JPH02323B2 - - Google Patents

Description

[Detailed description of the invention]

(Industrial Field of Application) The present invention relates to antibacterial oral compositions that enhance oral hygiene. BACKGROUND OF THE INVENTION Cationic antibacterial substances are well known in the art. For example, in the Encyclopedia of Chemical Technology edited by Kirk-Othmer, in the entry “Antisepties and Disinfectants”, “Quaternary Ammonium and Related
Section on "Compounds" (Vol. 2, 632-635)
Please refer to page. Cationic substances with antibacterial activity (ie, bactericides) have been used against bacteria and in oral compositions to prevent the formation of moss by bacteria in the oral cavity. The most common of these antibacterial and antibacterial moss quaternary ammonium compounds is benzethonium chloride, also known as Hyomine 1622, or diisobutylphenoxyethoxyethyldimethylbenzylammonium chloride. In oral preparations, this substance is highly effective in enhancing oral hygiene by reducing the formation of fungal moss and tartar, and caries formation and periodontal disease are generally reduced at the same time. In addition to this type, cationic antibacterial agents are available, for example, in U.S. Patent No. 2984639.
3325402, 3431208 and 3703583, and British Patent No. 1319396. Other antibacterial and antibacterial moss quaternary ammonium compounds are
One or two of the substituents attached to the quaternary nitrogen have a carbon chain (typically an alkyl group) having about 8 to 20, typically 10 to 18 carbon atoms; If the substituent has fewer carbon atoms (typically an alkyl or benzyl group), e.g.
It has 7 carbon atoms, typically a methyl or ethyl group. Dodecyltrimethylammonium bromide, benzyldimethylstearylammonium chloride, cetylpyridinium chloride and quaternized 5-amino-1,3-bis(2
-ethylhexyl)-5-methylhexahydro-
Pyrimidine is a typical quaternary ammonium antimicrobial agent. Other types of cationic antimicrobial agents that are desirable to include in oral compositions to promote oral health by reducing moss formation are amidines such as substituted guanidines, such as chlorhexidine and its corresponding compound alexidine. (having a 2-ethylhexyl group instead of a chlorophenyl group), and
German patent application published on January 10, 1974
Other bis-biguanides as described in P2332383. In the specification, it is shown by the following formula. The compound represented by the following formula is used as a pharmaceutically suitable acid. (In the formula, A and A' are (1) a phenyl group (which can have up to 2 alkyl or alkoxy groups having 1 to about 4 carbon atoms, a nitro group, or a halogen atom as a substituent); (2) an alkyl group having 1 to about 12 carbon atoms, or (3) an alicyclic group having 4 to about 12 carbon atoms; X and X' are C _1-3 alkylene groups; Z
and Z' are 0 or 1; R and R' are either a hydrogen atom, an alkyl group having 1 to about 12 carbon atoms, or an aralkyl group having 7 to about 12 carbon atoms; n is 2
~12; the polyethylene chain (CH _{2 )} may be interrupted by up to 5 ether, thioether, phenyl or naphthyl groups) Another substituted guanidine is N′-(4-chlorobenzyl)- N ⁵ -(2,4-dichlorobenzyl)biguanide; p-chlorobenzylbiguanide; 4-
Chlorbenzhydrylguanylurea; N-3-lauroxypropyl-N ⁵ -p-chlorobenzyl biguanide; 5,6-dichloro-2-guanidobenzimidazole; N-p-chlorphenyl-N ⁵
-Lauryl biguanide. The antibacterial/antibacterial moss compound has a phenol coefficient against Staphylococcus aureus well above 50, more preferably above 100, for example about 200.
Preferably, those with antibacterial activity such that the phenolic coefficient (AOAC) of benbetonium chloride is
410 as indicated by the manufacturer. Cationic antimicrobial agents are generally monomeric (and possibly dimeric) substances with a molecular weight of much less than 2000, such as less than about 1000. However, it is also within the scope of this invention to use polymeric cationic antimicrobial agents. The cationic antimicrobial agent is present in its orally acceptable salt forms, such as chloride, bromide, sulfate, alkyl sulfonates (e.g. methylsulfonate and ethylsulfonate), phenylsulfonates (e.g. p-methylphenylsulfonate), nitrate. , acetate, gluconate, etc. Cationic antibacterial agents effectively enhance oral hygiene, especially by removing dental plaque. However, due to its use, stains or discolorations have been observed on the tooth surface other than those caused by normal contact of the tooth surface with food, drinks, tobacco, etc. The reason why such tooth stains form in the presence of antibacterial and antibacterial moss agents is not entirely clear. The enamel of human teeth is usually covered with a protein film (derived from salivary proteins), and a fungal moss layer may exist on the surface of this film. The enamel is
Contains a high proportion (approximately ⁹⁵ %) of hydroxyapatite containing Ca ⁺⁺ and _PO4-3 ions. In the absence of dental moss, additional Ca ⁺⁺ and PO ₄ ^-3 (particularly from saliva) can be deposited on the dental membrane over the enamel, and such deposits eventually become hardened deposits. They may contain color bodies that stain teeth. A cationic antibacterial agent denatures proteins derived from saliva in the oral environment when removing dental plaque, and this denatured protein becomes a nucleating agent in which Ca ⁺⁺ ions and PO ₄ ^-3 ions are deposited. It is possible that hydroxyapatite acts as hydroxyapatite and then crystallizes as hydroxyapatite. The small hydroxyapatite crystals provide a large surface area on which tooth stains or discolorations are retained. Additives conventionally used to reduce tooth staining with cationic antibacterial and antibacterial lichen agents also generally measurably reduce the activity of the antibacterial agents, ie, their ability to act against tooth lichens. Victamide (Victamine C), a condensation product of ammonia and phosphorus pentoxide, actually increases staining even in the absence of cationic antibacterial/antibacterial moss agents, and it also has the effect of increasing staining, as well as dizodium-ethane-1-1. Other known phosphorus-containing agents such as hydroxy-1,1-diphosphonic acid (EHDP) precipitate in the presence of antimicrobial agents such as bisbiguanide compounds, thus reducing the antimicrobial efficacy of antimicrobial agents. Lower it. (Problems to be Solved by the Invention) One advantage of the present invention is that the antibacterial agent prevents stains on tooth enamel caused by the use of a cationic antibacterial agent without substantially impairing the antibacterial and antibacterial moss activity of the agent. The point is to provide a nuclear additive. Other advantages will be apparent in view of the disclosure below. (Means for Solving the Problems) In its specific embodiments, the present invention provides an oral vehicle; a cationic antibacterial/antibacterial moss agent; and (A) formula: (In the formula, R′ is a C ₁ to C ₂₀ alkyl group, and R″ is
It is _a C1- _C6 alkylene group, and M is an orally acceptable cation. ) A water-soluble quaternary aminoalkylene phosphonic compound represented by the formula (B): (wherein R' is independently H, a C _1-6 alkyl group or a C _2-6 hydroxyalkyl group; X is an orally acceptable cation) Compound; (C) Formula: (wherein A' is -CH ₂ CH ₂ OH, -CH ₂ COOX or CH ₂ PO ₃ X ₂ ; A'' is -CH ₂ CH ₂ OH or -
CH ₂ COOX; A' is the same as A'' when A' is not -CH ₂ PO ₃ X ₂ ; X is an orally acceptable cation) (D) Phosphonoacetic acid (PAA) represented by the formula: H ₂ O ₃ P—CH ₂ —COOH or an orally acceptable salt thereof; and (E) the formula: (In the formula, R ¹ is H or a C _1-4 alkyl group;
R ² is - PO ₃ H ₂ ,

