WO2025009453A1 - Biofilm formation inhibitor, method for inhibiting formation of biofilm, resin composition, molded article, and coating agent - Google Patents

Abstract

Provided are: a biofilm formation inhibitor that can inhibit the formation of a biofilm even when used at a low concentration at which antibacterial activity is not exhibited; a method for inhibiting the formation of a biofilm; a resin composition; a molded article; and a coating agent. The biofilm formation inhibitor comprises a diterpene compound (A) having an octanol/water partition coefficient (logP) of 6 or more.

Description

Biofilm formation inhibitor, biofilm formation inhibition method, resin composition, molded body, and coating agent

The present invention relates to a biofilm formation inhibitor, a method for inhibiting biofilm formation, a resin composition, a molded body, and a coating agent.

Biofilms are communities of organisms encapsulated in a viscous substance formed by bacteria, and are problematic in various industrial fields, including the medical field dealing with oral diseases and infectious diseases, and the water treatment field dealing with water supply and wastewater treatment. Biofilms protect bacteria from antibacterial agents and disinfectants, making disinfection and sterilization difficult, and the viscosity of the biofilm allows them to adhere firmly, making their removal difficult as well. Therefore, once a biofilm is formed, it causes a deterioration in environmental hygiene, and in medical settings, it can lead to the worsening of diseases such as infectious diseases. Therefore, inhibiting the formation of biofilms can greatly contribute to improving environmental hygiene and the quality of medical care.

In the medical field, gram-positive cocci such as enterococci may form biofilms on the surfaces of medical instruments, etc., so an oral composition containing a carrier such as water or glycerin and a terpenoid dispersed in the carrier has been proposed to inhibit the formation of biofilms by enterococci (see, for example, Patent Document 1). In addition, in the medical field, gram-positive cocci such as Staphylococcus aureus may form biofilms on the surfaces of medical instruments, so a biofilm formation inhibitor containing abietic acid or dehydroabietic acid has been proposed to inhibit the formation of biofilms by Staphylococcus aureus (see, for example, Patent Document 2).

Special Publication No. 2004-521880 International Publication No. 2010/119638

However, the compositions described in Patent Documents 1 and 2 are not effective enough in inhibiting biofilm formation.

The present invention was made in consideration of these conventional problems, and aims to provide a biofilm formation inhibitor, a method for inhibiting biofilm formation, a resin composition, a molded body, and a coating agent that can inhibit the formation of biofilms.

One embodiment of the biofilm formation inhibitor of the present invention that solves the above problems is a biofilm formation inhibitor that contains diterpenes (A) having an octanol/water partition coefficient (logP) of 6 or more.

In addition, one embodiment of the method for inhibiting biofilm formation of the present invention is a method for inhibiting biofilm formation in which the biofilm formation inhibitor is brought into contact with at least one of a target object or a target location.

Furthermore, a resin composition according to one embodiment of the present invention is a resin composition containing the diterpenes (A) and a resin.

The molded article according to one embodiment of the present invention is a molded article obtained by molding the above-mentioned resin composition.

The coating agent according to one embodiment of the present invention is a coating agent that contains the diterpenes (A) described above.

<Biofilm formation inhibitor>
A biofilm formation inhibitor according to one embodiment of the present invention contains diterpenes (A) having an octanol/water partition coefficient (log P) of 6 or more.

The octanol/water partition coefficient (log P) is preferably 6 or more. In this embodiment, the inclusion of diterpenes (A) having an octanol/water partition coefficient (log P) of 6 or more allows the formation of a biofilm to be suppressed. Although the details are unclear, the following speculation is conceivable. In this embodiment, the octanol/water partition coefficient (log P) of the diterpenes (A) is 6 or more, so it is speculated that the biofilm formation inhibitor has high affinity with bacterial cells and biofilms. Therefore, it is speculated that the biofilm formation inhibitor is easy to inhibit the formation of biofilms because the diterpenes (A) easily act on bacterial cells and biofilms. In addition, the biofilm formation inhibitor of this embodiment has the characteristic of being able to suppress the formation of biofilms even at a low concentration that does not exhibit antibacterial properties (for example, a concentration that is 1/8 of the MIC (minimum inhibitory concentration)).

Such effects are obtained by containing diterpenes (A) with an octanol/water partition coefficient (log P) of 6 or more, and cannot be obtained with abietic acid (AA, log P: 5.75) or dehydroabietic acid (DAA, log P: 5.66), which have an octanol/water partition coefficient (log P) of less than 6.

The octanol/water partition coefficient (log P) is the ratio of the substance concentration in octanol to the substance concentration in water when the substance is dissolved in a mixture of octanol and water, and is an index value of the hydrophobicity (or hydrophilicity) of a substance, with a higher value indicating a tendency for the substance to be more hydrophobic (lipophilic). The octanol/water partition coefficient (log P) can be calculated using software from the structure of the substance (see, for example, JP 2018-188420 A, JP 2019-043985 A, JP 2021-522873 A, and WO 2020/045514), and can also be calculated from the structure of diterpenes (A) using the software "MOE (Molecular Operating Environment) 2022.02 (MOLSIS)". In this embodiment, the value calculated from the structure of diterpenes (A) using the software "MOE (Molecular Operating Environment) 2022.02 (MOLSIS)" is used.

The diterpenes (A) are not particularly limited as long as they have an octanol/water partition coefficient (logP) of 6 or more. For example, the diterpenes (A) are diterpenes such as labdanes, pyramans, and abietanes, and various derivatives of these diterpenes. The diterpenes (A) may be used alone or in combination of two or more. Among these, the diterpenes (A) are preferably diterpenes having a structure represented by the following general formula (1). This makes it easier for the biofilm formation inhibitor to inhibit biofilm formation, and can inhibit biofilm formation even at a low concentration that does not exhibit antibacterial properties.

(In formula (1), * indicates a bonding site with other substituents. Also, the dashed line portion indicates that a carbon-carbon bond may be present there. When a carbon-carbon bond is present at a dashed line portion, a carbon-carbon bond is present at any one of all dashed line portions.)

Diterpenes having the structure shown in general formula (1) are compounds that can be extracted from plants of the Pinaceae family, such as pine and cedar, and plants of the Lamiaceae family. There are no particular limitations on the diterpenes having the structure shown in general formula (1). As an example, diterpenes having the structure shown in general formula (1) include diterpenes having the structure shown in general formula (2) below, diterpenes having the structure shown in general formula (3) below, etc.

(In formula (2), * indicates a bonding site with other substituents.)

(In formula (3), * indicates a bonding site with other substituents. Also, each broken line indicates that there is a carbon-carbon bond at one of the broken lines, and a carbon-carbon bond exists at any one of the broken lines.)

Diterpenes having a structure shown in general formula (2) are diterpenes having a skeleton derived from tetrahydroabietic acid. Diterpenes having a skeleton derived from tetrahydroabietic acid are not particularly limited. 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.)), etc. Diterpenes having a structure shown in general formula (3) are not particularly limited. For example, diterpenes having a structure shown in general formula (3) include diterpenes having a skeleton derived from dihydroabietic acid, etc. Diterpenes having a skeleton derived from dihydroabietic acid are not particularly limited, but examples include dihydroabietic acid (logP: 6.12) and various derivatives of dihydroabietic acid (esters, salts, amides (primary amides, secondary amides, tertiary amides, etc.), alcohols, amines (primary amines, secondary amines, tertiary amines, etc.)).

The alcohols that form the esters in the various derivatives of tetrahydroabietic acid and various derivatives of dihydroabietic acid are not particularly limited. Examples of such alcohols include dihydric alcohols such as ethylene glycol, diethylene glycol, triethylene glycol, propylene glycol, neopentyl glycol, dimer diol, bisphenol A, bisphenol F, etc.; trihydric alcohols such as glycerin, trimethylolethane, trimethylolpropane, etc.; tetrahydric alcohols such as pentaerythritol, diglycerin, etc.; and hexahydric alcohols such as dipentaerythritol, etc. The above alcohols may be used alone or in combination of two or more.

The salts of the various derivatives of tetrahydroabietic acid and the various derivatives of dihydroabietic acid are not particularly limited. For example, such salts are alkali metal salts, alkaline earth metal salts, amine salts, and ammonium salts. The alkali metal contained in the alkali metal salt is not particularly limited. For example, the alkali metal is sodium, potassium, etc., and these alkali metals may be used alone or in combination of two or more. The alkaline earth metal contained in the alkaline earth metal salt is not particularly limited. For example, the alkaline earth metal is beryllium, magnesium, calcium, strontium, barium, etc., and these alkaline earth metals may be used alone or in combination of two or more.

The diterpenes (A) of this embodiment may be diterpenes having a structure represented by the above general formula (1), or may be diterpenes having a structure other than the structure represented by general formula (1).

Diterpenes having a structure other than that shown in general formula (1) are not particularly limited. Examples of diterpenes having a structure other than that shown in 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.)), various derivatives of abietic acid (esters, salts, amides (primary amides, secondary amides, tertiary amides, etc.), alcohols, amines (primary amines, secondary amines, tertiary amines, etc.)), etc. The alcohols forming the esters in the various derivatives of dehydroabietic acid and various derivatives of abietic acid are not particularly limited, and examples thereof are as described above. Furthermore, the salts in the various derivatives of dehydroabietic acid and various derivatives of abietic acid are not particularly limited, and examples thereof are as described above.

The log P values of representative examples of diterpenes having the structure shown in general formula (1) and diterpenes having structures other than the structure shown in general formula (1) are shown in Table 1 below. For reference, Table 1 also shows some diterpenes with log P values of less than 6.

Details of the abbreviations in Table 1 are as follows.
DAA skeleton: a skeleton derived from dehydroabietic acid, AA skeleton: a skeleton derived from abietic acid, THAA skeleton: a skeleton derived from tetrahydroabietic acid, DHAA skeleton: a skeleton derived from dihydroabietic acid, Me: methyl, Na: sodium, K: potassium, Gly: glycerin, Gly diester: a diester in which two molecules of diterpene carboxylic acid are esterified to one molecule of glycerin, Gly triester: a triester in which three molecules of diterpene carboxylic acid are esterified to one molecule of glycerin, TEG monoester: a monoester in which one molecule of diterpene carboxylic acid is esterified to one molecule of triethylene glycol, TEG diester: a diester in which two molecules of diterpene carboxylic acid are esterified to one molecule of triethylene glycol.

