JPH0247963B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to an oral composition containing an antibacterial stone. Tartar is a hard mineral body that forms on the surface of teeth. Regular brushing prevents these rapid build-ups, but is not sufficient to remove all of the tartar from the teeth. Dental calculus forms on the tooth surface when calcium phosphate crystals are deposited within a thin film of dental plaque and extracellular matrix and become sufficiently dense to form aggregates that resist deformation.
There is no complete consensus on the route by which calcium and orthophosphate ultimately form a crystalline product called hydroxyapatite (HAP).
However, at high saturations, ie, values above the critical saturation value, it is generally said that the precursor of crystalline hydroxyapatite is microcrystalline calcium phosphate. “Amorphous calcium phosphate” is related to hydroxyapatite, but differs in terms of atomic structure, particle morphology, and stoichiometry. The X-ray diffraction pattern of amorphous calcium phosphate shows the broad peaks typical of amorphous materials, but it does not have the long range atomic order characteristics of all crystalline materials, including hydroxyapatite. It is proposed that the mechanism by which the non-toxic anti-calculus agent of the present invention inhibits tartar formation includes that the agent binds amino groups in the oral matrix system and cross-links proteins at physiological pH and temperature. has been done. For example, bis-biguanide compounds and quaternary ammonium compounds such as benzethonium chloride,
A number of different types of compounds and compositions have been developed for use as antibacterial, antiplaque, and anticalculus agents, including cationic materials such as cetylpyridinium chloride (disclosed in U.S. Pat. No. 4,080,441). There is. However, these cationic substances tend to cause tooth stains with continued use. A first object of the present invention is to provide an improved anti-calculus oral composition that has relatively little or no tendency to stain teeth. A second object is to provide an oral composition that inhibits the transformation of amorphous calcium phosphate into the hydroxyapatite crystal structure normally associated with dental calculus. A third objective is to provide an improved method for inhibiting tartar formation. Other objects and advantages will be apparent from the description herein. In one aspect, the present invention provides an orally acceptable vehicle that does not contain antibacterial antiplaque agents that cause tooth staining, and an anticalculus effective amount of at least one.
bis(o-carboxyphenyl) esters of _C2-8 aliphatic dicarboxylic acids and _their application to teeth. The free acid form of the antibacterial stone agent of the present invention can be represented by the following formula. _{(Preferably, R is individually H, C 1-4 ,} alkyl,
Preferably it is H, and n is an integer from 0 to 6, preferably 2. ) A preferred antimicrobial stone agent is therefore bis(o)succinate.
-carboxyphenyl) (BOCS). (−
CRR) - _{The o} group is a single bond if _n is 0 as in the oxalic acid bisester; It is separated by the S chain,
Optionally substituted with _{C1-4 alkoxy} . −
When CRR is part of an ethylene group, one or both of R may be zero, that is, a bond. The following bis(o-carboxyphenyl) esters of aliphatic dicarboxylic acids are illustrative of antimicrobial stones of the present invention. Oxalic acid (ethanedioic acid) Malonic acid (propanedioic acid) Succinic acid (butanedioic acid) Glutanic acid (pentanedioic acid) Adipic acid (hexanedioic acid) Pimelic acid (heptanedioic acid) Suberic acid (octanedioic acid) Maleic acid (1,2-ethylenedicarboxylic acid
HOOCCH: CH−COOH) Itaconic acid (methylene succinic acid HOOCC(:
CH ₂ ) CH ₂ −COOH) Isosuccinic acid (2-methylpropanedioic acid) Muconic acid (2,4-hexadienedioic acid)
HOOCCH:CHCH:CH−COOH) Dihydromuconic acid (HOOCCH ₂ CH ₂ CH:
CHCOOH) dihydroitaconic acid (methylsuccinic acid) 3-ethylhexanedioic acid In addition, one or both phenyl moieties of this agent may contain one or more C _1-4 alkyl or alkoxy such as _methyl or isobutoxy, Cl, Br, I Alternatively, the nucleus may be substituted with halo such as F. A suitable method for making these anti-tartar agents is disclosed in the above-mentioned U.S. patent.
