COMPOSITION AND METHOD FOR INHIBITING PLAQUE FORMATION

Abstract: The object of the invention is to provide a dentrifice composition for inhibiting plaque formation on teeth. Said composition contains a compound having the formula (R<uf>u)<um>u YX wherein R<uf>u is a fluoroaliphatic radical having from about 4 to 16 carbon atoms, Y is a calcium-complexing moiety, X is a terminal group which does not interfere with the complexing ability of said calcium-complexing moiety, and m is an integer of at least one.

Description: Description Composition and Method for Inhibiting Plaque Formation Technical Field This invention relates to compositions and methods useful in inhibiting the growth of cariogenic bacteria and the formation of- plaque on teeth in an oral envi¬ ronment. Background Art The prevention of the formation of dental plaque is a highly desired result. Dental plaque results when cariogenic bacteria (e.g., Streptococcus Mutans) col¬ lect in colonies on the teeth and form a tenacious de¬ posit thereon. The presence of the bacteria and the deposits is extremely detrimental to the health of the teeth because if left unchecked they may cause infec¬ ted gingival tissue, the formation of dental caries and peridontal disease. In extrene cases they may ul¬ timately result in the loss of the teeth. Many attempts have been made to control the forma¬ tion of plaque. Thus, fluoride solutions and gels have been used. Such are typically performed in a dental office at periodic, but not frequent, intervals so as to render the tooth enamel more resistant to the acid action caused by plaque. Such treatments do not, however, result in plaque control for an extended per¬ iod of time. Even when the frequency of application of such so¬ lutions and gels is increased only partial control has been shown. For example, studies wherein a fluoride- containing solution (1% fluoride concentration) was ap¬ plied four to five times in the course of a year demon¬ strated only limited success. Moreover, the daily ap¬ plication of a fluoride gel by means of a custom-fitted polyvinyl mouthpiece for a period of 21 months also showed no substantial change in plaque formation among treated and untreated patients. See "Clinical Anti- caries Effect of a Repeated Sodium Fluoride Application by Mouthpiece", Journal of the American Dental Associa- tion, V . . 75, No. 3, September, 1967, pp. 638-644. Other attempts at inhibiting the formation of plaque have also been made. Thus British patent 1,319,247 de¬ scribes dental compositions which comprise a dental ve¬ hicle and a zinc, copper or zirconium complex of a fluorinated beta-diketone. These compounds are said to reduce the solubility of tooth enamel in the acids pro¬ duced by bacteria in the mouth. Disclosure of Invention The present invention provides a dentifrice composi- tion, substantially free from materials containing ++ ++ polyvalent metal elements (e.g. Ca , Mg , etc.) which contains a fluorochemical material having the formula (R £ t)mYX. In this formula R f is a fluoroaliphatic radical having from about 4 to 16 carbon atoms; Y is a calcium-complexing moiety which has a forma¬ tion constant in the range of about 0.5 to 8, wherein said calcium complexing moiety forms a complex struc¬ ture with calcium, which structure contains up to about 20 atoms in its backbone; X is a terminal group which does not interfere with the ability of said complexing moiety to form ' ;• said complex structure with calcium; and m is an integer of at least one. Preferably compositions of the present invention comprise at least about 0.05%- by weight, and most pre- ferably from about 0.1% to 1% by weight, of the fluoro- chemical compound. In another embodiment of the present invention there is provided a method for inhibiting plaque for¬ mation which comprises contacting teeth with an ef- fective amount of the above-described dentifrice compo¬ sition. As it is used throughout the specification, the term "dentifrice" refers to compositions for topical application to teeth. • Representative of such composi- tions are liquids (e.g. mouthwashes and rinses, etc.) and toothpastes (in the form of gels, powders or pastes) etc. Best Mode for Carrying Out the Invention The dentifrice compositions of the invention may be applied to teeth by a variety of techniques including, for example, painting or brushing, spraying, bathing and rinsing. Other means of application are also pos¬ sible and will be obvious to those skilled in the art as a result of this disclosure. Fluorochemical materials, useful in the invention have the formula set forth above. In this formula R f is a fluorinated, saturated, usually