[Formula] or

[Formula]) Preferably the formula: (In the formula, R ² is −PO ₃ H ₂ or

Formed by the nitrogen-containing antibacterial/anti-algesic agent selected from the group consisting of a water-soluble phosphone-containing compound represented by [formula], a mixture thereof, or an orally acceptable salt thereof; The present invention relates to an oral composition comprising: a drug that eliminates the mechanism of Typical orally acceptable cations include H ₁ metals (e.g., Na and K), ammonium, C _1-18 mono-, di-, and tri-substituted ammoniums (e.g., mono-, di-, and tri-ethanolammonium). alkanol substituted product). Among the (A) group compounds, preferred are those in which n is 3;
R′ is a C _1-6 lower alkyl group, more preferably C _1-4
a lower alkyl group, most preferably a methyl group;
R″ is a methylene group. Such compounds have the formula: It is indicated by. In the above formulas, the cation M is, for example, H, an alkali metal (e.g. Na, K, Li), ammonium, or a C _1-18 mono-, di-, tri-substituted ammonium (e.g. mono-, di-, tri-ethanol). Substituted ammonium, such as alkanol substituted ammonium (alkanol substituted with ammonium). Examples of usable phosphonocarboxylic acids represented by the above formula (E) include (a) 1-phosphonoethane-1,2-dicarboxylic acid; (b) 2-phosphonopropane-2,3-dicarboxylic acid; ( c) 2-phosphonobutane-2,3-dicarboxylic acid; (d) 1-phosphonopropane-1,2-dicarboxylic acid; (e) 1-phosphonopropane-1,2,3-tricarboxylic acid; (f) 1-phosphonobutane-2,3,4-tricarboxylic acid; (g) 2-phosphonobutane-2,3,4-tricarboxylic acid; (h) 1-phosphonobutane-1,2,3-tricarboxylic acid; (i) 2- Phosphonopentane-2,3,4-tricarboxylic acid; (j) 1,1-diphosphonopropane-2,3-dicarboxylic acid; (k) 1,1-diphosphonobutane-2,3-dicarboxylic acid; (l ) 2,2-diphosphonobutane-3,4-dicarboxylic acid; (m) 1,1-diphosphono-2-methylpropane-2,3-dicarboxylic acid; Compounds (a) and (j) are preferred. Antibacterial agents that are cationic disinfectants that can be used in the practice of the present invention are as described above.
They are typically used in amounts such that the oral product will contain about 0.001-15% by weight. Approximately 0.01 in the final oral product to obtain the desired anti-alcohol effect.
~5% by weight of the agent, most preferably about 0.25-1% by weight. These amounts are the free base amount of the agent. Staining, which generally occurs on tooth enamel surfaces, is unexpectedly prevented when quaternary aminoalkylene phosphonic acids or water-soluble salts thereof are used. These substances are anti-nucleating agents. They are effective in reducing tartar formation without excessively removing calcareous material from enamel even in the absence of cationic anti-milk antimicrobial agents. However, not all anti-nucleating agents are effective in preventing stains caused by cationic antibacterial agents while retaining their anti-alcohol activity. U.S. Pat. No. 3,934,002 discloses the combination of the bis-biguanide anti-tartar agent with various anti-tartar agents (some of which contain phosphono groups), but it is compatible with phosphono-containing additives. Nothing that does is used. The most preferred group (A) additive is N-methylaminotri(methylenephosphonic acid) (hereinafter referred to as QMATMP).
) and its water-soluble salts (for example, Na, K, and ammonium salts). Other preferred compounds are N
-ethylaminotri(methylenephosphonic acid), N
-n-propylaminotri(methylenephosphonic acid), N-methylaminotri(ethylenephosphonic acid), and water-soluble salts of these acids, such as Na,
K is an ammonium salt. Mixtures of the above may also be used in the practice of this invention. These quaternary aminoalkylene phosphonates can be prepared by any convenient method, such as the teachings of US Pat. No. 3,925,453. The most preferred group (B) phosphono compounds are pyrrolidone-5,5-diphosphonic acid and its water-soluble salts (eg, Na, K, ammonium salts). Other compounds include N-methylpyrrolidone-5,5-diphosphonic acid, N-ethylpyrrolidone-5,5-diphosphonic acid, N-isopropylpyrrolidone-5,5-diphosphonic acid, N-2-hydroxyethylpyrrolidone-5, 5-diphosphonic acid and water-soluble salts of these acids, such as Na, K, ammonium salts. Mixtures of the above diphosphonopyrrolidones can also be used in the practice of this invention. These phosphonopyrrolidone compounds can be prepared by any convenient method, for example according to the teachings of published German Application No. 2343147. The most preferred N-methylene phosphonic compounds of group (C) are iminodiacetic-N-methylene phosphonic acid (hereinafter referred to as IDANMPA) and its water-soluble salts (eg, Na, K, and ammonium salts). Other N-methylenephosphonate compounds include N-carboxymethyl-amino-dimethylenephosphonic acid; monoethanol-dimethylenephosphonic acid; diethanol-amino-methylenephosphonic acid; and water-soluble salts of these acids, such as Na, K , is an ammonium salt. Mixtures of the above may also be used in the practice of this invention. These N-methylenephosphonic acid compounds can be prepared by any expedient method, such as in British Patent No. 1394035.
It can be manufactured according to the teaching of the No. 2 invention. The phosphonocarboxylic acids of group (E) and their suitable salts used in the present invention may be prepared by any convenient method, for example according to the teachings of British Patent No. 1,394,172. Although the content of nitrogen-containing antibacterial and anti-alcohol agents in the oral composition for removing stains caused by such agents can vary widely,
Typically it is 0.01% by weight or more. There is no upper limit to the amount used, other than cost or incompatibility with the vehicle. Generally used at about 0.01-10% by weight. Reduce the amount of stain remover in oral compositions that may be accidentally digested during normal use.
That is, the mouthwash of the present invention contains less than 3% by weight of stain remover. 0.01 to 0.01 for dentifrice compositions, topical solutions, and prophylactic pastes (administered under the direction of a physician)
10% by weight, preferably 0.1 to 5% by weight of stain remover can be included. Most desirably, the removal agent is present in molar excess (based on free base) over the amount of antimicrobial/antimicrobial agent to best prevent stains caused by the antimicrobial/antimicrobial agent. In certain particularly preferred forms of the invention, the oral composition is substantially a liquid, such as a mouthwash or rinse. In such preparations, the vehicle is typically a water-alcohol mixture. Generally, the ratio of water to alcohol is from about 1:1 to about 20:1, preferably from 3:1 to 20:1, and most preferably about 17:3 by weight. The total amount of water-alcohol mixture in this type of preparation typically ranges from about 70 to 99.9% by weight. The pH of such liquid preparations is generally about
