isomerization at 150°C for 2 hours, the rosin oil and p-toluenesulfonic acid were removed by vacuum distillation, followed by crude crystallization. Dihydroabietic acid was obtained by recrystallizing the crude crystal four times in acetone. The obtained dihydroabietic acid had an octanol / water partition coefficient logP of 6.12 and a solubility in water at 20°C of 0.00%.

[0314] Manufacturing Example 3

[0315] Hydrogenated rosin (55% tetrahydroabsic acid and 25% dihydroabsic acid) was placed in a vacuum distillation vessel, heated to 250°C and held for 1 hour, then distilled under nitrogen-sealed conditions at a reduced pressure of 1 kPa to obtain hydrogenated rosin 1. The obtained hydrogenated rosin 1 is a hydrogenated rosin containing 60% tetrahydroabsic acid and 27% dihydroabsic acid, and its solubility in water at 20°C is 0.05%.

[0316] Manufacturing Example 4

[0317] 100 parts of Chinese-made rosin and 0.2 parts of 5% palladium on carbon (50% water content) were charged into a 3-liter autoclave as a hydrogenation catalyst. After removing oxygen from the system, the system was pressurized to 100 kg / cm³ using hydrogen. 2 Then, the temperature was raised to 260°C with stirring, and a hydrogenation reaction was carried out at this temperature for 3 hours to obtain unrefined hydrogenated rosin. Next, the unrefined hydrogenated rosin was distilled under nitrogen sealing and reduced pressure of 3 mmHg to obtain the main fraction distilled at 195°C–250°C as hydrogenated rosin 2. The obtained hydrogenated rosin 2 is a hydrogenated rosin containing 28% tetrahydroabsic acid and 52% dihydroabsic acid, and its solubility in water at 20°C is 0.03%.

[0318] Manufacturing Example 5

[0319] In Comparative Manufacturing Example 1 described later, 650 parts of an ethanolic potassium hydroxide solution (trade name "0.5 mol / L potassium hydroxide solution (ethanolic) (N / 2)", manufactured by Kanto Chemical Co., Ltd.) were added dropwise to 100 parts of dehydroabietic acid. Acetone was added, and the mixture was filtered to obtain the potassium salt of dehydroabietic acid as the filter material. The obtained potassium salt of dehydroabietic acid had an octanol / water partition coefficient logP of 6.29 and a solubility in water at 20°C of 99.1%.

[0320] Manufacturing Example 6

[0321] 600 parts of hydrogenated rosin (manufactured by Guangxi Wuzhou Richeng Forestry Chemical Co., Ltd.) were placed in a 1-liter flask and distilled under reduced pressure of 400 Pa to obtain the component distilled at 195℃~250℃. 100 parts of the component distilled at 195℃~250℃, 1.5 parts of 5% palladium alumina, and 200 parts of cyclohexane were placed in a 1-liter autoclave. After fully purging the system with hydrogen, the initial hydrogen pressure was set to 6 MPa. The temperature was raised to 200℃, and the hydrogen pressure was set to 10 MPa. The reaction was carried out for 4 hours while gradually increasing the pressure to reduce the component. The catalyst was filtered and separated, and the cyclohexane was removed by reduced pressure distillation to obtain hydrogenated rosin.

[0322] Add 650 parts of an ethanolic potassium hydroxide solution (trade name "0.5 mol / L potassium hydroxide solution (ethanolic) (N / 2)", manufactured by Kanto Chemical Co., Ltd.) dropwise to 100 parts of the hydrogenated rosin. Add acetone to the solution and filter to obtain the potassium salt of hydrogenated rosin as the filter material. The obtained potassium salt of hydrogenated rosin is a potassium salt of hydrogenated rosin containing 95% tetrahydroabietic acid and 1% dihydroabietic acid. The octanol / water partition coefficient logP of the potassium salt of tetrahydroabietic acid is 7.27, the octanol / water partition coefficient logP of the potassium salt of dihydroabietic acid is 6.75, and the solubility of the potassium salt of hydrogenated rosin in water at 20°C is 97.9%.

