WO2017022827A1 - バイオフィルム形成予防剤および口腔用組成物 - Google Patents
バイオフィルム形成予防剤および口腔用組成物 Download PDFInfo
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- WO2017022827A1 WO2017022827A1 PCT/JP2016/072955 JP2016072955W WO2017022827A1 WO 2017022827 A1 WO2017022827 A1 WO 2017022827A1 JP 2016072955 W JP2016072955 W JP 2016072955W WO 2017022827 A1 WO2017022827 A1 WO 2017022827A1
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- hydrogen atom
- biofilm formation
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/81—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions involving only carbon-to-carbon unsaturated bonds
- A61K8/8141—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides or nitriles thereof; Compositions of derivatives of such polymers
- A61K8/8158—Homopolymers or copolymers of amides or imides, e.g. (meth) acrylamide; Compositions of derivatives of such polymers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/67—Vitamins
- A61K8/678—Tocopherol, i.e. vitamin E
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/81—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions involving only carbon-to-carbon unsaturated bonds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/81—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions involving only carbon-to-carbon unsaturated bonds
- A61K8/8141—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides or nitriles thereof; Compositions of derivatives of such polymers
- A61K8/8147—Homopolymers or copolymers of acids; Metal or ammonium salts thereof, e.g. crotonic acid, (meth)acrylic acid; Compositions of derivatives of such polymers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/81—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions involving only carbon-to-carbon unsaturated bonds
- A61K8/8141—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides or nitriles thereof; Compositions of derivatives of such polymers
- A61K8/8152—Homopolymers or copolymers of esters, e.g. (meth)acrylic acid esters; Compositions of derivatives of such polymers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
Definitions
- the present invention relates to a biofilm formation preventive agent and an oral composition containing the preventive agent.
- the oral environment refers to the condition of the entire oral cavity surrounding the teeth, gums, tongue, oral mucosa, etc. If the oral environment deteriorates, it can cause bad breath, dental caries, periodontal disease, etc. Leading to a decline. Deterioration of the oral environment begins with the formation of dental plaque, which is an accumulation of bacteria, and when this is matured over time, it leads to the formation of a biofilm that is a living aggregate of a plurality of bacteria. Dental plaque is relatively easy to remove by brushing, but biofilm is difficult to remove by brushing.
- Caries and periodontal disease pathogens produced from biofilms stick to the heart valve and proliferate, causing bacterial endocarditis or entering the bloodstream for the elderly, coronary It can also cause circulatory problems such as arterial disease, heart disease, and myocardial infarction.
- an oral composition containing a bactericidal component, an anti-inflammatory component, and a blood circulation promoting component is used in order to keep the oral environment continuously good and prevent maturation into a biofilm.
- the composition for oral cavity is usually used after being used in the oral cavity, it is exhaled, or the oral cavity is sprinkled with tap water. Short contact time.
- the medicine is in contact with the affected area, it may be washed away with saliva. For this reason, there is a problem in that even if drugs according to the purpose are used, those effects are not sufficiently exhibited. Accordingly, measures have been taken to increase the concentration of the drug or lengthen the processing time in order to fully exert the effect of the drug.
- some drugs may cause inflammation as a side effect, and it is inconvenient for the user to increase the treatment time. Therefore, the above measures are not always sufficient.
- Patent Literature 1 discloses a method for improving the retention of bactericides and vitamins in the oral cavity with a viscous non-anionic water-soluble polymer. In this method, there remains a problem in that a viscosity is given to the oral composition, which gives a heavy feeling to the user, and because a certain viscosity is required, the dosage form is limited.
- Patent Document 2 discloses a combination of a water-soluble monofluorophosphorylated polymer compound having excellent fluoride retention and fluoride release and a surfactant. Techniques relating to oral compositions are disclosed. However, this technique still has a problem in that it is limited to the improvement in retention and release of fluoride, which is a specific drug.
- compositions for oral cavity using a phosphorylcholine group-containing polymer are known.
- Patent Document 3 discloses a composition for oral cavity that keeps the oral cavity moist
- Patent Document 4 discloses a PC polymer as an antimicrobial component, a water-soluble polysaccharide as a binder component, and a poly (meth) acrylic acid derivative as a compatibilizing component.
- the technology regarding the antimicrobial adhesion agent for oral cavity characterized by including this is disclosed.
- Patent Document 3 does not describe or suggest the use of a PC polymer as a biofilm formation preventive agent.
- the problem of the present invention is to improve the sustainability of the effect of the drug without increasing the drug concentration and treatment time, to keep the oral environment continuously good, and to prevent the biofilm from maturing
- An object of the present invention is to provide a formation preventive agent and a composition for oral cavity containing the preventive agent.
- the present inventors have determined that a specific structure is used to suppress coaggregation, which is adhesion of other microorganisms to microorganisms that have already adhered as biofilm formation preventive agents.
- the inventors Using the (meth) acrylic copolymer containing a phosphorylcholine group, the inventors have found that the amount of drug adsorbed on the tooth surface can be controlled and the drug can be released slowly, and the present invention has been completed.
- the present invention is as follows. 1. A weight average molecular weight of 10,000 to 5,000,000, A structural unit (A) based on 2- (meth) acryloyloxyethyl phosphorylcholine (A) of 10 to 90 mol%, Structural unit (B1) based on alkyl group-containing (meth) acrylic monomer, structural unit (B2) based on quaternary ammonium group-containing (meth) acrylic monomer, and (meth) acrylamide monomer A biofilm formation preventive agent comprising a copolymer containing 90 to 10 mol% of at least one structural unit selected from the group consisting of structural units (B3) based thereon.
- R 1 represents a hydrogen atom or a methyl group.
- R 2 represents a hydrogen atom or a methyl group
- R 3 represents an alkyl group having 4 to 18 carbon atoms.
- R 4 represents a hydrogen atom or a methyl group
- R 5 , R 6 and R 7 each independently represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms
- X ⁇ represents a halogen ion or an acid residue.
- R 8 represents a hydrogen atom or a methyl group
- R 9 and R 10 each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
- the structural unit (A) is a structural unit based on 2- (meth) acryloyloxyethyl phosphorylcholine
- the structural unit (B2) is a structural unit based on 2-hydroxy-3-methacryloyloxypropyltrimethylammonium chloride.
- the biofilm formation preventive agent according to 1. 5 The structural unit (A) is a structural unit based on 2- (meth) acryloyloxyethyl phosphorylcholine
- the structural unit (B1) is a structural unit based on stearyl methacrylate
- the structural unit (B3) is N, N-dimethylaminopropyl.