It is disclosed in Publication No. 4080441. Another improved method is described in Example A below. The free acid forms of these anti-tartar agents can be combined with alkali metals (e.g. Na, K), alkaline earth metals (e.g. Ca,
Mg), ammonia, mono-, di- or tri-C ₁
~ ₁₈ It is clear that alkyl or alkanol (e.g. methyl, ethyl, hydroxyethyl) substituted ammonium or salts can be converted into their equivalent salts by treatment with bases containing orally acceptable cations such as organic amines. It is. The antimicrobial calculus agents of the present invention are anti-nucleating agents, and the oral compositions of the present invention containing them are effective in reducing calculus formation without excessively demineralizing tooth enamel, and the cationic In contrast to antibacterial, antiplaque and antibacterial stone agents, it has been found to have little or no tendency to stain teeth and, furthermore, to effectively reduce or prevent gingivitis. The concentration of these anti-calculus agents in oral compositions can vary widely, but is typically about 0.01% by weight or higher, and there is no upper limit on the amount used other than from a cost or vehicle incompatibility standpoint. Generally about 0.01-10% by weight, preferably about
0.05-8.0%, more preferably about 0.1-4%.
Concentrations in the lower part of the above range are preferred since oral compositions are likely to be ingested during normal usage situations. The water solubility of these anti-calculus agents varies depending on their molecular weight, the nature and properties of salt-forming cations, but even at the low concentrations used in the present invention, they are sufficiently soluble in aqueous media, such as in the oral cavity. It can be called water-soluble. However, it has been unexpectedly discovered that oral compositions containing such agents in an aqueous medium undergo significant hydrolytic or other degradation during storage. In another embodiment of the invention, substantially anhydrous (e.g., about 0 to 0.2
It is preferred to provide oral compositions containing less than molar amounts of water. When the oral composition of the present invention is in the form of a liquid, paste, or cream, such as a mouthwash, rinse, toothpaste, or dental cream, it is water-miscible (preferably water-soluble), organic, and generally liquid in the oral cavity. Preferably, a vehicle is used. Typically such vehicles include water-soluble _C2-4 mono- and polyhydric alkanes and their
C _1-4 alkyl ethers, such as ethanol, ethylene glycol, their methyl, ethyl, butyl ethers (methyl, ethyl, butyl cellosolve), propylene glycol, tetramethylene glycol and glycerin, aqueous poly(ethylene glycol), such as diethylene glycol, their methyl, Ethyl, diethyl, butyl ethers (methyl, ethyl, diethyl, butyl carbitol), triethylene glycol, low molecular weight polyethylene glycols (eg 400600), and mixtures thereof. polyvalent compounds in the groups mentioned herein,
In particular, propylene glycol, glycerin, and low molecular weight polyethylene glycols also generally serve as humectants, which are desired components of the oral compositions of the present invention. The many types of such water-miscible liquid vehicles that can be used include polar neutral solvents such as dimethylformamide, sulfoxide, N-methylpyrrolidone, sulfolane, tetramethylsulfone, acetonitrile, with ethylene carbonate and propylene carbonate being preferred. Liquid vehicles that are essentially water-immiscible and organic are also used, typical examples being hydrocarbons, oils of fatty acids and fatty acid esters, such as mineral oil, tetradecane, pentane, caproic acid, enantylic acid, caproic acid, methyl laurate. ester, ethylene glycol dicaprylate, etc. Of course, mixtures of the same and/or different types of liquid vehicles may also be employed. The proportion of the liquid vehicle used in these oral compositions will obviously depend in large part on the degree of fluidity or viscosity desired, and in each case can be readily determined in a conventional manner. Typically, by weight, liquid compositions such as mouthwashes, rinses, etc. contain about 70-99.9% such liquid vehicle, toothpastes, dental creams about 10-80%, of which about 10-100% are moisturizers. It is. Humectants, usually solids, such as sorbitol can also be included. The oral compositions of the present invention are typically prepared in an aqueous medium, e.g. in the oral cavity, a 20% aqueous slurry in the form of a solution of about 3.5 to 8, preferably about 4 to 7, more preferably about 4 to 6, It has a pH of Such pH is determined by adding the required amount of acidic substances (e.g. citric acid, benzoic acid), basic substances (e.g. NaOH) and/or buffers (e.g.