[0323] Manufacturing Example 7

[0324] 0.03 parts of 5% palladium on carbon (50% moisture content) were added to 100 parts of unrefined Chinese rosin as a disproportionation catalyst. The mixture was stirred at 280°C for 4 hours under nitrogen sealing to obtain unrefined disproportionated rosin. Next, the unrefined disproportionated rosin was distilled under reduced pressure of 3 mmHg under nitrogen sealing. The main fraction with a general constant of 176.5 acid value, 82°C softening point, and Gardner 4 color was designated as refined disproportionated rosin. Then, 100 parts of the refined disproportionated rosin and 0.3 parts of 5% palladium on carbon (50% moisture content) were charged into a 1-liter vibrating autoclave. After removing oxygen from the system, the system was pressurized to 0.5 kg / cm³ using hydrogen. 2 The temperature was raised to 275°C, and a dehydrogenation reaction was carried out at this temperature for 3 hours to obtain disproportionated rosin. The obtained disproportionated rosin is a disproportionated rosin containing 12% tetrahydroabsic acid and 8% dihydroabsic acid, and its solubility in water at 20°C is 0.02%.

[0325] Manufacturing Example 8

[0326] 100 parts of hydrogenated rosin (manufactured by Guangxi Wuzhou Richeng Forestry Chemical Co., Ltd.) and 50 parts of triethylene glycol were placed in a 1-liter flask. The mixture was heated to 200°C under an argon atmosphere to melt, then reacted at 250°C for 5 hours, followed by a further reaction at 270°C for 5 hours to obtain hydrogenated rosin ester. The obtained hydrogenated rosin ester is a rosin ester containing 40% TEG diester of hydrogenated rosin containing tetrahydroabsic acid and dihydroabsic acid, and 45% TEG monoester of the same hydrogenated rosin. Its solubility in water at 20°C is 0.66%. Furthermore, the octanol / water partition coefficients (logP) of the TEG diester of tetrahydroabsic acid, the TEG diester of dihydroabsic acid, the TEG monoester of tetrahydroabsic acid, and the TEG monoester of dihydroabsic acid in the hydrogenated rosin ester are 13.05, 14.11, 6.78, and 6.25, respectively. Furthermore, the hydrogenated rosin in the hydrogenated rosin ester is a hydrogenated rosin containing 12.7% tetrahydroabsic acid and 81.5% dihydroabsic acid.

[0327] Comparative Manufacturing Example 1

[0328] Disproportionated rosin (acid value 167, softening point 77℃, manufactured by Arakawa Chemical Industry Co., Ltd.) was melted in an argon atmosphere and heated under reduced pressure of 133 Pa to obtain a distillation fraction (refined disproportionated rosin) at 195℃–200℃. 100 parts of the previously refined disproportionated rosin were dissolved in 240 parts of ethanol, and 20 parts of monoethanolamine were added. After reacting under reflux for 1 hour, 250 parts of water were added. The obtained dehydroabietic acid monoethanolamine salt was extracted twice with 200 mL of isooctane to remove unsaponifiables and dihydroabirate. After standing overnight, the crystals were filtered, and then recrystallized three times with 125 parts of ethanol to fully improve the purity of the dehydroabietic acid. The amine salt was then decomposed with hydrochloric acid and filtered. The crystals were dissolved in ether, thoroughly washed with water, and completely solidified. Recrystallization was then performed again in ethanol to obtain dehydroabietic acid. The obtained dehydroabietic acid has an octanol / water partition coefficient logP of 5.66 and a solubility in water at 20°C of 0.00%.

[0329] Comparative Manufacturing Example 2

[0330] Commercially available abietic acid (manufactured by Kanto Chemical Co., Ltd.) was recrystallized four times in acetone and dried under reduced pressure to obtain abietic acid. The obtained abietic acid had an octanol / water partition coefficient logP of 5.75 and a solubility in water at 20°C of 0.65%.