- a biofilm formation preventive agent comprising the following steps: A weight average molecular weight of 10,000 to 5,000,000, A structural unit (A) based on 2- (meth) acryloyloxyethyl phosphorylcholine (A) of 10 to 90 mol%, Structural unit (B1) based on alkyl group-containing (meth) acrylic monomer, structural unit (B2) based on quaternary ammonium group-containing (meth) acrylic monomer, and (meth) acrylamide monomer
- a biofilm formation preventive agent comprising a copolymer containing 90 to 10 mol% of at least one structural unit selected from the group consisting of a structural unit (B3) based on or a composition for oral cavity containing the preventive agent, Administering to the oral
- R 2 represents a hydrogen atom or a methyl group
- R 3 represents an alkyl group having 4 to 18 carbon atoms.
- R 4 represents a hydrogen atom or a methyl group
- R 5 , R 6 and R 7 each independently represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms
- X ⁇ represents a halogen ion or
- R 8 represents a hydrogen atom or a methyl group
- R 9 and R 10 each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. 8).
- a weight average molecular weight of 10,000 to 5,000,000 A structural unit (A) based on 2- (meth) acryloyloxyethyl phosphorylcholine (A) of 10 to 90 mol%, Structural unit (B1) based on alkyl group-containing (meth) acrylic monomer, structural unit (B2) based on quaternary ammonium group-containing (meth) acrylic monomer, and (meth) acrylamide monomer
- a copolymer for preventing biofilm formation comprising 90 to 10 mol% of at least one structural unit selected from the group consisting of structural units (B3) based thereon.
- R 1 represents a hydrogen atom or a methyl group.
- R 2 represents a hydrogen atom or a methyl group
- R 3 represents an alkyl group having 4 to 18 carbon atoms.
- R 4 represents a hydrogen atom or a methyl group
- R 5 , R 6 and R 7 each independently represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms
- X ⁇ represents a halogen ion or
- R 8 represents a hydrogen atom or a methyl group
- R 9 and R 10 each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
- a weight average molecular weight of 10,000 to 5,000,000 A structural unit (A) based on 2- (meth) acryloyloxyethyl phosphorylcholine (A) of 10 to 90 mol%, Structural unit (B1) based on alkyl group-containing (meth) acrylic monomer, structural unit (B2) based on quaternary ammonium group-containing (meth) acrylic monomer, and (meth) acrylamide monomer Use of a copolymer containing 90 to 10 mol% of at least one structural unit selected from the group consisting of the structural unit (B3) based as a biofilm formation preventive agent.
- R 1 represents a hydrogen atom or a methyl group.
- R 2 represents a hydrogen atom or a methyl group
- R 3 represents an alkyl group having 4 to 18 carbon atoms.
- R 4 represents a hydrogen atom or a methyl group
- R 5 , R 6 and R 7 each independently represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms
- X ⁇ represents a halogen ion or
- R 8 represents a hydrogen atom or a methyl group
- R 9 and R 10 each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
- the biofilm formation preventive agent of the present invention can prevent maturation into a biofilm due to the biofilm formation preventive effect of a (meth) acrylic copolymer containing a phosphorylcholine group. Furthermore, since the composition for oral cavity of the present invention contains the biofilm formation preventive agent and the drug, the amount of the drug adsorbed on the tooth surface can be controlled, so that the side effect due to the drug can be reduced and the adsorbed drug can be reduced. By slow release, the effect of the drug can be sustained for a long time, and the effect of preventing biofilm formation can be further enhanced to suppress co-aggregation, which is the attachment of other microorganisms to already attached microorganisms, and in the oral cavity Can be prevented.
- the biofilm formation preventive agent of the present invention comprises a structural unit (A) based on 2- (meth) acryloyloxyethyl phosphorylcholine, a structural unit (B1) based on an alkyl group-containing (meth) acrylic monomer, and quaternary ammonium.
- a structural unit (B2) based on a group-containing (meth) acrylic monomer and a structural unit (B3) based on a (meth) acrylamide monomer More specifically, it comprises a structural unit (A) based on 2- (meth) acryloyloxyethyl phosphorylcholine, a structural unit (B1) based on an alkyl group-containing (meth) acrylic monomer, and quaternary ammonium.
- Structural unit (B2) based on group-containing (meth) acrylic monomer, or structural unit based on (meth) acrylamide monomer Comprising a copolymer containing B3) and.
- the structural unit (A) based on 2- (meth) acryloyloxyethyl phosphorylcholine is more specifically represented by the following formula (A), and is obtained by polymerization of a monomer represented by the formula (A ′). .
- R 1 may be either a hydrogen atom or a methyl group, but is preferably a methyl group.
- the copolymer used for this invention can control the excessive adsorption
- the content of the structural unit (A) in the copolymer used in the present invention is 10 to 90 mol%, preferably 20 to 90 mol%, more preferably 30 to 90 mol%. If the content is too low, excessive adsorption cannot be suppressed (the effect of suppressing excessive adsorption becomes low), and if it is too high, the effect itself becomes low because it flows out into water due to its super hydrophilicity.
- 2- (meth) acryloyloxyethyl phosphorylcholine examples include 2-methacryloyloxyethyl phosphorylcholine.
- “(meth) acryl” means acryl or methacryl (methacryl)
- “(meth) acryloyl” means acryloyl or methacryloyl (methacryloyl)
- “(meth) acrylate” Acrylate or methacrylate (methacrylate).
- the structural unit (B1) based on the alkyl group-containing (meth) acrylic monomer is more specifically represented by the following formula (B1), and by polymerization of the monomer represented by the formula (B1 ′). can get.
- the copolymer used for this invention can improve the adsorptivity to the tooth surface of a copolymer more by having a structural unit (B1) in a molecular chain.
- R 2 may be either a hydrogen atom or a methyl group, but is preferably a methyl group.
- R 3 may be any linear or branched alkyl group having 4 to 18 carbon atoms.
- linear alkyl group having 4 to 18 carbon atoms examples include n-butyl group, n-pentyl group, n-hexyl group, n-heptyl group, n-octyl group, n-nonyl group, n-decyl group, Examples thereof include n-undecyl group, n-dodecyl group, n-tridecyl group, n-tetradecyl group, n-pentadecyl group, n-hexadecyl group, n-heptadecyl group and n-octadecyl group.
- Examples of the branched alkyl group having 4 to 18 carbon atoms include t-butyl, isobutyl, isopentyl, t-pentyl, neopentyl, isohexyl, isoheptyl, isooctyl, isononyl, isodecyl, isoundecyl Group, isododecyl group, isotridecyl group, isotetradecyl group, isopentadecyl group, isohexadecyl group, isoheptadecyl group, isooctadecyl group and the like.
- R 3 is more preferably an n-butyl group, an n-dodecyl group, an n-octadecyl group, or the like.
- the alkyl group-containing (meth) acrylic monomer include butyl (meth) acrylate, lauryl (meth) acrylate, stearyl (meth) acrylate, 2-ethylhexyl (meth) acrylate and the like.
