FR289F - Oral compositions for the prevention of cavities - Google Patents

Description

FRENCH REPUBLIC

MINISTRY DD INDUSTRIAL AND SCIENTIFIC DEVELOPMENT

SERVICE OF INDUSTRIAL PROPERTY

1 "ADDITION

PATENT OF INVENTION

JV 7.277 M

P.V. 157.012 International Classification:

N ° 289 CAM A 61 k // C 07 f

Oral compositions for the prevention of cavities. (Invention: Robert John Graben-stetter, James Stone Widder and William John Griebstein.)

Company known as: THE PROCTER & GAMBLE COMPANY residing in the United States of America

The main claim taken on December 29, 1967. Indl. Cfldo133

Requested June 28, 1968, at 12:10, in Paris. 1 ÛKT. > 371 Issued by decree of December 8, 1969.

(Official Bulletin of Industrial Property [B.S.M.], No. 3 of 19 January 1970.)

The present invention relates to improvements, changes and additions to the main patent in which new distanous gem-diphosphonates, and oral compositions, containing these products for the prophylaxis of caries and calculus have been disclosed. In particular, the distanous salts of gem-diphos-phonic acids of formula

Ri \ r / P0> H '

R / XP03H:

wherein R1 is selected from hydrogen, halogen, hydroxyl, benzyl, alkyl, hydroxyalkyl, methoxyalkyl or carboxyalkyl containing from 1 to 12 carbon atoms and R2 is selected from hydrogen, halogens, hydroxyl groups, acetyl, phenyl, benzyl and alkyl, hydroxyalkyl, methoxyalkyl or carboxyalkyl containing from 1 to 12 carbon atoms.

The oral compositions described are used in the form of: toothpaste, mouthwash, chewing gum, prophylactic paste, local solutions, etc., containing (1) a soluble fluoride in an amount sufficient to give from 100 to about 4000 ppm of fluoride ion and ( 2) from 0.05 to 5.0% by weight of a distillate salt of a gem-diphosphonic acid described above, the pH of the composition being from about 2.5 to about 7.0.

Novel stannous polyphosphonates have now been found which are resistant to hydrolysis and transformation into inactive species when used in oral compositions. In addition, these newly discovered stannous polyphosphonates also possess the properties 0 210030 7

anti-caries and anti-scale distal gem-diphosphonates described.

The stannous polyphosphonates according to the invention are the stannous salts of polyphosphonic acids of formulas:

(1) R. "

h 1

C

POjîI,

-r.

POjHj

(11) r3-c-r4

P03H,

wherein R 1 and R 2 are both selected from hydrogen and CH 2 OH; n is an integer of 2 to 10; R 1 is selected from phenyl-thenyl, amino, amino-substituted (eg, dimethylamino, diethylamino, N-hydroxy-N -ethylamino and acetylamino), -CH 2 -P0 3H 2, -CH 2 PO 2 H (OH), -CH 2 CH ( P03H2) 2, -CH2CH2POSH2, cycloalkyl (for example cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), alkyl containing from 13 to 20 carbon atoms and alkenyl containing from 2 to 20 carbon atoms; R4 is selected from hydrogen, amino, hydroxyl, -CH2-PO3H2, aryl, benzyl, and alkyl, hydroxyalkyl, methoxyalkyl or carboxyalkyl containing from 1 to 12 carbon atoms.

Among the polyphosphonic acids of formula I above that can be used to prepare the corresponding stannous polyphosphonates, according to the invention, mention may be made of the following compounds: propane-1,2,3-triphosphonic acid;

butane butane 1,2,3,4-tetraphosphonic acid;

hexane-hexaphosphonic acid-1,2,3,4,5,6;

hydroxyl-1-hexane pentaphosphinic acid -2.3.4,

5.6;