monovalent, ali¬ phatic radical. The , radicals are stable, inert, nonpolar moieties which can be both olephobic and hy- drophobic. They can be straight chain or branched chain radicals. Additionally, if the radicals are sufficiently large, they may be cyclic or combinations _0MPI__ of cyclic, branched and straight chain (e.g. alkyl- cycloaliphatic radicals) . The skeletal chain of the R f radical can include catenary oxygen and/or trivalent nitrogen hetero atoms bonded only to carbon atoms. Such hetero atoms provide stable linkages between fluorocarbon groups and do not interfere with the in¬ ert character of the radical. R_ has from about 4 to 16 (preferably from about 6 to 12) carbon atoms. Additionally the R f radical is preferably fully or substantially fully fluorinated. Thus the preferred R f radicals are perfluoroalkyl groups (e.g. C F_ .-i-)- Moreover, the terminal portion of the _e group preferably contains a -CF, group, and most preferably the terminal .portion also has at least three fully fluorinated carbon atoms (e.g. CF 3 CF 2 CF 2 -) . Generally the R f radical contains about 40-80 per¬ cent by weight (preferably 50-80 percent by weight) fluorine. As a result, the corresponding fluorochemi- cals contain from about 4 to 70 percent by weight fluorine. Complexing moieties (Y) useful in the present in¬ vention may be mono- or polyderitate. The fluorochemi- cals form complex (e.g. chelate) structures with cal- cium through the Y group. These complex structures may contain up to about 10 atoms in their backbone. Preferably they contain from about 5 to 6 members therein. Additionally, the calcium complexing moi¬ eties have a formation constant within a defined range. This constant is expressed in terms of log, 0 K. Useful calcium complexing moieties have a formation constant in the range of about 0.5 to 8. Values of more than 8 indicate very strong calcium chelators. Such chelators are undesirable because they decalcify the tooth (i.e. withdraw the calcium from the tooth) thereby weakening its resistance to disease and wear. The formation constant is based upon a complex formed between the fluoroche ical and an organic li- gand. The value is determined at about 25°C. and an ionic strength approaching 0 from the following: M + L t~== ML In these formulae [M] represents the concentration of the complexing agent; [L] represents the concentration of the organic ligand; and [ML] represents the concen¬ tration of the complex at equilibrium. The chelate structure formed between the fluoro- chemical and calcium of the tooth may be represented by the general structure: r wherein R f , Y, X and m are as described above. For purposes of discussion the Y group is hereinafter some¬ times represented by the formula -A-Z-A-. Thus struc¬ ture I_ may also be represented by - --C * -,a++ ' ~ - wherein each R f , R and m are as described above; each A is an electron donating moiety that may be the same or different and is selected from (i) hetero atoms se¬ lected from oxygen, nitrogen and sulfur, provided that when- A is nitrogen it is either a primary or sec¬ ondary nitrogen; and (ii) groups which contain said oxygen, nitrogen and sulfur hetero atoms; and Z is a connecting group which does not interfere with the for- mation of the chelate structure. Representative examples of useful A groups are ke- tone groups, hydroxyl groups, carboxyl groups, amino groups, sulfhydryl groups, thionogroups, thiologroups, mercapto groups, etc. Fluorochemicals which contain more than one of these A groups are also useful (e.g. hydroxy-carboxylic, sulfhydryl-carboxylic, sulfhydryl- thiolo, sulfhydryl thiono, amino-mercapto, etc.). Representative examples of useful Z groups include alkylene radicals containing from about 1 to 20 carbon atoms; and arylene radicals of from about 5 to 20 car¬ bons. Hetero atoms (e.g nitrogen, oxygen and sulfur) may appear in the Z groups. However they must not in¬ terfere with chelation of the calcium. Still other Y groups useful in the present inven- tion comprise quaternary nitrogen groups. These groups may be represented by the formula R 6 ΘN - R 5 wherein R 4 and R5 are methyl and R6 is -fCH p thW wherein b is an integer of from about 1 to 6 and is selected from the group consisting of hydrogen, hydroxyl and Typically the quaternary nitrogen moieties are as¬ sociated with an anionic moiety. ex¬ amples of such anionic moieties -NO- (r). Still other anionic moieties are also useful O - as will be understood by those skilled in the art. X groups useful in the fluorochemical materials do not interfere with the ability of the Y group to form complex structures with calcium. Representative ex- amples of