KR840001946B1 - Non-staining antigin gi-vits composition - Google Patents

Abstract

The discoloration of dental surfaces by tranexamic acid [Trans-4- (aminomethyl)cyclohexane-1-carboxylic acid (I) in antigingivitis compounds was prevented or prohibited by incorporating K4P2O8(corresponding compds: K3P2O8, Li4P2O8, KNa3P2O8, KNaH2P2O8, Zn2P2O8, CaH2P2O8) in the original compound. Thus, an aq. soln. of 1% I and 2% K4P2O8 prevented any coloration of dental surfaces . Dentifrices containing 1% I and 3% K4P2O8 were also prepared. K4 P2O8 had no effect on the antigingivitis activity of I.

Description

Non-pigmented antigingival salt composition

The present invention relates to oral compositions that enhance oral hygiene, and more particularly to such compositions for treating, controlling and / or inhibiting gingivitis.

To control plugs, tartar, stones, caries, tooth decay and gingivitis in the oral cavity, many substances have already been proposed and used, but none have been completely satisfactory. For example, some of these materials have been shown to be unstable in the presence of nonionic surfactants commonly present in conventional oral formulations. A large number of substances, such as cationic quaternary ammonium drugs, unpleasantly exert antibacterial functions that tend to disrupt or destroy normal food groups in the oral and / or digestive systems.

Trans-4- (aminomethyl) -cyclohexane-1-carboxylic acid (hereinafter referred to as transexamic acid or TA) of the following structural formula has been known as a very effective agent for controlling, inhibiting or preventing gingivitis (Japan See Patent Publication No. 39818/74)

This compound is non-antibacterial and differs from antibacterial agents, in particular inhibiting inflammation, bleeding and / or swelling of the gums. TA is a white crystalline powder with a decomposition temperature of about 380-390 ° C. It has a unique infrared absorption band at 1637,1535 and 1383 cm ⁻¹ .

It is very well soluble in water, slightly soluble in heated ethanol and practically insoluble in most organic solvents. Its synthesis or isolation from its cis-trans mixture is described in US Pat. No. 3,499,925.

Although TA is known to have a very desirable inhibitory function against gingivitis, etc., it is known to seriously reduce the wider use of such a function as it can stain or discolor the tooth surface when used orally.

It is therefore an object of the present invention to provide a TA-containing oral composition which does not color or discolor the tooth surface relatively little or not at all and a method for producing the same. Other objects and advantages will emerge as the description is given.

Including a phosphate salt of peroxy, particularly tetrapotassium peroxydiphosphate, in a TA-containing oral composition prevents pigmentation or discoloration of the tooth surface normally caused by TA without substantial or significant reduction of antigingival salt and other desired effects of TA. The object can be attained by the present invention based on my finding of preventing or inhibiting.

According to this aspect, the present invention provides an effective color-inhibiting amount of peroxydiphosphate salt, preferably as an oral (oral) medium, a transexamic acid (or a salt thereof) for coloring teeth, and an anti-coloring additive. Relates to an oral composition consisting of tetrapotassium peroxydiphosphate (K ₄ P ₂ O ₈ ).

Many peracid compounds are known to be effective in preventing or removing pigmentation of teeth. Peroxymonosulfate (oxone) is effective in reducing the intensity of orthodontic pigmentation.

U.S. Patent NO. In 3,988,433 it is known to prevent or eliminate the coloring by non-microbial antibacterial agents using organic peroxides. However, these substances mentioned above are not preferable for use in the oral cavity because they release free radicals which are unstable in the aqueous system and susceptible to soft tissues in the oral cavity too quickly.

U.S. Patent NO. 4,041,149 is known and claimed the use of such peroxydiphosphate salts, themselves, to control and prevent bad breath. These salts, which do not exhibit significant antibacterial activity, are themselves seldom to form peroxymonophosphate anions, which are rarely stable in water-soluble media and are slowly hydrolyzed to hydrogen peroxide and orthophosphate at a rate directly proportional to the phosphatase concentration. It is desired to add the phosphatase enzyme found in the bar. As such, extremely low phosphatase concentrations may result in continuous production of hydrogen peroxide and orthophosphate over extended periods of time, for example over several months.

