Oral care compositions comprising 3-phenyl-1-propanol and alkanediol and 4-isopropyl-3-methylphenol

Abstract

The present invention relates to an oral care composition comprising 3-phenyl-1-propanol, an alkanediol, preferably decane diol, and 4-isopropyl-3-methylphenol, for use in the treatment of bacterial and fungal infections in the oral cavity and in the reduction of bad breath.

Description

Technical Field

[0001] The present invention relates to an oral care composition for treating bacterial and fungal infections in the oral cavity and reducing oral malodor, comprising 3-phenyl-1-propanol, alkylene glycol and 4-isopropyl-3-methylphenol, wherein the alkylene glycol is preferably decylene glycol. Background Art

[0002] Oral malodor is mainly caused by the enzymatic degradation of proteins and amino acids. The malodorous components usually formed include volatile sulfur compounds such as hydrogen sulfide, methanethiol and dimethyl sulfide; indole and skatole. Generally, a higher abundance of anaerobic Gram-negative bacteria such as Porphyromonas and Fusobacterium is associated with stronger malodor.

[0003] In addition to oral malodor, bacteria and fungi can have further negative impacts on oral hygiene, as they can cause dental infections, dental caries, periodontal infections, halitosis, gingivitis, candidiasis and other infections, especially those caused by anaerobic Gram-negative bacterial strains.

[0004] Therefore, oral malodor is undesirable both from a cosmetic and a medical perspective, as the unpleasant smell can usually also indicate an infection in the oral cavity; thus, efforts have been made to improve oral hygiene, for example by using mouthwashes or oral rinses.

[0005] Oral care compositions for reducing oral malodor usually contain antimicrobial compounds such as 4-isopropyl-3-methylphenol, as disclosed in WO 2008 / 126057.

[0006] According to WO 2013 / 08762, 4-isopropyl-3-methylphenol can also be used as an anti-inflammatory agent in compositions designed for oral care applications. Mouthwash preparations containing 4-isopropyl-3-methylphenol are further disclosed in WO 2021 / 074164.

[0007] An antibacterial system comprising 4-isopropyl-3-methylphenol, zinc ions and an anionic surfactant is disclosed in WO 2010 / 112577. The present invention can also be used in mouthwash compositions and is effective against bacterial strains present in the oral cavity, as shown by in vitro studies. Summary of the Invention

[0008] Technical problem Oral malodor is a common problem and is associated with oral diseases, which are even more problematic.

[0009] The present invention is made in view of the problems mentioned above, and the object of the present invention is to identify a composition or application that can generally reduce oral malodor and prevent common oral diseases.

[0010] These problems are generally related to bacteria. Therefore, another secondary problem of the present invention is to establish a composition for reducing the amount of bacteria in the oral cavity.

[0011] Problem solution and advantages of the present invention The present invention is an oral care composition, which comprises 3-phenyl-1-propanol, an alkanediol or a mixture of alkanediols (preferably decanediol), and 4-isopropyl-3-methylphenol. Surprisingly, it has been found that the aforementioned composition strongly reduces the amount of bacteria and fungi in the oral cavity, and thus is capable of treating oral infections. However, the composition also has antifungal activity. In addition, the combination of these three substances is more effective in reducing oral malodor.

[0012] The effects of the present invention have been examined by in vivo experiments. Specifically, it has been demonstrated that the oral care composition has improved antibacterial properties compared with the prior art. In addition, the oral care composition has antifungal properties.

[0013] Preferably, the above-mentioned alkanediol or mixture of alkanediols forming part of the composition is selected from straight-chain 1,2-diols, 2,3-diols or 4,5-diols. Further preferably, the alkanediol has a chain length of 5 to 20 carbon atoms. Preferably, the alkanediol is selected from the group consisting of 1,2-pentanediol, 1,2-hexanediol, 1,2-heptanediol, 1,2-octanediol, 1,2-nonanediol and 1,2-decanediol. More preferably, the alkanediol is 2,3-hexanediol and / or 2,3-heptanediol and / or 2,3-octanediol. Further preferably, the alkanediol is a combination of 1,2-hexanediol and 2,3-hexanediol, or 1,2-heptanediol and 2,3-heptanediol, or 1,2-octanediol and 2,3-octanediol. More preferably, the alkanediol contains 1,2-octanediol or 1,2-decanediol, and also preferably 1,2-hexanediol, 1,2-octanediol and / or 1,2-decanediol. Most preferably, the alkanediol is 1,2-decanediol.

[0014] In a further more preferred variant, the above-mentioned alkanediol is selected from the group consisting of alkanediols having 5 to 8 lower carbon atoms, namely pentanediol, hexanediol, heptanediol, octanediol and any mixture thereof, or from the group consisting of alkanediols having 6 to 8 carbon atoms, namely hexanediol, heptanediol, octanediol and any mixture thereof, or from the group consisting of alkanediols having 7 and 8 carbon atoms, namely heptanediol, octanediol and any mixture thereof.