It is in the range of 4.5-9, typically about 5.5-8. Preferably, the PH is within the range of about 6-8.0. The composition of the present invention provides a pH of less than 5 without substantially removing calcareous material from tooth enamel.
It is noteworthy that it has now become possible to use these phosphono compounds. Such liquid oral preparations may also include surfactants and/or fluorinating compounds. In certain other desirable forms of the invention, the oral composition can be a substantially solid or paste, such as a toothpaste, a dental tablet, or a toothpaste or dental cream. The vehicle for such solid or pasty oral preparations includes an abrasive. Examples of abrasives are water-insoluble sodium metaphosphate, potassium metaphosphate, calcium phosphate, dihydrated calcium phosphate, anhydrous dicalcium phosphate, calcium pyrophosphate, magnesium orthophosphate, trimagnesium phosphate, calcium carbonate, alumina, hydrated alumina. , aluminum silicate, zircon silicate, silica, bentonite, and mixtures thereof. Preferred abrasives have a particle size of up to 5 microns, an average particle size of up to 1.1 microns, a maximum of
Crystalline silica, silica gel, complex amorphous alkali metal aluminosilicate, hydrated alumina (eg α-alumina trihydrate) with a surface area of 50000 cm ² /g. Alumina, specifically sold as C333 by Alcoa, has an alumina content of 64.9% by weight, a silica content of 0.008%, a ferric oxide content of 0.003%, and a water content of
0.37% (110℃), specific gravity 2.42, particle size, 100%
Particularly preferred are alpha-alumina trihydrates that are less than 50 microns, with 84% being less than 20 microns. When using a gel that is clear to the naked eye, Syloid72,
Colloidal silica abrasives and alkali metal aluminosilicate complexes, such as those sold under the trademark SYLOID, such as Syloid 74, or sold under the trademark SANTOCEL, such as Santocel 100, are particularly useful. This is because they have a refractive index close to that of gelling agent-liquid (including water and/or humectants) systems commonly used in tooth brushing. Many of the so-called "water-soluble" abrasives are anionic and also contain small amounts of soluble materials. For example, insoluble sodium metaphosphate is described in Jhorpe, “Dictionary of Applied Chemistry”, Vol.
4th Edition, pages 510-511, by any suitable method. Madrell's salt, Kurrol's salt
Another example of a suitable material is the form of insoluble sodium metaphosphate known as . Since these metaphosphates have low water solubility, they are generally called insoluble metaphosphates. It takes a small amount (usually 2 by weight)
~3%, at most 4%) soluble phosphate is present as an impurity. The amount of soluble phosphate material (which in the case of insoluble sodium metaphosphate is considered to include soluble sodium trimetaphosphate) can be reduced by washing with water if desired. Insoluble alkali metal metaphosphates are typically used in powder form with a particle size of at most 1% greater than 37 microns. Abrasives generally account for about 20-99% of the weight of the oral preparation
exists in an amount of Preferably, about 20
It is present in ~75% of the amount and in toothpaste in about 70-99% of the amount. In the production of toothpaste, it is sufficient to mechanically mix the various solid ingredients in appropriate quantities and particle sizes, for example by comminution. In paste oral preparations, the combination of the antibacterial/anti-algesic agent and the horseshonic compound should be compatible with the other ingredients of the preparation. Thus, in toothpastes, the liquid vehicle consists of water and a humectant and is present in an amount of about 10-90% by weight. Glycerin, sorbit, polyethylene glycols may also be present as humectants or binders. A particularly preferred liquid component is a mixture of water, glycerin and sorbitol. For clear gels where the refractive index is an important consideration, it is preferable to use about 3 to 30% by weight of water, about 0 to 80% by weight of glycerin, and about 20 to 80% by weight of sorbitol. gelling agents, such as natural or synthetic gums or gummy substances, typically ice cream;
sodium carboxymethylcellulose, methylcellulose, or hydroxyethylcellulose,
can be used. Other gelling agents that can be used are gum tragacanth, polyvinylpyrrolidone, and starch. They are normally present in toothpastes in amounts of up to 10% by weight, preferably from about 0.5 to
Present within 5%. Preferred gelling agents are methylcellulose and hydroxyethylcellulose. In toothpastes or gels, liquids and solids are balanced to form a creamy or gelled mass. This can be extruded from a pressurized container or from a coppable, eg aluminum or lead tube. Typically measured at 20% slurry from about 4.5 to
9, generally about 5.5 to 8, preferably about 6 to 8
Solid or pasty oral preparations with a PH of 8.0 may also include surfactants and/or fluorinating compounds. As usual, the oral preparations of the present invention are sold or otherwise supplied in appropriately labeled containers. For example, a jar containing mouthwash will have a label stating that the contents are a mouth rinse or rinse, and will also specify directions for use; toothpaste will usually have a collapsible tube (typical (alumina tube or lined lead tube) or other squeeze dispenser for dispensing the contents, with a label on the surface stating that the contents are toothpaste or dental cream. Surfactants are often present in oral compositions such as mouthwashes and toothpastes, for example to enhance foaming. It is preferable to use its nonionic counterpart rather than anionic surfactant. Examples of water-soluble nonionic surfactants are those that are reactive with ethylene oxide and have long hydrophobic chains (e.g. _C12-20 aliphatic chains).