The structures of the pimaric acid-derived skeleton, DAA skeleton, AA skeleton, THAA skeleton, and DHAA skeleton in Table 1 are shown in the following general formulas (4) to (8).

(In formula (4), * indicates a bonding site with other substituents.)

(In formula (5), * indicates a bonding site with other substituents.)

(In formula (6), * indicates a bonding site with other substituents.)

(In formula (7), * indicates a bonding site with other substituents.)

(In formula (8), * indicates a bonding site with other substituents. Also, each broken line indicates that there is a carbon-carbon bond at one of the broken lines, and a carbon-carbon bond exists at any one of the broken lines.)

Among these, the diterpenes (A) preferably include at least one selected from the group consisting of diterpenes having a structure represented by general formula (2), diterpenes having a structure represented by general formula (3), and various derivatives of dehydroabietic acid, more preferably at least one selected from the group consisting of tetrahydroabietic acid (in which the THAA skeleton represented by general formula (7) is bonded to COOH), various derivatives of tetrahydroabietic acid, dihydroabietic acid (in which the DHAA skeleton represented by general formula (8) is bonded to COOH), various derivatives of dihydroabietic acid, and various derivatives of dehydroabietic acid, and even more preferably at least one of tetrahydroabietic acid and dihydroabietic acid. This makes it easier for the biofilm formation inhibitor to inhibit biofilm formation, and it can inhibit biofilm formation even at a low concentration that does not exhibit antibacterial properties.

The diterpenes (A) may be rosins containing the above-mentioned diterpenes. Such rosins are not particularly limited, but examples include hydrogenated rosin, disproportionated rosin, rosin esters, alkali metal salts of rosin, alkaline earth metal salts of rosin, rosin amines, rosin alcohols, and rosin amides. The rosins may be used alone or in combination of two or more kinds.

(Hydrogenated rosin)
Hydrogenated rosin can be obtained by using various known means. Specifically, for example, it can be obtained by hydrogenating natural rosin (gum rosin, tall oil rosin, wood rosin) derived from Pinus massoniana, Slash pine (Pinus elliottii), Merkusii, Caribbean pine (Pinus caribaea), Pinus kesiya, Loblolly pine (Pinus taeda), and Daio pine (Pinus palustris) or refined rosin (hereinafter, natural rosin and refined rosin are collectively referred to as unmodified rosin) using known hydrogenation conditions. For example, the hydrogenation conditions include a method of heating unmodified rosin to about 100 to 300° C. under a hydrogen pressure of about 2 to 20 MPa in the presence of a hydrogenation catalyst. The hydrogen pressure is preferably about 5 to 20 MPa, and the reaction temperature is preferably about 150 to 300° C. As the hydrogenation catalyst, various known catalysts such as supported catalysts and metal powders can be used. Supported catalysts include palladium-carbon, rhodium-carbon, ruthenium-carbon, platinum-carbon, and the like. Metal powders include nickel and platinum. Among these, palladium, rhodium, ruthenium, and platinum-based catalysts are preferred because they increase the hydrogenation rate of unmodified rosin and shorten the hydrogenation time. The amount of the hydrogenation catalyst used is usually about 0.01 to 5 parts by mass, and preferably about 0.01 to 2 parts by mass, per 100 parts by mass of unmodified rosin.

If necessary, hydrogenation may be carried out with the unmodified rosin dissolved in a solvent. There are no particular limitations on the solvent used, so long as it is inert to the reaction and easily dissolves the raw materials and products. Examples of solvents include cyclohexane, n-hexane, n-heptane, decalin, tetrahydrofuran, dioxane, etc., and these can be used alone or in combination of two or more. There are no particular limitations on the amount of solvent used, but it is usually sufficient to use a solvent so that the solid content is 10% by mass or more, preferably in the range of about 10 to 70% by mass, relative to the unmodified rosin.

Furthermore, the hydrogenated rosin obtained may be subjected to various treatments such as purification, hydrogenation, and disproportionation, which will be described later, either alone or in combination of two or more. There are no particular limitations on the purification treatment. Examples include distillation, extraction, recrystallization, and adsorption.

In order to improve the color tone, the hydrogenated rosin may be further subjected to a dehydrogenation treatment. The dehydrogenation treatment is not particularly limited, and ordinary conditions can be adopted. For example, the dehydrogenation treatment is performed in a closed vessel with hydrogenated rosin in the presence of a dehydrogenation catalyst at an initial hydrogen pressure of less ^than 10 kg/cm2, preferably less than 5 kg/ ^cm2 , and at a reaction temperature of about 100 to 300°C, preferably in the range of a lower limit of 200°C and an upper limit of 280°C. As the dehydrogenation catalyst, various known catalysts can be used without any particular limitation, and preferred examples include palladium-based, rhodium-based, and platinum-based catalysts, which are usually used supported on a carrier such as silica or carbon. The amount of the catalyst used is usually about 0.01 to 5% by weight, preferably a lower limit of 0.05% by weight and an upper limit of 3% by weight, based on the hydrogenated rosin.

(Disproportionated rosin)
Disproportionated rosin can be obtained by various known means. Specifically, for example, it can be obtained by a method (disproportionation) in which unmodified rosin is heated in the presence of a disproportionation catalyst. As the disproportionation catalyst, various known catalysts such as supported catalysts on palladium-carbon, rhodium-carbon, platinum-carbon, etc.; metal powders such as nickel and platinum; and iodides such as iodine and iron iodide can be used. The amount of the catalyst used is usually about 0.01 to 5 parts by mass, preferably about 0.01 to 1 part by mass, based on 100 parts by mass of unmodified rosin. The reaction temperature is about 100 to 300° C., preferably about 150 to 290° C.

In addition, the disproportionated rosin obtained may be further subjected to the above-mentioned various treatments of purification, disproportionation, and hydrogenation, either alone or in combination of two or more thereof.

In addition, to improve color tone, disproportionated rosin may be subjected to the above-mentioned dehydrogenation treatment in the same manner as hydrogenated rosin.

(rosin esters)
The rosin esters are not particularly limited. Examples of the rosin esters include a reaction product of unmodified rosin and alcohol (unmodified rosin ester), a reaction product of hydrogenated rosin and alcohol (hydrogenated rosin ester), a reaction product of disproportionated rosin and alcohol (disproportionated rosin ester), etc. The alcohol in the rosin esters is not particularly limited, and examples thereof include those mentioned above.

In addition, in order to improve the color tone, the above-mentioned dehydrogenation treatment may be performed on the refined rosin, just as with the hydrogenated rosin.

Rosin esters can be obtained by various known means. Specifically, for example, unmodified rosin, hydrogenated rosin, disproportionated rosin and alcohol are reacted at a temperature of about 150 to 300°C for about 1 to 24 hours. There are no particular restrictions on the amounts of unmodified rosin, hydrogenated rosin, disproportionated rosin and alcohol charged, but they are usually determined so that the OH group of the alcohol/COOH group of the rosins (equivalent ratio) is in the range of about 0.8 to 8, preferably about 1.1 to 1.3.

In the method for producing rosin esters, the obtained rosin esters may be further subjected to various treatments such as the above-mentioned purification, hydrogenation, disproportionation, etc. Furthermore, the various treatments may be performed alone or in combination of two or more kinds.

The method for producing hydrogenated rosin ester and disproportionated rosin ester may involve subjecting the reaction product of unmodified rosin with alcohol to a modification reaction by hydrogenation or disproportionation, respectively.

(Alkali metal salt of rosin)
An alkali metal salt of rosin (hereinafter also simply referred to as an alkali metal salt) is a neutralized salt of rosin with a metal compound containing an alkali metal (hereinafter also simply referred to as an alkali metal compound).

The rosin in the alkali metal salt is not particularly limited as long as it is a rosin-based resin having a carboxyl group. For example, the rosin in the alkali metal salt is unmodified rosin, hydrogenated rosin, or disproportionated rosin.

The alkali metal contained in the alkali metal salt is not particularly limited. For example, the alkali metal contained in the alkali metal salt is sodium, potassium, etc. The alkali metal may be used alone or in combination of two or more kinds.

There are no particular limitations on the alkali metal compound, so long as it forms a salt with rosin. Examples of alkali metal compounds include hydroxides, oxides, chlorides, nitrates, acetates, sulfates, carbonates, etc. of alkali metals. One type of alkali metal compound may be used alone, or two or more types may be used in combination.

The alkali metal compound is preferably sodium hydroxide or potassium hydroxide. The form of the alkali metal compound is not particularly limited, but is preferably an aqueous solution.

Alkali metal salts are obtained by reacting (neutralizing) rosin with an alkali metal compound.

Methods for reacting rosin with an alkali metal compound include, for example, a method in which rosin is directly reacted with an alkali metal compound in the presence or absence of a solvent (direct method), and a method in which a metal salt of rosin other than an alkali metal is reacted with an alkali metal compound in the presence of a solvent to effect salt exchange (double decomposition method). The reaction temperature is not particularly limited, but is usually in the range from room temperature to the boiling point of the solvent, and the reaction time varies depending on the reaction temperature, but is usually about 10 minutes to 24 hours. After completion of the reaction, the solvent may be distilled off.

The solvent is not particularly limited. Examples of the solvent include water; alcohol-based solvents such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, ethylene glycol, and propylene glycol; ether alcohol-based solvents such as diethylene glycol, triethylene glycol, and 2-methoxyethanol; aromatic hydrocarbon-based solvents such as toluene and xylene; ester-based solvents such as ethyl acetate and butyl acetate; and ketone-based solvents such as methyl ethyl ketone and methyl isobutyl ketone. Water is a preferred solvent.

The reaction between rosin and an alkali metal compound is carried out so that the amount of alkali metal introduced relative to the COOH groups of the rosin is usually 5 to 100 equivalent percent, preferably 10 to 100 equivalent percent.

