SE456403B - Means for inhibiting the tartar CONTAINING AN ALKYLENDEAMINETETRA- (METHYLENEPHOSPHONIC ACID) OR SALT OF IT - Google Patents

Description

Furthermore, DE-OS 19 08 067 discloses a tris- (methylene-phosphonic acid) -amine of the formula N- (CH 2 -PO 3 H 2) 3 (NTMP), which in a similar concentration together with a carrier can inhibit tartar formation without thereby removing the calcium contained in the tooth enamel or resulting in other damage to the tooth structure when used in oral preparations within certain pH limits.

However, the effect of this amine compound with nitrogen-bonded methylene-phosphonic acid residues also leaves much to be desired.

FR-PS 1515 665, which relates to a process for the preparation of aminophosphonic anhydrides, mentions among many other compounds and compound groups alkylenediamino-tetra- (methylenephosphonic acids) as starting materials for the production of anhydride. For the anhydrides produced, on page 4, the right column, the last paragraph to page 5, the left column, the first paragraph of the said French patent specification are randomly listed a number of most varied uses, including also as an additive in dentifrices. However, specific instructions, such as the effect obtained and the possible benefits obtained from these very different structured anhydrides in dentifrices, do not appear in this publication. The possibility of using the alkylenediamino-tetra- (methylenephosphonic acid) or corresponding tetramethylenephosphonate mentioned as starting material for the anhydride production in the dental field and any reference to its very beneficial tartar-inhibiting effect can also not be read from the said French patent specification. It has now been found that certain polyamine polyphosphonates, namely certain alkylenediamine tetra- (methylenephosphonic acids) or their pharmaceutically acceptable, water-soluble salts, have the surprising property that they inhibit the formation of tartar without thereby removing calcium from each other and also without any other adverse effects on the tooth structure when used in oral preparations, which are kept within certain pH limits.

Unlike organic polyphosphates, such as pyrophosphates, the polyamine polyphosphonates used in the formulations of the invention are hydrolysis resistant in aqueous products and do not suffer any loss of power during storage.

The agent according to the invention for inhibiting tartar with a content of 0.01 - 10% by weight of a compound with methylene phosphonic acid residues bound to nitrogen atoms or a pharmaceutically acceptable water-soluble salt thereof and a carrier, the pH of the preparation being in the range of about 5, 0 - 11.0, is characterized in that it contains an alkylenediamine tetra- (methylenephosphonic acid) or a salt thereof of the formula H2O3PH2C \ - / CH2PO3H2 /////, N- (CH2) nN \\\\\\\ H2O3PH2C CHZPOBHZ where n is 1 or an integer from 3 - 10.

Useful polyamine polyphosphonates are preferably pentamethylenediamine tetra- (methylenephosphonic acid), hexamethylenediamine tetra- (methylenephosphonic acid), octamethylene-diamine-tetra- (methylenephosphonic acid) as well as water-soluble pharmaceutically acceptable salts of sodium salts. potassium and ammonium salts. In the composition according to the invention, hexamethylenediamine tetra- (methylenephosphonic acid) is particularly preferred.

Mixtures of the above-mentioned polyamine polyphosphonates can also be used in the formulations according to the invention.

The polyamine polyphosphonates and their salts can be prepared in any known manner, for example according to what is described in US-PS 32 28 846.

The tartar-inhibiting concentration of the polyamine polyphosphonate in the formulations of the invention can vary widely. The upper limit of the quantity used is in principle determined solely by the cost or by the fact that it is no longer borne by the carrier. Quantities of less than 0.01% by weight generally do not inhibit tartar formation.

In general, concentrations of 0.01 to about 10% by weight can be used. Formulations which are temporarily absorbed during normal use may contain lower concentrations of the polyamine polyphosphonate. A mouthwash according to the invention therefore preferably contains less than 3% by weight of polyamine polyphosphonate. Dental care agents, solutions for optical use and prophylactically acting pastes may contain up to about 10% by weight, preferably about 0.1 to 5% by weight of polyamine polyphosphonate. The pH of the formulations of the invention may be between about 5.0 and 11. At a pH lower than 5.0, tooth enamel can be damaged despite the relative safety of the polyamine polyphosphonates.