The condensation products (“ethoxamers”) include, for example, ethylene oxide and fatty acids, fatty alcohols, and fatty amides (alcohols such as sorbitan monostearate). (i.e., Pluronic materials) or condensation products with polypropylene oxide (i.e., Pluronic materials). In certain embodiments of the invention, fluoridating compounds are present in the oral preparation. These compounds may be slightly or completely water soluble. They are characterized by the ability to release fluoride ions into water and by virtually no reaction 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, copper fluoride (e.g. cuprous fluoride), zinc fluoride, tin fluoride (e.g. stannic fluoride, stannous chlorofluoride), barium fluoride, sodium fluorosilicate , ammonium fluorosilicate, sodium fluorozirconate, sodium monofluorophosphate, aluminum mono-, di-fluorophosphate,
It is sodium calcium fluorine pyrophosphate.
Fluorides of alkali metals and tin, such as sodium fluoride and stannous fluoride, sodium monofluorophosphate and mixtures thereof, especially sodium fluoride and sodium monofluorophosphate, are preferred. The amount of fluorinating compound will depend in part on its type, its solubility, and the type of oral preparation, but should be a non-toxic amount. In solid oral preparations such as toothpastes and tooth powders, the amount of such compounds is considered satisfactory if it releases up to about 1% by weight of the preparation. Although any suitable minimum amount may be used, it is preferred to use an amount of the compound sufficient to release about 0.005 to 1%, preferably about 0.1%, of fluoride ions. Typically, in the case of the alkali metal fluoride, stannous fluoride, this component is present in a maximum of 2%, preferably in the range of 0.05 to 1% by weight of the preparation. In the case of sodium monofluorophosphate, this compound is
It can be present in amounts up to 7.6% by weight, more typically 0.76%. When present in admixture, the ratio of sodium monofluorophosphate to sodium fluoride is preferably from about 1:1 to 3:1, based on the fluorine provided by each. In liquid oral preparations such as mouthwashes, fluorine-providing compounds typically contain up to 0.13% by weight;
Preferably 0.0013-0.1%, most preferably 0.0013
Present in sufficient amounts to release ~0.05 fluoride ions. A variety of other substances can also be incorporated into the oral preparations of the present invention. Examples are brighteners, preservatives, silicones, chlorophyll compounds, urea, ammoniated substances such as diammonium phosphate, and mixtures thereof. When present, these adjuvants are incorporated into the preparation in amounts that do not substantially impair their properties and characteristics. Any suitable flavoring or sweetening agent may be used. Examples of suitable flavoring ingredients are perfume oils such as spearmint, peppermint, wintergreen, satsafras,
Oils of clove, sage, eucalyptus, marjoram, cinnamon, lemon and orange, and methyl salicylate. Suitable sweetening agents include sucrose, lactose, maltose, sorbitol, sodium cyclamate, perilartine, soluble saccharin, and the like. Flavoring and sweetening agents together account for 0.01 of the preparation.
Appropriately, it accounts for ~5% or more. In preparing intraoral compositions in an oral vehicle (typically containing water) according to the present invention, the phosphonoadditive is mixed with the other ingredients (perhaps except for some water), i.e., brought into contact with each other. It is highly desirable, although not an essential requirement, to avoid the tendency to form precipitates and the like. For example, mouth rinses or mouth rinses may contain ethanol and water, flavored oils, nonionic surfactants, humectants, cationic antibacterial and anti-alcoholic agents (e.g. benzethonium chloride, cetylpyridinium chloride or chlorhexidine), sweeteners and colorants. mixed with ingredients,
It can then be prepared by adding the stain remover compound and adding water if desired. Toothpastes use moisturizers, thickeners such as gums or hydroxyethylcellulose, and sweeteners to form a gel, along with abrasives, flavorings, and antibacterial agents (such as benzethonium chloride, cetylpyridinium chloride, or chlorhexidine). and additional water, followed by the addition of a stain remover. If sodium carboxymethyl cellulose is used as a gelling agent, the US patent
The process of either No. 3,842,168 or No. 3,843,779 is modified and followed by the inclusion of a quaternary aminoalkylene phosphonic compound. In the practice of this invention, an effective amount of cationic or long-chain amine antibacterial agents to enhance oral health may be used.
Oral compositions of the present invention, such as mouthwashes or toothpastes, comprising an anti-milk agent and an amount of a stain remover effective to reduce tooth surface stains caused by the presence of the anti-microbial and anti-milk agent. It is applied regularly to the tooth enamel, preferably from about 5 times a week to about 3 times a month, at a pH of about 4.5-9, generally about 5.5-8, preferably about 6-8. The following specific examples further illustrate the nature of the invention. It should be understood that the present invention is not limited thereto. The composition is manufactured in a conventional manner,
In addition, amounts and proportions are based on weight unless otherwise specified. Examples 1-3 Mouthwashes having the following compositions were manufactured and tested. Partly flavored alcohol 15 Pluronic F-108 (polyalkene oxide block polymer) 3 Glycerin 10 Benzethonium chloride (BC) 0.075 Soluble saccharin 0.03 QMATMP Preparation) All compositions were clear with no visible precipitates. QMATMP [N-methylaminotri(methylenephosphonic acid)] and about 10 parts of water were added to the other premixed ingredients. The in vitro stain properties of the compositions were tested in this and other examples as follows. Stain test 250mg of medium albumin (3 times crystallized)
In addition to 2 g of hydroxyapatite (HAP) powder (Biogel), which serves as a stain matrix, the protein becomes the apparent tooth membrane and also provides an "amine source". A mouthwash was added to the above mixture, followed by 7.5% buffered acetaldehyde, which served as the carbonyl source. The resulting mixture was shaken at 37°C for 18 hours. The stained HAP was separated from the solution by filtration and dried at 37°C. The color of the powder surface was red using a Gardner colorimeter. The color level was measured with a Gardner colorimeter before and after applying the test composition to the colored material. The following table shows the stain prevention results when the indicated amount (X) of QMATMP was used in the above mouthwash formulation.