(Rosin alkaline earth metal salts)
The alkaline earth metal salt of rosin (hereinafter also simply referred to as alkaline earth metal salt) is a neutralized salt of rosin with a metal compound containing an alkaline earth metal (hereinafter also simply referred to as alkaline earth metal compound).

The rosin in the alkaline earth metal salt is not particularly limited as long as it is a rosin-based resin having a carboxyl group. For example, the rosin in the alkaline earth metal salt is unmodified rosin, hydrogenated rosin, or disproportionated rosin.

The alkaline earth metal contained in the alkaline earth metal salt is not particularly limited. Examples of alkaline earth metals include beryllium, magnesium, calcium, strontium, barium, etc. One type of alkaline earth metal may be used alone, or two or more types may be used in combination.

The alkaline earth metal is preferably at least one selected from the group consisting of magnesium and calcium.

There are no particular limitations on the alkaline earth metal compound, so long as it forms a salt with rosin. Examples of alkaline earth metal compounds include hydroxides, oxides, chlorides, nitrates, acetates, sulfates, carbonates, etc. of alkaline earth metals. One type of alkaline earth metal compound may be used alone, or two or more types may be used in combination.

Preferred alkaline earth metal compounds are magnesium hydroxide, magnesium oxide, calcium hydroxide, and calcium oxide.

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

　Methods for reacting rosin with an alkaline earth metal compound include, for example, a method in which rosin is directly reacted with an alkaline earth metal compound in the presence or absence of an organic solvent (direct method); and a method in which a metal salt of rosin other than an alkaline earth metal is reacted with an alkaline earth metal compound in the presence of water and/or an organic solvent to effect salt exchange (double decomposition method). There are no particular limitations on the reaction temperature, but in the direct method it is usually about 150 to 270°C, and in the double decomposition method it 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 usually about 10 minutes to 24 hours. After completion of the reaction, the solvent may be distilled off.

The organic solvent is not particularly limited. Examples include 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.

The reaction between rosin and an alkaline earth metal compound is carried out so that the amount of alkaline earth metal introduced relative to the COOH groups of the rosin is usually 5 to 100 equivalent percent, preferably 10 to 100 equivalent percent.

(rosin amines)
The rosin amines are not particularly limited. For example, the rosin amines are amines obtained by reacting rosin with ammonia and then hydrogenating the rosin (U.S. Pat. No. 2,534,297), or amines obtained by producing rosin amides described below from rosin and amines and reducing the amide group in the rosin amides (hydride reduction, hydrogenation). The rosin in the rosin amines is not particularly limited as long as it is a rosin-based resin having a carboxyl group. For example, the rosin in the rosin amines is unmodified rosin, hydrogenated rosin, disproportionated rosin, etc. Note that amines obtained from unmodified rosin are also referred to as unmodified rosin amines, amines obtained from hydrogenated rosin are also referred to as hydrogenated rosin amines, and amines obtained from disproportionated rosin are also referred to as disproportionated rosin amines.

(rosin alcohols)
The rosin alcohols are not particularly limited. For example, rosin alcohols are alcohols obtained by a method of hydrogenating and reducing carboxyl groups in rosin (JP 2014-133866 A). The rosin in the rosin alcohols is not particularly limited as long as it is a rosin-based resin having a carboxyl group. For example, the rosin in the rosin alcohols is unmodified rosin, hydrogenated rosin, disproportionated rosin, etc. Note that alcohol obtained from unmodified rosin is also referred to as unmodified rosin alcohol, alcohol obtained from hydrogenated rosin is also referred to as hydrogenated rosin alcohol, and alcohol obtained from disproportionated rosin is also referred to as disproportionated rosin alcohol.

(Rosin amides)
The rosin amides are not particularly limited. For example, rosin amides are amides obtained by reacting (amidating) rosin with ammonia or amines. The rosin in the rosin amides is not particularly limited as long as it is a rosin-based resin having a carboxyl group. For example, the rosin in the rosin amides is unmodified rosin, hydrogenated rosin, disproportionated rosin, etc. Note that an amide obtained from unmodified rosin is also referred to as unmodified rosin amide, an amide obtained from hydrogenated rosin is also referred to as hydrogenated rosin amide, and an amide obtained from disproportionated rosin is also referred to as disproportionated rosin amide.

The amines in the rosin amides are not particularly limited as long as they have at least one amino group in the molecule. For example, the amines in the rosin amides are aliphatic monoamines, aliphatic polyamines, alicyclic monoamines, alicyclic polyamines, aromatic monoamines, aromatic polyamines, etc. Furthermore, the amino groups in the amines are also not particularly limited. For example, the amino groups in the amines are primary amino groups, secondary amino groups, tertiary amino groups, etc.

The method for reacting rosin with amines is not particularly limited, and various known methods can be used. Specifically, for example, rosin is converted into an acid chloride by the thionyl chloride method, and this is reacted (amidated) with amines in the presence or absence of an organic solvent.

The organic solvent is not particularly limited as long as it is inactive to the reaction components. Examples of the organic solvent include benzene, toluene, xylene, dimethyl ether, diisobutyl ether, tetrahydrofuran, acetone, methyl ethyl ketone, and methyl isobutyl ketone.

In the reaction (amidation), a basic substance or a tertiary amine may be used as a catalyst, if necessary. The basic substance is not particularly limited, and examples thereof include sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, and sodium carbonate. The tertiary amine is not particularly limited, and examples thereof include trimethylamine, triethylamine, tributylamine, and pyridine. The above-mentioned tertiary amines can also be used as reaction solvents when the above-mentioned aromatic monoamine is soluble in them.

The diterpenes (A) may also be rosins containing diterpenes having the structure shown in general formula (1). Such rosins are not particularly limited, but as an example, rosins containing diterpenes having the structure shown in general formula (1) include rosins containing at least one of the diterpenes having the structure shown in general formula (2) above and the diterpenes having the structure shown in general formula (3) above.

The rosins containing at least one of the diterpenes having the structure shown in general formula (2) and the diterpenes having the structure shown in general formula (3) are not particularly limited, but examples include the above-mentioned hydrogenated rosin containing at least one of tetrahydroabietic acid and dihydroabietic 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, amine salts of hydrogenated rosin, hydrogenated rosin esters ... disproportionated rosin containing at least one of tetrahydroabietic acid and dihydroabietic acid, various derivatives of such disproportionated rosin (disproportionated rosin ester, various salts of disproportionated rosin (alkali metal salt of disproportionated rosin, alkaline earth metal salt of disproportionated rosin, amine salt of disproportionated rosin, disproportionated rosin ammonium salt), disproportionated rosin amide, disproportionated rosin alcohol, disproportionated rosin amine), etc.

The diterpenes (A) may be rosins containing diterpenes having a structure other than that shown in general formula (1). For example, rosins containing diterpenes having a structure other than that shown in general formula (1) include various derivatives of the above disproportionated rosin containing dehydroabietic 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), various derivatives of the above 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.

Among these, the diterpenes (A) are preferably at least one selected from the group consisting of diterpenes having a structure represented by general formula (2), rosins containing at least one of the diterpenes having a structure represented by general formula (3), and various derivatives of disproportionated rosin containing dehydroabietic acid; more preferably at least one selected from the group consisting of hydrogenated rosin containing at least one of tetrahydroabietic acid or dihydroabietic acid, various derivatives of the hydrogenated rosin, disproportionated rosin containing at least one of tetrahydroabietic acid or dihydroabietic acid, various derivatives of the disproportionated rosin, and various derivatives of disproportionated rosin containing dehydroabietic acid; and even more preferably at least one selected from the group consisting of hydrogenated rosin containing at least one of tetrahydroabietic acid or dihydroabietic acid, and esters of the hydrogenated rosin (hydrogenated rosin esters). This makes it even easier for the biofilm formation inhibitor to inhibit biofilm formation, and it can inhibit biofilm formation even at low concentrations that do not exhibit antibacterial properties.

When the diterpenes (A) of this embodiment are the rosins, the content of the diterpenes having the structure represented by the general formula (1) in the rosins is not particularly limited. For example, the content of the diterpenes having the structure represented by the general formula (1) is preferably 5% by mass or more, more preferably 10% by mass or more, even more preferably 15% by mass or more, even more preferably 20% by mass or more, even more preferably 30% by mass or more, even more preferably 40% by mass or more, even more preferably 50% by mass or more, even more preferably 60% by mass or more, even more preferably 70% by mass or more, even more preferably 80% by mass or more, and particularly preferably 90% by mass or more. In addition, the content of the diterpenes having the structure represented by the general formula (1) is preferably 100% by mass or less, based on 100% by mass of the rosins. By containing diterpenes having the structure represented by general formula (1) within the above range, the biofilm formation inhibitor is more likely to inhibit biofilm formation, and can inhibit biofilm formation even at a low concentration that does not exhibit antibacterial properties.

When the diterpenes (A) of this embodiment are the rosins, the content of the diterpenes having the structure represented by the general formula (2) in the rosins is not particularly limited. For example, the content of the diterpenes having the structure represented by the general formula (2) is preferably 5% by mass or more, more preferably 10% by mass or more, even more preferably 15% by mass or more, even more preferably 20% by mass or more, even more preferably 30% by mass or more, even more preferably 40% by mass or more, even more preferably 50% by mass or more, even more preferably 60% by mass or more, even more preferably 70% by mass or more, even more preferably 80% by mass or more, and particularly preferably 90% by mass or more. In addition, the content of the diterpenes having the structure represented by the general formula (2) is preferably 100% by mass or less, based on 100% by mass of the rosins. By containing diterpenes having a structure represented by general formula (2) within the above range, the biofilm formation inhibitor is more likely to suppress biofilm formation, and can suppress biofilm formation even at a low concentration that does not exhibit antibacterial properties.

