3,639,571 United States Patent Office Patented Feb. 1, 1972 2 3,639,571. One of the problems encountered in inhibiting bac COMPOSITION AND METHOD FOR RETARDING terial deposits is the provision of an anti-bacterial agent PLAQUE AND DENTAL CALCULUS that will be effective in a neutral or mildly acidic en Samuel Turesky, 84 Wallis Road, Chestnut Hill, Mass. Vironment. Thus, for example, the compositions disclosed 02167, and Irving Glickman, 24 Manor House Road, by Buonocore et al., in U.S. Pat. 2,955,984 and incorpo NoNewton, Drawing. Mass. Continuation-in-part 02159 of application Ser. No. rating compounds of the formula 530,781, Mar. 1, 1966, which is a continuation-in-part OR3 of application Ser. No. 679,994, Nov. 2, 1967, which in turn is a continuation-in-part of application Ser. No. R-0--0 763,491, Sept. 23, 1968. This application Jan. 29, 1970, 10 Ó R, Ser. No. 6,933 (wherein an R1,R2 and Rs are variously alkyls, aralkyls, Int, C. A61k 7/16 hythrogens, ammonium or alkali metal) are not fully U.S. C. 424-54 13 Claims Satisfactory because they tend to have the greatest effect at lower pH levels than those experienced in the mouth, ABSTRACT OF THE DISCLOSURE 15 and other less acidic environments, over any long period of time. Formation of bacteria, e.g. of the type resulting in for Another problem encountered in inhibiting bacterial mation of bacteria, e.g. of the type resulting in the for deposits is the provision of an anti-bacterial agent that mation of dental plaque and dental calculus, is retarded will remain effective in environments wherein the agent by exposing surfaces to be protected to a composition 20 may be subjected to attack by enzymes. The human containing compounds of the formula: mouth is also a good example of such an environment. Accordingly, an object of the present invention is to R provide dentifrice compositions which retard the forma Ri- p scO tion of dental plaque and dental calculus. R2 25 A further object of the invention is to provide a denti Where one of R1, R2 and R is an amine group or sub frice of the above type whose calculus inhibiting effect stituted amine group and R2 and Rs are physiologically does not require the use of an abrasive. tolerable organic radicals. Yet another object of the invention is to provide a method of retarding the formation of dental calculus 30 without the use of an abrasive. CROSS-REFERENCE TO RELATED APPLICATION Another object of the invention is to provide useful This application is a continuation-in-part of our appli compositions useful for treating surfaces to avoid bac terial deposits thereon even when there is a substantial cation Ser. No. 530,781, filed on Mar. 1, 1966, our appli enzyme concentration in the environment in which the cation Ser. No. 679,994, filed on Nov. 2, 1967, and appli 35 surface is to be protected. cation Ser. No. 763,491, filed on Sept. 23, 1968, all now Other objects of the invention will in part be obvious abandoned. and will in part appear hereinafter. BACKGROUND OF THE INVENTION The invention accordingly comprises the method and Field of the invention 40 the composition possessing the features, properties, and This invention relates to a method and composition for the relation of constituents which are exemplified in the avoiding bacterial growth on surfaces and especially for following detailed disclosure, and the scope of the inven retarding formation of dental plaque and the dental cal tion will be indicated in the claims. culus or tartar which evolves from the formulation of SUMMARY OF THE INVENTION such plaque. More specifically, it relates to dentifrices Briefly, we have found that certain organophosphorous containing as active ingredients certain organophospho compounds, and oligomers of such compounds, retard rous surface-active agents which resist phosphatase-type plaque and calculus formation, specifically those charac enzymes. The prior art terized by the structure. There has been a considerable amount of work devoted to the avoidance of bacterial growth on various surfaces. Many surfaces which must be maintained free of bac teria are found in chemical processing plants or like where one of R1, R2 and R3 is an amine group or substi sensitive environments. However, among the more im tuted amine group preferably containing between eight portant problems has been the formation of bacteria on and sixteen carbon atoms. The other two of R, R and surfaces within the mouth. R3 are, for example, OH groups, alkali metal salt forms, The role of dental calculus in promoting gingival irri alkyl groups, aralkyl groups, alkaryl groups, aryl groups tation and periodontoclasia is well known, though per both substituted and non-substituted-alkoxy groups, haps not completely understood. It is formed by harden 60 amine groups, amido groups or other substituents that ing of plaque (a soft, adhesive, bacterial, concrescent, are