The above results demonstrate that the quaternary aminoalkylene phosphonic acid compounds exemplified by QMATMP substantially and significantly reduced tooth stains commonly caused by BC. These tests
I adjusted the pH to about 7.0. PH before adjustment is approximately 4
It was ~4.8. Similar results were obtained by adjusting the formulation to a PH of approximately 5-8. Examples 4-7 QMATMP used in Examples 2 and 3 was replaced with equivalent amounts of the following phosphono-containing compounds to produce formulations that unexpectedly reduced tooth stains. Examples Quaternary aminoalkylene phosphonates 4 N-ethylaminotri(methylenephosphonic acid) 5 N-isobutylaminotri(methylenephosphonic acid) 6 N-ethylaminotri(ethylenephosphonic acid) 7 N-methylaminotri(butylenephosphonic acid) ) Examples 8-14 Replacing the BC used in Examples 2-7 with equivalent amounts of the following antibacterial and anti-alcohol agents produced formulations that unexpectedly reduced tooth stains. Example 8 Chlorhexidine diacetate 9 Chlorhexidine digluconate 0 Alexidine dihydrochloride 11 Dodecyltrimethylammonium bromide 12 Benzyldimethylstearylammonium chloride 13 Cetylpyridinium chloride The above exemplary formulation containing the indicated amount of a quaternary aminoalkylene phosphonic compound It is also noteworthy that the anti-algesic activity of the compounds is substantially equivalent to the corresponding formulations lacking such compounds. Examples 14 and 15 The following formulations are illustrative of toothpastes with anti-alcohol activity and low stain-forming power.