When the diterpenes (A) of this embodiment are the rosins, the content of the diterpenes having the structure represented by the general formula (3) in the rosins is not particularly limited. For example, the content of the diterpenes having the structure represented by the general formula (3) is preferably 5% by mass or more, more preferably 10% by mass or more, even more preferably 15% by mass or more, even more preferably 20% by mass or more, even more preferably 30% by mass or more, even more preferably 40% by mass or more, even more preferably 50% by mass or more, even more preferably 60% by mass or more, and particularly preferably 70% by mass or more, based on 100% by mass of the rosins. The content of the diterpenes having the structure represented by the general formula (3) is preferably 100% by mass or less based on 100% by mass of the rosins. By having the content of the diterpenes having the structure represented by the general formula (3) within the above range, the biofilm formation inhibitor is more likely to suppress the formation of a biofilm, and can suppress the formation of a biofilm even at a low concentration that does not exhibit antibacterial properties.

When the diterpenes (A) of this embodiment are the rosins, the content of tetrahydroabietic acid in the hydrogenated rosin is not particularly limited. For example, the content of tetrahydroabietic acid is preferably 10% by mass or more, more preferably 15% by mass or more, even more preferably 20% by mass or more, even more preferably 30% by mass or more, even more preferably 40% by mass or more, even more preferably 50% by mass or more, even more preferably 60% by mass or more, even more preferably 70% by mass or more, even more preferably 80% by mass or more, and particularly preferably 90% by mass or more, based on 100% by mass of hydrogenated rosin. By having the content of tetrahydroabietic acid within the above range, the biofilm formation inhibitor is more likely to suppress the formation of a biofilm, and can suppress the formation of a biofilm even at a low concentration that does not exhibit antibacterial properties.

When the diterpenes (A) of this embodiment are the rosins, the content of dihydroabietic acid in the hydrogenated rosin is not particularly limited. For example, the content of dihydroabietic acid is preferably 1% by mass or more, more preferably 5% by mass or more, even more preferably 10% by mass or more, even more preferably 15% by mass or more, even more preferably 20% by mass or more, even more preferably 30% by mass or more, even more preferably 40% by mass or more, even more preferably 50% by mass or more, even more preferably 60% by mass or more, and particularly preferably 70% by mass or more, based on 100% by mass of hydrogenated rosin. By having the content of dihydroabietic acid within the above range, the biofilm formation inhibitor is more likely to suppress the formation of a biofilm, and can suppress the formation of a biofilm even at a low concentration that does not exhibit antibacterial properties.

When the diterpenes (A) of this embodiment are the rosins, the content of tetrahydroabietic acid in the disproportionated rosin is not particularly limited. For example, the content of tetrahydroabietic acid is preferably 10% by mass or more, more preferably 15% by mass or more, even more preferably 20% by mass or more, even more preferably 30% by mass or more, and particularly preferably 40% by mass or more, relative to 100% by mass of disproportionated rosin. The content of tetrahydroabietic acid is preferably less than 50% by mass relative to 100% by mass of disproportionated rosin. By having the content of tetrahydroabietic acid within the above range, the biofilm formation inhibitor is more likely to suppress biofilm formation, and can suppress biofilm formation even at a low concentration that does not exhibit antibacterial properties.

When the diterpenes (A) of this embodiment are the rosins, the content of dihydroabietic acid in the disproportionated rosin is not particularly limited. For example, the content of dihydroabietic acid is preferably 5% by mass or more, more preferably 10% by mass or more, even more preferably 15% by mass or more, even more preferably 20% by mass or more, even more preferably 30% by mass or more, and particularly preferably 40% by mass or more, relative to 100% by mass of disproportionated rosin. The content of dihydroabietic acid is preferably less than 50% by mass relative to 100% by mass of disproportionated rosin. By having the content of dihydroabietic acid within the above range, the biofilm formation inhibitor is more likely to suppress biofilm formation, and can suppress biofilm formation even at a low concentration that does not exhibit antibacterial properties.

The diterpenes (A) of this embodiment may be derived from natural products extracted from the above-mentioned plants, or may be synthetic compounds. The diterpenes (A) of this embodiment include all stereoisomers (diastereomers, epimers, enantiomers, etc.) or racemates.

The physical properties of the diterpenes (A) of this embodiment are not particularly limited except for the octanol/water partition coefficient (logP). The solubility of the diterpenes (A) in water at 20°C is not particularly limited, but is preferably 1% by mass or less, and more preferably 0.1% by mass or less. By having a solubility in water within the above range, when the biofilm formation inhibitor is applied (for example, coated) to an object or a target location where a biofilm may be formed, the breakdown of the coating film due to moisture in the environment or human sweat, or the exudation of the diterpenes (A) from the coating film can be suppressed. Therefore, the biofilm formation inhibitor has excellent durability of the coating film. Diterpenes having a solubility in water of more than 1% by mass at 20°C are not particularly limited, but examples thereof 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.

The biofilm formation inhibitor of this embodiment may contain additives as necessary. The additives are not particularly limited. Examples of additives include solvents, abrasives, gelling agents, wetting agents, anti-corrosive agents, flavoring agents, sweetening agents, pain relievers, anti-calculus agents, whitening agents, surfactants, binders, preservatives, opacifying agents, colorants, pH buffers, disinfectants, etc. These may be used alone or in combination of two or more types. The content ratio of the additives is set appropriately depending on the purpose and application.

The type of bacteria from which the biofilm formation inhibitor of this embodiment can be targeted is not particularly limited. For example, the type of bacteria may be gram-positive bacteria, gram-negative bacteria, etc.

Gram-positive bacteria are not particularly limited. Examples of gram-positive bacteria include Staphylococcus (e.g., Staphylococcus aureus, Staphylococcus epidermidis), Enterococcus, Streptococcus (e.g., diplococcus, tetrastreptococcus, octostreptococcus, etc., Streptococcus pneumoniae, hemolytic streptococcus, and Clostridium mutans), Bacillus (e.g., Bacillus anthracis, Bacillus subtilis), and Clostridium (e.g., Clostridium tetani, Clostridium botulinum). bacteria), Micrococcus (Micrococcus: e.g. Micrococcus luteus), Corynebacterium (Corynebacterium xerosis, Corynebacterium diphtheriae), Propionibacterium (Propionibacterium: e.g. Propionibacterium acnes), Mycobacterium (Mycobacterium; e.g. Mycobacterium tuberculosis), Actinomyces (Actinomyces; e.g. A. israelii), etc.

Gram-negative bacteria are not particularly limited. Examples of 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., Burkholderia cepacia), Klebsiella (e.g., Klebsiella pneumoniae), Vibrio (Vibrio parahaemolyticus), Rickettsia, Spirochaetes, etc.

Among these, the biofilm formation inhibitor of the present embodiment preferably inhibits the formation of a biofilm derived from gram-positive bacteria. This makes it easy for the biofilm formation inhibitor to preferably inhibit the formation of a biofilm, particularly in applications where a biofilm derived from gram-positive bacteria is formed.

In particular, it is preferable that the Gram-positive bacteria is at least one selected from the group consisting of the genera Staphylococcus, Enterococcus, and Streptococcus. This makes it easier for the biofilm formation inhibitor to inhibit the formation of biofilms derived from the genera Staphylococcus, Enterococcus, and Streptococcus.

Furthermore, it is preferable that the gram-positive bacteria is at least one selected from the group consisting of Staphylococcus aureus, Staphylococcus epidermidis, and Streptomyces mutans. This makes it easier for the biofilm formation inhibitor to inhibit the formation of biofilms derived from Staphylococcus aureus, Staphylococcus epidermidis, and Streptomyces mutans in particular.

The content of diterpenes (A) in the biofilm formation inhibitor of this embodiment may be any concentration as long as it is capable of inhibiting biofilm formation, but it has the characteristic that an excellent biofilm formation inhibitory effect can be obtained even at a concentration below the MIC for the above biofilm. Note that MIC refers to the minimum inhibitory concentration, and represents the minimum drug concentration that can inhibit bacterial growth when a drug susceptibility test is performed using the agar plate dilution method or the broth microdilution method.

The content of diterpenes (A) in the biofilm formation inhibitor of this embodiment is such that an excellent biofilm formation inhibitory effect is obtained even at a concentration less than the MIC, an excellent biofilm formation inhibitory effect is obtained even at a concentration equal to or less than half the MIC, an excellent biofilm formation inhibitory effect is obtained even at a concentration equal to or less than one-quarter of the MIC, and an excellent biofilm formation inhibitory effect is obtained even at a concentration equal to or less than one-eighth of the MIC. In other words, the biofilm formation inhibitor of this embodiment can inhibit the formation of a biofilm without exhibiting antibacterial properties. Therefore, the biofilm formation inhibitor can suppress the occurrence of drug-resistant bacteria. In addition, the content of diterpenes (A) in the biofilm formation inhibitor of this embodiment is preferably equal to or more than one-hundredth of the MIC, and more preferably equal to or more than one-sixty-fourth of the MIC, in order to obtain an excellent biofilm formation inhibitory effect.

<Method for inhibiting biofilm formation>
A method for inhibiting biofilm formation according to one embodiment of the present invention is a method in which the above-described biofilm formation inhibitor is brought into contact with at least one of a target object or a target location.

　The object or the target location is not particularly limited as long as it is an object or location where microorganisms are likely to grow and a biofilm can be formed. For example, the object or the target location may be a water-related area such as a kitchen, a bathroom, a washroom, or a toilet, facilities, equipment, or parts related to the water-related area, wastewater and water treatment facilities in a general home or other business, equipment and parts related to the wastewater and water treatment facilities, and the oral cavity (e.g., teeth, dentures, gums, tongue, oral mucosa, etc.). The object or the target location may also be a hospital, medical facilities, medical equipment, etc. The medical equipment is not particularly limited. For example, the medical equipment may be a respiratory device endoscope, a gastroscope, a hematological flow channel, a dialysis device equipment, a respiratory path maintenance device, an ISE, an HPLC, and a catheter used in these applications. The medical equipment may also be an artificial heart, a stent, an artificial joint, a dental implant material, etc.

The biofilm formation inhibition method of this embodiment inhibits the formation of a biofilm by contacting at least one of the target object or target location with a biofilm formation inhibitor. As described above, the biofilm formation inhibitor can inhibit the formation of a biofilm even at a low concentration that does not exhibit antibacterial properties. Therefore, the biofilm formation inhibition method of this embodiment can easily and effectively inhibit the formation of a biofilm in the target object or target location, and can also inhibit the emergence of drug-resistant bacteria, even when a biofilm formation inhibitor at a low concentration that does not exhibit antibacterial properties is used.