- R 4 may be either a hydrogen atom or a methyl group, but is preferably a methyl group.
- R 5 , R 6 and R 7 each independently represent a hydrogen atom or an alkyl group having 1 to 8 (more preferably 1 to 3) carbon atoms, and the alkyl group is any of linear, branched and cyclic. May be.
- R 5 , R 6 and R 7 methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group Group, n-hexyl group, isohexyl group, n-heptyl group, isoheptyl group, n-octyl group, isooctyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group and the like.
- R 5 , R 6 and R 7 are preferably a methyl group, an ethyl group, a propyl group or an isopropyl group, and more preferably a methyl group.
- X ⁇ include halogen ions such as fluorine ion, bromine ion and chlorine ion (chloride ion), and acid residues such as sulfate ion and methyl sulfate ion. Of these, halogen ions are preferred.
- Preferable examples of the quaternary ammonium group-containing (meth) acrylic monomer include 2-hydroxy-3-methacryloyloxypropyltrimethylammonium chloride.
- the copolymer used for this invention can improve the adsorptivity to the tooth surface of a copolymer more by having a structural unit (B2) in a molecular chain.
- the structural unit (B3) based on the (meth) acrylamide monomer is represented by the following formula (B3), and is obtained by polymerization of the monomer represented by the formula (B3 ′).
- the copolymer used in the present invention has the structural unit (B3) in the molecular chain, the copolymer can have a high molecular weight, and the adhesion of the copolymer to the tooth surface can be further increased.
- R 8 may be a hydrogen atom or a methyl group, but is preferably a hydrogen atom.
- R 9 and R 10 each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and the alkyl group may be linear, branched or cyclic.
- R 9 and R 10 are preferably a hydrogen atom, a methyl group, an ethyl group, a propyl group, or an isopropyl group, and more preferably a methyl group.
- the (meth) acrylamide monomer include N, N-dimethylaminopropylacrylamide.
- the copolymer used in the present invention has at least one structural unit selected from the group consisting of (B1), (B2) and (B3) in the molecular chain.
- the copolymer used in the present invention may have only one constituent unit selected from the group consisting of (B1), (B2) and (B3) in the molecular chain, (B1), Even though it has two structural units ⁇ for example (B1) and (B2), (B1) and (B3), (B2) and (B3) ⁇ selected from the group consisting of (B2) and (B3) Well, you may have all the structural units of (B1), (B2), and (B3).
- the copolymer used in the present invention has the structural units (B1) to (B3) in the molecular chain, the persistence of the phosphorylcholine group-containing polymer on the tooth surface can be enhanced. Furthermore, the copolymer used in the present invention has not only (B1) to (B3) but also the structural unit (A) in the same polymer chain, thereby suppressing the excessive adsorption of the drug and the sustained release. It will have a sex.
- Preferred examples of combinations of the structural unit (A) and the structural units (B1) to (B3) contained in the molecular chain of the copolymer used in the present invention are as follows. For convenience, the combination is described by the name of the monomer. 2- (meth) acryloyloxyethyl phosphorylcholine (A) and butyl methacrylate (B1); 2- (meth) acryloyloxyethyl phosphorylcholine (A) and stearyl methacrylate (B1); 2- (meth) acryloyloxyethyl phosphorylcholine (A) and 2-hydroxy-3-methacryloyloxypropyltrimethylammonium chloride (B2); And 2- (meth) acryloyloxyethyl phosphorylcholine (A), N, N-dimethylaminopropylacrylamide (B3), and stearyl methacrylate (B1).
- the copolymer used in the present invention may contain a structural unit other than the structural unit (A) and the structural units (B1) to (B3), but preferably the structural unit (A) and the structural unit (B1). ), (B2), and (B3).
- the copolymer used in the present invention is a polymer (1) obtained by polymerization according to the method of JP-A-11-0356605, and obtained by polymerization according to the method of JP-A-2004-196868.
- Polymer (2), polymer (3) obtained by polymerization according to the method of JP 2004-196868 A, polymer (4) obtained by polymerization according to the method of JP 2004-189678 A ), Polymer (5) obtained by polymerization according to the method of JP-A-2013-018749, and the like can be used.
- the weight average molecular weight of the copolymer used in the present invention is 10,000 to 5,000,000, preferably 50,000 to 1,000,000. If the weight average molecular weight is too low, an effect commensurate with the blending amount cannot be obtained. If the weight average molecular weight is too high, the effect can be obtained, but the feeling of use becomes worse, for example, the film feeling becomes too strong during use.
- biofilm formation preventive agent when the above-mentioned biofilm formation preventive agent is applied to the oral composition, particularly effective agents include bactericides (C), anti-inflammatory agents (D), vitamins (E) and the like.
- C bactericides
- D anti-inflammatory agents
- E vitamins
- medical agents are not specifically limited, The following are mentioned.
- the fungicide (C) is selected from the group consisting of isopropylmethylphenol, depotassium chloride, benzalkonium chloride, benzethonium chloride, alkyldiaminoethylglycine hydrochloride, chlorhexidine hydrochloride, chlorhexidine gluconate, triclosan, and 1,8-cineole.
- One or more fungicides are selected from the group consisting of isopropylmethylphenol, depotassium chloride, benzalkonium chloride, benzethonium chloride, alkyldiaminoethylglycine hydrochloride, chlorhexidine hydrochloride, chlorhexidine gluconate, triclosan, and 1,8-cineole.
- One or more fungicides is selected from the group consisting of isopropylmethylphenol, depotassium chloride, benzalkonium chloride, benzethonium chloride, alkyldiaminoeth
- the anti-inflammatory agent (D) is one or more fungicides selected from the group consisting of sodium azulene sulfonate, allantoin, glycyrrhizic acid and salts thereof, and ⁇ -glycyrrhizic acid.
- the vitamin (E) is one or more vitamins selected from the group consisting of ascorbic acid and salts thereof, pyridoxine hydrochloride, dl- ⁇ -tocopherol acetate, and dl- ⁇ -tocopherol nicotinate.
- the oral composition of the present invention can be applied to a mouthwash, a mouthwash, a dentifrice, a mouth freshener, a chewable agent, and the like, and its form is not particularly limited, such as a liquid, a viscous liquid, or a gel.
- the oral composition of the present invention is a drug, buffering agent, wetting agent, surfactant, antiseptic disinfectant, sweetener, thickening agent, solvent, color that can be generally used in the oral composition as necessary.
- Materials, organic acids, inorganic salts, antioxidants, stabilizers, preservatives, sequestering agents, fragrances, flavoring agents, cooling agents, pigments and the like can be blended.
- Drugs other than the bactericide (C), the anti-inflammatory agent (D), and the vitamin (E) can be contained in the oral composition of the present invention in an amount that can be formulated pharmacologically.