[0015] In an even more preferred variant, the alkanediol is selected from the group consisting of alkanediols having 9 to 12 higher carbon atoms, namely nonanediol, decanediol, undecanediol, dodecanediol, and any mixture thereof, or is selected from the group consisting of alkanediols having 9 to 11 carbon atoms, namely nonanediol, decanediol, undecanediol, and any mixture thereof, or is selected from the group consisting of alkanediols having 9 and 10 carbon atoms, namely nonanediol, decanediol, and any mixture thereof.

[0016] In an even more preferred variant, the alkanediol is pentanediol, hexanediol, heptanediol, or octanediol, or any mixture thereof. In an even more preferred variant, the alkanediol is nonanediol, decanediol, undecanediol, or dodecanediol, or any mixture thereof. In the most preferred variant, the alkanediol is decanediol.

[0017] The term "alkanediol" in the context of the present invention also includes its constitutional isomers or positional isomers. Constitutional isomers are compounds having the same molecular formula and different connectivity. Positional isomers (a specific form of constitutional isomerism) are structural isomers that can be considered to differ only in the position of the functional groups on the parent structure, in this case, particularly the position of the two alcohol functional groups.

[0018] Depending on the number of carbon atoms in the carbon chain of the alkanediol, there are various positional isomers of the alkanediol: (x,x + 1) constitutional isomers; (x,x + 2) constitutional isomers; (x,x + 3) constitutional isomers, etc.; and α,ω constitutional isomers when the alcohol functional groups are located at the ends of the carbon chain, where x represents the number of carbon atoms in the alkanediol chain that are chemically bonded to the OH groups of the alkanediol. For example: If x is 1, the two OH groups of the alkanediol are chemically bonded to the C1 and C2 carbon atoms in the alkanediol chain; if x is 2, the two OH groups of the alkanediol are chemically bonded to the C2 and C3 carbon atoms in the alkanediol chain, etc.

[0019] In the (x,x + 1) constitutional isomer, the two OH functional groups are attached adjacent to two different adjacent carbon atoms in the chain. In the (x,x + 2) constitutional isomer, the two OH functional groups are attached to two different carbon atoms in the chain, where the two carbon atoms are separated by one C atom. In the (x,x + 3) constitutional isomer, the two OH functional groups are attached to two different carbon atoms in the chain, where the two carbon atoms are separated by two C atoms. In the α,ω constitutional isomer, the two functional groups are attached to the first C atom and to the terminal C atom.

[0020] In a preferred variant of the oral care composition, the alkanediol having a carbon chain of 5 to 12 carbon atoms is preferably an ortho-(x,x+1) diol selected from the group consisting of 1,2-diols, 2,3-diols, 3,4-diols, 4,5-diols, further (x,x+1) diols, and mixtures thereof, preferably an α,β-1,2-constitutional isomer.

[0021] Thus, according to a preferred variant of the oral care composition, the alkanediol is an (x,x+1) constitutional isomer, where x represents the number of the carbon atom in the alkanediol chain that is chemically bonded to the OH group of the alkanediol, in particular 1,2-alkanediol, 2,3-alkanediol, 3,4-alkanediol, or mixtures thereof, preferably 1,2-alkanediol or 2,3-alkanediol.

[0022] In a further preferred variant of the oral care composition, the alkanediol having a carbon chain of 5 to 12 carbon atoms is preferably a non-ortho-(x,x+2) diol selected from the group consisting of 1,3-diols, 2,4-diols, 3,5-diols, further (x,x+2) diols, and mixtures thereof, preferably an α,γ-1,3-constitutional isomer.

[0023] In a preferred variant of the oral care composition, the alkanediol having a carbon chain of 5 to 12 carbon atoms is a non-ortho-(x,x+2) diol selected from the group consisting of 1,3-diols, 2,4-diols, 3,5-diols, 4,6-diols, further (x,x+2) diols, and mixtures thereof, preferably an α,γ-1,3-structural isomer.

[0024] In a further preferred variant of the oral care composition, the alkanediol having a carbon chain of 5 to 12 carbon atoms is preferably a non-ortho-(x,x+3) diol selected from the group consisting of 1,4-diols, 2,5-diols, further (x,x+3) diols, and mixtures thereof, preferably an α,δ-1,4-constitutional isomer.

[0025] In a preferred variant of the oral care composition, the alkanediol is preferably an α,ω-alkanediol, more preferably 1,7-heptanediol or 1,8-octanediol.

[0026] According to the present invention, ortho-(x,x+1) diols are most preferred, such as α,β or β,γ or γ,δ, etc.

[0027] In a more preferred variant of the oral care composition, the alkanediol is 1,2-alkanediol, 2,3-alkanediol, 3,4-alkanediol, or mixtures thereof, more preferably 2,3-alkanediol.