[289 CAM / 7.227 M) -

2,3,4-dihydroxy-hexanetetraphosphonic acid;

pentane pentaphosphonic acid 1,2,3,4,5;

heptane heptaphosphonic acid 1,2,3,4,5,6,7; octane octaphosphonic acid 1,2,3,4,5,6,7,8; 1,2,3,4,5,6,7,8,9 nonaphosphonic nonane acid. The propane triphosphonic acid-1,2,3, butane-1,2,3,4-tetraphosphonic acid and the higher aliphatic vicinal polyphosphonic acids mentioned above can be prepared by reacting an aicyne of general formula R In which R 'is hydrogen or a radical -CH 1 X, and X is a halogen atom, or a hydroxyl radical, m is an integer of 1 to 4, with an acid dialkyl phosphite ester, the alkyl radical containing from 1 to 6 carbon atoms, in the presence of sodium, potassium, lithium or one of their hydrides, the ester obtained is then converted into corresponding acid in a manner known per se.

The higher aliphatic vicinal polyphosphonic acids listed above may be prepared by a method described by D. AUan Nichol-son and Darrel Campbell in US Patent Application Serial No. 693,898 filed December 27, 1967.

The polyphosphonic acids represented by formula II above, from which the stannous gem-poly-phosphonates derived according to the invention are derived, are as follows:

1,1,2-ethanetriphosphonic acid;

1,1,3,3-tetraphosphonic propane acid;

amino acid • 1 • ethanediphosphonic-1,1; hydroxy-1-propanetriphosphonic acid-1,1,3; hydroxy-2-ethanetriphosphonic acid-1,1,2; methane-cyclohexylhydroxy diphosphonic acid;

1,1-tetradecane diphosphonic acid;

hexadecane diphosphonic acid-1,1;

1,1-octadecane diphosphonic acid;

hydroxy-1-pentene-4-diphosphonic acid

1.1; .

hydroxy - 1 - octadecene - 9 - diphosphonic acid - 1,1 phenyl - 3 - diphosphono - 1,1 - propene • 2;

phenylamino methane diphosphonic acid;

naphthylamino methane diphosphonic acid; N, N-dimethylamino methane diphosphonic acid;

N - (hydroxy - 2 - ethyl) amino methane diphosphonic acid;

N - acetylamino methane diphosphonic acid; aminomethane diphosphonic acid.

Ethane triphosphonic acid 1,1,2 and related compounds of formula II can be prepared by the method described in "Journal of the Chemical Society" (London) June 1963, pages 3351 to 3360. Propane tetraphosphonic acid-1 , 1,3,3, and related compounds of formula II may be prepared by reacting an alkali metal carbanion of a tetraalkyl methylenediphosphonate with a dihalomethane in the presence of an organic solvent.

Other compounds represented by Formula II may be prepared by methods set forth in the main patent.

The stannous salts of each of the above-mentioned polyphosphonic acids are prepared by reacting aqueous solutions of the respective acids with SnCl 3. In the present invention, a sufficient amount of SnCU is used to give a molar ratio of stannous tin and polyphosphonic acid of 2 -1 to 10: 1, depending on the number of phosphonic acid groups in the compound. One mole of stannous tin is preferably used for each phosphonic acid group.

The preferred stannous polyphosphonate according to the invention is propane triphosphonate-1,2,3 trh-tanneux.

From the viewpoint of the compositions, the present invention is directed to oral compositions for the prophylaxis of tartar and caries comprising (1) a water-soluble fluoride in an amount sufficient to provide from about 100 to about 4000 ppm of fluoride ion and (2) from about 0.05 to 5.0% of a stannous polyphosphonate described above, the pH of this solution being between about 2.5 and 7.0.

Other details such as examples of usable fluorides, description of dentifrice components and preferred concentrations of these components are given in the main patent.

The following examples are representative of the oral compositions according to the invention.

Example 1

A toothpaste having the following composition is prepared by common methods:

%

• n weight

Calcium pyrophosphate 37.80

Sorbitol (30% aqueous solution) 19.38

Glycerin 9.69

Sodium carboxymethylcellulose 1,02

Silicate of magnesium and aluminum .... 0,39

Sodium lauryl sulfate 2,35

Saccharin sodium 0.14

Fragrance and coloring 1.45

Stannous fluoride 0.39

Ethane triphosphonate-1,1,2-tristnose .... 0,48

Water, pH 6.2 supplement

The toothpaste of this example having been subjected to tests described in the main patent, has been shown to contain substantially higher stannous tin contents after aging.

a control composition formulated with equivalent concentrations of stannous tin but without ethane triphosphonate • 1,1,2 tiistanneux. This composition, applied to the brush in the usual way, delays the formation of tooth decay and tartar even after prolonged storage.