At a pH value exceeding about 11.0, problems arise in the preparation of the product with satisfactory -ß (TI U \ 43 CD CJ taste and softness. A preferred pH range is from about 7.0 to about 10. The pH of the composition is is of course consistent with the salt form of the polyamine polyphosphonates contained therein.

The agent for inhibiting tartar formation according to the invention is significantly more effective than the agent according to DE-AS 16 17 724, which contains about 0.01 to 10% by weight of ethane-1-hydroxy-1,1-diphosphonic acid or a water-soluble salt of this acid and a carrier suitable for oral use which has a pH of 5.0 - 11.0. As can be seen from column 1, lines 56-67, fully formed tartar consists of calcium phosphate, which is present in crystalline hydroxylapatite lattice structure. upon the formation of tartar, a deposit is first formed, which to a large extent consists of amorphous calcium phosphate. As can be seen from column 2, lines 19-23, the chemical way to prevent tartar formation is to prevent the formation of calcium phosphate, which is a precursor to tartar.

The effect of ethane-1-hydroxy-1,1-diphosphonic acid on the precipitation of calcium phosphate from its solution was compared with the inhibitory effect of the polyamine phosphonate of the present invention, referring to the works of J. L. Meyer and G. H. Nacollas, Calc.Tiss.Res. 13, 295-303 (1973), Springer-Verlag 1973, where these experiments are described.

According to page 298, third paragraph, the experiments are carried out in such a way that the tested inhibitors are added to stable, supersaturated calcium phosphate solutions and immediately before the addition of seed crystals of synthetic hydroxyl apatite. The temperatures of the calcium phosphate solutions were kept at 2s, o ° c can pia value of 7.4. In Fig. 1 of said publication, the formula for the inhibitors tested is indicated.

The active compound according to DT-AS 16 17 729 is referred to as "HEDP", and a polyamine polyphosphonate according to the present invention (with a value of n = 6) is referred to as "TENTMP". As can be seen from Table 1 on page 298 of that publication, all the compounds tested inhibit the precipitation of calcium phosphate already at a concentration of 1,1'6 phonate (abbreviated "ENTMP"), which constitutes the active ingredient, but in addition to ethylene-diamine tetra- (methylene phosphodiene in a tartar inhibitor according to the main patent number 72 14 567-5 (publ. no. 393 530), the compound of the present invention is by far the most effective. "ENTMP" prevents precipitation of calcium phosphate from the supersaturated the solution for more than 24 hours - and "TENTMP" for 12 hours, whereas the compound according to DT-AS 16 17729 (which due to a printing error is denoted by "HEDEP" in the table) already after 4 hours leads to a measurable velocity of the seed crystals to The fourth test compound is also a clearly inferior inhibitor than the polyamine polyphosphonate according to the invention.

Given the even lower concentration of the inhibitors of 5 x 10-7 moles, Fig. 2 on page 299 of the said reference shows that this concentration in terms of "TENTMP" and "HEDP" is obviously not sufficient to occupy a sufficient number of sites on the crystal surfaces by adsorption and in this way ensure that the sites responsible for crystal growth are inactivated.

For this reason, at this extremely low concentration, the actual difference in inhibitory effect between "TENTMP" and "HEDP" is hidden. It is clear that the difference still exists and that the alkylenediamine tetra- (methylenephosphonic acids) or their pharmaceutically acceptable salts proposed according to the invention as tartar-forming agents are considerably better inhibitors than "HEDP". not only of the above test results with "TBNTMP" and "HEDP" as examples at a concentration of 1x 10-6 mol but also confirmed by the experiments described below in which the lowest concentration for each of the tested the substances are indicated, which are required to inhibit a hydroxylapatite formation.

The test was performed according to the work of W W Brinner and M D Francis, Calc.Tiss.Res. ll, pages l0-22 (1973), in particular page ll lower part to page 12, first paragraph, as follows: At room temperature and stationary pH, 4 to lx 10-5 molar aqueous solution was mixed with the substances to be examined and each 1.0 ml of a 1 x 10 -10 molar sodium dihydrogen phosphate solution with 22 - 23 ml of distilled water with constant stirring and under a nitrogen atmosphere in a reaction flask. To the mixture was added 1 ml of a 0.1 molar CaCl 2 solution, and the pH was adjusted with NaOH to 7.41 0.05. The final concentration of Ca PO43_ ions was 4 x 10-3 mol. The consumption of 0.1 n NaOH was automatically recorded with a pH measuring device (radiometer, Copenhagen). The hydroxylapatite formation took place in this test in two different steps. First, a rapid basic consumption took place within 1-4 minutes, then a significantly smaller consumption followed for 1.5-20 minutes, after which, as a rule, in a second step, a rapid basic consumption again took place. A delay in time until the second rapid base consumption or a complete absence of second base consumption indicates that a disturbance or an inhibition of the crystal growth of hydroxylapatite 456 403 has occurred. Agents that cause such a disturbance or inhibition are effective as tartar inhibitors.