[0028] In a preferred variant of the oral care composition, the alkane diol is selected from the group consisting of: 1,2-pentanediol, 2,3-pentanediol, 3,4-pentanediol, 1,2-hexanediol, 2,3-hexanediol, 3,4-hexanediol, 1,2-heptanediol, 2,3-heptanediol, 3,4-heptanediol, 1,2-octanediol, 2,3-octanediol, 3,4-octanediol, 1,2-nonanediol, 2,3-nonanediol, 3,4-nonanediol, 1,2-decanediol, 2,3-decanediol, 3,4-decanediol, 1,2-undecanediol, 2,3-undecanediol, 3,4-undecanediol, 1,2-dodecanediol, 2,3-dodecanediol, 3,4-dodecanediol, and any mixture thereof.

[0029] According to a preferred variant, in the oral care composition, the alkane diol is selected from the group consisting of: 1,2-pentanediol, 2,3-pentanediol, 1,2-hexanediol, 2,3-hexanediol, 1,2-heptanediol, 2,3-heptanediol, 1,2-octanediol, 2,3-octanediol, 1,2-nonanediol, 2,3-nonanediol, 1,2-decanediol, 2,3-decanediol, 1,2-undecanediol, 2,3-undecanediol, 1,2-dodecanediol, 2,3-dodecanediol and any mixture thereof.

[0030] Among the above linear alkane diols, the following (x,x + 1) structural isomers are preferred: 1,2-pentanediol, 2,3-pentanediol, 1,2-hexanediol, 2,3-hexanediol, 1,2-heptanediol, 2,3-heptanediol, 2,3-octanediol, 2,3-nonanediol, 2,3-decanediol, 2,3-undecanediol, 2,3-dodecanediol or a mixture thereof. The alkane diol is liquid at a purity of 90% to 99%.

[0031] Among the above liquid alkane diols, 1,2-pentanediol, 2,3-pentanediol, 1,2-hexanediol, 2,3-hexanediol, 1,2-heptanediol, 2,3-heptanediol, 2,3-octanediol, 2,3-nonanediol or a mixture of the liquid alkane diols is particularly preferred.

[0032] In a further preferred variant of the oral care composition, the alkane diol is selected from the group consisting of: 1,2-pentanediol, 2,3-pentanediol, 1,2-hexanediol, 2,3-hexanediol, 1,2 - heptanediol, 2,3 - heptanediol, 1,2 - octanediol, 2,3 - octanediol, 1,2 - nonanediol, 2,3 - nonanediol, 1,2 - decanediol, 2,3 - decanediol, 1,2 - undecanediol, 2,3 - undecanediol, 1,2 - dodecanediol, 2,3 - dodecanediol, and any mixture thereof.

[0033] More preferably, the alkanediol is selected from the group consisting of mixtures of 1,2 - and 2,3 -: 1,2 - pentanediol and 2,3 - pentanediol, 1,2 - hexanediol and 2,3 - hexanediol, 1,2 - heptanediol and 2,3 - heptanediol, 1,2 - octanediol and 2,3 - octanediol, 1,2 - nonanediol and 2,3 - nonanediol, 1,2 - decanediol and 2,3 - decanediol, 1,2 - undecanediol and 2,3 - undecanediol, 1,2 - dodecanediol and 2,3 - dodecanediol, and any mixture thereof.

[0034] Further preferred in the oral care composition is that the alkanediol mixture is a combination of 1,2 - heptanediol and 2,3 - heptanediol, or 1,2 - decanediol and 2,3 - decanediol.

[0035] Further preferred in the oral care composition is that the alkanediol is selected from the group consisting of 1,2 - pentanediol, 2,3 - pentanediol, and mixtures thereof, or selected from the group consisting of 1,2 - hexanediol, 2,3 - hexanediol, and mixtures thereof. However, the straight - chain alkanediol or the first straight - chain alkanediol may also preferably be selected from the group consisting of 1,2 - octanediol, 2,3 - octanediol, and mixtures thereof.

[0036] The oral care composition preferably contains 3 - phenyl - 1 - propanol, phenoxyethanol, or methyl benzyl alcohol, and more preferably the composition contains 3 - phenyl - 1 - propanol.

[0037] Alternative antimicrobial agents used in the sense of the present invention preferably include isomers of isopropylmethylphenol, namely 4 - isopropyl - 3 - methylphenol (o - cymene - 5 - ol), 2 - isopropyl - 5 - methylphenol (thymol), 3 - isopropyl - 5 - methylphenol (m - cymene - 5 - ol), and 5 - isopropyl - 2 - methylphenol (carvacrol).

[0038] In one aspect of the present invention, the oral care composition comprises 4-isopropyl-3-methylphenol, preferably together with other compounds selected from the group consisting of flavoring agents, sweetening agents, and / or additional additives.

[0039] In a preferred further development, the oral care composition according to the present invention is used for treating and / or preventing and / or reducing oral malodor, preferably for cosmetic mouthwash applications.

[0040] In the sense of the present invention, cosmetic mouthwash applications should be understood to provide temporary control of unpleasant breath or taste. After using a cosmetic mouthwash, a fresh and pleasant taste is also obtained. However, cosmetic mouthwashes generally do not provide long-term control of bacteria associated with oral malodor, i.e., do not kill bacteria to a sufficient extent.