physiologically tolerable for use in oral hygiene ap and primarily organic deposit on the teeth) through a plications and which do not completely prohibit the com calcification process which appears to involve the seeding pound from being dissolved or dispersed. of calcium phosphate crystals. Thus, the most effective It should be obvious to those skilled in the art that method of inhibiting calculus formation has been to the precise treating composition useful in inhibiting bacte cleanse the teeth to remove therefrom the plaque from rial growth on a particular surface will depend in large which the calculus is evolved. However, thorough cleans part on whether the surface is to be exposed to aromatic, ing requires the use of an abrasive, and an abrasive is aliphatic, or an aqueous environment during the period contained in most dentifrices although it abrades the protection is to be maintained. Thus a rather hydrophillic enamel to some extent. Even the plaque that forms on 70 and oleophobic inhibitor will be used if bacterial growth the teeth between cleanings provides a sufficient basis is to be inhibited in an aliphatic or aromatic environment. for harmful calculus formation and growth. On the other hand, a relatively hydrophobic and oleophil 3,639,571. 3 4 lic compound will be used if the active inhibitor is to be cleansers and mouth fresheners which may be used with applied to surfaces known to be subjected to aqueous out such equipment. washing action. Teeth are examples of such surfaces. Animal testing has indicated that the anti-bacterial and The precise choice of particular active compound may enzyme-resistant radical which is incorporated into the also depend, of course, on the particular kind of bacteria anti-bacterial surface-treating compositions of the inven to be avoided and the vigor with which the surface is sub tion is not toxic. For example the heart, spleen, esophagus, jected to any washing action. Thus, those skilled in the trachea, pancreas, thyroid, stomach duodenum, descend art will understand that the basic requirements of the in ing colon, urinary bladder, thymus, prostate, testis ovary vention are only that an amount of the bactericidal agent and tube, adrenal, and brain of rats remained normal when be coated on the surfaces which amount is effective in the 10 they were given, orally, up to 5.0 grams per kilogram of particular environment. It is, however, a particular advan monoethyl dodecylphosphoramidate. In general, no drug tage of the invention that the treating compositions com related gross abnormalities or micropathology could be prise active anti-bacterial agents which are useful in neu detected. tral and only slightly acidic environments and that they Moreover, closely supervised studies on human volun are resistant to enzyme attack. teers were carried out on dodecyl ammonium O-ethyl It should also be understood that the anti-bacterial N-dodecyl phosphoramidate and other compounds, all in agents should usually be applied either directly or in a dicating the physiological tolerability of these materials. liquid vehicle in which they are at least miscible but not entirely soluble. If applied from solution, it is usually ILLUSTRATIVE EXAMPLES OF THE INVENTION necessary to remove the solvent from the surface by evap 20 Characteristic of the compounds suitable for use in our oration to achieve the desirable coating. Washing alone invention are those described generally in U.S. Patent may not deposit enough active ingredient. When the active 2,406,423. These compounds contain alkyl amine groups ingredients are applied from a vehicle in which they are and are markedly effective in inhibiting calculus forma only partly soluble, they tend to deposit out on the sur tion. They are phosphoramidates and phosphonamidates face and a mere washing of the surface is sufficient to 25 which include lauryl ammonium N-lauryl ethoxy phos obtain a good retention of the inhibitor on the surface; phoramidate: therefore, washing is the preferred way to apply a mouth wash. However, when the active ingredients are present in an essentially insoluble form, they must be emulsified in a carrying liquid or utilized as coatings. In some appli 30 cations, one may wish to resort to evaporation of any and its chloromethyl analog, lauryl ammonium N-lauryl vehicle to leave a substantial amount of anti-bacterial chloromethyl phosphonamidate: agent on the surface to be protected or to a "painting” process whereby it is assured some of the material is (H. C coated on each portion of the surface to be treated. 35 Chanti-p-o When used in dentifrices, it appears that compounds ONH3C19H25 have the requisite amino-phosphorous linkage to attach On the other hand, N,N dilauryl chloromethyl phos themselves to surfaces, and because of their bactericidal phonic diamide: qualities, interfere with the formation of bacterial growth, e.g.