It can be controlled by containing citric acid, benzoic acid, bicarbonate, sodium carbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate) or a mixture thereof. The vehicle in solid or pasty compositions such as tooth powders, tablets, toothpastes, dental creams, etc. generally contains an abrasive. Examples are water-insoluble sodium metaphosphate (IMP), potassium metaphosphate,
Tricalcium phosphate, anhydrous, monohydrated, dihydrated calcium or dicalcium phosphate, calcium pyrophosphate, magnesium orthophosphate, trimagnesium phosphate, magnesium or calcium salts of carbonate or sulphate, alumina, hydrated alumina, aluminum silicate , alkali metal or alkaline earth metal salts of aluminosilicate, zirconium silicate, silica, bentonite and mixtures thereof. Preferred abrasives are crystalline or colloidal silica, silica gel, complex amorphous alkali metal aluminosilicates, hydrated alumina, IMP, and the like. Alumina content 64.9% by weight; silica content 0.008
%; ferric oxide 0.003%; moisture content 0.37% (110
C); specific gravity 2.42; particle size: 100% of the particles less than 50 microns; 84% of the particles less than 20 microns; alumina, especially hydrated alumina sold by Alcoa as C333, is very effective. When using macroscopically clear gels, colloidal silica-based abrasives, such as those sold under the trademark SYLOID as SYLOID 72, 74, 244 or under the trademark SANTOCEL as SANTOCEL 100, are particularly useful. This is because it has a refractive index close to that of the gelling agent-liquid system commonly used for toothpaste. Many so-called "water-insoluble" abrasives are anionic and also contain small amounts of soluble material. For example, insoluble sodium metaphosphate is found in Thorpe's Dictionary of
Applied Chemistry, Volume 9, 4th Edition, 510-511
It can be formed by any suitable method, as illustrated in page 1. Another example of a suitable material is the form of insoluble sodium metaphosphate known as Madrell's salt or Kroll's salt. These metaphosphates exhibit little water solubility and are therefore commonly referred to as insoluble natalates. Small amounts as impurities (usually up to 4W%)
of soluble phosphate substances are present. The amount of soluble phosphate material (believed to include soluble sodium trimetaphosphate in the case of insoluble metaphosphates) can be reduced by washing with water if desired. The insoluble alkali metal metaphosphate salt is typically used in powder form with a particle size of less than about 1% greater than about 37 microns. Abrasives are generally present in an amount of about 20-99W% of the oral formulation. Approximately 20-75% is preferred for toothpastes and approximately 70-99% for toothpastes. In the production of toothpaste, it is sufficient to mechanically mix, for example by kneading, suitable amounts and particle sizes of the various solid components. In toothpastes, creams, and gels, liquids and solids are typically in suitable proportions to form a creamy or gel-like mass that can be extruded from a pressurized container or collapsible tube. Thickening to the appropriate desired viscosity or fluidity is typically accomplished by using natural or synthetic gums or gums, typically iris gums,
Pluronic, sodium salts of carboxymethylcellulose or carboxyethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxybutylmethylcellulose, Laponite CP or SP
(synthetic hectorite from Laporte Industries), viscarin, gelatin, glucose, sucrose, Carbopol (e.g. 934, 940, 941), gum karaya, gum arabic, gum tragacanth, polyvinylpicaridone, polyvinyl alcohol, starch, etc. be done. Usually alone or in amounts up to about 10W%, preferably about
Present in an amount of 0.5-5W%. Preferred gelling agents are pluronic and hydroxypropylcellulose. Pluronics such as F108 and F127 are polyoxypropylene polyoxyethylene block polymers that also act as nonionic surfactants. The oral compositions of the present invention generally include about 0.05 to 10,
Non-soap synthetic, fully water soluble organic anionic or nonionic surfactants may also be included to enhance wetting, cleaning and foaming properties, preferably at a concentration of about 0.5-5 W%. In U.S. Patent No. 4,041,149, column 4
Appropriate anionic surfactants are disclosed in lines 31-38, column 8, lines 30-68, and appropriate nonionic surfactants in column 9, lines 1-12. In certain embodiments of the invention, a fluorine-providing compound is present in the oral formulation. These compounds may be slightly or fully water soluble. They are characterized by being able to release fluorine-containing ions into water and by not substantially reacting with other compounds in oral preparations. These substances include inorganic fluorine salts, such as soluble alkali metal, alkaline earth metal, and heavy metal salts, such as sodium fluoride, potassium fluoride, ammonium fluoride, calcium fluoride, and cuprous fluoride. Copper fluoride, zinc fluoride, tin fluoride such as stannic fluoride and stannic fluoride, barium fluoride, sodium fluorosilicate, ammonium fluorosilicate, sodium fluorozirconate, monofluor Sodium phosphate, mono- or difluoroaluminum phosphate, fluorinated calcium sodium pyrophosphate, and the like. Fluorides of alkali metals and tin, such as sodium fluoride, stannous fluoride, sodium monofluorophosphate, and mixtures thereof are preferred. The amount of fluorine-providing compound will depend in part on the type of compound, solubility, and type of oral formulation, but should be a non-toxic amount. For thickened or solid oral formulations such as toothpastes and tooth powders, amounts that release up to about 1% of the agent by weight are preferred. Such compounds can be used in any suitable minimum amount, but from about 0.005 to 1%, preferably about 0.1%.