[0041] In a preferred aspect of the present invention, the oral care composition comprises 4-isopropyl-3-methylphenol in an amount of from 0.01% to 0.2% by weight of the total composition, preferably from 0.03% to 0.08% by weight. It has been found that lower concentrations of 4-isopropyl-3-methylphenol are less effective or not sufficiently effective, while in some cases, amounts higher than those given in the foregoing range can lead to problems with, for example, the solubility, taste, and odor of the oral care composition. In addition, higher concentrations conflict with the limits of compounds permitted for use in cosmetics.

[0042] In another aspect, the oral care composition according to the present invention comprises 3-phenyl-1-propanol, an alkanediol (preferably decanediol), and 4-isopropyl-3-methylphenol in a total amount of from 0.01% to 0.5% by weight of the total composition. These three components act together to provide particularly significant anti-odor advantages. They are also more effective together in reducing the bacterial count, as Figure 5 and Figure 6 shown.

[0043] In a further development, the oral care composition of the present invention additionally comprises an antioxidant, preferably p-hydroxyacetophenone. Advantageously, p-hydroxyacetophenone is present in an amount of from 0.05% to 1.0% by weight. As Figure 9 shown, the antioxidant has a strengthening effect on the efficacy of the oral care composition.

[0044] Furthermore, the alkanediol provides a surprising synergistic effect in combination with the foregoing compositions, especially a mixture comprising 3-phenyl-1-propanol, an alkanediol (preferably decanediol), and 4-isopropyl-3-methylphenol. In combination, the alkanediol can enhance the effect of preventing and / or reducing malodor in the cosmetic composition.

[0045] Preferably, the above mixture contains an additional secondary linear alkanediol, more preferably a linear 1,2-alkanediol having 5 to 12 carbon atoms for this purpose, preferably 1,2-pentanediol, 1,2-hexanediol, 1,2-heptanediol, 1,2-octanediol, 1,2-nonanediol, 1,2-decanediol, 1,2-undecanediol or 1,2-dodecanediol. In addition to 1,2 C5 to C12 diols, 2,3-alkanediols are also preferred, with 2,3-hexanediol or 2,3-heptanediol being particularly preferably used as the secondary additional alkanediol.

[0046] Furthermore, the additional secondary alkanediol may itself be a mixture of alkanediols, thereby forming a tri- or tetra-hydric alkanediol mixture in the overall oral care composition.

[0047] Finally, the additional secondary alkanediol is preferably any alkanediol or alkanediol mixture as mentioned above for the primary alkanediol or alkanediol mixture.

[0048] In a further preferred aspect of the present invention, the oral care composition comprises the additional alkanediol or alkanediol mixture in an amount of 0.01 to 5.0 wt % in total.

[0049] When hydrophilic additives are added to the aforementioned compositions, they also provide a surprising synergistic effect because they improve the solubility of the components in the aqueous solvent. Additives for this purpose are preferably selected from the group consisting of alcohols, glycols, polyols, phenols or esters having good solubilizing properties, preferably selected from the group consisting of ethanol, 1-propanol, isopropanol, phenoxyethanol, benzyl alcohol, ethylene glycol, propylene glycol, 1,3-propanediol, butylene glycol, pentylene glycol, 1,2-hexanediol, hexylene glycol, dipropylene glycol, ethoxyethylene glycol, propylene carbonate, glyceryl carbonate, butylene carbonate, triethyl citrate, ethyl lactate, butyl lactate, ethyl acetate, diethyl malonate, diacetin, dimethyl isosorbide, diethylene glycol, PPG-3 methyl ether or any mixture thereof.

[0050] In a further aspect of the present invention, the oral care composition preferably comprises a hydrophilic additive selected from propylene glycol, glycerol, 1,3-propanediol, butylene glycol, dipropylene glycol and ethanol. More preferably, the composition comprises propylene glycol and / or glycerol in an amount of 0.5 wt% to 20 wt% in total.

[0051] In oral care compositions, flavoring agents serve several purposes, such as masking the unpleasant taste of active ingredients or providing a fresh breath. Figure 7 As shown, flavoring mixtures such as Optamint ®, may also have antimicrobial strain activity. Flavoring agents commonly used in oral care compositions include compounds or mixtures of compounds that exhibit flavors such as menthol, mint, citrus, or rose. In some cases, the flavor of the oral care composition is also defined as fragrance. Preferably, the flavoring agent comprises one or more compounds selected from the following: L-menthol; trans-menthone; (E)-anethole; 5-methyl-2-(1-methylethyl) cyclohexyl lactate; menthol; L-menthan-3-one; cineole; isomenthone; menthyl acetate; 2-isopropyl-N,2,3-trimethylbutanamide; 2-hydroxypropyl (5-methyl-2-prop-2-ylcyclohexyl) carbonate; 2-hydroxyethyl (5-methyl-2-prop-2-ylcyclohexyl) carbonate; (±)-neomenthol; 4,5,6,7-tetrahydro-3,6-dimethylbenzofuran; (S)-p-mentha-1,8-diene; (-)-menthyl lactate; thymol; camphene; pin-2(10)-ene; (R)-p-mentha-1,8-diene; pin-2(3)-ene and / or p-mentha-1,3-diene.