Moreover, peroxydiphosphate is persistent with respect to the oral surface and provides long-term effects by binding to or reacting with the enamel surface of the tooth, ie Ca ⁺⁺ ions of the enamel. Since peroxydiphosphate favors H ₂ O ₂ at a low rate, there is no initial bursting effect of the permissible dark haired H ₂ O ₂ . At the average concentration of peroxydiphosphate compound and hydrogen peroxide, the amount of useful oxygen is one tenth of hydrogen peroxide. Thus, as known and claimed herein, it is surprising that such peroxydiphosphates are rarely effective anti-coloring additives. Alkali metal peroxydiphosphates or their corresponding acid salts which are water soluble up to about 0.01 weight fraction may be used in the compositions of the present invention. Examples include potassium peroxydiphosphate (K ₃ P ₂ O ₈ ), lithium peroxydiphosphate (Li ₄ P ₂ O ₈ ), sodium peroxydiphosphate (Na ₄ P ₂ O ₈ ), tripotassium monosodium peroxydiphosphate ( K ₃ NaP ₂ O ₈ ), dipotassium disodium peroxydiphosphate (K ₂ Na ₂ P ₂ O ₈ 2H ₂ O), monopotassium trisodium peroxydiphosphate (KNa ₃ P ₂ O ₈ ), monopotassium monosodium di Hydrogen peroxydiphosphate ((KNaH ₂ P ₂ O ₈ ), trilithium monopotassium peroxydiphosphate (Li ₃ KP ₂ O ₈ ), dilithium dipotassium peroxydiphosphate (Li ₂ K ₂ P ₂ O ₈ ), mono Lithium tripotassium peroxydiphosphate (Li ₂ Na ₂ P ₂ O ₈ ), trilithium monosodium peroxydiphosphate (Li ₃ NP ₂ O ₃ ), dilithium disodium peroxydiphosphate (Li ₂ NaP ₂ O ₃ ), mono lithium tri-sodium phosphate peroxydicarbonate _{(LiNa 3 P 2 O 3)} , mono Lyrium monosodium dihydrogen peroxy depot space (LiNaH ₂ P ₂ O ₃₎ and mono lithium mono potassium dihydrogen peroxydicarbonate phosphate _{(LiKH 3 P 2 O 8)} , dia open peroxydicarbonate phosphate _{(Zn 2 P 2 O 8)} , tetra ammonium peroxydisulfate phosphate dihydrate ( (NH ₄ ) ₄ P ₂ O ₈ 2H ₂ O) and also include acid salts of bimetallic groups such as barium dihydrogen peroxyphosphate (BaH ₂ P ₂ O ₈ ), calcium dihydrogen peroxyphosphate (CaH ₂ P ₂ O ₈ ) and the like.

-61℃에서 47-51% 수용성이나 보통용매 즉 아세토니트릴, 알코올류, 에테르류, 케톤류, 디메틸포름아미드, 디메틸설폭시드 등에서는 불용성이다. 2%수용액은 약 9.6의 pH를 가지고 그의 포화용액은 약 10.9의 pH를 갖는다. 25℃에서의 10% 수용액은 4달후에 활성산소손실이 없었고, 50℃에서의 10% 용액은 6달 후에 3%의 활성산소손실을 보여주었다. 이런 안정도는 상기퍼옥시디포스페이트 화합물을 함유하는 구강조성물들의 장기 저장수명을 가능하게 한다.Preferred tetrapotassium peroxydiphosphate is a stable, odorless, finely divided and free flowing white non-absorbing crystalline solid with a molecular weight of 346.35 and containing 4.5% of active oxygen. Potassium peroxydiphosphate is 0

It is 47-51% water soluble at -61 ° C but insoluble in common solvents such as acetonitrile, alcohols, ethers, ketones, dimethylformamide, dimethyl sulfoxide and the like. The 2% aqueous solution has a pH of about 9.6 and its saturated solution has a pH of about 10.9. The 10% aqueous solution at 25 ° C. showed no free radical loss after 4 months, and the 10% solution at 50 ° C. showed 3% free oxygen loss after 6 months. This stability enables long term shelf life of oral compositions containing the peroxydiphosphate compounds.

The concentration of such additives in the oral composition can vary widely and is typically up to about 0.01% (weight ratios) but there is no upper limit unless it is in conflict with the cost or agent. The effective and / or optimal coloring-inhibition amount of such additives in all examples is readily determined by constant experimentation. Typically, a concentration ratio of about 0.01% to about 10%, preferably about 0.1% to about 6%, more preferably about 0.3% to about 3.0% is used. Oral compositions in common use can preferably be inadvertently ingested when they contain low concentrations of such additives. As such, the fern according to the invention preferably contains up to about 3% by weight of an additive, preferably about 0.5 to about 2.5% by weight. The toothpaste compositions, the solution in question and the propyllatic paste (the latter being taken professionally) preferably contain 1.0 to about 6% by weight of the additive. In order to minimize coloring and to suppress or prevent coloring, it is most preferable that an additive exists more than equivalent in comparison with the quantity of TA anti silver salt salt.