The experiments were performed with "ENTMP" (n = 2), butylenediaminetetra- (methylenephosphonic acid), abbreviated "BNTMP" (n = 4), "TENTMP" (n = 6), octamethylenediaminetetra- (methylenephosphonic acid), abbreviated "ONTMP" (n = 8) and decamethylenediaminetetra- (methylenephosphonic acid), abbreviated "DNTMP" (n = 10) as well as for comparison with the known inhibitors "HEDP" «(in the form of the trisodium salt) and tris- (methylenephosphonic acid) - amine ("NTMP", in the form of the pentasodium salt). The results are summarized below: Table 1 Minimum concentration for crystal growth inhibition for hydroxyapatite Compound E (in mol) (in Egm) ENTMP 2 6.6 x 10-6 6.6 BNTMP 4 8.6 x 10'6 8.6 TENTMP ss, 1zx 1o'6 8.12 oNTMP 8 7.7 x 1o'6 7.7 DNTMP lo 7.3 x 10-6 7.3 HEDP - 3.5 x 1o'5 35 NTMP - 6.8 x 1o It follows that the substance proposed according to the invention has an excellent inhibitory effect, which is close to that of'ENTMP 'and which is clearly better than that of "HEDP" or "NTMP". Thus, for example, only about 23% of the amount of "HEDP" in order to achieve a comparable inhibitory effect with "TENTMP". Thus, the dentifrice inhibitor of the invention is clearly superior to known inhibitors in its inhibitory action, such as "HEDP" and "NTMP".

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

The surprising inhibition of the formation of calcium hydroxyapatite has been shown by a series of experiments, which determine the effect of polyamine polyphosphonates on the formation of calcium phosphate by the addition of orthophosphate ions to calcium ions at a constant ambient pH, which corresponds to the natural salivary fluid. the constituents of the salivary fluid are described in "Art and Science of Dental Caries Research, Academic Press, New York and Lond0nJG¶átel VI". Table 2 comprises the inorganic constituents of saliva adopted according to the said publication and the concentrations for this experiment.

Table 2 Ingredient Oorg constituents of saliva (mmol / l) Parotid saliva Submandibular Concentration salivation ostim. shoal. ostim. shoal.

Ca 1.3 1.6 2.1 2.4 2.0 P 8.0 3.2 6.0 3.3 5.0 Mg 0.1 0.02 0.08 0.03 - Na 2.5 35.0 10 25 20 K 37.0 21.0 17 14 20 Cl 33.0 32.0 25 25 36 HCO3 l, O 20.0 4 25 - ps 5.5 7.4 6.4 7.4 7 .0 ionic strength * 49.6 61.2 39.7 48.4 48 456 403 10 * Assumed lzl distribution of HPO4- and HZPO4- - at pH 7.0 ostim - unstimulated stimulated II shoal.

The composition of saliva varies widely, depending on the source (parotid or submandibular glands), the condition (unstimulated or stimulated) and flow rate, which depends on the degree of stimulation.

The main inorganic constituents of saliva are calcium, phosphorus, sodium, potassium, chloride, bicarbonate and dissolved carbon dioxide. Since the calcium salts precipitate under dynamic conditions in the mouth, arithmetic mean values for the values given in Table 2 for each element were used in this study as representative ionic concentrations in the saliva. For the preparation of the stock solution, only the chloride and phosphate forms were used to provide the required elements.

Carbonate was not added. The ionic strength of the stimulated chemical environment was 48 millimol / l.

Two milliliters of a solution containing 0.1 mol of CaCl2.