[0052] In a further development, the oral care composition according to the invention preferably comprises at least one flavoring compound or fragrance, wherein the flavoring agent is preferably present in an amount of 0.1% to 1.0% by weight.

[0053] As Figure 8 shown, if the flavoring mixture Optamint ® is combined with the oral care composition according to the invention, a synergistic effect with respect to microbial activity is achieved.

[0054] In oral care compositions, sweeteners are used to mask the unpleasant taste of the composition. However, in the context of oral care applications, sweeteners should be added only in small amounts. Compounds suitable for use as sweeteners in oral care compositions include, for example, sorbitol or sodium saccharin.

[0055] In a further aspect of the invention, the oral care composition preferably comprises a sweetener in an amount of 0.01% to 0.5% by weight, preferably the sodium salt of saccharin.

[0056] In another aspect of the invention, the oral care composition is used as a cosmetic or a medicament, namely a therapeutic mouthwash.

[0057] In the context of the present invention, a therapeutic mouthwash should be understood as a mouthwash containing active chemical or biological ingredients. Thus, a therapeutic mouthwash is intended to help control or reduce disease conditions, such as bad breath (halitosis), gingivitis, and / or dental caries, by effectively killing bacteria associated with the aforementioned conditions.

[0058] In a preferred aspect, the oral care composition according to the present invention is preferably used for treating and / or preventing oral bacterial infections and oral fungal infections, preferably dental infections and inflammations, dental caries, dental decay, periodontal infections and inflammations, bad breath, gingivitis, candidiasis and / or Gram-negative bacterial strain infections, preferably Fusobacterium nucleatum and Porphyromonas gingivalis infections.

[0059] The abundance of bacteria and fungi in the oral cavity is usually determined by collecting oral saliva. Preferably, the collected oral saliva sample is placed in a sample collection tube, and the biological sample is placed in a sterile EP tube. An appropriate amount of lysis buffer is added to the EP tube and mixed, and then bacterial genomic DNA is extracted from the sample using a bacterial DNA extraction kit. Quantitative evaluation is preferably completed using Q-PCR.

[0060] In a preferred aspect of the present invention, by examining the collection of oral saliva, the oral care composition preferably reduces the abundance of the Gram-negative bacterial strains Fusobacterium nucleatum (F. nucleatum) and Porphyromonas gingivalis (P. gingivalis) in the oral cavity by at least 20% after 4 weeks, preferably by at least 40% after 4 weeks and more preferably by at least 80% after 4 weeks. Most preferably, the abundance of the bacterial strains is reduced by 95% or more.

[0061] Oral malodor is mainly caused by the enzymatic degradation of proteins and amino acids. The malodorous components usually formed include volatile sulfur compounds such as hydrogen sulfide, methanethiol and dimethyl sulfide. The aforementioned compounds can preferably be detected in the breath using a portable sulfide detector, which is commercially known and available as a Halimeter © obtained.

[0062] In another aspect, by examining with a sulfide detector (Halimeter © ), the oral care composition according to the present invention preferably reduces the oral abundance of volatile organic sulfur compounds containing methanethiol and dimethyl sulfide by at least 30% after 4 weeks, preferably by at least 40% after 4 weeks and more preferably by at least 65% after 4 weeks. Most preferably, the abundance of the volatile organic sulfur compounds is reduced by 95% or more than 95%.

[0063] In a further aspect, the oral care composition according to the present invention is preferably used as a mouthwash, a cosmetic mouthwash, a therapeutic mouthwash, a toothpaste component, a dental gel component, a subgingival gel component or an oral malodor reducing agent, including for use in oral sprays, chewable tablets and / or chewing gums. BRIEF DESCRIPTION OF THE DRAWINGS

[0064] Figure 1It is a graph showing the average concentration of methanethiol in the breath of testers using the mouthwash composition according to the present invention or a placebo mouthwash composition. The graph shows the concentration of methanethiol after 0 days, 7 days, and 28 days and includes the corresponding standard deviations.

[0065] Figure 2 It is a graph showing the average concentration of dimethyl sulfide in the breath of testers using the mouthwash composition according to the present invention or a placebo mouthwash composition. The graph shows the concentration of dimethyl sulfide after 0 days, 7 days, and 28 days and includes the corresponding standard deviations.

[0066] Figure 3 It is a graph showing the average concentration of the bacterial strain Porphyromonas gingivalis in the oral saliva of testers using the mouthwash composition according to the present invention or a placebo mouthwash composition. The graph shows the concentration of Porphyromonas gingivalis after 0 days and 28 days and includes the corresponding standard deviations.