TA agents can be used in the free acid form or in the form of oral salts thereof and are water soluble, i.e., alkali metals (eg Na or K), ammonium, or C ₁ -C ₁₈ mono-, di- or tri-substituted Ammonium (eg mono-, di-, or tri-ethanol ammonium) cations are preferred. Typically, TA pharmaceutical agents in a weight ratio of about 0.001- about 10.0%, preferably about 0.01- about 5.0%, more preferably about 0.03- about 3.0% are used in the oral composition of the present invention.

In a very preferred form of the present invention, the hard structure may be substantially liquid, such as a toothbrush or rinse. The media in such formulations are typically water alcohol mixtures. Generally, the ratio of water to alcohol is a weight ratio of about 1: 1 to about 20: 1, preferably 3: 1-20: 1, most preferably about 17: 3. The total amount of water-alcohol mixture in this type of formulation is typically from about 70-about 69.9% by weight of the formulation. The pH of such liquids and other formulations of the invention is generally in the range of about 4.5 about 9 and typically about 5.5-8. The pH is preferably in the range of about 6 to about 8.0. It is noteworthy that the compositions of the present invention can be applied orally at pH 5 or less without actually demineralizing tooth enamel.

Such liquid oral compositions may contain surfactants and / or fluorine providing compounds.

In another preferred form of the invention, the hard structure may be substantially a solid or a paste, ie a dental powder, a dental tablet, a dental paste or a dental cream. The medium of such solid or paste-type oral preparations contains a glossy substance. Examples of such polishes include sodium metaphosphate, potassium metaphosphate, tricalcium phosphate, calcium pyrophosphate, magnesium orthophosphate, trimagnesium phosphate, calcium carbonate, alumina, hydrated alumina, aluminum silicate, zirconium silicate, Silica, bentonite, and compounds thereof. Preferred gloss materials include particle sizes up to 5 microns, average particle sizes up to 1.1 microns and surface areas up to 50,000 cm 2 / gm crystalline silica, silica gel amorphous alkali metals, aluminosilicate complexes, hydrated alumina, di Calcium phosphate is included.

Alumina, especially hydrated alumina sold as Alcoa C333 (Alcoa), which contains 64.9% by weight of alumina, 0.008% silica, 0.003% iron oxide and 0.37% wetting at 110 ° C. with a specific gravity of 2.42 and 100% of the particles. Particular preference is given to such hydrated alumina having up to 50 microns and 84% of particles up to 20 microns.

When using visually clear gels, colloidal silica polishes are particularly useful, i.e., siloids 72 and siloids 74 branded siloids or santocel 100 branded santocel and alkali metal aluminosilicate complexes, because they are toothpaste. This is because it has a refractive index close to that of the gel-liquid (including water and / or humectant) systems normally used in the process.

Many of the so-called "insoluble" gloss have anionic properties and also contain small amounts of solubles. As such, insoluble sodium metaphosphate may be formed by any suitable method, as described in Torff Dictionary of Applied Chemistry, Vol. 9, 4th Edition, 510-511p. The form of insoluble sodium metaphosphate, known as the Madrel and Kurol salts, is another example of a suitable substance. These metaphosphate salts are usually called insoluble metaphosphates because they exhibit fine solubility in water. A small amount of soluble phosphate material therein is present as an impurity, usually as little as 4% by weight. The amount of soluble phosphate material, which is believed to include soluble sodium trimetaphosphate in the case of insoluble metaphosphate, can be reduced by washing with water, if desired. Insoluble alkali metal metaphosphate is typically used in the form of a powder having a particle size of only about 1% greater than 37 microns.

Gloss materials are generally present in the range of about 10- about 99% by weight of the oral formulation. Preferably from about 10 to about 75% in toothpaste and from about 70 to about 99% in dental powder. In dental powder preparations, it is usually sufficient to mechanically, for example, grind and mix various solid components in suitable amounts and particle sizes.

In pasty oral formulations, the combinations defined above for the antigingiva salt agent and additives must be compatible with the other ingredients of the formulation. As such, in dental pastes, the liquid medium may typically contain about 10 to about 90 weight percent of the formulation and water and humectant. Glycerin, sorbitol, or polyethylene glycol may be present as wetting or binder. Particularly advantageous liquid components are polyethylene glycol and polypropylene glycol. Also useful are liquid mixtures of water, glycerin and sorbitol. For clear gels where refractive index is a major concern, about 3-30% by weight of water, 0-about 80% by weight of glycerin, and about 20-80% by weight of sorbitol are preferably used.

