NO124095B - - Google Patents

Description

Oral care agents for inhibition of calculus.

The present invention relates to oral care products which inhibit the formation of tartar.

The term "mouth care agent" as used here denotes a product which, during normal use, remains in the oral cavity for a time sufficient to come into contact with essentially all tooth surfaces. Such products are e.g. dentifrices, mouthwashes, tablets or lozenges, and solutions for local application.

Tartar is a deposit that forms on the surfaces of the teeth at the gingival border. Supragingival calculus mainly appears in the areas near the openings for the salivary ducts, e.g. on the linear surfaces of the lower incisors and on the cheek-facing surfaces of the first and second molars,•

and on the posterior surfaces of the posterior molars.

Tartar consists of an inorganic part which is mostly calcium phosphate arranged in a hydroxyapatite crystal lattice structure similar to bone, enamel and dentin. An organic part is also present and consists of desquamated epithelial cells, leukocytes, food residues and different species of microorganisms.

During the development of tartar, an initial deposit is formed which is mostly amorphous calcium phosphate as determined by X-ray analysis. As calculus develops through a crystal growth phase, it becomes visibly white or yellowish in color, with minor staining or discolouration by some agent. Apart from being visible and undesirable from an ethical point of view, tartar deposition is a constant source of irritation to the gums and further to gingivitis and other diseases of the supporting parts of the teeth,

and irritation reduces the tissue's resistance to endogenous and exogenous organisms.

A number of chemical and biological agents have been proposed for

to inhibit tartar formation or remove tartar after it has formed. Periodic removal of tartar by the dentist is, of course, routine treatment at the dentist.

It has generally been proposed to inhibit tartar formation chemically by chelating calcium which prevents calcium phosphate tartar precursor from forming and/or breaking down formed tartar by removing calcium. A number of chelating agents, such as ethylenediaminetetraacetic acid, nitrilotriacetic acid and certain lactones of sugar acids, have been used for this purpose. However, the chemical similarity of tartar to the tooth structure limits the usefulness of chelating agents, as the more effective chelating agents can seriously damage the tooth structure by decalcification, as shown by Grossman, "Oral Surgery, Oral Medicine and Oran Pathology 7, 484-487 (1954) " and Draus et al. "Dental

Progress 3, No. 2, 79 - 81 (1963)". Thus has the development

of oral care products that effectively inhibit tartar by calcium chelation has been hampered by safety considerations.

It has now been found that ethane-1-hydroxy-1,1-diphosphonic acid and water-soluble salts thereof possess the surprising ability to inhibit the development of calculus without removing lime from the tooth enamel or otherwise damaging the tooth structure when used in mixtures such as kept within specified pH limits.

The present invention relates to an oral care agent as defined here, which contains from 0.01 to 10% by weight of ethane-1-hydroxy-1,1-diphosphonic acid or a water-soluble salt thereof, preferably the trisodium salt, the pH of the agent being kept within the range 5 - 11, preferably 7 - 10, and any abrasive which is essentially free of water-soluble calcium.

Ethane-1-hydroxy-1,1-diphosphonic acid has molecular formula

CH^CtOH) (PO 3 H 2 ) 2 . (According to the nomenclature for radicals, the acid can also be called 1-hydroxyethylidenediphosphonic acid). The most easily crystallizable salt of this acid is obtained when three acid hydrogen atoms are replaced by sodium. Consequently, a preferred salt for use in the oral care agent according to the invention is trisodium hydrogen salt which has the structure:

This compound normally crystallizes as hexahydrate which loses some water during air drying and gives a mixture of hexa- and monohydrate with an average of 3 to 4 molecules of water of hydration.

Although any alkali metal, ammonium or substituted ammonium salt of ethane-1-hydroxy-1,1-diphosphonic acid can be used in the practice of the invention, tetrasodium salt, trisodium hydrogen salt, disodium dihydrogen salt, monosodium trihydrogen salt, and mixtures thereof preferred. The other sodium, potassium, ammonium and mono-, di- and triethanol ammonium salts and mixtures thereof are also suitable.

In the following description, ethane-hydroxy-diphosphonic acid is referred to as EHDP, which term is intended to indicate both the acid form and all the water-soluble salts thereof. When the form of EHDP is not stated, % EHDP means the percentage of trisodium hydrogen EHDP and the molar equivalents of the free acid and other water-soluble salts.

Concentration of EHDP in the oral care products according to the present invention can be 0.01% to 10% by weight. Oral care products which, during normal use, will accidentally be swallowed in significant quantities, must contain lower concentrations of EHDP. Thus, a mouthwash in accordance with the present invention preferably contains less than approx. 3% and tablets and chewing gum less than approx. 1 wt% EHDP. Dental care products and solutions for local use, where the latter is administered professionally, can contain up to approx. 10% by weight, preferably from 0.1 to 5.0% by weight EHDP.