[0067] Figure 4 It is a graph showing the average concentration of the bacterial strain Fusobacterium nucleatum in the oral saliva of testers using the mouthwash composition according to the present invention or a placebo mouthwash composition. The graph shows the concentration of Fusobacterium nucleatum after 0 days and 28 days and includes the corresponding standard deviations.

[0068] Figure 5 It is a graph showing the antimicrobial efficacy of a composition containing only the antimicrobial agent 4-isopropyl-3-methylphenol.

[0069] Figure 6 It is a graph showing the antimicrobial efficacy of a composition containing the antimicrobial agent 4-isopropyl-3-methylphenol and 1,2-alkanediols, namely decanediol and 3-phenyl-1-propanol.

[0070] Figure 7 It is a graph showing the antimicrobial efficacy of a composition containing the flavoring mixture Optamint ®

[0071] Figure 8 It is a graph showing the antimicrobial efficacy of a composition containing the flavoring mixture Optamint ®

[0072] Figure 9 It is a graph showing the antimicrobial efficacy of a composition containing the flavoring mixture Optamint ® Detailed Description

[0073] Experimental part By using a sulfide detector (Halimeter © ) and evaluating relevant bacterial strains in oral saliva, the effect of the oral care composition according to the present invention on oral malodor is determined.

[0074] Prepare an oral care composition (Sample 2) containing 4-isopropyl-3-methylphenol, 3-phenyl-1-propanol, and decanediol according to Table 1. The corresponding placebo composition (Sample 1) is also described in Table 1.

[0075] Table 1: Oral care compositions containing 4-isopropyl-3-methylphenol, 3-phenyl-1-propanol and decanediol (Sample 2) and placebo (Sample 1) 。

[0076]

[0077] The oral care composition (Sample 2) of the present invention and the placebo composition (Sample 1) are administered to 35 healthy testers twice a day (in the morning and evening) in the form of a mouthwash for 28 days. On the first day of the test and after 7 days and 28 days of use, the breath of the subjects is evaluated by a sulfide detector. Oral saliva is collected on the first day of the test and after 28 days of use.

[0078] The results of the breath analysis of the testers using a portable sulfide detector (Halimeter © ) are summarized in Table 2. This table shows the average oral ppb concentration of volatile organic sulfur compounds, namely hydrogen sulfide (H2S), methanethiol (CH3SH), and dimethyl sulfide (CH3SCH3), and the corresponding standard deviations.

[0079] Table 2: Analysis results of volatile organic sulfur compounds in the breath of testers using a portable sulfide detector (Halimeter © ) over time Figure 1

[0080] From the data in Table 2, it can be seen that Sample 2 reduces the amount of volatile organic sulfur compounds present in the oral cavity. For hydrogen sulfide, the effect is only weakly significant. However, for methanethiol (also see Figure 2 ) and dimethyl sulfide (also see Table 3: Analysis results of oral saliva of testers ), a significant decrease in the concentration of volatile sulfur compounds is observed. In contrast, when Sample 1 is used as a mouthwash, no decrease is observed.

[0081] The evaluation procedure of oral saliva is as follows. The collected oral saliva sample is placed in a sample collection tube, and the biological sample is placed in a sterile EP tube. Then, an appropriate amount of lysis buffer is added to the EP tube and mixed evenly. Bacterial genomic DNA is extracted from the clinical sample using a bacterial DNA extraction kit. Quantitative evaluation of Streptococcus mutans, Porphyromonas gingivalis, and Fusobacterium nucleatum is completed using Q-PCR.

[0082] The oral saliva analysis results of the testers are summarized in Table 3. This table shows the average oral ppm concentrations of the bacterial strains, namely Streptococcus mutans, Porphyromonas gingivalis, and Fusobacterium nucleatum, and the corresponding standard deviations.

[0083] Figure 3

[0084] From the data in Table 3, it can be seen that Sample 2 reduces the bacteria in the oral cavity, especially the amounts of Porphyromonas gingivalis and Fusobacterium nucleatum (see also Figure 4 and Comparative Example 1: Synergistic effect among 4-isopropyl-3-methylphenol, 3-phenyl-1-propanol and decanediol ). However, Sample 2 is less effective against Streptococcus mutans, but a relatively small increase can be seen compared to the placebo (Sample 1). As expected, the placebo composition does not reduce the amount of bacteria in the oral cavity.

[0085] Table 4: Sample compositions containing 4-isopropyl-3-methylphenol, 3-phenyl-1-propanol and decanediol (Sample In another experiment, the antimicrobial efficacy of the composition according to the present invention was compared with the efficacy of 4-isopropyl-3-methylphenol alone. For this purpose, Sample Composition 3 and Sample Composition 4 were prepared according to Table 4.

[0086] The amount of the mixture of 3-phenyl-1-propanol, 4-isopropyl-3-methylphenol, and decanediol in Sample 4 at 0.20% by weight corresponds to the amount of pure 4-isopropyl-3-methylphenol at 0.04% by weight. Therefore, Sample 3 contains significantly more antimicrobial agents than Sample 4.