Gelling agents, ie natural or synthetic gums or similar gum materials, typically irisimos, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose. Gum tragacanth, polyvinylpyrrolidone, starch and preferably hydroxypropyl methyl cellulose and carbopols (eg 934,940 and 941), etc., up to about 10% by weight, preferably about 0.5- about 5% It is usually present in the dental paste to the extent. In dental pastes and gels, liquids and solids are proportional to the formation of a creamy or gelled scalpel ejected from a crushing container or a collapsible tube such as aluminum or lead tubes. Solid or paste-type oral formulations, typically having a pH of about 4.5-9, generally about 5.5-about 8 and preferably about 6-about 8.0, measured on a 20% slurry, may also contain surfactants and / or fluorine-providing compounds. It may contain.

Typically, it will be appreciated that oral formulations should be sold in containers with appropriate levels. Such mouthrinse disease, in fact, will have to be labeled with a level that describes it as a mouthrinse or mouthwash and directs its use: and dental paste is usually a collapsible tube, typically It can be enclosed in aluminum or lead tubes or a squeeze dispenser can be used to measure the volume, and in practice, a level describing it as a dental paste or dental cream should be applied. Oral compositions of the present invention are generally non-soap synthetic synthetic water soluble organic anionic or nonionic surfactants at concentrations of about 0.05- about 10, preferably about 0.5-5% by weight to enhance wetting, cleansing and foaming properties. It can contain enough. Such suitable surfactants are described in US Pat. Known in 4,041,149.

In another embodiment of the present invention, a fluorine providing compound is present in the oral formulation. These compounds may be weakly soluble in water or completely soluble in water. They are determined by the practical freedom from the reaction of fluoride ions in water with other compounds in oral preparations. Among these substances are inorganic fluorides, such as soluble alkali metals, alkaline earth metals and heavy metals such as sodium fluoride, potassium fluoride, ammonium fluoride, calcium fluoride, copper fluorides, ie copper fluoride, zinc fluoride, tin fluoride Ie ditin or fluorinated tin tin, barium fluoride, sodium fluorosilicate, ammonium fluorosilicate, sodium monofluorozirconate, sodium monofluorophosphate, aluminum mono- and di-fluorophosphate and Sodium fluoride calcium pyrophosphate. Preferred are alkali metals and stannic fluorides, ie sodium and stannous fluoride, sodium monofluorophosphate and mixtures thereof.

The amount of fluorine providing compound, to some extent, depends on the form of the compound, its solubility and the form of the oral formulation, but must be non-toxic. It is considered satisfactory that the amount of such compound is advantageous in solid oral formulations, i.e., dental pastes or dental powders, which favor a maximum of about 1% by weight of the formulation. Any suitable minimum amount of such compounds may be used but it is preferred to use enough compounds to liberate about 0.005-1%, preferably about 0.1%, of fluorine ions. Typically, for alkali metal fluoride and stannous fluoride, these components are present up to about 2% by weight, preferably about 0.05-1%, based on the weight of the formulation. For sodium monofluorophosphate, the compound may be present at up to 7.6% by weight more typically up to about 0.76%.

In liquid mouth preparations such as mouthwashes, the fluorine-providing compound is typically present in an amount sufficient to liberate up to about 0.13%, preferably about 0.0013-0.1%, most preferably up to about 0.0013% by weight fluorine.

In the oral composition of the present invention, the inclusion of fluorine-containing compounds, especially MFP (sodium monofluorophosphate), should be very wise and selective. Because such inclusions are sometimes found to be oral compositions that turn yellow or brown over time and / or with storage, since the F-containing compound is distinctly due to the effects on the stability of the TA drug.

Various other materials may be incorporated into the oral formulations of the present invention. Examples include bleach preservatives, silicones, chlorophyll compounds, and ammonium materials such as urea, diamonium phosphate and mixtures thereof. When present, these suppositories are incorporated into the formulation in amounts that do not actually adversely affect the desired properties or characteristics of the formulation. All flavors or sweeteners can also be used. Examples of suitable perfume ingredients include perfume oils such as spearmint, peppermint, camellia, sasapras, clove, saz, eucalyptus, marjoram, cinnamon, leman and orange oil and methyl salicylate.