[0331] (Calculation of MIC for each sample)

[0332] For each sample, the minimum inhibitory concentrations (MICs) for *Streptococcus mutans* (strain 8148) and *Staphylococcus aureus* (strain N315) were determined using the microdilution method. Miller-Hayden medium supplemented with Strepto Haemosupplement was used for *Streptococcus mutans*, and Miller-Hayden medium supplemented with cationic ions was used for *Staphylococcus aureus*. Using each medium, a two-fold dilution series of the reagents was prepared in 96-well plates, with approximately 10,000 viable bacteria added to each well. After static incubation at 37°C for 24 hours, the minimum concentration at which bacteria could not be visually identified was set as the MIC.

[0333] <Examples 1 to 11 and Comparative Examples 1 to 4>

[0334] For each of the samples, the biofilm formation rate against Streptococcus mutans or Staphylococcus aureus was evaluated using the following methods. The results are shown in Tables 2 and 3.

[0335] (Method for calculating the biofilm formation inhibition rate)

[0336] *Streptococcus mutans* (strain 8148) was diluted 100-fold using brain heart infusion medium (with 1% glucose). *Staphylococcus aureus* (strain N315) was also diluted 100-fold using the same medium. 100 μL of each dilution was then dispensed into each well of a 96-well plate. Dimethyl sulfoxide (DMSO) was added to each well to dilute the sample to a suitable concentration. The concentration in each medium was then adjusted to 1 / 8 of the MIC. A control medium without the sample was used. The plates were incubated at 37°C for 24 hours. This resulted in biofilm formation on the 96-well plates. Planktonic bacteria were then washed away with distilled water, and the formed biofilm was stained with crystal violet. After washing each well with distilled water, the absorbance at 570 nm was measured using crystal violet dissolved in 200 μL of 30% acetic acid to determine the biofilm formation rate (relative to the control).

[0337] [Table 2]

[0338] Table 2

[0339]

[0340] [Table 3]

[0341] Table 3

[0342]

[0343] The details of the abbreviations in Tables 2 and 3 are as follows.

[0344] THAA: Tetrahydroabietic acid, DHAA: Dihydroabietic acid, DAA: Dehydroabietic acid, AA: Abietic acid, K: Potassium

[0345] As shown in Table 2, when using the samples of Examples 1 to 6 of the present invention (containing diterpenoids with logP of 6 or more), the biofilm formation rate against Streptococcus mutans was less than 50%, even at a concentration of 1 / 8 of the MIC. On the other hand, when using the samples of Comparative Examples 1 to 2 (logP less than 6), the biofilm formation rate against Streptococcus mutans exceeded 50%.

[0346] Furthermore, as shown in Table 3, when using the samples of Examples 7 to 11 of the present invention (containing diterpenoids with logP of 6 or more), the biofilm formation rate against Staphylococcus aureus was less than 30%, even at a concentration of 1 / 8 of the MIC. On the other hand, when using the samples of Comparative Examples 3 to 4 (logP less than 6), the biofilm formation rate against Staphylococcus aureus exceeded 30%.

[0347] (Preparation of the resin composition)

[0348] <Example 12>

[0349] 95 parts of polypropylene (manufactured by Nippon Polypropylene Co., Ltd., trade name "Laboplastomill Model 10C100") and 5 parts of hydrogenated rosin 1 from Manufacturing Example 3 were added to a roller mixer type mixing apparatus (manufactured by Toyo Seiki Co., Ltd., apparatus name "Laboplastomill Model 10C100"). The mixture was mixed for 10 minutes at a roller speed of 40 rpm and a temperature of 190°C to obtain a compound (resin composition).

[0350] <Example 13>

[0351] 95 parts of polypropylene (manufactured by Nippon Polypropylene Co., Ltd., equipment name "Laboplastomill Model 10C100") and 5 parts of hydrogenated rosin 2 from Manufacturing Example 4 were added to a roller mixer type mixing apparatus (manufactured by Toyo Seiki Co., Ltd., apparatus name "Laboplastomill Model 10C100"). The mixture was mixed for 10 minutes at a roller speed of 40 rpm and a temperature of 190°C to obtain a compound (resin composition).