Table: Examples 16-22 Basic mouthwash formulations were prepared and tested as follows. Mouthwash formulation flavored alcohol 15 Pluronic F108 (polyalkene oxide block polymer) 3 Glycerin 10 Benzethonium chloride (BC) 0.075 Soluble saccharin 0.03 Pyrrolidone-5,5-diphosphonic acid (PYDP)
X Appropriate amount of water 100 PH7.0 (adjusted with 5N NaOH) Appearance, stability Clear PYDP and about 10 parts of water were added to the other ingredients previously mixed. The following table shows the in vitro anti-stain effect when the indicated amount (X) of PYDP is used in the above mouthwash formulation.

【table】

TABLE The above results demonstrate that the pyrrolidone diphosphonic acid additive of the present invention, exemplified by PYDP, substantially reduced tooth stains normally produced by BC. These tests were conducted by adjusting the pH of the formulation to approximately 7.0. PH before adjustment is approximately 3.5-4.6
It was. Formulations adjusted to a pH of about 5-8 showed similar results. Examples 23-29 PYDP used in Examples 17-22 was replaced with equivalent amounts of the following phosphono-containing compounds to produce formulations that unexpectedly reduced tooth stains. Example phosphono compound 23 N-methylpyrrolidone-5,5-diphosphonic acid 24 N-ethylpyrrolidone-5,5-diphosphonic acid 25 N-butylpyrrolidone-5,5-diphosphonic acid 26 N-(2-hydroxyethyl)pyrrolidone -5,5-diphosphonic acid 27 3-butylpyrrolidone-5,5-diphosphonic acid 28 3,4-tetramethylpyrrolidone-5,5
-Diphosphonic acid 29 4,4-diethylpyrrolidone-5,5-diphosphonic acid Examples 30-34 The BC used in Examples 17-29 was replaced with an equal amount of the following antibacterial/anti-algesic agent. A formulation has been produced that unexpectedly reduces age spots. Examples of antibacterial and anti-alcohol agents 30 Chlorhexidine diacetate 31 Chlorhexidine digluconate 32 Dodecyltrimethylammonium bromide 33 Cetylpyridinium chloride 34 Alexidine dihydrochloride Examples 35, 36 The following formulations have low anti-alcohol activity This is an example of a toothpaste with stain-forming properties.