suitable X groups are hetero atoms such as hydrogen and alkali metals (e.g. potassium and sodium) , alkyl radicals, especially those containing from about 1-4 carbons, carboxyl and sulfonate radicals, aryl radicals (e.g. those- containing from about 5 to 6 car¬ bon atoms), ammonium radicals and heteroatoms. In an alternative embodiment of the present inven¬ tion the fluorochemical material may be represented by the formula (R f ) QYZ wherein R f , Y, X and m are each as described above and wherein Q is a polyvalent (i.e. at least divalent) linking group through which R^ and Y are bonded together. Representative examples of use¬ ful Q groups include polyvalent aliphatic; polyvalent aromatic, oxy, thio, carbonyl, sulfone, sulfoxy, imino, and combinations thereof such as oxyalkylene, iminoal- kylene, iminoarylene, sulfonamideo, carbonamido, sul- fonamidoalkylene, carbonamidoalkylene, urethane, etc. Representative examples of polyvalent aliphatic Q groups include -CH 2 -CH 2 ~ and -CH 2 C (CP 2 0) 2 ~. Repre¬ sentative examples of polyvalent aromatic Q groups in- elude Representative examples of imino Q groups include -NH- and -N(C„H 5 )-. Representative of suitable urethane Q groups include -CH 2 CH 2 OCONH- and , _O PI_ Specific examples of fluorochemical materials which conform to the formulae described previously are set forth in Table 1. The specific formula and the portion of each material attributable to each element of the generic formula are given. TABLE 1 SPECIFIC FORMULA C Q F 1 [C 8 F [C 8 F TABLE 1 (continued) SPECIFIC FORMULA R * Q C 8 F 17 S0 2 (CH 2 ) 10 COOH •SO. ■ tl(CH 2 ) 10 • C S-0 C 8 F 17 CQF 17 SO 2 N(C 2 H 5 )CH 2 CO 2 H(COCH 2 CH 2 ) 3 N 0 2 - -H(H0CH 2 CH 2 ) 3 N C 8 F 17 SO, -N(C 2 H 5 )CH 2 C Other ingredients may also be added to the compo¬ sitions of the present invention. Thus, for example, prophylactic agents, polishing agents, surfactants, flavoring and sweetening agents, thickening agents and humectants may be included using techniques which are known to the art. Such other ingredients must be substantially free of polyvalent metal (e.g. calcium, magnesium, etc.). The presence of such " metals in these ingredients pre- vents the compositions of the invention from exhibit¬ ing the desired control over cariogenic bacteria and plaque formation. While the reason for this is not fully understood, it is believed that these metals interact with the fluorochemical materials before ap- plication of the composition to teeth thereby prevent¬ ing them from interacting with the calcium of the teeth. Thus while these ingredients may contain a minor amount of polyvalent metal, the total amount of such ions present must not prevent the fluorochemical materials from interacting with the teeth. Preferably these other ingredients are completely free from any polyvalent metal. Representative prophylactic agents include supple¬ mental caries-preventing materials such as sodium flu- oride, stannous fluoride, potassium fluoride, hexyl- amine hydrofluoride, myristylamine hydrofluoride, be- taine fluoride, glycine potassium fluoride, etc. A particularly preferred fluoride is sodium fluoride. Typically the prophylactic agents are present in suf- ficient concentration so as to provide an available fluoride ion concentration of up to about 2% by weight, and preferably in the range- of about 0.5-2% by weight, of the dentifrice composition. Suitable polishing agents include, for example, water-impervious cross! inked thermosetting resins such as the condensation products of melamine and urea with formaldehyde. Other suitable polishing agents will be obvious to those skilled in the art as a result of this disclosure. Preferably the polishing agent is not so abrasive so as to scratch or unduly abrade the surface or the dentin. Rather it only cleans the tooth surface. The polishing agents may comprise up to 95% by weight of the dentifrice composition. Surfactants may also be employed in compositions of the invention. Suitable surfactants include, for example, detergent materials and are preferably non- ionic. Representative examples of useful surfactants include lauric onoethanol ami de , 1 aur c-myristic mono- ethanolamide, ricinoleic al kanol mides , fatty acid al kanolamides (e.g., coconut diethanolamide) , lauryl . dimethyl amine oxide, glycerol monolaurate, glycerol monostearate, pentaerythri tol monooleate, sorbitan monooleate, ethoxylated castor oil, nonyl phenol ethoxolate, etc. The surfactants typically comprise up to about 5% by weight of the dentifrice composition. Suitable flavoring and sweetening agents which may be employed in compositions of the invention include, for example, the oils