When carrying out the method for inhibiting biofilm formation, the manner in which the biofilm formation inhibitor is brought into contact with the target object or the target location is not particularly limited. As an example, the manner in which the biofilm formation inhibitor is brought into contact with the target object or the target location is scattering, applying, spraying, coating, permeating, washing, kneading into resin, etc. These are appropriately selected depending on the form of the biofilm formation inhibitor.

<Resin composition and molded article>
A resin composition according to one embodiment of the present invention contains the diterpene (A) and a resin.

The resin is not particularly limited. Examples of the resin include vinyl chloride resin, styrene resin, polyamide, polyamideimide, polyimide, polyester, polycarbonate, polyacetal, ABS resin, phenoxy resin, polymethyl methacrylate resin, polyphenylene ether, polyphenylene sulfide, polyetherimide, liquid crystal polymer, polyetherketone, polyethersulfone, polysulfone, fluororesin, and polyolefin resin (e.g., polyethylene, polypropylene).

The content of diterpenes (A) is not particularly limited. As an example, the content of diterpenes (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. The content of diterpenes (A) in the resin composition is preferably 50% by mass or less, and more preferably 30% by mass or less. By having the content of diterpenes (A) within the above range, the resin composition can suppress the formation of a biofilm even when it contains a low concentration of diterpenes (A) that does not exhibit antibacterial properties.

The molded article of one embodiment of the present invention is a molded article obtained by molding the above-mentioned resin composition. The shape of the molded article is not particularly limited. For example, the shape of the molded article can be appropriately selected depending on the application and purpose. For example, the shape of the molded article can be a plate, plate, rod, sheet, film, cylinder, ring, circle, ellipse, polygon, irregular shape, hollow, frame, box, panel, etc.

The molded body of this embodiment may also be any of the various molded bodies that constitute the target object and target location described above in relation to the method for inhibiting biofilm formation.

The molding method of the molded body is not particularly limited. Examples of molding methods for the molded body include injection molding, injection compression molding, extrusion molding, profile extrusion, press molding, sheet molding, film molding, transfer molding, inflation molding, hollow molding, gas-assisted hollow molding, blow molding, extrusion blow molding, IMC (in-mold coating molding), rotational molding, multi-layer molding, two-color molding, insert molding, sandwich molding, foam molding, and pressure molding.

The uses of the obtained molded body are not particularly limited. Examples of uses of the molded body include packaging materials, agricultural materials, civil engineering materials, fibers, building materials, automobile parts, home appliance parts, sanitary and medical materials, and other industrial materials.

The molded article of this embodiment can suppress the formation of a biofilm even when it contains a low concentration of diterpenes (A) that do not exhibit antibacterial properties.

<Coating Agent>
The coating agent according to one embodiment of the present invention contains the diterpenes (A) described above. The coating agent is not particularly limited. For example, the coating agent may be any of various thermosetting coating agents, photocurable coating agents, etc.

The content of diterpenes (A) is not particularly limited. As an example, the content of diterpenes (A) in the coating agent is preferably 0.01% by mass or more, and more preferably 0.1% by mass or more. The content of diterpenes (A) in the coating agent is preferably 50% by mass or less, and more preferably 30% by mass or less. When the content of diterpenes (A) is within the above range, the coating agent can suppress the formation of a biofilm by applying it to an object or a target location, even if it contains a low concentration of diterpenes (A) that does not exhibit antibacterial properties.

The other components constituting the coating agent other than the diterpenes (A) are not particularly limited. For example, the other components of the coating agent may be any of those that are incorporated into conventionally known thermosetting or photocurable coating agents, such as binder resins (acrylic resins, urethane resins, polyester resins, epoxy resins, alkyd resins, phenolic resins, melamine resins, silicone resins, etc.), polymerization initiators (radical polymerization initiators, cationic polymerization initiators, anionic polymerization initiators, radical photopolymerization initiators, cationic photopolymerization initiators, anionic photopolymerization initiators, etc.), solvents (ketone solvents, aromatic solvents, alcohol solvents, glycol solvents, glycol ether solvents, ester solvents, petroleum solvents, haloalkane solvents, amide solvents, etc.), silicone oils, adhesion promoters such as silane coupling agents, fillers, leveling agents, rheology regulators, diluents, surfactants, dispersants, defoamers, dehydrating agents, antioxidants, antioxidants, antistatic agents, infrared absorbing agents, ultraviolet absorbing agents, light stabilizers, fluorescent agents, dyes, pigments, fragrances, abrasives, rust inhibitors, thixotropy-imparting agents, etc.

There are no particular limitations on the object or location to which the coating agent is applied. For example, the object or location may be the object or location described above in relation to the method for inhibiting biofilm formation.

By applying the coating agent of this embodiment to a target object or target location, the surfaces of the target object and target location can be endowed with an excellent biofilm formation inhibitory effect.

<Oral Composition>
An oral composition according to one embodiment of the present invention contains the diterpenes (A) described above.

The form of the oral composition is not particularly limited. Examples of the oral composition include toothpaste, gel, powder, solution (mouthwash, dental rinse), suspension, emulsion, troche (lozenge), vehicle, tablet, gum, etc. The method for preparing the oral composition is not particularly limited, and a known method may be used depending on the form of the oral composition.

The method of using the oral composition is not particularly limited, and a known method may be adopted depending on the form of the oral composition. For example, when the oral composition is a toothpaste, the oral cavity (e.g., teeth, dentures, gums, tongue, oral mucosa, etc.) is treated with the oral composition at any frequency.

The other components of the oral composition other than the diterpenes (A) are not particularly limited. For example, the other components of the oral composition may be any components that are incorporated into conventional oral compositions, such as water, surfactants, abrasives, humectants, monohydric alcohols, binders, flavorings, sweeteners, pH adjusters, preservatives, colorants, bactericides, natural polymers (e.g., gelatin, collagen, konjac mannan, pullulan, chitosan, starch, etc.), synthetic polymers (e.g., polyethylene glycol, carboxyvinyl polymers, etc.), polysaccharides (e.g., dextran, polyacryl dextran, etc.), lecithin (soybean lecithin, egg yolk lecithin, etc.), polylactic acid, polyglycolic acid, albumin, cyclodextrin, etc.

The method of using the oral composition is not particularly limited, and a known method may be adopted depending on the form of the oral composition. For example, when the oral composition is a toothpaste, the oral cavity (e.g., teeth, dentures, gums, tongue, oral mucosa, etc.) is treated with the oral composition at any frequency.

The above describes one embodiment of the present invention. The present invention is not particularly limited to the above embodiment. Note that the above embodiment mainly describes an invention having the following configuration.

(1) A biofilm formation inhibitor containing a diterpene (A) having an octanol/water partition coefficient (logP) of 6 or more.

　With this configuration, the biofilm formation inhibitor can inhibit the formation of biofilms.

(2) The biofilm formation inhibitor according to (1), wherein the diterpenes (A) have a structure represented by the following general formula (1).
(In formula (1), * indicates a bonding site with other substituents. Also, the dashed line portion indicates that a carbon-carbon bond may be present there. When a carbon-carbon bond is present at a dashed line portion, a carbon-carbon bond is present at any one of all dashed line portions.)

With this configuration, the biofilm formation inhibitor is more likely to inhibit the formation of biofilms.

(3) The biofilm formation inhibitor according to (1) or (2), wherein the diterpenes (A) include at least one of tetrahydroabietic acid and dihydroabietic acid.

With this configuration, the biofilm formation inhibitor is even more likely to inhibit the formation of biofilms.

(4) The biofilm formation inhibitor according to (1) or (2), wherein the diterpenes (A) are hydrogenated rosin containing at least one of tetrahydroabietic acid and dihydroabietic acid.

With this configuration, the biofilm formation inhibitor is even more likely to inhibit the formation of biofilms.

(5) The biofilm formation inhibitor according to (1) or (2), wherein the diterpenes (A) are rosin esters, and the rosin esters are reaction products of hydrogenated rosin containing at least one of tetrahydroabietic acid and dihydroabietic acid with an alcohol.

With this configuration, the biofilm formation inhibitor is even more likely to inhibit the formation of biofilms.

(6) A biofilm formation inhibitor according to any one of (1) to (5), in which the solubility of the diterpenes (A) in water at 20°C is 1% by mass or less.

With this configuration, when the biofilm formation inhibitor is applied (e.g., coated) to an object or a location where a biofilm may form, it can inhibit the breakdown of the coating film caused by moisture in the environment or human sweat, or the seepage of diterpenes (A) from the coating film. Therefore, the biofilm formation inhibitor provides excellent coating film durability.

(7) A biofilm formation inhibitor according to any one of (1) to (6), which inhibits the formation of a biofilm derived from a gram-positive bacterium.

With this configuration, the biofilm formation inhibitor is particularly suitable for use in applications where biofilms derived from gram-positive bacteria are formed, and is therefore likely to inhibit the formation of biofilms.

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

　With this configuration, the biofilm formation inhibitor is particularly likely to inhibit the formation of biofilms derived from the genera Staphylococcus, Enterococcus, and Streptococcus.

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

　With this configuration, the biofilm formation inhibitor is particularly likely to inhibit the formation of biofilms derived from Staphylococcus aureus, Staphylococcus epidermidis, and Streptococcus mutans.

(10) A method for inhibiting biofilm formation, comprising contacting at least one of a target object or a target location with a biofilm formation inhibitor described in any one of (1) to (9).

With this configuration, the biofilm formation inhibition method is more likely to inhibit the formation of biofilms on a target object (such as a medical catheter) or in a target location (particularly a bathroom or washbasin).

(11) A resin composition comprising the diterpene (A) described in any one of (1) to (9) and a resin.

With this configuration, the resin composition can suppress the formation of biofilms.

(12) A molded body obtained by molding the resin composition described in (11).

With this configuration, the molded body can suppress the formation of biofilms in the molded body.

(13) A coating agent comprising the diterpene (A) described in any one of (1) to (9).