Table: Examples 37-43 Mouthwash formulations were prepared and tested as follows. Perfumed alcohol 15 Pluronic F-108 (polyalkene oxide block polymer) 3 Glycerin 10 Benzethonium chloride (BC) 0.075 Soluble saccharin 0.03 IDANMPA It was clear with no visible precipitate. IDANMPA and approximately 10 parts water were added to the other previously mixed ingredients. The levels were measured in vitro using a Gardner colorimeter before and after applying the test composition to the colored substance. The following table shows the indicated amount (X)
This figure shows the anti-stain effect when IDANMPA is used in the above mouthwash formulation.

【table】

[Table] The above results demonstrate that the N-methylene phosphonate additive of the present invention exemplified by IDANMPA
It has been shown that the stains that normally occur on teeth are substantially reduced. These tests measure the PH approximately
I adjusted it to 7.0. The pH before adjustment was approximately 3.5 to 4.8. Formulations with a pH adjusted to about 5-8 showed similar results. Examples 44-46 IDANMPA used in Examples 38-43 was replaced with equivalent amounts of the following phosphono-containing compounds to produce formulations that unexpectedly reduced tooth stains. Example N-Methylenephosphonate 44 N-carboxymethylamino-di-methylenephosphonic acid 45 N-hydroxyethylamino-di-methylenephosphonic acid 46 N,N-dihydroxyethylaminomethylenephosphonic acid Examples 47-52 Examples 38- Replacing the BC used in 46 with equal amounts of the following antibacterial and anti-moist agents produced a formulation that unexpectedly reduced tooth stains. Examples Antibacterial and anti-alcohol agents 47 Chlorhexidine diacetate 48 Chlorhexidine digluconate 49 Alxidine dihydrochloride 50 Dodecyltrimethylammonium bromide 51 Benzyldimethylstearylammonium chloride 52 Cetylpyridinium chloride Add the indicated amount of phosphono-containing additive compound. It is also noteworthy that the anti-algesemic activity of the above-mentioned exemplary formulations was substantially equivalent to the corresponding formulations lacking such compounds. Example 53, 54

Table: Examples 55-61 The following mouthwash formulations were prepared and tested. Mouthwash formulation fragrance alcohol 15 Pluronic F108 (polyalkene oxide block polymer) 13 Glycerin 10 Benzethonium chloride (BC) 0.075 Soluble saccharin 0.03 Phosphonoacetic acid (PAA) Appearance, Stability Clear PAA and approximately 10 parts water were added to the other ingredients that had been premixed. The following table shows the in vitro anti-stain effect when the indicated amount (X) of PAA is used in the above mouthwash formulation.

【table】

[Table] The above results show that PAA at all amounts (X)
It has been shown that tooth stains commonly caused by BC were substantially and significantly reduced. These tests were performed with the PH adjusted to approximately 7.0, and the PH before adjustment was
It was about 3.5 to 4.6. Formulations adjusted to a pH of about 5-8 showed similar results. Examples 62-67 Replacing the BC used in Examples 56-61 with equivalent amounts of the following antibacterial and anti-alcohol agents produced formulations in which tooth stains were unexpectedly reduced. Examples Antibacterial/anti-alcohol agents 62 Chlorhexidine diacetate 63 Chlorhexidine digluconate 64 Alexidine dihydrochloride 65 Dodecyltrimethylammonium bromide 66 Benzyldimethylstearylammonium chloride 67 Cetylpyridinium chloride Antibiotics of the above exemplary formulations containing PAA Tooth moss activity is
It should also be noted that it was virtually equivalent to the corresponding formulation lacking PAA. The following formulation is illustrative of a toothpaste with anti-alcohol activity and low stain-forming power.

Table: Examples 70-95 Basic mouthwash formulations were prepared and tested as follows. 70 Mouthwash formulation Flavored alcohol 15 Pluronic F108 (polyalkene oxide block polymer) 3 Glycerin 10 Benzethonium chloride (BC) 0.075 Soluble saccharin 0.03 Phosphono-containing compound , Stability The phosphono-containing compound and about 10 parts of water were added to the other previously mixed ingredients. The following table shows the in.
Shows anti-stain effect in vitro.