of wintergreen, peppermint, spearmint, sassafras and anise. Additionally small amounts of sweetening agents such as saccharin, dex¬ trose, levulose, etc. may also be added to such compositions. These flavoring and sweetening agents may comprise up to about 5% by weight of the denti¬ frice composition. Suitable gelling or thickening agents which may be employed in compositions of the present invention in¬ clude, for example, natural gums such as gum karaya, gum arabic and gum tragacanth; and finely divided silica. Such thickening agents may comprise up to about 5% by weight of the dentifrice composition. Suitable humectants which may be employed in compo¬ sitions of the invention include glycerine, sorbitol, and other polyhydric alcohols. The humectants may com¬ prise up to about 35% by weight of the dentifrice com¬ position. The effectiveness of the present invention in inhib- iting the growth of plaque was demonstrated by both in vitro and in vivo tests. These tests are described more fully in the following examples. Example 1 In vitro tests were performed on plaque-free bovine teeth. The teeth were dipped into a composition of the invention for 30 minutes and then air dried for 30 min¬ utes. Untreated teeth were used as controls. The treated and untreated teeth were then suspended in tubes of a test media comprising 18 milliliters of ac- tinomyces broth, 2 milliliters of a 20% aqueous su¬ crose solution and 0.2 milliliters of a 24 hour viable culture of Streptococcus utans. The teeth and test tubes were incubated at 37°C. for 24 hours, after which the teeth were transferred to new test tubes of fresh test media and again incubated at 37°C. for 24 hours. The procedure was repeated for three days or until attachment of plaque to the control teeth was noted. The compositions used to treat the teeth comprised 1% by weight fluorochemical and 99%. by weight deionized water. Compositions containing the following fluoro- chemicals, each of which had a formation constant in the range of about 0.5 to 8, were found to prevent the formation of plaque in this test: C 8 F 17 SO 2 - -CH 2 COOH Et [C 8 F 1 ) 2 ]N0Θ 3 Example 2 In vivo tests were performed on Rhesus Monkeys. Each monkey received a complete dental prophylaxis wherein their teeth were ul trasonically cleaned and then polished using a soft rubber prophylaxis cup and standard pumice-filled prophylaxis paste. The test compounds were applied to the upper central and medial incisors of each monkey by brushing about 0.5 cc. of a solution of the fl uorochemical material in deionized water and allowing the teeth to air dry for about 30 seconds. Various concentrations of the fluoroche - icals were employed in the solutions tested. The lower central and medial incisors of the monkeys served as control teeth. Except for the initial dental prophylaxis, the control teeth received no treatment during the tests-. The teeth were observed for up to 14 days to determine the effect of the treatment upon the formation of plaque. The monkeys were fed twice a day with a diet which encouraged plaque formation. Each feeding consisted of about 135 grams of Purina R New World Monkey Chow R which had been softened with 200 grams distilled water and to which had been added 118 grams of sugar. The - R 3 Monkey Chow is commercially available from Ralston Purina Co. It has a guaranteed analysis of: Crude protein not less than 25.0% Crude' fat not less than 5.0% Crude fiber not more than 3.5% 0 Added minerals not more than 3.0% Ash not more than 6.0% The ingredients in the Monkey Chow were ground yellow corn, soybean meal, ground wheat, corn gluten meal, dried skimmed milk, animal fat preserved with BHA, su- 5 crose, brewers' dried yeast, salt, dehydrated alfalfa meal, vitamin B,„ supplement, riboflavin supplement, calcium pantothenate, niacin, choline chloride, men- adione sodium bisulfite (source of vitamin K activity) , folic acid, pyridoxine hydrochloride, thia in, ascor- 0 bic acid, vitamin A supplement, D activated animal sterol (source of vitamin D~), vitamin E supplement, " iron oxide, iron sulfate, manganese sulfate, calcium iodate, calcium carbonate, dicalcium phosphate, man- ganous oxide, copper oxide, cobalt carbonate and zinc 5 oxide. The effectiveness of plaque inhibition in this test was measured by means of a plaque index number. The plaque index was determined by applying Erythrosine B dye (further identified as FD&C Red dye #3, Color In- Q dex No. 45430) to the teeth. This dye stains plaque but not tooth enamel. The stained plaque was visually observed and assigned a number using the following scale. PLAQUE SCALE 0 No plaque 0 , . 