Preferably, the compound is used in an amount sufficient to release fluorine ions. Typically, in the case of an alkali metal fluoride, stannous fluoride, this component is present in an amount up to about 2% by weight of the agent, preferably from about 0.05 to 1% by weight. In the case of sodium monofluorophosphate, this compound can be present in amounts up to 7.6W%, more typically about 0.5-1W%. In liquid mouthwash formulations, such as mouthwashes, the fluorine-providing compound typically comprises about 0.0005 to 0.2%, preferably about 0.001 to 0.1%, and more preferably about 0.0013% by weight.
% of fluoride ions are released. The oral preparation of the present invention includes a whitening agent, a preservative,
Various other materials can also be included, such as silicones, chlorophyll compounds, other anti-calculus agents, anti-bacterial anti-plaque agents and/or ammonia substances such as urea, diammonium phosphate and mixtures thereof. Any suitable flavoring or sweetening agent may be used. Examples of suitable flavoring ingredients are flavored oils such as oils of spearmint, peppermint, wintergreen, satsafras, clove, sage, eucalyptus, majorana, cinnamon, lemon, orange, menthol, eugenol, cineole, methyl salicylate. Suitable sweeteners include sucrose, fructose, lytose, maltose, sorbitol, xylitol, sodium silamate, perillartine, APM (aspartyl phenylalanine methyl ester), saccharin, and the like. Suitably, the flavoring agents and sweeteners account for about 0.01 to 5% or more of the agent. In preparing the oral formulations of the present invention, it is preferred, but not essential, that the anti-calculus agent be added after mixing or contacting the other ingredients to avoid the tendency of the agent to settle. Like conventional products, the oral preparations of the present invention are distributed in the form of packages with appropriate labels attached. For example, mouthrinds are packaged in jars with labels that state that the contents are a mouthrinse or mouthwash and have instructions for use, and toothpastes are usually packaged in jars that say that the contents are a toothpaste or dental cream. in a collapsible tube (typically made of aluminum, lined lead or plastic) or other squeeze-type dispensing device for dispensing the contents, having a label as described. In the practice of the present invention, the oral composition of the present invention, such as a mouth rinse or toothpaste, containing an effective amount of the anti-calculus agent to inhibit tartar on the tooth surface is applied to the oral cavity, particularly tooth enamel, preferably once a day. Apply ~3 times regularly. Example A Bis(o-carboxyphenyl) succinate 0.4 mol salicylic acid (55.2 g) 0.4 mol pyridine (31.2 ml) 0.2 mol succinyl chloride (31.0 g) Salicylic acid and pyridine were dissolved in 90 ml acetone. To the resulting clear solution was added 90 ml of succinyl chloride in acetone under stirring at a rate that maintained reflux of the acetone for 30 minutes. During this addition, the desired BOCS product began to separate and the mixture turned black-purple in color. The reaction slurry was stirred for 30 minutes after the addition of total succinyl chloride. 200 ml of water was then added, the acetone was evaporated from the slurry on a rotary evaporator at 35°C, and the desired BOCS product was collected on a suction filter, washed with water, and vacuum dried at 60°C. Yield: 66.5g (93%), mp: 177-177.5℃;