- Hemostatic agents such as epsilon-aminocaproic acid and tranexamic acid; Hypersensitivity relieving agents such as potassium nitrate and aluminum lactate; Expectorants such as 1,8-cineole; Adsorbents such as zeolite; Anticalculus agents such as disodium dihydrogen pyrophosphate, sodium pyrophosphate, zinc chloride; Caries preventive agents such as sodium fluoride and sodium monofluorophosphate; Bad breath removers such as copper chlorophyllin sodium; Detergents such as polyoxyethylene lauryl ether (8-10E.O.), Sodium lauroyl sarcosine; Astringents such as sodium chloride and l-menthol; Plaque removers such as sodium monohydrogen phosphate, trisodium
- the buffering agent is not particularly limited, and examples thereof include citric acid, phosphoric acid, malic acid, gluconic acid, and salts thereof, and it is desirable to use at 0.01% by mass to 3% by mass.
- the wetting agent is not particularly limited, and examples thereof include polyhydric alcohols such as propylene glycol, butylene glycol, pentylene glycol, dipropylene glycol, polyethylene glycol, xylitol, mannitol, and erythritol, and are used at 1% by mass to 50% by mass. It is desirable.
- the surfactant is not particularly limited, and examples thereof include polyoxyethylene hydrogenated castor oil, sorbitan fatty acid ethylene adduct, polyglycerin fatty acid ester, acylamino acid salt, fatty acid aminopropyl betaine, fatty acid amide betaine, and the like.
- Castor oil and sorbitan fatty acid ethylene adduct are preferably used in an amount of 0.05 to 2% by mass.
- the antiseptic disinfectant is not particularly limited, and examples thereof include polyhexanide hydrochloride, benzoic acid and salts thereof, and parabens, and the compounding amount is usually 0.01 to 1% by mass.
- the sweetening agent is not particularly limited, and examples thereof include saccharin, stevioside, sucrose, aspartame, and licorice extract.
- the thickening agent is not particularly limited, but a cellulose-based thickening agent such as methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, hyaluronic acid and its salt, chondroitin sulfate and its salt, alginic acid and its Examples thereof include polysaccharides such as salts, dulan gum, xanthan gum and the like.
- a solvent is not specifically limited, Purified water and ethanol are mentioned. It is particularly preferable to use ethanol at 5.0 to 20% by mass.
- the composition for oral cavity containing the biofilm formation preventive agent of the present invention is such that the copolymer used in the present invention is 0.01 to 10.0% by mass in water, alcohol such as ethanol or a mixed solution thereof. It can be obtained by dissolving it in If the concentration of the copolymer is less than 0.01% by mass, the excessive adsorption suppressing effect and the sustained release effect of the drug are not sufficient, and if it exceeds 10.0% by mass, it may be difficult to control the amount of the adsorbed drug. .
- the concentration of the copolymer used in the present invention is more preferably 0.05 to 5.0% by mass, and still more preferably 0.5 to 5.0% by mass.
- the present invention is also directed to a biofilm formation prevention method including the following steps.
- a weight average molecular weight of 10,000 to 5,000,000 A structural unit (A) based on 2- (meth) acryloyloxyethyl phosphorylcholine (A) of 10 to 90 mol%, Structural unit (B1) based on alkyl group-containing (meth) acrylic monomer, structural unit (B2) based on quaternary ammonium group-containing (meth) acrylic monomer, and (meth) acrylamide monomer
- a biofilm formation preventive agent comprising a copolymer containing 90 to 10 mol% of at least one structural unit selected from the group consisting of a structural unit (B3) based on or a composition for oral cavity containing the preventive agent, Administering to the oral cavity of a mammal comprising (In the formula (A), R 1 represents a hydrogen atom or a methyl group.
- R 2 represents a hydrogen atom or a methyl group
- R 3 represents an alkyl group having 4 to 18 carbon atoms.
- R 4 represents a hydrogen atom or a methyl group
- R 5 , R 6 and R 7 each independently represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms
- X ⁇ represents a halogen ion or
- R 8 represents a hydrogen atom or a methyl group
- R 9 and R 10 each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
- the method for preventing biofilm formation of the present invention is not particularly limited.
- 15 to 25 mL of oral composition containing the biofilm formation preventive agent of the present invention is applied 1 to 10 times, 1 to 8 times per day, Examples include 1 to 6 times, 1 to 4 times, and 1 to 3 times (preferably in the morning, noon, and evening), including and rinsing in the mouth for 30 seconds or more per time.
- the target of the biofilm formation prevention method is not particularly limited, but is intended for mammals including humans.
- the present invention has a weight average molecular weight of 10,000 to 5,000,000, A structural unit (A) based on 2- (meth) acryloyloxyethyl phosphorylcholine (A) of 10 to 90 mol%, Structural unit (B1) based on alkyl group-containing (meth) acrylic monomer, structural unit (B2) based on quaternary ammonium group-containing (meth) acrylic monomer, and (meth) acrylamide monomer A biofilm formation-preventing copolymer containing 90 to 10 mol% of at least one structural unit selected from the group consisting of the structural unit (B3) based on it is also targeted.
- R 1 represents a hydrogen atom or a methyl group.
- R 2 represents a hydrogen atom or a methyl group
- R 3 represents an alkyl group having 4 to 18 carbon atoms.
- R 4 represents a hydrogen atom or a methyl group
- R 5 , R 6 and R 7 each independently represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms
- X ⁇ represents a halogen ion or
- R 8 represents a hydrogen atom or a methyl group
- R 9 and R 10 each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
- the present invention has a weight average molecular weight of 10,000 to 5,000,000, A structural unit (A) based on 2- (meth) acryloyloxyethyl phosphorylcholine (A) of 10 to 90 mol%, Structural unit (B1) based on alkyl group-containing (meth) acrylic monomer, structural unit (B2) based on quaternary ammonium group-containing (meth) acrylic monomer, and (meth) acrylamide monomer.
- Structural unit (B1) based on alkyl group-containing (meth) acrylic monomer
- structural unit (B2) based on quaternary ammonium group-containing (meth) acrylic monomer
- (meth) acrylamide monomer The use of a copolymer containing 90 to 10 mol% of at least one structural unit selected from the group consisting of the structural unit (B3) based on the production of a biofilm formation preventive agent is also an object.
- R 1 represents a hydrogen atom or a methyl group.
- R 2 represents a hydrogen atom or a methyl group
- R 3 represents an alkyl group having 4 to 18 carbon atoms.
- R 4 represents a hydrogen atom or a methyl group
- R 5 , R 6 and R 7 each independently represent a hydrogen atom or an alkyl group having 1 to 8 carbon atoms
- X ⁇ represents a halogen ion or an acid.