With this configuration, the coating agent can be applied to a target object or target location to suppress the formation of a biofilm.

　In addition, this disclosure provides the following:

(Item A1)
A biofilm formation inhibitor comprising a diterpene (A) having an octanol/water partition coefficient (log P) of 6 or more.
(Item A2)
The biofilm formation inhibitor described in the above item, wherein the diterpene (A) has a structure represented by the following general formula (1):
(In formula (1), * indicates a bonding site with other substituents. Also, the dashed line portion indicates that a carbon-carbon bond may be present there. When a carbon-carbon bond is present at a dashed line portion, a carbon-carbon bond is present at any one of all dashed line portions.)
(Item A3)
The biofilm formation inhibitor according to any one of the above items, wherein the diterpene (A) has a structure represented by the following general formula (2):
(In formula (2), * indicates a bonding site with other substituents.)
(Item A4)
The biofilm formation inhibitor according to any one of the above items, wherein the diterpenes (A) have a structure represented by the following general formula (3):
(In formula (3), * indicates a bonding site with other substituents. Also, each broken line indicates that there is a carbon-carbon bond at one of the broken lines, and a carbon-carbon bond exists at any one of the broken lines.)
(Item A5)
A biofilm formation inhibitor described in any of the above items, wherein the diterpenes (A) include at least one selected from the group consisting of diterpenes having a structure represented by the above general formula (2), diterpenes having a structure represented by the above general formula (3), and derivatives of dehydroabietic acid.
(Item A6)
A biofilm formation inhibitor described in any of the above items, wherein the diterpenes (A) include at least one selected from the group consisting of tetrahydroabietic acid, derivatives of tetrahydroabietic acid, dihydroabietic acid, derivatives of dihydroabietic acid, and derivatives of dehydroabietic acid.
(Item A7)
The biofilm formation inhibitor according to any one of the above items, wherein the diterpenes (A) include at least one of tetrahydroabietic acid and dihydroabietic acid.
(Item A8)
The biofilm formation inhibitor according to any one of the above items, wherein the diterpenes (A) are rosins containing diterpenes having the structure represented by the general formula (1) above.
(Item A9)
The biofilm formation inhibitor according to any one of the above items, wherein the diterpenes (A) are rosins containing diterpenes having the structure represented by the general formula (2) above.
(Item A10)
The biofilm formation inhibitor according to any one of the above items, wherein the diterpenes (A) are rosins containing diterpenes having the structure represented by the general formula (3) above.
(Item A11)
A biofilm formation inhibitor described in any of the above items, wherein the diterpenes (A) are rosins containing at least one selected from the group consisting of diterpenes having the structure represented by the above general formula (2), diterpenes having the structure represented by the above general formula (3), and derivatives of dehydroabietic acid.
(Item A12)
A biofilm formation inhibitor described in any of the above items, wherein the diterpenes (A) are rosins containing at least one selected from the group consisting of tetrahydroabietic acid, derivatives of tetrahydroabietic acid, dihydroabietic acid, derivatives of dihydroabietic acid, and derivatives of dehydroabietic acid.
(Item A13)
The biofilm formation inhibitor according to any one of the above items, wherein the diterpenes (A) are rosins containing at least one of tetrahydroabietic acid and dihydroabietic acid.
(Item A14)
The biofilm formation inhibitor described in any of the above items, wherein the diterpenes (A) are rosins containing at least one selected from the group consisting of disproportionated rosin containing at least one of tetrahydroabietic acid or dihydroabietic acid, derivatives of the disproportionated rosin, hydrogenated rosin containing at least one of tetrahydroabietic acid or dihydroabietic acid, and derivatives of the hydrogenated rosin.
(Item A15)
The biofilm formation inhibitor according to any one of the above items, wherein the diterpenes (A) are disproportionated rosin containing at least one of tetrahydroabietic acid and dihydroabietic acid.
(Item A16)
The biofilm formation inhibitor according to any one of the above items, wherein the diterpenes (A) are derivatives of disproportionated rosin containing at least one of tetrahydroabietic acid and dihydroabietic acid.
(Item A17)
The biofilm formation inhibitor according to any one of the above items, wherein the diterpenes (A) are hydrogenated rosin containing at least one of tetrahydroabietic acid and dihydroabietic acid.
(Item A18)
The biofilm formation inhibitor according to any one of the above items, wherein the diterpenes (A) are derivatives of hydrogenated rosin containing at least one of tetrahydroabietic acid and dihydroabietic acid.
(Item A19)
A biofilm formation inhibitor described in any of the above items, wherein the diterpenes (A) are rosin esters, and the rosin esters are reaction products of hydrogenated rosin containing at least one of tetrahydroabietic acid and dihydroabietic acid and alcohol.
(Item A20)
The diterpenes (A) are rosins containing diterpenes having the structure represented by the general formula (1),
A biofilm formation inhibitor according to any of the above items, wherein the content of diterpenes 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 rosins.
(Item A21)
The diterpenes (A) are rosins containing diterpenes having the structure represented by the general formula (2),
A biofilm formation inhibitor according to any of the above items, wherein the content of diterpenes 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 rosins.
(Item A22)
The diterpenes (A) are rosins containing diterpenes having the structure represented by the general formula (3),
A biofilm formation inhibitor according to any of the above items, wherein the content of diterpenes having the structure represented by the general formula (3) is 5% by mass or more and 100% by mass or less relative to 100% by mass of rosins.
(Item A23)
The diterpenes (A) are hydrogenated rosin containing tetrahydroabietic acid,
A biofilm formation inhibitor according to any of the above items, wherein the content of tetrahydroabietic acid is 10% by mass or more and 100% by mass or less relative to 100% by mass of hydrogenated rosin.
(Item A24)
The diterpenes (A) are hydrogenated rosin containing dihydroabietic acid,
The biofilm formation inhibitor according to any of the above items, wherein the content of dihydroabietic acid is 1% by mass or more and 100% by mass or less relative to 100% by mass of hydrogenated rosin.
(Item A25)
The diterpenes (A) are esters of hydrogenated rosin containing tetrahydroabietic acid,
A biofilm formation inhibitor according to any of the above items, wherein the content of tetrahydroabietic acid is 10% by mass or more and 100% by mass or less relative to 100% by mass of hydrogenated rosin.
(Item A26)
The diterpenes (A) are esters of hydrogenated rosin containing dihydroabietic acid,
The biofilm formation inhibitor according to any of the above items, wherein the content of dihydroabietic acid is 1% by mass or more and 100% by mass or less relative to 100% by mass of hydrogenated rosin.
(Item A27)
The diterpenes (A) are disproportionated rosin containing tetrahydroabietic acid,
A biofilm formation inhibitor according to any of the above items, wherein the content of tetrahydroabietic acid is 10% by mass or more and 100% by mass or less relative to 100% by mass of disproportionated rosin.
(Item A28)
The diterpenes (A) are disproportionated rosin containing dihydroabietic acid,
The biofilm formation inhibitor according to any of the above items, wherein the content of dihydroabietic acid is 5% by mass or more and 100% by mass or less relative to 100% by mass of disproportionated rosin.
(Item A29)
The biofilm formation inhibitor according to any of the above items, wherein the solubility of the diterpenes (A) in water at 20°C is 1 mass% or less.
(Item A30)
The biofilm formation inhibitor according to any of the above items, wherein the solubility of the diterpenes (A) in water at 20°C is 0.1 mass% or less.
(Item A31)
The biofilm formation inhibitor according to any of the above items, wherein the diterpenes (A) do not include an alkali metal salt of tetrahydroabietic acid, an alkali metal salt of dihydroabietic acid, an alkali metal salt of dehydroabietic acid, an alkali metal salt of abietic acid, or an alkali metal salt of rosins.
(Item A32)
A biofilm formation inhibitor according to any one of the above items, which inhibits the formation of a biofilm derived from Gram-positive bacteria.
(Item A33)
The biofilm formation inhibitor according to item A32, wherein the Gram-positive bacterium is at least one selected from the group consisting of the genus Staphylococcus, the genus Enterococcus, and the genus Streptococcus.
(Item A34)
The biofilm formation inhibitor according to item A32 or A33, wherein the gram-positive bacterium is at least one selected from the group consisting of Staphylococcus aureus, Staphylococcus epidermidis, and Streptococcus mutans.
(Item A35)
A method for inhibiting biofilm formation, comprising contacting at least one of a target object or a target location with a biofilm formation inhibitor described in any of the above items.
(Item A36)
A resin composition comprising the diterpene (A) according to any one of the above items and a resin.
(Item A37)
A resin composition comprising the diterpene (A) according to any one of the above items and a polyolefin resin.
(Item A38)
A molded article obtained by molding the resin composition according to item A37.
(Item A39)
A coating agent comprising the diterpenes (A) according to any one of the preceding items.

The present invention will be explained in more detail below with reference to examples. The present invention is not limited to these examples. Unless otherwise specified, "%" means "% by mass" and "parts" means "parts by mass". The materials used in the following examples and comparative examples are as follows. The units of values in the columns for each component and the total in the tables are "% by mass".