The pH for mixtures according to the present invention can be from 5.0 to 11. Below pH 5.0, damage to the tooth enamel can occur despite the relatively safe EHDP. Above pH 11.0, difficulties arise in putting together products that have a satisfactory taste and mildness. A preferred pH range is from 7.0 to 10. The mouth care agent's pH value naturally determines the extent of the neutralization of EHDP.

Although it is not intended that the present invention be limited

of a particular theory, it has been observed that EHDP interferes with the development of tartar formation from amorphous calcium phosphate through the crystal growth phase of calcium hydroxyapanite. Amounts of EHDP that are far too small to chelate any significant amounts of calcium have been found to inhibit the formation of calcium hydroxy-

apatite. This selective effect on the formation of tartar deposits without demineralization of the tooth enamel is surprising.

Effectiveness of the agents according to the present invention in preventing calculus was shown by the Rat Tartar Test which was carried out as follows: Two groups of 20 to 21 day old rats of the strain Holtsman-Sprague-Dawley, each group consisting of a male animal and a female animal from each of 10 litters was used in this trial, and one group serves as a control and the other as a test group. Both animal groups were fed a calculus-inducing diet consisting of 62% corn starch, 32% non-fat dry milk, 2% liver powder and 3% cellulose flour. Topical applications of a 0.5% aqueous solution of trisodium hydrogen ethane-1-hydroxy-1,1-diphosphonate adjusted to pH 10.0 were placed on the teeth of each of the animals in the test group twice daily for 3 weeks. Similar applications of water were made to each animal in the control group during the experimental period. 3 weeks after the start of the test, the animals were sacrificed and their molars were graded for calculus formation by examining the areas and depth of accumulation on each of the 44 tooth surfaces examined in each animal. Grading was done on a scale of 0 - 3 for each surface. 0 is no detectable lime deposit, 3 is coverage of essentially 100% of the surface with a thick deposit and the intermediate values represent gradations between these limits. The total calculus count for each animal was determined by adding the grade rings for each of the 44 surfaces.

The results obtained in two experiments are given in the table below.

It can be seen that significant reductions in tartar formation are achieved with locally applied oral care agents according to the present invention.

The safety of EHDP for use in contact with tooth surfaces was determined by a continuous immersion test performed as follows: Natural human teeth were immersed in aqueous solutions containing 3% EHDP at pH 7.0 and pH 10. Every four hours, teeth examined for decalcification.

In visible light, enamel decalcification can be detected by loss of gloss, white opaque points or slight roughness in the surfaces. The teeth were examined macroscopically and microscopically at the end of 7 days. No decalcification was observed during this period, indicating that these mixtures cause no damage to tooth enamel.

A dentifrice, particularly toothpaste containing EHDP is a preferred embodiment of the present invention. Toothpaste mixtures usually contain abrasive materials, foaming agents, binding agents, wetting agents, flavoring and sooting agents.

The abrasive materials and other auxiliaries used in dental care products according to the present invention are preferably essentially free of soluble calcium, so that the sequestering or crystal growth-inhibiting ability of EHDP is not reduced to such an extent that its anti-tartar effect is weakened. Thus, common abrasives such as dicalcium orthophosphate and calcium carbonate are preferably not used. However, predominantly p-phase calcium pyrophosphate which is prepared in accordance with US Pat

No. 3,112,247, which contains relatively little soluble calcium, is used. A particularly preferred class of abrasives for use herein are the particulate thermosetting polymerized resins described in US Patent No. 3,070,510. Suitable resins include melamines, phenolic resins, urea, melamine-urea, cross-linked epoxies and cross-linked polyesters.

Other suitable abrasives include aluminum oxide and the insoluble non-calcium metaphosphates, such as sodium metaphosphate. Mixtures of abrasives can also be used. In each case, the total amount of abrasives in dental care products according to the present invention can be from 0.5 to 95% by weight of the dental care product. Preferably, toothpaste contains from 20 to 60% by weight of abrasives. The abrasive particle size is preferably from 2 - 20 (j .