ZH 2 O, 1 mole of NaCl and 0.5 mole of KCl, which showed a pH of 7 with sodium hydroxide, were added to such an amount of deionized water that a final volume of 100 ml was obtained. To the solution was added 1 ml of dissolved 0.005 M hexamethylenediamine tetra- (methylenephosphonic acid) to give 25 ppm of the phosphonate and then 5 ml of a phosphate solution containing 1 M K HPO. 3H 2 3 2 Hydrochloric acid is adjusted to pH 7. A control experiment was carried out, which was also carried out with 456 403 μl, to which no phosphonate was added.

The samples were incubated at a temperature of 37 ° C. The precipitation conditions were observed for 3 hours.

In the container containing the control sample, the solution first became flocculent, then calcium phosphate began to precipitate after 10 - 20 minutes and coagulated after 2 hours to a fine precipitate. In the container containing the phosphonate, the mixture did not precipitate and was stable for several days.

After 3 hours, the solutions containing a precipitate were filtered off over a 0.45 nm millipore filter. The precipitate was air dried and analyzed by X-ray diffraction.

The solid calcium phosphate precipitated from the control solution described above without polyamine polyphosphonate shows a weakly crystalline hydroxyapatite lattice. The chemical analysis shows a Ca: P atomic ratio of 1: 2 - 1: 3. This is between the atomic ratio of dicalcium phosphate (1.0) to hydroxyapatite (1.67) and close to the Ca: P ratios found in dental coatings. By using polyamine polyphosphonate, the formation of tooth coating as well as a precipitate is prevented.

A dentifrice, especially a toothpaste containing polyamine polyphosphonate, constitutes a preferred embodiment of the present invention. Toothpastes generally contain abrasives, foaming agents, binders, moisturizers, flavoring and sweetening agents.

The abrasive and other additives used according to the invention should not release any large amounts of soluble calcium so that the polyphosphonate inhibitory effect is not depleted to such an extent that its tartar inhibiting activity is impaired. Conventional abrasives such as, for example, dicalcium orthophosphate dihydrate and calcium carbonate should preferably not be used.

On the other hand, calcium pyrophosphate, which is predominantly in the P-phase and which is prepared according to US-PS 31 13 247, can be used, as well as anhydrous dicalcium-orthophosphate, which contains relatively little soluble calcium. A particularly preferred class of abrasives for use in the invention are the particulate thermosets described in US-PS 30 70 510. Suitable are, for example, melamine plastics, phenoplasts, urea plastics, melamine urea plastics, melamine formaldehyde plastics, urea formaldehyde plastics, melamine urea -formaldehyde plastics, crosslinked epoxy plastics and crosslinked polyesters.

Other abrasives are alumina, insoluble metaphosphate which does not contain calcium, such as sodium metaphosphate, silica xerogel and alumina silicate. Mixtures of abrasives can also be used.

The total amount of abrasive in the dentifrices according to the invention can amount to 0.5 - 95% by weight of the dentifrice. Preferably, toothpastes contain 20 - 60% by weight of abrasive. The particle size of the abrasive can be between 3 - 20 Pm.

Suitable foaming agents are those which are sufficiently stable and which form foams over a wide pH range. Preferably they are anionic, organic synthetic detergents which are not soaps. Examples of such agents are water-soluble salts of alkyl sulphate having 10 to 18 carbon atoms in the alkyl radical, such as sodium lauryl sulphate; water-soluble salts of sulfonated monoglycerides from 456,403 fatty acids having 10 to 18 carbon atoms, such as sodium monoglyceride sulfonate; salts of C10 - C18 - fatty acid amides of taurine, such as N-methyl-N-palmitoyl tauride; salts of C10-C18 fatty acid esters of isothionic acid; and substantially saturated aliphatic acylamides of saturated monoaminocarboxylic acids having 2 to 6 carbon atoms, in which the acyl residue contains 12 to 16 carbon atoms, such as sodium N-lauroyl sarcoside.

The mixture of two or more foaming agents can also be used.

The foaming agent may be present in the dental care agent according to the invention in amounts of 0.5 - 5% by weight of the total preparation.