Neutralization equivalent: 179.9, Ken equivalent: 186.8 (Calculation of neutralization equivalent and Ken equivalent is based on (C ₁₈ H ₁₄ O ₈ ). The following examples are further illustrations of the present invention and are not intended to limit the present invention. In this specification, unless otherwise specified, amounts and proportions are by weight and temperatures are in degrees Celsius. Example 1 The following formulation is illustrative of the toothpaste of the present invention that is effective in inhibiting tartar. Parts by weight Propylene 42.0 Hydroxy Propyl cellulose 1.0 Polyethylene glycol 600 10.0 Sodium saccharin 0.2 TiO ₂ 0.4 IMP 28.0 Syloid 244 12.0 Sodium lauryl sulfate 1.5 Flavoring agent 1.0 BOCS 3.0 The following formulation is illustrative of the mouthwash of the present invention that is effective in inhibiting tartar. Example 2 3 4 Flavoring agent 0.22 0.22 0.22 Ethanol 15.0 15.0 15.0 Pluronic F108 3.0 3.0 3.0 Glycerin 10.0 10.0 10.0 Sodium saccharin 0.03 0.03 0.03 BOCS 0.05 0.50 1.0 Example 2 Add an equal amount of the BOCS used in recipe 5 to the following Even when a bisester compound was substituted, a formulation effective in inhibiting tartar was obtained. Example No. Bisester compound 5 Bis(2-carboxy-4-butoxyphenyl) oxalate 6 Bis(2-carboxy-4-glutarate) Propyl-6-chlorophenyl) 7 Bis(2-carboxy-4-methoxy-6-bromophenyl) adipate 8 Bis(2-carboxy-4-iodo-6-ethoxyphenyl) suberate 9 Bis(2-carboxy-piperate) 10 Bis(2-carboxy-5-methoxyphenyl) malonate 11 Bis(2-carboxy-6-butylphenyl) maleate 12 Bis(2-carboxyphenyl) itaconate 13 Bis(2-carboxyphenyl) muconate Example 14 In this experiment using 24 rats, the anti-inflammatory properties of water as a placebo and a 0.1% solution of BOCS in dimethyl sulfoxide (PH 7.10) as the test anti-calculus mouthwash were tested. Tartar formation effectiveness was evaluated for 30 days.
Osborne-Mendel rats were used. Day 21, 22
Strep-muta-nce in the oral cavity on the first day
Osborne of Actinomyces viscsous and tartar activity
- inoculated with excreta from Mendel rats;
Placebo and test mouth rinse were applied to the teeth of 12 rats in each group, twice a day from Monday to Friday, on a calculus-prone meal 580F supplemented with 0.2% P as Na ₂ PO ₄ . It was applied once a day on Saturday and Sunday for 30 days. Rats were weighed at the beginning and end of the experiment to ensure that they were otherwise normal. Finally, the tartar formation was evaluated in a routine manner and the following results were obtained.

[Table] Shows the average number of surfaces created.
The above results establish that topical application of 0.1% amount of BOCS is significantly effective (±99%) in reducing tartar formation. Although the invention has been described with reference to its preferred embodiments, variations and modifications thereof that are obvious to those skilled in the art are within the spirit and scope of the invention.

Claims (1)

[Scope of Claims] 1. A substantially anhydrous oral composition that is substantially free of tooth stain-inducing antibacterial and antibacterial plaque agents, an orally acceptable vehicle, and a small amount effective as an antibacterial stone. and one bis(o- _{carboxyphenyl} ) ester of a _C2-8 aliphatic dicarboxylic acid. 2. The composition according to claim 1, wherein the tartar agent is bis(o-carboxyphenyl) succinate. 3. The composition of claim 2, comprising about 0.01 to 10% by weight of said tartar agent. 4. The composition of claim 1 or 2, comprising about 0.05 to 5% by weight of the anti-calculus agent. 5 Contains a liquid vehicle, in an aqueous medium from about 3.5 to
Claim 1, which is a mouthwash having a pH of 8.
Or the composition according to item 2. 6. The composition of claim 1 or 2, which is a toothpaste comprising a liquid vehicle, a gelling agent, a dentally acceptable abrasive, and having a pH of about 3.5 to 8 in an aqueous medium.