- R 8 represents a hydrogen atom or a methyl group
- R 9 and R 10 each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
- MPC polymer (1) 2-methacryloyloxyethyl phosphorylcholine / butyl methacrylate copolymer (copolymerization composition ratio (molar ratio) 80/20, weight average molecular weight: 600,000), Examples of JP-A No. 11-035605 It was obtained by carrying out the polymerization by the method described.
- MPC polymer (2) 2-methacryloyloxyethyl phosphorylcholine / butyl methacrylate copolymer (copolymerization composition ratio (molar ratio) 30/70, weight average molecular weight: 142,000), Examples of JP-A 2004-196868 It was obtained by carrying out the polymerization by the method described.
- MPC polymer (3) 2-methacryloyloxyethyl phosphorylcholine / stearyl methacrylate copolymer [copolymerization composition (molar ratio) 33/67, weight average molecular weight: 164,000], described in Examples of JP-A-2004-196868 It was obtained by carrying out polymerization by the method.
- MPC polymer (4) 2-methacryloyloxyethyl phosphorylcholine / 2-hydroxy-3-methacryloyloxypropyltrimethylammonium chloride copolymer [copolymerization composition (molar ratio) 70/30, weight average molecular weight: 450,000] The polymerization was carried out by the method described in Examples of JP-A-2004-189678.
- MPC polymer (5) 2-methacryloyloxyethyl phosphorylcholine / N, N-dimethylaminopropylacrylamide / stearyl methacrylate copolymer [copolymerization composition (molar ratio) 90/2/8, weight average molecular weight: 820,000] And obtained by polymerization according to the method described in Examples of JP2013-018749A.
- Examples 1-1 to 1-35, Comparative Examples 1-1 to 1-15, Controls 1 to 5 Oral compositions containing the ingredients shown in Tables 1 to 3 were prepared according to a conventional method. ⁇ Evaluation of drug adsorption and retention> 1 mL of oral compositions of Controls 1 to 5, Examples 1-1 to 1-35, and Comparative Examples 1-1 to 1-15 were mixed with hydroxyapatite powder (Bio-Gel HTP Hydroxyapataite, BIO, which is a model of tooth surface). -Made by RAD) and contacted with 0.04 g for 10 minutes. This was centrifuged (3500 rpm, 1 minute), and the supernatant was recovered.
- hydroxyapatite powder Bio-Gel HTP Hydroxyapataite, BIO, which is a model of tooth surface
- This supernatant was filtered through a filter (“Advantech” cellulose acetate, manufactured by Toyo Roshi Kaisha, Ltd., pore size: 0.45 ⁇ m), the drug was quantified by liquid chromatography, and the amount of drug in the supernatant was calculated. And the unadsorbed rate of the chemical
- Drug non-adsorption rate (%) Amount of drug in supernatant / Amount of drug blended ⁇ 100 Formula 1
- the collected supernatant liquid after the stirring and the extracted liquid are respectively filtered through a filter (“ADVANTEC” cellulose acetate manufactured by Toyo Roshi Kaisha, Ltd., pore size: 0.45 ⁇ m), and the drug is quantified by liquid chromatography.
- ADVANTEC cellulose acetate manufactured by Toyo Roshi Kaisha, Ltd., pore size: 0.45 ⁇ m
- the amount of drug in the supernatant and the amount of drug in the extract were calculated.
- medical agent was computed by following formula 2.
- Drug adsorption retention rate (%) Amount of drug in the extract / Amount of drug in the supernatant liquid after stirring ⁇ 100 Formula 2
- the oral composition is based on the fact that the total value of the non-adsorption rate (%) and the adsorption retention rate (%) calculated as described above exceeds the total value in the control of each drug (controls 1 to 5). It was judged to have an effect of controlling the amount of adsorption of the tooth surface on the tooth surface (inhibition of excessive adsorption) and an effect of sustained drug release.
- Examples 1-1 to 1-35 satisfied all the above criteria. That is, the oral compositions of Examples 1-1 to 1-35 had the effect of controlling the amount of drug adsorbed on the tooth surface (inhibition of excessive adsorption) and the effect of sustained drug release.
- Controls 1 to 5 had a low drug non-adsorption rate and a low drug adsorption retention rate because the amount of excessive drug adsorption increased compared to the Examples.
- the composition for oral cavity containing the biofilm formation preventive agent of the present invention has a non-adsorption rate and an adsorption retention rate by increasing or decreasing the content of the polymer as shown in Examples 1-1 to 1-15.
- the amount of drug adsorbed that is, the amount of drug adsorbed can be controlled, and since the total value of the non-adsorption rate and the adsorption retention rate is high, it has a sustained release property, thus improving the biofilm formation prevention effect and It was confirmed that the suppression of coaggregation, which is the adhesion of other microorganisms to the existing microorganisms, and the prevention of stickiness in the oral cavity can be prevented.
- the drug non-adsorption rate and drug adsorption retention rate of Comparative Examples 1-1 to 1-15 are not different from those of the control 1 to 5 drug non-adsorption rate and drug adsorption retention rate. It was confirmed that there was no adsorption amount control effect or sustained release property.
- the biofilm formation preventive agent of the present invention shows an excellent adsorption amount control effect / sustained release effect, and enhance the biofilm formation preventive effect. Suppression of co-aggregation, which is adhesion of other microorganisms to attached microorganisms, and stickiness in the oral cavity can be prevented.
- Biofilm formation preventive agent, oral composition and bio which improve the sustainability of the effect of the drug without increasing the drug concentration and treatment time, keep the oral environment continuously good, and prevent maturation into the biofilm It is possible to provide an oral composition capable of preventing deterioration of the oral environment by the film formation prevention method and the biofilm formation prevention effect, and preventing the oral stickiness.