The samples used in this example are shown below. The octanol/water partition coefficient log P and the solubility in water at 20° C. were calculated by the following methods.
(Octanol/water partition coefficient log P)
The calculation was performed from the sample structure using the software "MOE (Molecular Operating Environment) 2022.02 (MOLSIS)."
(Solubility in water at 20°C)
The sample was pulverized into powder, and the pulverized sample was added to deionized water in a mass ratio of 1:10 and mixed at 20° C. for 2 hours. The mixture was filtered using a filter (Advantec membrane filter H050A047A) and the filtrate was collected. The collected filtrate was dried at a temperature of 105° C. for 5 hours, and the solubility was calculated from the mass after drying using the following formula.
(Sample concentration A)%=(ground sample)g/(ground sample+deionized water)g×100
(Non-volatile content B of aqueous solution)%=(mass after drying)g/(amount of filtrate collected)g×100
Solubility in water % = (non-volatile content of aqueous solution B) % / (concentration of sample A) %

The amounts of tetrahydroabietic acid and dihydroabietic acid in hydrogenated rosin 1, hydrogenated rosin 2, hydrogenated rosin K salt and disproportionated rosin used in this example were determined by the following method.
0.1 g of a sample was dissolved in 2.0 g of n-hexanol, and 0.1 g of this solution was mixed uniformly with 0.4 g of an on-column methylating agent (a methanol solution of phenyltrimethylammonium hydroxide (PTAH) (0.2 mol/L, manufactured by GL Sciences Inc.), and 1 μL of the solution was injected into a commercially available gas chromatograph mass spectrometer (GC/MS) for measurement. The total peak area of the component with mass number 320 was taken as the peak area showing the methyl ester form of tetrahydroabietic acid, and the total peak area of the component with mass number 318 was taken as the peak area showing the methyl ester form of dihydroabietic acid, and the respective peak area ratios to the total peak area showing methylated resin acids (the total peak area of components with mass numbers 314 to 320) were calculated to determine the contents of tetrahydroabietic acid and dihydroabietic acid. The analytical apparatus and column are shown below.
Gas chromatograph mass spectrometer: "Agilent 6890", "Agilent 5973N" manufactured by Agilent Technologies, Inc. Column: "Advance-DS" manufactured by Shinwa Kako Co., Ltd.

The amounts of tetrahydroabietic acid and dihydroabietic acid in the hydrogenated rosin ester used in this example were determined by the following method.
Hydrogenated rosin ester and potassium hydroxide were added to n-hexanol and reacted (hydrolyzed) under reflux for 2 hours, and then the mixture was neutralized with hydrochloric acid to obtain a resin acid. 0.1 g of the resin acid was dissolved in 2.0 g of n-hexanol, and 0.1 g of this solution was uniformly mixed with 0.4 g of an on-column methylating agent (a methanol solution of phenyltrimethylammonium hydroxide (PTAH) (0.2 mol/L, manufactured by GL Sciences Inc.), and 1 μL of the solution was injected into a commercially available gas chromatograph mass spectrometry (GC/MS) for measurement. The total peak area of the component with mass number 320 was taken as the peak area showing the methyl ester form of tetrahydroabietic acid, and the total peak area of the component with mass number 318 was taken as the peak area showing the methyl ester form of dihydroabietic acid, and the respective peak area ratios to the total peak area showing the methylated resin acid (the total peak area of the components with mass numbers 314 to 320) were calculated to determine the contents of tetrahydroabietic acid and dihydroabietic acid. The analytical apparatus and column are shown below.
Gas chromatograph mass spectrometer: "Agilent 6890", "Agilent 5973N" manufactured by Agilent Technologies, Inc. Column: "Advance-DS" manufactured by Shinwa Kako Co., Ltd.

Furthermore, the contents of triethylene glycol (hereinafter also referred to as TEG) monoester and TEG diester in the hydrogenated rosin ester used in this example were calculated from gel permeation chromatography (GPC) of the hydrogenated rosin ester, the area ratio of the peak derived from the TEG monoester to the total peak area, and the area ratio of the peak derived from the TEG diester to the total peak area. The measurement conditions are described below.
(Measurement conditions)
Apparatus: Tosoh Corporation high-speed GPC apparatus HLC-8320GPC
Column: TSKgel guard column HXL-L/G2000HXL/G1000HXL manufactured by Tosoh Corporation
Eluent: tetrahydrofuran Flow rate: 1.0 mL/min Temperature: 40° C.
RI detector: Tosoh Corporation, Bryce type double path, double flow method, red LED (wavelength: 630 to 670 nm)
Measurement sample: The rosin concentration was diluted with the above eluent to 0.1%.

(Sample Production)
Production Example 1
600 parts of hydrogenated rosin produced in China (manufactured by Guangxi Wuzhou Richeng Lin Chemical Co., Ltd.) were charged into a 1-liter flask and distilled under a reduced pressure of 400 Pa to obtain a component distilled at 195 to 250°C. 100 parts of the component distilled at 195 to 250°C, 1.5 parts of 5% palladium alumina, and 100 parts of cyclohexane were charged into a 1-liter autoclave, and the system was fully replaced with hydrogen gas, after which the initial hydrogen pressure in the reaction was set to 6 MPa, the temperature was raised to 200°C, and then the hydrogen pressure was set to 10 MPa, and the reaction was carried out for 4 hours while appropriately replenishing the pressure reduction. The catalyst was filtered off, and cyclohexane was distilled off by reduced pressure distillation to obtain hydrogenated rosin. The hydrogenated rosin obtained was recrystallized twice in acetone and dried under reduced pressure to obtain tetrahydroabietic acid. The resulting tetrahydroabietic acid had an octanol/water partition coefficient log P of 6.65 and a solubility in water at 20° C. of 0.01%.

Production Example 2
An autoclave was charged with 100 parts of unrefined Chinese gum rosin, 100 parts of mineral turpentine, and 5 parts of Raney nickel catalyst as a hydrogenation catalyst, and the mixture was pressurized to 10 MPa after hydrogen replacement and reacted at 110°C for 5 hours. The catalyst was filtered under a nitrogen atmosphere to obtain a mineral turpentine solution of semi-hydrogenated rosin. 0.2 parts of paratoluenesulfonic acid was added to 100 parts of this solution, and the mixture was isomerized at a reaction temperature of 150°C for 2 hours, and then the mineral turpentine and paratoluenesulfonic acid were distilled off by vacuum distillation to obtain crude crystallization. The crude crystals were recrystallized four times in acetone to obtain dihydroabietic acid. 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%.

Production Example 3
Hydrogenated rosin (55% tetrahydroabietic acid, 25% dihydroabietic acid) was charged into a reduced pressure distillation vessel, heated to 250° C. and held for 1 hour, and then distilled under a nitrogen seal at a reduced pressure of 1 kPa to obtain hydrogenated rosin 1. The obtained hydrogenated rosin 1 was a hydrogenated rosin containing 60% tetrahydroabietic acid and 27% dihydroabietic acid, and had a solubility in water at 20° C. of 0.05%.

Production Example 4
A 3-liter autoclave was charged with 100 parts of Chinese gum rosin and 0.2 parts of 5% palladium carbon (water content: 50%) as a hydrogenation catalyst, and after removing oxygen from the system, the system was pressurized to 100 kg/ ^cm2 with hydrogen, and the temperature was raised to 260°C with stirring, and hydrogenation reaction was carried out at the same temperature for 3 hours to obtain an unrefined hydrogenated rosin. Next, the unrefined hydrogenated rosin was distilled under a nitrogen seal at a reduced pressure of 3 mmHg, and the main fraction distilled at 195 to 250°C was obtained as hydrogenated rosin 2. The obtained hydrogenated rosin 2 was a hydrogenated rosin containing 28% tetrahydroabietic acid and 52% dihydroabietic acid, and had a solubility in water at 20°C of 0.03%.

Production Example 5
To 100 parts of dehydroabietic acid obtained in Comparative Production Example 1 described below, 650 parts of an ethanolic potassium hydroxide solution (product name "0.5 mol/L potassium hydroxide solution (ethanolic) (N/2)", manufactured by Kanto Chemical Co., Ltd.) was added dropwise. Acetone was added thereto, and filtration was performed to obtain a potassium salt of dehydroabietic acid as a residue. 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%.

Production Example 6
600 parts of hydrogenated rosin produced in China (manufactured by Guangxi Wuzhou Richeng Lin Chemical Co., Ltd.) were charged into a 1-liter flask and distilled under a reduced pressure of 400 Pa to obtain a component distilled at 195 to 250° C. 100 parts of the component distilled at 195 to 250° C., 1.5 parts of 5% palladium alumina, and 200 parts of cyclohexane were charged into a 1-liter autoclave, and the system was sufficiently substituted with hydrogen gas, after which the initial hydrogen pressure in the reaction was set to 6 MPa, the temperature was raised to 200° C., and then the hydrogen pressure was set to 10 MPa, and the reaction was carried out for 4 hours while appropriately replenishing the reduced pressure. The catalyst was filtered off, and cyclohexane was distilled off by reduced pressure distillation to obtain hydrogenated rosin.
To 100 parts of the hydrogenated rosin, 650 parts of an ethanolic potassium hydroxide solution (product name "0.5 mol/L potassium hydroxide solution (ethanolic) (N/2)" manufactured by Kanto Chemical Co., Ltd.) was dropped. Acetone was added thereto, and filtration was performed to obtain a potassium salt of hydrogenated rosin as a filtrate. The obtained potassium salt of hydrogenated rosin was a potassium salt of hydrogenated rosin containing 95% tetrahydroabietic acid and 1% dihydroabietic acid, and the octanol/water partition coefficient log P of the potassium salt of tetrahydroabietic acid was 7.27, the octanol/water partition coefficient log P of the potassium salt of dihydroabietic acid was 6.75, and the solubility of the potassium salt of hydrogenated rosin in water at 20°C was 97.9%.

Production Example 7
100 parts of unrefined Chinese gum rosin was added with 0.03 parts of 5% palladium carbon (water content 50%) as a disproportionation catalyst, and the mixture was stirred under nitrogen blanket at 280°C for 4 hours to carry out a disproportionation reaction, thereby obtaining an unrefined disproportionated rosin. Next, the unrefined disproportionated rosin was distilled under a reduced pressure of 3 mmHg under nitrogen blanket, and a main fraction having an acid value of 176.5, a softening point of 82°C, and a general constant of color Gardner 4 was obtained as a refined disproportionated rosin. Next, 100 parts of the refined product of the disproportionated rosin and 0.3 parts of 5% palladium carbon (water content 50%) were charged into a 1-liter shaking autoclave, and oxygen in the system was removed, and then the system was pressurized with hydrogen to 0.5 kg/ ^cm2 and heated to 275°C, and a dehydrogenation reaction was carried out at the same temperature for 3 hours to obtain a disproportionated rosin. The resulting disproportionated rosin contained 12% tetrahydroabietic acid and 8% dihydroabietic acid, and had a solubility in water at 20° C. of 0.02%.