Suitable foaming agents are those which are reasonably stable and form foam over a wide pH range, preferably anionic organic synthetic cleaning agents. Examples of such agents are water-soluble salts of alkyl sulfate having from 10 to 18 carbon atoms in the alkyl radical, such as sodium lauryl sulfate, water-soluble salts of sulfonated monoglycerides of fatty acids with 10 to 18 carbon atoms, such as sodium monoglyceride sulfonate, salts of C-^Q - C^g fatty acid amides of taurine, such as sodium-N-methyl 1-N-palmitoy 1-tauride, salts of - C-^g fatty acid esters of isethionic acid, and essentially saturated aliphatic acylamides of saturated monoaminocarboxylic acids with from 2 to 6 carbon atoms and in which the acyl radical contains 12

to 16 carbon atoms, such as sodium N-lauroyl sarcoside. Mixtures of two or more foaming agents can be used.

The foaming agent can be present in the dentifrices according to the present invention in an amount from 0.5 to 5% by weight of the total agent.

When making toothpaste, it is necessary to add a thickening material to give the desired consistency. Preferred thickeners are hydroxyethyl cellulose and water-soluble salts of cellulose ethers, such as sodium carboxymethyl cellulose and sodium carboxymethyl hydroxyethyl cellulose. Natural gums, such as gum karaya, gum arabic and gum tragacanth can also be used. Colloidal magnesium aluminum silicate or finely divided silica can be used as part of the thickening agents in an amount of from 0.5 to 5.0% by weight of the total mixture can be used.

It is also desirable to include a humectant in a toothpaste to prevent hardening. Suitable humectants include glycerin,

sorbitol and other edible polyhydric alcohols. Moisturize

the agent can make up to about 36% by weight of the toothpaste mixture.

Suitable flavoring agents include oil of wintergreen, peppermint oil, oil of green myrtle, sassafras oil and clove oil. Blackening agents that can be used include saccharin, dextrose, levulose and sodium cyclamate.

Several representative oral care products that illustrate the present invention are given in the following examples.

EXAMPLE I

A toothpaste with the following mixtures was prepared by conventional methods:

This composition effectively inhibits calculus formation on tooth enamel and when tested by a continuous immersion test as described herein, no decalcification was noted after the 7 day test.

EXAMPLE II

A toothpaste was prepared which was identical in composition to the toothpaste according to Example I, except that 3.0 parts instead of 1.5 parts disodium dihydrogen ethane-1-hydroxy-1,1-diphosphonate and 30.08 parts in instead of 31.58 parts of water was used. This mixture was also found to be effective and caused no damage to tooth enamel after 7 days of treatment.

The disodium dihydrogen salt of ethane-1-hydroxy-1,1-diphosphonic acid in the aforementioned toothpaste can be replaced with ethane-1-hydroxy-1,1-diphosphonic acid or potassium, ammonium or substituted ammonium salts thereof with essentially equivalent results.

EXAMPLE III

Another toothpaste was produced with the following composition:

When used in the usual way, this toothpaste inhibits the formation of tartar and no decalcification of the tooth enamel was observed after a 7-day trial.

EXAMPLE IV

A toothpaste containing 3 parts of disodium dihydrogen-ethane-1-hydroxy-1,1-diphosphonate and 38.08 parts of water, but otherwise identical to the toothpaste according to example III was prepared. This paste was found to be effective and caused no observable decalcification of tooth enamel after 7 days of testing.

The disodium dihydrogen salt of ethane-1-hydroxy-1,1-diphosphonic acid used in this example can be replaced by dipotassium dihydrogen-ethane-1-hydroxy-1,1-diphosphonate, diammonium dihydrogen-ethane-1-hydroxy -1,1-diphosphonate or bis(triethanolammonium)-dihydro-gen-ethane-1-hydroxy-1,1-diphosphonate with equivalent results.

Several mouthwash compositions were prepared in accordance with the present invention as follows:

When used in the same manner as conventional mouthwashes, at least once daily, each of the above mouthwashes materially reduces the accumulation of limescale on the surface of the teeth. No decalcification was observed after 7 days of testing on tooth enamel using these mouthwashes.

EXAMPLE IX

A chewing gum in accordance with the present invention was composed as follows:

This composition provides an effective means of inhibiting calculus formation without damaging the tooth structure when chewing regularly in the usual way.

EXAMPLE X

A prophylactic paste for use by the dentist to remove stains and polish the teeth after mechanical removal of tartar deposits is composed as follows:

When applied to the teeth using a prophylactic rubber cup in the usual way, this paste inhibits the development of new tartar deposits.

Claims (1)

Dental or oral care agent effective for inhibiting calculus formation without adversely affecting the tooth structure, characterized in that it contains from 0.01 to 10% by weight of ethane-1-hydroxy-1,1-diphosphonic acid or a water-soluble salt thereof, preferably the trisodium salt, the pH of the agent being kept within the range 5 - 11, preferably 7 - 10, and any abrasive which is essentially free of water-soluble calcium.