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Abstract
Description
本出願は、参照によりここに援用されるところの日本出願特願2015-155410号優先権を請求する。
そこで、薬剤の効果を十分に発揮するために、薬剤濃度を高めたり、処理時間を長くしたりする対策が取られてきた。しかしながら、薬剤濃度を高めると薬剤によっては副作用として炎症が出ることがあったり、処理時間を長くすることは使用者にとって不便であったりするため、上述の対策は必ずしも十分なものではない。
また、吸着性と徐放性を向上させる技術としては、特許文献2には、フッ化物の滞留性やフッ化物の放出性に優れた水溶性モノフルオロリン酸化高分子化合物と界面活性剤を組み合わせた口腔用組成物に関する技術が開示されている。しかしながら、この技術では、特定の薬剤であるフッ化物の滞留性と放出性の向上に限定されてしまう点で課題が残る。
しかしながら、特許文献3ではPC重合体をバイオフィルム形成予防剤として使用することに関する記載又は示唆はない。また、特許文献4の技術では、口腔内で微生物が付着することを防止できる技術であるが、既に付着している微生物へ他の微生物が付着である共凝集を抑制するバイオフィルム形成予防剤に関しては記載がない。
以上により、薬剤濃度や処理時間を高めることなく、口内環境を持続的に良好に保ち、バイオフィルムへの成熟を防止する口腔用組成物が求められているのである。
1.重量平均分子量10,000~5,000,000であり、
2-(メタ)アクリロイルオキシエチルホスホリルコリンに基づく構成単位(A)10~90モル%と、
アルキル基含有(メタ)アクリル系単量体に基づく構成単位(B1)、4級アンモニウム基含有(メタ)アクリル系単量体に基づく構成単位(B2)、および(メタ)アクリルアミド系単量体に基づく構成単位(B3)からなる群から選ばれる少なくとも1種の構成単位90~10モル%と
を含有する共重合体からなるバイオフィルム形成予防剤。
2.構成単位(A)が2-(メタ)アクリロイルオキシエチルホスホリルコリンに基づく構成単位であり、構成単位(B1)がブチルメタクリレートに基づく構成単位である、請求項1に記載のバイオフィルム形成予防剤。
3.構成単位(A)が2-(メタ)アクリロイルオキシエチルホスホリルコリンに基づく構成単位であり、構成単位(B1)がステアリルメタクリレートに基づく構成単位である、請求項1に記載のバイオフィルム形成予防剤。
4.構成単位(A)が2-(メタ)アクリロイルオキシエチルホスホリルコリンに基づく構成単位であり、構成単位(B2)が2-ヒドロキシ-3-メタクリロイルオキシプロピルトリメチルアンモニウムクロライドに基づく構成単位である、請求項1に記載のバイオフィルム形成予防剤。
5.構成単位(A)が2-(メタ)アクリロイルオキシエチルホスホリルコリンに基づく構成単位であり、構成単位(B1)がステアリルメタクリレートに基づく構成単位であり、構成単位(B3)がN,N-ジメチルアミノプロピルアクリルアミドに基づく構成単位である、請求項1に記載のバイオフィルム形成予防剤。
6.前記1~5のいずれか1に記載のバイオフィルム形成予防剤と、殺菌剤(C)、抗炎症剤(D)およびビタミン(E)からなる群より選択される1種または2種以上の薬剤とを含有する口腔用組成物。
7.以下の工程を含む、バイオフィルム形成予防方法、
重量平均分子量10,000~5,000,000であり、
2-(メタ)アクリロイルオキシエチルホスホリルコリンに基づく構成単位(A)10~90モル%と、
アルキル基含有(メタ)アクリル系単量体に基づく構成単位(B1)、4級アンモニウム基含有(メタ)アクリル系単量体に基づく構成単位(B2)、および(メタ)アクリルアミド系単量体に基づく構成単位(B3)からなる群から選ばれる少なくとも1種の構成単位90~10モル%と
を含有する共重合体からなるバイオフィルム形成予防剤又は該予防剤を含む口腔用組成物を、ヒトを含む哺乳類の口腔に投与する工程。
8.重量平均分子量10,000~5,000,000であり、
2-(メタ)アクリロイルオキシエチルホスホリルコリンに基づく構成単位(A)10~90モル%と、
アルキル基含有(メタ)アクリル系単量体に基づく構成単位(B1)、4級アンモニウム基含有(メタ)アクリル系単量体に基づく構成単位(B2)、および(メタ)アクリルアミド系単量体に基づく構成単位(B3)からなる群から選ばれる少なくとも1種の構成単位90~10モル%と
を含有するバイオフィルム形成予防用共重合体。
9.重量平均分子量10,000~5,000,000であり、
2-(メタ)アクリロイルオキシエチルホスホリルコリンに基づく構成単位(A)10~90モル%と、
アルキル基含有(メタ)アクリル系単量体に基づく構成単位(B1)、4級アンモニウム基含有(メタ)アクリル系単量体に基づく構成単位(B2)、および(メタ)アクリルアミド系単量体に基づく構成単位(B3)からなる群から選ばれる少なくとも1種の構成単位90~10モル%と
を含有する共重合体をバイオフィルム形成予防剤の製造としての使用。
本発明のバイオフィルム形成予防剤は、2-(メタ)アクリロイルオキシエチルホスホリルコリンに基づく構成単位(A)と、アルキル基含有(メタ)アクリル系単量体に基づく構成単位(B1)、4級アンモニウム基含有(メタ)アクリル系単量体に基づく構成単位(B2)、および(メタ)アクリルアミド系単量体に基づく構成単位(B3)からなる群から選ばれる少なくとも1種の構成単位とを含有する共重合体からなり、より詳しくは、2-(メタ)アクリロイルオキシエチルホスホリルコリンに基づく構成単位(A)と、アルキル基含有(メタ)アクリル系単量体に基づく構成単位(B1)、4級アンモニウム基含有(メタ)アクリル系単量体に基づく構成単位(B2)、または(メタ)アクリルアミド系単量体に基づく構成単位(B3)とを含有する共重合体からなる。
2-(メタ)アクリロイルオキシエチルホスホリルコリンに基づく構成単位(A)は、より具体的には下記の式(A)で表され、式(A')で表される単量体の重合によって得られる。
本発明に用いる共重合体は、分子鎖中に構成単位(A)を有することによって、薬剤の過剰な吸着を制御することができる。本発明に用いる共重合体中の構成単位(A)の含有量は、10~90モル%であり、好ましくは20~90モル%であり、より好ましくは30~90モル%である。含有量が低すぎると過剰な吸着を抑えることができず(過剰吸着抑制効果が低くなり)、高すぎるとそれ自身が超親水性のために水中に流れ出てしまうために効果が低くなる。
2-(メタ)アクリロイルオキシエチルホスホリルコリンの好適な例として、2-メタクリロイルオキシエチルホスホリルコリンが挙げられる。
なお、本発明において「(メタ)アクリル」は、アクリルまたはメタアクリル(メタクリル)を意味し、「(メタ)アクリロイル」は、アクリロイルまたはメタアクリロイル(メタクリロイル)を意味し、「(メタ)アクリレート」は、アクリレートまたはメタアクリレート(メタクリレート)を意味する。