25 Light plaque covering about 1/4 of tooth surface 0. , 5 Light plaque covering about 1/2 of tooth surface 0. , 75 Light plaque covering about 3/4 of tooth surface 1 . , 0 Light plaque covering entire tooth surface 1 . . 25 Heavy plaque on 1/4 of tooth surface, light plaque on remainder 1.50 Heavy plaque on 1/2 of tooth surface, light plaque on remainder 1.75 Heavy plaque on 3/4 of tooth surface, light plaque on remai nder 2.0 Heavy plaque on entire tooth surface The teeth were stained and observed visually periodi¬ cally throughout the test. The ratings were average to form the reported plaque index. The results of these tests are set forth in Table The fluoro- chemical materials employed were [C 8 F 1 ) 2 ]N0 Θ 3 [CgF n 2 ]H,P0 Θ CgF 17 S0 2 (C 2 H 5 )CH 2 C0 2 H (H0CH 2 CH 2 ) 2 N TABLE 2 FLUORO¬ PLAQUE CONCEN¬ TEST INDEX CHEMICAL APPLICATION TRATION LENGTH , TREATED CONTROL MONKEY MATERIAL METHOD ( t. %) (Days) TEETH TEETH 1 A * 2 14 0.25 1.687 2 A * 1 14 0.125 1.375 3 A * 0. 5 14 0.125 3.437 4 A * 0. 25 14 0.50 1.375 5 A * 0. 125 14 0.666 2.50 10 1 A ** 1 13 0.35 1.15 1 A ** 1 8 0.333 1.75 6 , A ** 1 10 0.375 1.31 7 A ** 1 10 0.187 1.56 8 A ** 1 12 0.4 1.35 9 A ** 1 8 0.166 2.0 1 B * 1 14 0.70 1.60 6 B * 1 8 0.5 2.0 7 B * 1 8 0.208 1.50 10 B * 1 10 0.125 1.3125 2 C * 1 10 0 1.125 2 C * 1 14 0.1 1.35 TABLE 2 (continued) FLUORO¬ CONCEN¬ TEST PLAQUE INDEX CHEMICAL APPLICATION TRATION LENGTH TREATED CONTROL MONKEY I MATERIAL METHOD ( t. &) (Days) TEETH TEETH 10 C * 1 14 0.416 1.58 4 D * 1 14 1.083 1.875 11 D * 1 13 0.11 1.39 12 E * 1 10 0 1.00 Application Techniques * Daily brushing with fluorochemical solution ** Daily rinsing with fluorochemical solution * -* I

Claims: Claims 1. A dentifrice composition, substantially -free from polyvalent metal, which composition contains a fluorochemical compound having the formula (R f ) YX wherein R is a fluoroaliphatic radical having from about 4 to 16 carbon atoms; Y is a calcium-complexing moiety which has a formation constant in the range of about 0.5 to 8, wherein said calcium complexing moiety forms a complex structure with calcium, which structure contains up to about 20 atoms in its backbone; X is a terminal group which does not inter¬ fere with the ability of said calcium complexing moiety to form said complex structure with calcium; and m is an integer of at least one. 2. A composition in accordance with claim 1 wherein said fluorochemical comprises at least about 0.05% by weight of said composition. 3. A composition in accordance with claim 2 wherein R f comprises perfluoroalkyl groups. 4. A composition in accordance with claim 3 wherein laid fiuόr&ehemical forms a chelate structure with 5. A composition in accordance with claim 1 wherein Y comprises a quaternary nitrogen group. 6. A composition in accordance with claim 1 wherein X is selected from the group consisting of alkyl radicals containing from about 1 to 4 carbon atoms, carboxyl radicals, sulfonate radicals, aryl radi- cals containing from about 5 to 6 carbon atoms and heteroatoms selected from the group consisting of hydrogen and alkali metals. 7. A composition in accordance with claim 1 wherein said fluorochemical has the formula CoFl,_/S0 ΔNjCH 2.COOM C 2 H 5 wherein M is selected from the group consisting of hydrogen, alkali metal and ammonium radicals. 8. A composition according to claim 1 wherein said fluorochemical has the formula 9. A composition according to claim 1 wherein said fluorochemical has the formula C 7 F lc CCH C- 0 O 10. A composition according to claim 1 wherein said fluorochemical compound has the formula (R f ) QYX wherein Q is a polyvalent linking group through which R- and Y are bonded together and which does not interfere with the calcium-complexing ability of Y. 11. The method of inhibiting plaque formation compris¬ ing contacting teeth, in an oral environment, with an effective amount of a dentifrice composition, substantially free from polyvalent metal ions, which composition contains a fluorochemical com¬ pound having the formula (R f ) YX wherein R f is a fluoroaliphatic radical having from about 4 to 16 carbon atoms; Y is a calcium-complexing moiety which has a formation constant in the range of about 0.5 to 8, wherein said calcium-complexing moiety forms a complex structure with calcium, which structure contains up to about 20 atoms in its backbone; X is a terminal group which does not.inter- fere with the ability of said calcium complexing moiety to form a complex with calcium; and m is an integer of at least 1.

Inventors: CHANG R, ENGLE M, FLEUR L
Applicants: MINNESOTA MINING & MFG, MINNESOTA MINING & MFG CO
Application year: 1978
Main classification: A61K7
IPC codes: A61K8, A61Q11