The above results demonstrate that the phosphonoalkane polycarboxylic acid additives of the present invention, exemplified by DPPD and PEDA, substantially reduced tooth stains commonly caused by BC. These tests are performed by adjusting the PH of the formulation to approximately 7.0, and the PH before adjustment is
was about 3.5 to 5.0. Formulations with a pH adjusted to about 5-8 showed similar results. Substituting equivalent amounts of the following phosphono-containing compounds for those used in Examples 71-84 produced formulations in which tooth stains were unexpectedly reduced. Example phosphono-containing compound 85 2-phosphonopropane-2,3-dicarboxylic acid 86 2-phosphonobutane-2,3-dicarboxylic acid 87 1,1-diphosphonobutane-2,2-dicarboxylic acid 88 1-phosphonopropane-1 , 2,3-tricarboxylic acid 89 2-phosphonobutane-2,3,4-tricarboxylic acid Replacing the BC used in Examples 71 to 89 with an equal amount of the following antibacterial/anti-algesic agent, produced a formulation in which the EXAMPLE Antibacterial/anti-algesic agents 90 Chlorbexidine diacetate 91 Chlorhexidine digluconate 92 Dodecyltrimethylammonium bromide 93 Cetylpyridinium chloride 94 Alxidine dihydrochloride In vitro of the above exemplary formulations containing the indicated phosphono-containing additive compounds It is also noteworthy that the anti-alcohol activity was substantially equivalent to the corresponding formulations lacking such compounds. Example 95 In vivo test of anti-mosses and anti-stain activity was carried out at 0.075
The mouthwash formulation of Example 6 containing 1 part BC and 0.5 part DPPD, the control formulation of Example 1 containing 0.075 parts BC and no DPPD, and the placebo lacking along with BC and DPPD were used to test Peagle dogs. I went there. The peagle dogs were first subjected to caries prophylaxis to remove any soft and hard plaque present. disclosing solution
solution) was used to complete the removal. Application was carried out by gentle spraying twice a day, 5 days a week for 6 weeks. The stains were evaluated relative to each other by visual observation of the oral cavity. Tooth moss formation was measured after spraying the exposure solution on the teeth. The results were as follows.

[Table] From the above results, it is clear that the phosphono-containing additive compound of the present invention, exemplified by DPPD,
It is clear that the antibacterial/anti-algesic agent exemplified by the authors significantly and substantially (by 42.3%) reduced tooth stains caused by the antibacterial/anti-alcohol agent, and that it caused fewer stains than the actual placebo. These results also indicate that such additive compounds do not impair the anti-alges activity of the stain-producing anti-microbial/anti-alges agent. Examples 96, 97 The following formulations are illustrative of toothpastes with anti-alcohol activity and low stain-forming power.

[Table] Although the present invention has been described above with respect to its preferred embodiments, it will be understood that changes and modifications obvious to those skilled in the art are within the scope of the present invention.

Claims (1)

[Scope of Claims] 1. An oral composition comprising: an oral vehicle; at least one nitrogen-containing antibacterial/antibacterial moss agent selected from cationic antibacterial/antibacterial moss agents; and the nitrogen-containing antibacterial/antibacterial moss agent. Excluding the stain formed, (A) formula: (wherein R' is a _C1 - _C20 alkyl group, R'' is a _C1 - _C6 alkylene group, and M is an orally acceptable cation.) Aminoalkylenephosphonic compound, (B) formula: (wherein R' is independently H, a _C1 - _C6 alkyl group or a _C2 - _C6 hydroxyalkyl group,
X is an orally acceptable cation. ) A water-soluble diphosphonopyrrolidone compound represented by (C) formula: (where A′ is —CH ₂ CH ₂ OH, —CH ₂ COOX or —CH ₂ PO ₃ X ₂ , A″ is —CH ₂ CH ₂ OH or —CH ₂ COOX, and A′ is A 'but-
CH ₂ PO ₃ When not X ₂ , it is the same as A″, and X
is a cation that is acceptable in the oral cavity. ); (D) a phosphonoacetic acid (PAA) or an orally acceptable salt thereof; and (E ₎ a phosphonoacetic acid ( _PAA ) or an orally acceptable salt thereof _; : (In the formula, R ₁ is H or a C ₁ to C ₄ alkyl group, and R ² is -PO ₃ H ₂ , [Formula] or [Formula].) or an orally acceptable salt thereof; 2. The antibacterial/antibacterial moss agent is substituted guanidine;
The oral composition according to claim 1. 3. The oral composition according to claim 2, wherein the antibacterial/antibacterial moss agent is a pharmaceutically acceptable water-soluble salt of a drug selected from the group consisting of chlorhexidine and alexidine. 4. The oral composition according to claim 3, wherein the antibacterial/antibacterial moss agent is a pharmaceutically acceptable water-soluble salt of chlorhexidine. 5. The oral composition according to claim 1, wherein the antibacterial/antibacterial moss agent is benzethonium chloride. 6. The oral composition according to claim 1, wherein the antibacterial/antibacterial moss agent is a quaternary ammonium compound having 8 to 20 carbon atoms and 1 to 2 alkyl groups. 7. The oral composition according to claim 6, wherein the antibacterial/antibacterial moss agent is cetylpyridinium chloride. 8. The oral composition of any of claims 1 to 7, wherein the vehicle is a hydroalcohol and the composition is a mouthwash having a PH of about 4.5 to 9.0. 9. Claim 1, wherein the vehicle comprises a liquid vehicle and a gelling agent, a dentally acceptable abrasive is present, and the composition is a toothpaste having a pH of about 4.5 to 9.0. 9. The oral composition according to any one of items 8 to 8.