アルキル基含有(メタ)アクリル系単量体に基づく構成単位(B1)は、より具体的には下記の式(B1)で表され、式(B1')で表される単量体の重合によって得られる。
本発明に用いる共重合体は、分子鎖中に構成単位(B1)を有することによって、共重合体の歯面への吸着性をより高めることが出来る。
R3は、より好ましくは、n-ブチル基、n-ドデシル基、n-オクタデシル基等である。
アルキル基含有(メタ)アクリル系単量体の好適な例として、ブチル(メタ)アクリレート、ラウリル(メタ)アクリレート、ステアリル(メタ)アクリレート、2-エチルヘキシル(メタ)アクリレート等が挙げられる。
4級アンモニウム基含有(メタ)アクリル系単量体に基づく構成単位(B2)は、より具体的には下記の式(B2)で表され、式(B2')で表される単量体の重合によって得られる。
具体的には、R5、R6およびR7としてメチル基、エチル基、プロピル基、イソプロピル基、n-ブチル基、イソブチル基、sec-ブチル基、tert-ブチル基、n-ペンチル基、イソペンチル基、n-ヘキシル基、イソヘキシル基、n-ヘプチル基、イソヘプチル基、n-オクチル基、イソオクチル基、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基などが挙げられる。
R5、R6およびR7として好ましくはメチル基、エチル基、プロピル基、イソプロピル基であり、より好ましくはメチル基である。
X-としては、例えば、フッ素イオン、臭素イオン、塩素イオン(クロライドイオン)などのハロゲンイオン、硫酸イオン、メチル硫酸イオンなどの酸残基が挙げられる。これらの中では、ハロゲンイオンが好ましい。
本発明に用いる共重合体は、分子鎖中に構成単位(B2)を有することによって、共重合体の歯面への吸着性をより高めることが出来る。
(メタ)アクリルアミド系単量体に基づく構成単位(B3)は、より具体的には下記の式(B3)で表され、式(B3')で表される単量体の重合によって得られる。本発明に用いる共重合体は、分子鎖中に構成単位(B3)を有することによって、共重合体を高分子量化し、共重合体の歯面への密着性をより高めることが出来る。
R9およびR10として好ましくは、水素原子、メチル基、エチル基、プロピル基もしくはイソプロピル基であり、より好ましくはメチル基である。
(メタ)アクリルアミド系単量体の好適な例としては、N,N-ジメチルアミノプロピルアクリルアミド等を挙げることができる。
本発明に用いる共重合体中の構成単位(B1)~(B3)の含有量{(B1)~(B3)のうち1つの構成単位のみ含有する場合は当該構成単位の含有量、(B1)~(B3)のうち2つ又は3つの構成単位を含有する場合はそれらの構成単位の含有量の合計}は、10~90モル%であり、好ましくは10~80モル%であり、より好ましくは10~70モル%である。含有量が低すぎると共重合体の親水性が高いために水中での使用時に流れてしまうために徐放効果が低くなり、高すぎると吸着する薬剤量が制御できなくなる(過剰に薬剤が吸着してしまう)。
2-(メタ)アクリロイルオキシエチルホスホリルコリン(A)及びブチルメタクリレート(B1);
2-(メタ)アクリロイルオキシエチルホスホリルコリン(A)及びステアリルメタクリレート(B1);
2-(メタ)アクリロイルオキシエチルホスホリルコリン(A)及び2-ヒドロキシ-3-メタクリロイルオキシプロピルトリメチルアンモニウムクロライド(B2);
並びに
2-(メタ)アクリロイルオキシエチルホスホリルコリン(A)、N,N-ジメチルアミノプロピルアクリルアミド(B3)、及びステアリルメタクリレート(B1)。
該薬剤としては、
イプシロン-アミノカプロン酸、トラネキサム酸等の止血剤;
硝酸カリウム、乳酸アルミニウム等の知覚過敏緩和剤;
1,8-シネオール等の去痰剤;
ゼオライト等の吸着剤;
ピロリン酸二水素二ナトリウム、ピロリン酸ナトリウム、塩化亜鉛等の歯石沈着防止剤;
フッ化ナトリウム、モノフルオロリン酸ナトリウム等の虫歯予防剤;
銅クロロフィリンナトリウム等の口臭除去剤;
ポリオキシエチレンラウリルエーテル(8~10E.O.)、ラウロイルサルコシンナトリウム等の洗浄剤;
塩化ナトリウム、l-メントール等の収斂剤;
リン酸1水素ナトリウム、リン酸三ナトリウム、ポリエチレングリコール、ポリビニルピロリドン等の歯垢除去剤;
等が挙げられる。
湿潤剤は、特に限定されないが、プロピレングリコール、ブチレングリコール、ペンチレングリコール、ジプロピレングリコール、ポリエチレングリコール、キシリトール、マンニトール、エリスリトールなどの多価アルコールが挙げられ、1質量%~50質量%で使用されることが望ましい。
界面活性剤は、特に限定されないが、ポリオキシエチレン硬化ヒマシ油、ソルビタン脂肪酸エチレン付加物、ポリグリセリン脂肪酸エステル、アシルアミノ酸塩、脂肪酸アミノプロピルベタイン、脂肪酸アミドベタインなどが挙げられ、特にポリオキシエチレン硬化ヒマシ油、ソルビタン脂肪酸エチレン付加物を0.05質量%~2質量%で使用されるのが好ましい。
甘味剤は、特に限定されないが、サッカリン、ステビオシド、スクロース、アスパルテーム、甘草抽出物が挙げられる。
溶剤は、特に限定はされないが、精製水、エタノールが挙げられる。特に好ましくは、エタノールを5.0~20質量%で使用されるのが好ましい。
加えて、本発明に用いる共重合体の濃度は、より好ましくは、0.05~5.0質量%であり、さらに好ましくは0.5~5.0質量%である。
重量平均分子量10,000~5,000,000であり、
2-(メタ)アクリロイルオキシエチルホスホリルコリンに基づく構成単位(A)10~90モル%と、
アルキル基含有(メタ)アクリル系単量体に基づく構成単位(B1)、4級アンモニウム基含有(メタ)アクリル系単量体に基づく構成単位(B2)、および(メタ)アクリルアミド系単量体に基づく構成単位(B3)からなる群から選ばれる少なくとも1種の構成単位90~10モル%と
を含有する共重合体からなるバイオフィルム形成予防剤又は該予防剤を含む口腔用組成物を、ヒトを含む哺乳類の口腔に投与する工程。
バイオフィルム形成予防方法の対象は、特に限定されないが、ヒトを含む哺乳類を対象とする。
2-(メタ)アクリロイルオキシエチルホスホリルコリンに基づく構成単位(A)10~90モル%と、
アルキル基含有(メタ)アクリル系単量体に基づく構成単位(B1)、4級アンモニウム基含有(メタ)アクリル系単量体に基づく構成単位(B2)、および(メタ)アクリルアミド系単量体に基づく構成単位(B3)からなる群から選ばれる少なくとも1種の構成単位90~10モル%と
を含有するバイオフィルム形成予防用共重合体も対象とする。
2-(メタ)アクリロイルオキシエチルホスホリルコリンに基づく構成単位(A)10~90モル%と、