Substantially equivalent results are obtained by using instead of ethane triphosphonate-1,1,2 tristane in the toothpaste of this example, propane triphosphonate-1,2,3-tristane, butane tétraphosphonate 1, 2,3,4-tetrastamous, hexane hexaphosphonate-1,2,3,4,5,6 hexastanneux and 1,6-dihydroxyhexane tétraphosphonate-2,3,4,5-tétrastanneux.

Example 2

Usual methods of preparing a mouthwash having the following formula:

%

• n weight

Ethanol (50% aqueous) 83.00

Glycerin 13,76

Perfume 0,85

Saccharin 0.12

Sodium fluoride 0.27

Propane tetraphosphonate-1,1,3,3-grouse

tanneux 2.00

pH 6.5

Used in the usual way the mouthwash of this example is an effective prophylactic of caries and tartar. Notable levels of available stannous tin do not vary during the storage of the product.

Comparable results are obtained with mouthwashes formulated as in Example II but replacing ethane tetraphosphonate-1,1,3,3-tetrastanneux by one of the following components, in an amount sufficient to give an equivalent concentration of tin stannous:

distanous amino - 1 - ethanediphosphonate hydroxy - 1 - propane triphosphonate - 1,1,3 - tris - tanneux;

hydroxy-2-ethane triphosphonate-1,1,2-tris-tanneux;

distanous cyclohexylhydroxydiphosphonate methane;

hexadecanediphosphonate e-1,1-distannous;

hydroxy - 1 - octadecene - 9 - diphosphonate - 1, 1 - diamagnet;

phenyl - 3 - diphosphono - 1,1 - propene - 2 distannous.

Example 3

Chewing gums of the formulation conforming to that of Example XXIII of the main patent are prepared by replacing pentadecane diphos-

3 - [289 CAM / 7.227 MJ

a distanous 8,8-phonate by one of the following:

distanous phenylamino methane diphosphonate;

Distanous N, N-dimethylamino methane diphosphonate;

Distanous N - (hydroxy - 2 - ethyl) amino methane diphosphonate;

N-acetylaminomethanediphosphonatedistanneux;

distanous aninomethanediphosphonate.

These compositions effectively retard tooth decay and scale formation. The stannous tin content remains in stable form and is available for prolonged periods.

resume

The subject of the invention is:

1 ° As new drugs the stannous salts of polyphosphonic acids of structural formulas:

(1) HiFi t

C

POJH;

-R,

POJH; (11) R3-C-R, POjH,

wherein R 1 and R 2 are selected from hydrogen and -CH 2 OH; n is an integer of 2 to 10; Ra is selected from phenylethenyl, amino, substituted amino -CH2PO3H2, -CHfPOjH1) (OH), -CH2CH (PO3H1) 2, -CH2-CH2-PO3H2, cycloalkyl, alkyl containing from 13 to 20 carbon atoms and alkenyl containing from 2 to 20 carbon atoms; R "is selected from hydrogen, amino, hydroxyl, aryl, benzyl and alkyl, hydroxyalkyl, methoxyalkyl or carboxyalkyl containing from 1 to 12 carbon atoms.

(2) As a particular new drug, propane triphosphonate-1,2,3 tristane.

(3) An oral composition for the prophylaxis of caries and tartar, comprising (1) water-soluble fluoride in an amount sufficient to provide from 100 to 4,000 ppm of fluoride ion and (2) from 0,05 to 5 About 0% by weight of a stannous salt of a polyphosphonic acid described above, the pH of this composition being between 2.5 and 7.0.

4. In such a composition the complementary characteristic according to which the fluoride is stannous fluoride or sodium fluoride.

Company known as: THE PROCTER & GAMBLE COMPANY

By proxy:

Harlé & Lechopiez