[0087] 4) and a sample composition containing only 4-isopropyl-3-methylphenol (IPMP) (Sample 3) Figure 5 .

[0088]

[0089] Sample 3 was prepared as follows. Stearyl heptanoate, stearyl octanoate, ethylhexyl isononanoate, and stearyl alcohol were heated to approximately 80 °C to form Phase A. In parallel, glyceryl stearate citrate and water were also added to reach approximately 80 °C to form Phase B. Carbomer was added to Phase A and homogenized, and then Phase B was added to Phase A and emulsified using an Ultra Turrax stirrer. The emulsification step was carried out at 4000 min -1The rotation speed is carried out for 2 minutes. Use a blade stirrer to cool the obtained emulsion. In a separate container, premix 4-isopropyl-3-methylphenol, 4-hydroxyacetophenone and dipropylene glycol and heat to 80 °C to form Phase D. In the post-emulsification step after cooling, i.e., add the premixed Phase D to the combined Phase A + B at a temperature T < 60 °C. Reduce the stirring speed while cooling the emulsion. Finally, adjust the pH of the emulsion to 5.8 by adding an aqueous sodium hydroxide solution (w = 10%, Phase C).

[0090] Sample 4 was prepared as follows. Heat stearyl heptanoate, stearyl octanoate, ethylhexyl isononanoate and stearyl alcohol to approximately 80 °C to form Phase A. In parallel, also add glyceryl stearate citrate and water to approximately 80 °C to form Phase B. Add carbomer to Phase A and homogenize, then add Phase B to Phase A and emulsify using an Ultra Turrax stirrer. The emulsification step was carried out at a rotation speed of 4000 min -1 The rotation speed is carried out for 2 minutes. Use a blade stirrer to cool the obtained emulsion. In a separate container, premix 4-isopropyl-3-methylphenol, 3-phenyl-1-propanol, decanediol, 4-hydroxyacetophenone and dipropylene glycol to form Phase D. In the post-emulsification step after cooling, i.e., add the premixed Phase D to the combined Phase A + B at a temperature T < 60 °C. Reduce the stirring speed while cooling the emulsion. Finally, adjust the pH of the emulsion to 5.8 by adding an aqueous sodium hydroxide solution (w = 10%, Phase C).

[0091] Examine the obtained Samples 3 and 4 under a microscope on the day after formulation to see if crystals are visible. For both emulsions, crystals could not be identified under the microscope.

[0092] Test different microbial strains of Sample Composition 3 and Sample Composition 4 disclosed in Table 4 in vitro, namely Escherichia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa), Staphylococcus aureus (S. aureus), Candida albicans (C. albicans) and Aspergillus brasiliensis (A. brasiliensis). Examine the amount of microbial species present at the start and after 2 days, 7 days, 14 days and 28 days.

[0093] As can be seen from Figure 6 it, 4-isopropyl-3-methylphenol (Sample 3) reduces the amount of the corresponding microbial species. The abundance of some strains, such as Escherichia coli or Pseudomonas aeruginosa, has decreased significantly after 2 days. However, the complete elimination of all tested microbial strains was only achieved after 28 days. In contrast, Sample 4 additionally containing 3-phenyl-1-propanol and decanediol showed enhanced efficacy as all tested microbial strains had been completely eliminated after 7 days (see Comparative Example 2: Synergistic effect among 4-isopropyl-3-methylphenol, 3-phenyl-1-propanol, decanediol, flavoring composition and antioxidant). Therefore, the components 3-phenyl-1-propanol, 4-isopropyl-3-methylphenol and decanediol in Sample 4 have an obvious synergistic effect.

[0094] Both formulations passed the challenge test. In particular, Sample 4 passed the European Pharmacopoeia (Ph.Eur.): Standard A, while Sample 3 passed the European Pharmacopoeia: Standard B.

[0095] The foregoing results are surprising because, compared with only a 2.5-fold increase in the amount of the active ingredient as in Sample 3, the synergistic effect of Sample 4 produces better efficacy against the tested microbial strains.

[0096] Table 5: A sample composition containing a flavor mixture Optamint as the single active ingredient (Sample 5) and another In a further study, the synergistic effect between the flavoring composition Optamint ® and the oral care composition according to the present invention was examined. The synergistic effect of the antioxidant 4-hydroxyacetophenone was investigated in the same study. For this purpose, Sample Compositions 5 to 7 were prepared according to Table 5.

[0097] composition containing 4-isopropyl-3-methylphenol, 3-phenyl-1-propanol and decanediol (Sample 6) or a composition containing 4-isopropyl ® 3-methylphenol, 3-phenyl-1-propanol, decanediol and 4-hydroxyacetophenone (Sample 7) Figure 7 Figure 8 .

[0098]

[0099] Different microbial strains of Sample Compositions 5 to 7 disclosed in Table 5 were tested in vitro, namely Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Candida albicans and Aspergillus brasiliensis. The amount of the microbial species present was examined at the beginning and after 2 days, 7 days, 14 days and 28 days.