Production Example 8
A 1-liter flask was charged with 100 parts of hydrogenated rosin produced in China (manufactured by Guangxi Wuzhou Richeng Forest Chemical Co., Ltd.) and 50 parts of triethylene glycol, and the mixture was heated to 200° C. in an argon stream to melt, and then reacted for 5 hours at 250° C. and then for 5 hours at 270° C. to obtain a hydrogenated rosin ester. The obtained hydrogenated rosin ester was a rosin ester containing 40% TEG diester of hydrogenated rosin containing tetrahydroabietic acid and dihydroabietic acid and 45% TEG monoester of the hydrogenated rosin, and had a solubility in water at 20° C. of 0.66%. The octanol/water partition coefficients log P of the TEG diester of tetrahydroabietic acid, the TEG diester of dihydroabietic acid, the TEG monoester of tetrahydroabietic acid, and the TEG monoester of dihydroabietic acid in the hydrogenated rosin ester were 13.05, 14.11, 6.78, and 6.25, respectively. Furthermore, the hydrogenated rosin in the hydrogenated rosin ester was a hydrogenated rosin containing 12.7% tetrahydroabietic acid and 81.5% dihydroabietic acid.

Comparative Production Example 1
Disproportionated rosin (acid value 167, softening point 77°C, manufactured by Arakawa Chemical Industries, Ltd.) was melted in an argon stream, and then heated under reduced pressure of 133 Pa to obtain a fraction of 195-200°C (purified disproportionated rosin). 100 parts of the purified disproportionated rosin was dissolved in 240 parts of ethanol by heating, and 20 parts of monoethanolamine was added thereto and reacted under reflux for 1 hour, after which 250 parts of water was added. The obtained monoethanolamine salt of dehydroabietic acid was extracted twice with 200 mL of isooctane to remove unsaponifiable matter and dihydroabietic acid salt. After standing overnight, the crystals were filtered, and further recrystallized three times with 125 parts of ethanol to sufficiently increase the purity of dehydroabietic acid, and then the amine salt was decomposed with hydrochloric acid and filtered. The crystals were dissolved in ether, thoroughly washed with water, completely solidified, and then recrystallized again in ethanol to obtain dehydroabietic acid. The resulting dehydroabietic acid had an octanol/water partition coefficient log P of 5.66 and a solubility in water at 20° C. of 0.00%.

Comparative Production Example 2
Abietic acid was obtained by recrystallizing commercially available abietic acid (Kanto Chemical Co., Ltd.) four times in acetone and drying under reduced pressure. The abietic acid had an octanol/water partition coefficient log P of 5.75 and a solubility in water at 20° C. of 0.65%.

(Calculation of MIC for each sample)
The MICs of each of the above samples for Streptococcus mutans (strain 8148) and Staphylococcus aureus (strain N315) were measured by broth microdilution. Mueller-Hinton medium supplemented with streptohemosupplement was used for Streptococcus mutans, and Mueller-Hinton medium supplemented with cations was used for Staphylococcus aureus. Using each medium, a two-fold dilution series of the drug was prepared in a 96-well plate, and about 10,000 live bacteria were added to each well. Static culture was performed at 37°C for 24 hours, and the minimum concentration at which the growth of bacteria could not be confirmed visually was determined as the MIC.

<Examples 1 to 11 and Comparative Examples 1 to 4>
The biofilm formation rate of each of the above samples against Streptococcus mutans or Staphylococcus aureus was evaluated by the following method. The results are shown in Tables 2 and 3.

(Method of calculating biofilm formation inhibition rate)
Streptococcus mutans (strain 8148) was diluted 100-fold with brain heart infusion medium (1% glucose added). Staphylococcus aureus (strain N315) was also diluted 100-fold with brain heart infusion medium (1% glucose added). Then, 100 μL of each dilution was dispensed into a 96-well plate. A sample solution in which each of the above samples was diluted to an appropriate concentration with DMSO as a solvent was added thereto. At this time, the concentration in each medium was adjusted to 1/8 of the MIC. The control was a medium containing no sample. These were cultured at 37° C. for 24 hours. This allowed a biofilm to form on the 96-well plate. Then, the floating bacteria were washed and removed with distilled water, and the formed biofilm was stained with crystal violet. After washing each well with distilled water, the crystal violet was eluted with 200 μL of 30% acetic acid, and the absorbance at 570 nm was measured to determine the biofilm formation rate (relative to the control).

Details of the abbreviations in Tables 2 and 3 are as follows.
THAA: tetrahydroabietic acid, DHAA: dihydroabietic acid, DAA: dehydroabietic acid, AA: abietic acid, K: potassium

As shown in Table 2, when samples of Examples 1 to 6 of the present invention (containing diterpenes with a log P of 6 or more) were used, the biofilm formation rate against mutans streptococci was less than 50%, even though the concentration was one-eighth the MIC. On the other hand, when samples of Comparative Examples 1 and 2 (with a log P of less than 6) were used, the biofilm formation rate against mutans streptococci exceeded 50%.

Also, as shown in Table 3, when samples of Examples 7 to 11 of the present invention (containing diterpenes with a log P of 6 or more) were used, the biofilm formation rate against Staphylococcus aureus was less than 30%, even though the concentration was one-eighth the MIC. On the other hand, when samples of Comparative Examples 3 and 4 (with a log P of less than 6) were used, the biofilm formation rate against Staphylococcus aureus exceeded 30%.

(Production of resin composition)
Example 12
95 parts of polypropylene (manufactured by Japan Polypropylene Corporation, product name "Novatec MA3") and 5 parts of hydrogenated rosin 1 of Production Example 3 were placed in a roller mixer type kneading apparatus (manufactured by Toyo Seiki Seisakusho, Ltd., apparatus name "Labo Plastomill Model 10C100") and kneaded for 10 minutes at a roller rotation speed of 40 rpm and a temperature of 190°C to obtain a kneaded product (resin composition).

<Example 13>
95 parts of polypropylene (manufactured by Japan Polypropylene Corporation, product name "Novatec MA3") and 5 parts of hydrogenated rosin 2 of Production Example 4 were placed in a roller mixer type kneading apparatus (manufactured by Toyo Seiki Seisakusho, Ltd., apparatus name "Labo Plastomill Model 10C100") and kneaded for 10 minutes at a roller rotation speed of 40 rpm and a temperature of 190°C to obtain a kneaded product (resin composition).

<Comparative Example 5>
100 parts of polypropylene (manufactured by Japan Polypropylene Corporation, product name "Novatec MA3") was added to a roller mixer type kneading device (manufactured by Toyo Seiki Seisakusho, Ltd., device name "Labo Plastomill Model 10C100") and kneaded for 10 minutes at a roller rotation speed of 40 rpm and a temperature of 190°C to obtain a kneaded product (resin composition).

The biofilm formation rate of each of the above resin compositions against Staphylococcus aureus was evaluated using the following method. The results are shown in Table 4.

(Method of calculating biofilm formation inhibition rate)
The resin compositions of Examples 12 to 13 and Comparative Example 5 were injection molded using a hand truder (manufactured by Toyo Seiki Seisakusho Co., Ltd.) at a resin melting temperature of 200°C and a mold temperature of 40°C to prepare test pieces (length 1 cm x width 1 cm x thickness 1 mm). Next, Staphylococcus aureus (N315 strain) cultured overnight was diluted 100 times with brain heart infusion medium (1% glucose added), and 0.75 mL of each dilution was dispensed into a 24-hole plate, to which each of the above test pieces was added and overlaid with a washer. The test piece obtained from the resin composition of Comparative Example 5 was used as a control. These were cultured at 37°C for 24 hours. This allowed a biofilm to form on the surface of the test piece. Thereafter, the floating bacteria were washed and removed with distilled water, and the formed biofilm was stained with crystal violet. After washing and removing excess crystal violet with distilled water, the crystal violet was eluted with 1 mL of 30% acetic acid. The absorbance of crystal violet at 570 nm was measured to determine the biofilm formation rate (relative to the control).

As shown in Table 4, in the case of the resin compositions containing hydrogenated rosins 1 and 2 of the present invention (containing diterpenes with a log P of 6 or more), the biofilm formation rate against Staphylococcus aureus was significantly lower than that of the resin compositions not containing diterpenes.

Claims (13)

A biofilm formation inhibitor containing diterpenes (A) having an octanol/water partition coefficient (logP) of 6 or more. The biofilm formation inhibitor according to claim 1, wherein the diterpene (A) has a structure represented by the following general formula (1):
(In formula (1), * indicates a bonding site with other substituents. Also, the dashed line portion indicates that a carbon-carbon bond may be present there. When a carbon-carbon bond is present at a dashed line portion, a carbon-carbon bond is present at any one of all dashed line portions.) The biofilm formation inhibitor according to claim 1 or 2, wherein the diterpenes (A) include at least one of tetrahydroabietic acid and dihydroabietic acid. The biofilm formation inhibitor according to claim 1 or 2, wherein the diterpenes (A) are hydrogenated rosin containing at least one of tetrahydroabietic acid and dihydroabietic acid. The diterpenes (A) are rosin esters,
The biofilm formation inhibitor according to claim 1 or 2, wherein the rosin ester is a reaction product of a hydrogenated rosin containing at least one of tetrahydroabietic acid and dihydroabietic acid and an alcohol. The biofilm formation inhibitor according to claim 1 or 2, wherein the solubility of the diterpenes (A) in water at 20°C is 1% by mass or less. The biofilm formation inhibitor according to claim 1 or 2, which inhibits the formation of a biofilm derived from gram-positive bacteria. The biofilm formation inhibitor according to claim 7, wherein the gram-positive bacteria is at least one selected from the group consisting of Staphylococcus, Enterococcus, and Streptococcus. The biofilm formation inhibitor according to claim 7, wherein the gram-positive bacteria is at least one selected from the group consisting of Staphylococcus aureus, Staphylococcus epidermidis, and Streptococcus mutans. A method for inhibiting biofilm formation, comprising contacting at least one of a target object or a target location with the biofilm formation inhibitor described in claim 1 or 2. A resin composition comprising the diterpenes (A) according to claim 1 or 2 and a resin. A molded article made from the resin composition according to claim 11. A coating agent comprising the diterpenes (A) according to claim 1 or 2.