アルキル基含有(メタ)アクリル系単量体に基づく構成単位(B1)、4級アンモニウム基含有(メタ)アクリル系単量体に基づく構成単位(B2)、および(メタ)アクリルアミド系単量体に基づく構成単位(B3)からなる群から選ばれる少なくとも1種の構成単位90~10モル%と
を含有する共重合体をバイオフィルム形成予防剤の製造としての使用も対象とする。
MPCポリマー(2): 2-メタクリロイルオキシエチルホスホリルコリン・ブチルメタクリレート共重合体〔共重合組成比(モル比)30/70、重量平均分子量:142,000〕であり、特開2004-196868の実施例記載の方法によって重合を行って得られた。
MPCポリマー(3): 2-メタクリロイルオキシエチルホスホリルコリン・ステアリルメタクリレート共重合体〔共重合組成(モル比)33/67、重量平均分子量:164,000〕であり、特開2004-196868の実施例記載の方法によって重合を行って得られた。
MPCポリマー(5): 2-メタクリロイルオキシエチルホスホリルコリン・N,N-ジメチルアミノプロピルアクリルアミド・ステアリルメタクリレート共重合体〔共重合組成(モル比)90/2/8、重量平均分子量:820,000〕であり、特開2013-018749の実施例記載の方法によって重合を行って得られた。
ホモポリマー(A):2-メタクリロイルオキシエチルホスホリルコリンの重合体〔重量平均分子量:200,000〕であり、特開平8-333421の実施例記載の方法によって重合を行って得られた。
表1~3に示す成分配合の口腔用組成物を常法にしたがって調製した。
<薬剤の吸着性及び滞留性の評価>
対照1~5、実施例1-1~1-35、及び比較例1-1~1-15の口腔用組成物1mLを、歯面のモデルであるハイドロキシアパタイト粉末(Bio-Gel HTP Hydroxyapataite ,BIO-RAD社製)0.04gに10分間接触させた。これを遠心分離(3500rpm、1分間)し、上澄み液を回収した。この上澄み液をフィルター(東洋濾紙(株)製「アドバンテック」セルロースアセテート、孔径0.45μm)でろ過し、薬剤に関して液体クロマトグラフィーで定量を行い、上澄み液中の薬剤量を算出した。そして、下記式1で薬剤の未吸着率を算出した。
さらに、洗浄を3回繰り返した後、残ったハイドロキシアパタイト粉体に精製水5mLを加え、超音波で30分間処理を行い、吸着している薬剤を抽出した(抽出液の回収)。
最後に、回収した該撹拌後上澄み液及び該抽出液を、それぞれ、フィルター(東洋濾紙(株)製「アドバンテック」セルロースアセテート、孔径0.45μm)でろ過し、さらに薬剤に関して液体クロマトグラフィーで定量を行い、撹拌後上澄み液中の薬剤量及び抽出液中の薬剤量を算出した。そして、下記式2で薬剤の吸着保持率を算出した。
すなわち、実施例1-1~1-35の口腔用組成物は、薬剤の歯面への吸着量制御効果(過剰吸着抑制効果)、および、薬剤徐放性効果を有していた。
対照1~5は、実施例と比較したとき、薬剤の過剰吸着量が多くなることから、薬剤の未吸着率が低く、薬剤の吸着保持率も低かった。
これに対し、本発明のバイオフィルム形成予防剤を含む口腔用組成物は、実施例1-1~1-15で示すように、そのポリマーの含有量の増減により、未吸着率と吸着保持率の合計値、すなわち薬剤の吸着量を制御でき、さらに、未吸着率と吸着保持率の合計値が高かったことにより徐放性を有することから、バイオフィルム形成予防効果を高め、既に付着している微生物への他の微生物の付着である共凝集の抑制及び口腔内のネバツキを予防することができることを確認した。
一方で、比較例1-1~1-15の薬剤の未吸着率及び薬剤の吸着保持率は、対照1~5の薬剤の未吸着率及び薬剤の吸着保持率と比較して、差がなく、吸着量制御効果や徐放性を有していないことを確認した。
以上により、本発明のバイオフィルム形成予防剤、該予防剤を含む口腔組成物およびバイオフィルム形成予防方法は、優れた吸着量制御効果・徐放効果を示し、バイオフィルム形成予防効果を高め、既に付着している微生物への他の微生物の付着である共凝集の抑制及び口腔内のネバツキを予防することができる。
Claims (6)
- 重量平均分子量10,000~5,000,000であり、
2-(メタ)アクリロイルオキシエチルホスホリルコリンに基づく構成単位(A)10~90モル%と、
アルキル基含有(メタ)アクリル系単量体に基づく構成単位(B1)、4級アンモニウム基含有(メタ)アクリル系単量体に基づく構成単位(B2)、および(メタ)アクリルアミド系単量体に基づく構成単位(B3)からなる群から選ばれる少なくとも1種の構成単位90~10モル%と
を含有する共重合体からなるバイオフィルム形成予防剤。
- 構成単位(A)が2-(メタ)アクリロイルオキシエチルホスホリルコリンに基づく構成単位であり、構成単位(B1)がブチルメタクリレートに基づく構成単位である、請求項1に記載のバイオフィルム形成予防剤。
- 構成単位(A)が2-(メタ)アクリロイルオキシエチルホスホリルコリンに基づく構成単位であり、構成単位(B1)がステアリルメタクリレートに基づく構成単位である、請求項1に記載のバイオフィルム形成予防剤。
- 構成単位(A)が2-(メタ)アクリロイルオキシエチルホスホリルコリンに基づく構成単位であり、構成単位(B2)が2-ヒドロキシ-3-メタクリロイルオキシプロピルトリメチルアンモニウムクロライドに基づく構成単位である、請求項1に記載のバイオフィルム形成予防剤。
- 構成単位(A)が2-(メタ)アクリロイルオキシエチルホスホリルコリンに基づく構成単位であり、構成単位(B1)がステアリルメタクリレートに基づく構成単位であり、構成単位(B3)がN,N-ジメチルアミノプロピルアクリルアミドに基づく構成単位である、請求項1に記載のバイオフィルム形成予防剤。
- 請求項1~5のいずれか1に記載のバイオフィルム形成予防剤と、殺菌剤(C)、抗炎症剤(D)およびビタミン(E)からなる群より選択される1種または2種以上の薬剤とを含有する口腔用組成物。
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JP2019116425A (ja) * | 2017-12-26 | 2019-07-18 | 小林製薬株式会社 | 炎症及び/又は細菌感染を伴う歯肉の活性化剤 |
JP2019116427A (ja) * | 2017-12-26 | 2019-07-18 | 小林製薬株式会社 | 歯周病の予防又は改善剤 |
JP2019116424A (ja) * | 2017-12-26 | 2019-07-18 | 小林製薬株式会社 | 歯肉の活性化剤 |
WO2021193398A1 (ja) * | 2020-03-27 | 2021-09-30 | 日油株式会社 | 口腔用組成物 |
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