Suitable sweeteners include sucrose, lactose, maltose, sorbitol, sodium cyclate, perarylatin, APM (aspartylphenylalanine methyl ester) and saccharin. Suitable flavoring and sweetening agents may together contain about 0.1-5% or more of the formulation.

In preparing an oral composition of the present invention, which typically comprises combining an anti-gingival salt and an additive as defined above in an oral preparation comprising water, the additives after mixing or contacting each of the other ingredients (excluding some water), respectively. It is preferred to add.

For example, mouthrinses or mouthwashes can be prepared by mixing ethanol and water with perfume oils, nonionic surfactants, wetting agents, TA antigingival salts, sweetener colorants and the additives described above and, if desired, adding another water.

Dental pastes can be prepared by forming a gel with a humectant, gum or thickening agent such as hydroxyethyl cellulose, a sweetening agent and adding to it a brightening agent, a flavoring agent, an antigingival salt, additional water and the additives defined above.

In the practice of the present invention, the oral composition according to the present invention, i.e., the color of the tooth surface due to the presence of an effective amount of TA antigingival salt to enhance oral hygiene, or the presence of dental paste and antigingival salt A defined amount of additive effective to reduce is generally about 5.5-about 8, preferably about 6-8, at a pH of about 4.5-about 9, about 5 times-about 3 times per day, dental enamel It is desirable to apply it regularly.

It is to be understood that the following specific examples further illustrate the nature of the present invention and are not intended to be limiting thereof. All amounts and proportions mentioned and added herein are by weight unless otherwise indicated. Table I below describes the anti-coloring activity of the preferred K ₃ P ₂ O ₈ additives. Tooth coloring properties of aqueous controls, aqueous solutions containing 1.0 wt% TA and aqueous solutions containing 1.0 wt% TA and 2.0 wt% K ₄ P ₂ O ₈ , respectively, were defined as hydroxyaparite (biogel), special saliva protein, carbon. Slurry with a member (eg acetaldehyde) and pH7 phosphate buffer to evaluate. The mixture is shaken at 37 ° C. for 18 hours. The colored HAP powder is filtered, isolated and dried, and then the coloring level (reflection unit) is measured on a Gardner color discrimination meter.

Example 1

TABLE I

The results shown in Table I show the surprising efficacy of the peroxydiphosphate salt additive used here to inhibit tooth pigmentation caused by TA.

Example 2

40 15-24 month-old purebred small hounds are anesthetized (Na-Nembutal), and the hard, calcified deposits on the tooth surface are removed and hardened and completely polished. An exposure solution (erythrozin-provided hoist wrap) was used to completely remove the soft and hard deposits. The animals were fed soft food. It was soaked in water to make soft corn porridge. Hard materials were banned during this study. Animals were divided into 4 groups and each group was treated twice daily with test solution. The solution pointed was slowly sprayed (with a spray bottle) onto all orthodontic surfaces. The mouths of all dogs were closed for 1 minute to allow the solution to contact the dentition. About 5-6 ml of solution was used for the processing. This treatment was continued for 5 days a week for 6 weeks during the trial. There were blind spots in this study. Plug and gingival salt formation was assessed on P ⁴ , P ³ , P ² , CI ', P ₄ P ₃ , P ₂ I' and teeth on the left and right sides by Loe and Silness method. The exposure solution was used to see the plug.

Gently squeezed the gums with the fingertips and bleeding gums appeared. Table II below shows the results of experiments with the indicated solutions.

TABLE II

The results shown in Table II show the surprising efficacy of this additive for suppressing the pigmentation normally produced by TA without reducing antigingival salt activity. In fact, the additives actually reduced more severe gum bleeding.

Example 3

^* About 60% methyl salicylate, 32% methanol, 3% eugenol, and 5% cinemaol

Example 4

^* About 60% methyl salicylate, 32% methanol, 2% jugenol, and 3% cinemaol

Examples 3 and 4 describe toothpaste formulations with reduced coloration according to the present invention. Other conventional components can be substituted or added as known above. For example, polyethyleneglycol 600 may be substituted by other gelling agents, such as Pluronic F-127 (polyethylenated polyoxypropylene), laponite (Mg-Al-Si clay) or Catabopol 940.

It will be appreciated that the present invention, with respect to the preferred embodiments, is well known to those skilled in the art and its modifications are within the spirit and scope of the present application and within the appended claims.

Claims (1)

Oral formulations, non-antibacterial anti-dilutions that have been observed to pigment or decolorize the tooth surface, include transexamic acid as a salt and an anti-pigmentation additive, containing an effective anti-pigmentation amount of foroxydiphosphate salt.