[0352] <Comparative Example 5>

[0353] 100 parts of polypropylene (manufactured by Nippon Polypropylene Co., Ltd., trade name "Laboplastomill Model 10C100") were added to a roller mixer type mixing device (manufactured by Toyo Seiki Co., Ltd., device name "Laboplastomill Model 10C100") and mixed for 10 minutes at a roller speed of 40 rpm and a temperature of 190°C to obtain a mixture (resin composition).

[0354] For each of the resin compositions, the biofilm formation rate against Staphylococcus aureus was evaluated using the following methods. The results are shown in Table 4.

[0355] (Method for calculating the biofilm formation inhibition rate)

[0356] Test pieces (1 cm long × 1 cm wide × 1 mm thick) were prepared by injection molding using a hand truder (manufactured by Toyo Seiki Co., Ltd.) at a resin melt temperature of 200°C and a mold temperature of 40°C. Next, Staphylococcus aureus (strain N315) cultured overnight was diluted 100-fold with brain heart infusion medium (with 1% glucose added). 0.75 mL of each dilution was dispensed into each well of a 24-well plate, and the respective test pieces were added, with spacers overlapped. Test pieces obtained from the resin composition of Comparative Example 5 were used as controls. These were incubated at 37°C for 24 hours. A biofilm formed on the surface of the test pieces. The airborne bacteria were then washed away with distilled water, and the formed biofilm was stained with crystal violet. Excess crystal violet was washed away with distilled water, and then dissolved in 1 mL of 30% acetic acid. For crystal violet, the absorbance at 570 nm was measured to determine the biofilm formation rate (relative to the control).

[0357] [Table 4]

[0358] Table 4

[0359]

[0360] As shown in Table 4, in the case of the resin composition of the present invention containing hydrogenated rosin 1 and hydrogenated rosin 2 (containing diterpenoids with a logP of 6 or more), the biofilm formation rate against Staphylococcus aureus is significantly lower compared with the resin composition not containing diterpenoids.

Claims

1. A biofilm formation inhibitor comprising a diterpenoid (A) having an octanol / water partition coefficient (logP) of 6 or higher.

2. The biofilm formation inhibitor according to claim 1, wherein, The diterpenoid (A) has the structure represented by the following general formula (1); [Chemistry 1] (In formula (1), * indicates the bonding site with other substituents; in addition, the dashed part indicates that there may be a carbon-carbon bond at this point; when a carbon-carbon bond exists in the dashed part, a carbon-carbon bond exists at any point in all the dashed parts).

3. The biofilm formation inhibitor according to claim 1 or 2, wherein, The diterpenoid (A) comprises at least one of tetrahydroabsic acid or dihydroabsic acid.

4. The biofilm formation inhibitor according to claim 1 or 2, wherein, The diterpenoid (A) is a hydrogenated rosin containing at least one of tetrahydroabsic acid or dihydroabsic acid.

5. The biofilm formation inhibitor according to claim 1 or 2, wherein, The diterpenoid (A) is rosin ester. The rosin ester is a reaction product of hydrogenated rosin containing at least one of tetrahydroabsic acid or dihydroabsic acid and an alcohol.

6. The biofilm formation inhibitor according to claim 1 or 2, wherein, The diterpenoid (A) has a solubility of less than 1% by mass in water at 20°C.

7. The biofilm formation inhibitor according to claim 1 or 2, which inhibits the formation of biofilms derived from Gram-positive bacteria.

8. The biofilm formation inhibitor according to claim 7, wherein, The Gram-positive bacteria are selected from at least one species in the group consisting of Staphylococcus, Enterococcus, and Streptococcus.

9. The biofilm formation inhibitor according to claim 7, wherein, The Gram-positive bacteria are selected from at least one species in the group consisting of Staphylococcus aureus, Staphylococcus epidermidis, and Streptococcus mutans.

10. A method for inhibiting biofilm formation, comprising contacting the biofilm formation inhibitor according to claim 1 or 2 with at least one of the object or the object location.

11. A resin composition comprising the diterpenoid (A) according to claim 1 or 2 and a resin.

12. A molded article formed from the resin composition according to claim 11.

13. A coating agent comprising the diterpenoid (A) according to claim 1 or 2.

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