In the preparation of toothpastes, thickeners are required in order to obtain the desired consistency. Preferred thickeners are hydroxyethylcellulose and water-soluble salts of cellulose ethers, such as sodium carboxymethylcellulose and sodium carboxymethylhydroxyethylcellulose. Natural rubber, such as Carragen, Gummi arabicum and Tragantgummi, can also be used. For further texture improvement, colloidal magnesium-aluminum silicate or finely divided silica can also be used as constituents in the thickener. Thickeners can be used in amounts of 0.5 - 5.0% by weight of the total preparation.

Example gel 1 In a conventional manner, a toothpaste having the following composition was prepared: 456 403 14 parts by weight Water 31.58 Sorbitol 6.25 Saccharin 0.12 Calcium pyrophosphate * 39.00 Glycerin 18.00 Sodium alkyl (coconut) sulphate 0.40 Sodium ( coconut) -monoglyceride sulfonate 0.75 Sodium carboxymethylcellulose 1.15 Magnesium aluminum silicate 0.40 Flavor 0.85 Methylenediamine tetra- (methylenephosphonic acid) 1.50 pH 5.90 * prepared according to US-PS 31 12 247 Example 2 A second toothpaste with the following composition was prepared: Water 39.58 Sorbitol 6.25 Saccharin 0.12 Abrasives (precipitated urea / formaldehyde condensate) 31.00 Glycerin 18.00 Sodium alkyl (coconut) sulphate 0.40 Sodium (coconut ) -monoglyceride sulfonate 0.75 Sodium carboxymethylcellulose 1.15 Magnesium aluminum silicate 0.40 Flavor 0.95 Hexamethylenediamine tetra- (methyl fl 'phosphonic acid) 1.50 nn »456 403 A number of other toothpastes were also prepared which had essentially the same composition the toothpaste described in Exempe 1 2, using instead the disodium salt of hexamethylenediaminetetra- (methylene-phosphonic acid), the trisodium salt of hexamethylenediamine-tetra- (methylenephosphonic acid) and the tetrasodium salt of hexamethylenediamine-tetra- (methylenephenphosphonic acid).

The pH of the formulations was adjusted to 7.0. These toothpaste compositions effectively inhibited the formation of tartar on the tooth enamel without any calcification occurring thereon.

A number of mouthwashes with the following composition were prepared: Ingredients Examples (parts by weight) _š_ _4_ Glycerin 10.0 10.0 Ethyl alcohol 16.5 16.5 Water 67,172 67,172 Tween so 1) 0.12 0.12 Saccharin 0.045 0.45 Sodium cyclamate 0.75 0.075 Flavor o, oäs o, us Polyamine polyphosphonate 3.0 2) 3.0 3) pH 7.0 10.0 l) Polyoxyethylene (20 moles of ethylene oxide) -sorbitan monooleate, a non-ionized emulsifier; 2) Hexamethylenediamine tetra- (methylenephosphonic acid); 3) Hexamethylenediamine tetra- (methylenephosphonic acid) 456 403 16 Mouthwash corresponding to Example 4 was prepared, wherein the dipotassium salt of hexamethylenediamine tetra- (methylenephosphonic acid) and the dipotassium salt of hexamethylenediamine tetra- (methylenephetyraphenylene) methylene phosphonic acid) and the pH was adjusted to 8.0.

Example 5 A prophylactically effective paste for use by dentists to remove stains and polish teeth after mechanical removal of tartar was prepared as follows: Parts by weight Navajo pumice 77.10 TiO 2 4.00 Glycerin 17.75 Hydroxyethylcellulose 0.22 Saccharin 0.33 Trisodium salt of hexamethylenediamine-tetra- (methylenephosphonic acid) 8.0 pH 8.0 The paste described above is modified by replacing the trisodium salt of hexamethylenediamine tetra- (methylenephosphonic acid) with the trisodium salt of hexaethylenediaminephetrosene-tetra-methinophenosine-tetra-

M.

Claims (1)

A tanning agent, which has a content of 0.01 to 10% by weight of a compound having methylene phosphonic acid residues attached to nitrogen atoms or a pharmaceutically acceptable water-soluble salt thereof and a carrier, wherein the pH of the preparation is in the range of about 5.0 - 11.0, characterized in that it contains an alkylenediaminetetra- (methylenephosphonic acid) or a salt thereof of the formula HO PH C 2 3 2 / Cnz Posnz / N- (cs2) nN \ a2o3Pn2c where n is 1 or an integer from 3 - 10. CH2 PO3H2