[0100] As can be seen from Figure 9 the flavoring mixture Optamint ® (Sample 5) reduces the amount of the corresponding microbial species. The abundance of some strains, such as Escherichia coli or Staphylococcus aureus, has already decreased significantly after 2 days. However, the complete elimination of the tested microbial strains (except Aspergillus brasiliensis) was achieved only after 14 days. In contrast, Sample 6 additionally containing 4-isopropyl-3-methylphenol, 3-phenyl-1-propanol and decanediol showed enhanced efficacy because, except for Aspergillus brasiliensis, all the tested microbial strains had been completely eliminated after 7 days ( ​ ). In addition, Sample 6 showed high efficacy against Pseudomonas aeruginosa, which is one of the bacterial strains particularly associated with oral malodor. If 4-hydroxyacetophenone is added (Sample 7), further enhanced microbial activity is achieved because then the composition is also more active against Candida albicans (see ​). Thus, the flavorant mixture Optamint ® showed a significant synergistic effect with 3-phenyl-1-propanol, 4-isopropyl-3-methylphenol, and decanediol in Sample 6, and also with 4-hydroxyacetophenone additionally present in Sample 7.

[0101] Sample 7 passed the challenge tests, especially the European Pharmacopoeia: Standard A. The foregoing results are surprising because the synergistic effect of the flavorant mixture with 4-isopropyl-3-methylphenol, 3-phenyl-1-propanol, and decanediol generally produces better efficacy against the tested microbial strains, and this efficacy is further enhanced by another synergistic effect upon addition of 4-hydroxyacetophenone. Specifically, 4-hydroxyacetophenone enhances the antifungal efficacy.

Claims

1. An oral care composition, the oral care composition comprising 3-phenyl-1-propanol, an alkanediol, and 4-isopropyl-3-methylphenol, the alkanediol preferably being decanediol.

2. An oral care composition, the oral care composition comprising 4-isopropyl-3-methylphenol.

3. The oral care composition according to claim 1 or 2, the oral care composition being used for treating or preventing or reducing oral malodor.

4. The oral care composition according to any one of claims 1 to 3, wherein 4-isopropyl-3-methylphenol is present in an amount of 0.01% to 0.2% by weight of the total composition, more preferably 0.03% to 0.08% by weight.

5. The oral care composition according to claim 1 or any one of claims 3 to 4, wherein 3-phenyl-1-propanol, the alkanediol, and 4-isopropyl-3-methylphenol are present in total in an amount of 0.01% to 0.5% by weight of the composition, the alkanediol preferably being decanediol.

6. The oral care composition according to any one of claims 1 to 5, the oral care composition further comprising p-hydroxyacetophenone, preferably in an amount of 0.05% to 1.0% by weight.

7. The oral care composition according to any one of claims 1 to 6, the oral care composition further comprising an additional alkanediol or mixture of alkanediols, preferably 1,2-hexanediol and / or 1,2-octanediol, preferably in an amount of 0.01% to 5.0% by weight of the total composition.

8. The oral care composition according to any one of claims 1 to 7, the oral care composition further comprising a hydrophilic additive, preferably such hydrophilic additive comprising propylene glycol and / or glycerol, preferably in an amount of 0.5% to 20.0% by weight.

9. The oral care composition according to any one of claims 1 to 8, the oral care composition further comprising a flavoring compound or fragrance, preferably in an amount of 0.1% to 1.0% by weight.

10. The oral care composition according to any one of claims 1 to 9, the oral care composition further comprising a sweetening agent, preferably the sweetening agent comprising sodium saccharin, preferably in an amount of 0.01% to 0.5% by weight.

11. The oral care composition according to any one of claims 1 to 10, the oral care composition being used as a drug or a cosmetic.

12. The oral care composition according to any one of claims 1 to 11, the oral care composition being used for treating or preventing oral bacterial infections and oral fungal infections, particularly preferably tooth infections and inflammations, dental caries, dental caries, periodontal infections and inflammations, halitosis, gingivitis, candidiasis, and infections by Gram-negative bacterial strains, more preferably infections by Fusobacterium nucleatum and Porphyromonas gingivalis.

13. The oral care composition according to claims 10 and 12, wherein upon examination by collecting oral saliva and measurement according to the tests in this specification, the abundance of the bacterial strains Fusobacterium nucleatum and Porphyromonas gingivalis in the oral cavity is reduced by at least 40% after 4 weeks.

14. The oral care composition according to claims 10 to 13, wherein upon detection by a sulfide detector and measurement according to the tests in this specification, the oral abundance of organic sulfur compounds is reduced by at least 40% after 4 weeks, and the organic sulfur compounds preferably include methanethiol and dimethyl sulfide.

15. Use of the oral care composition according to any one of claims 1 to 10 as a mouthwash, a cosmetic mouthwash, a toothpaste component, a dental gel component, a subgingival gel component or an oral malodor reducing agent, the use including use in an oral spray, a chewable tablet or a chewing gum.

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