CA1328224C - Oral compositions - Google Patents

Abstract

ORAL COMPOSITIONS
Abstract Anticalculus and antiplaque oral care compositions containing geminal diphosphonate polymer anticalculus agents and a pharmaceutically acceptable carrier, and method for inhibiting formation of calculus and plaque in the oral cavity by treatment with geminal diphosphonate polymers.

Description

:
` ORAL COMPOSITIONS
Charles Raymond Degenhardt Barbara Ann Kozikowski , ~b~i~
This invention relates to oral care compositions which contain anticalculus and antiplaque agents, and to a method for inhibiting the formation of calculus and plaque in the oral cavity.
Backnround of t e Invention Dental calculus and plaque are two undesirable, but unfortunately common, dental condit;ons experienced by the general population.
Dental calculus, or tartar as it is sometimes called, is a deposit which forms on the surfaces of the $eeth at the gingival ~, 15 margin. Supragingival calculus appears principally in the areas near the orifices of the salivary ducts; e.g., on the lingual surfaces of the lower anterior teeth and on the buccal surfaces of the upper first and se~cond molars, and on the dista1 surfaces of ~, the posterior molars.
Mature calculus consists of an inorganic portion which is largely calcium phosphate arranged in a hydroxyapatite crystal y lattice structure similar to bone, enamel and dentin. An organic ; portion is also present and consists of desquamated epithelial cells, leukocytes, salivary sediment, food debris and various `! 25 types of microorganisms.
As the mature calculus develops, it becomes visibly white or yellowish in color unless stained or discolored by some extraneous agent. In addit~on to being unsightly and undesirable from an aesthetic standpoint, the mature calculus deposits are constant sources of irritation of the gingiva.
~` Another source of irritation in the oral cavity is p1aque.
Plaque is a combination of minerals and bacteria found in the mouth. The bacteria associated with plaque can secrete enzymes and endotoxins which can irritate the gums and cause an inflammatory gingivitis. As ths gums become increasingly irritated by this process, they have a tendency to bleed, 1 '1 `., A .1 /

~ 1 328224 . . .

their toughness and resiliency, and separate fFrom the teeth, leaving periodontal pockets in which debris, secretions, more - bacter;a and toxins further accumulate. It is also possible for ~ food to accumulate in these pockets, thereby providing nourishment :. 5 for increased growth of bacter;a and production of endotoxins and destructive enzymes.
Mechanical removal of calculus periodically by the dentist ~ is, of course, routine dental office procedure. However, .~ effective compositions and methods for inhibiting calculus ~ formation between dental offfice visits are desirable for enhancing .. ' oral hygiene. A wide variety of chemical agents have becn suggested in the art to retard calculus formation or to remove : calculus afFter it is formed.
Inhibiting the formation of calculus between dentist visits has generally been accomplished with chemicals that involve chelation of calcium ion and/or crystal growth inhibition which ~, prevents the calculus from form; ng and/or breaks down mature ~:, calculus by removing calc;um.
`. The art discloses a number of chelating agents for this purpose. British Patent 490,384, February 15, 1937, discloses ~; oral compositions containing ethylenediam;netetraacet k acid, '~. nitr~lotriacet k acid and re1ated compounds as anticalculus ~, agents. These anticalculus agents have relatively low efffective-~'~ 25 ness.
j Also disclosed in the art are oral care compositions con-.lf, taining soluble pyrophosphate saltsO Included among such dis-closures are U.S. Patent 2,941,926, June 21, 1960 to Salzmann et . al. which discloses dental powders containing chlorophyll and pyrophosphate salts; U.S. Patent 3,137,632, June 16, 1964 to . 30 Schiraldi, which d;scloses toothpastes contain~fng pyrophosphate 'u salts; U.S. Patent 3,~27,201 and 3,927,202, December 16, 1975 to .~ Baines et al. and Harvey et al., respect;vely, which disclose ~'!,J, toothpastes which utilize soluble pyrophosphates as abrasivesi ~ U.S. Patent 4,244,931, January 13, 1981, and U.S. Patent i~î 35 4,247,526, January 27, 1981 to Jarvis et al., which disclose ~ pyrophosphate salts in d;calcium phosphate systems; Japanese ':f f ~ . . .

Patent Application Disclosure No. 4945-1974, which discloses soluble pyrophosphates in a variety of dentifrice systems; U.S.
Patent 4,333,551, April 6, 1982 to Parran, which discloses tetra-alkali metal salts in mouthwash compositions; U.S. Patent 4,515,772, May 7, 1985, to Parran et al., U.S. Patent 4,590,066, May 20, 1986 to Parran et a1., and U.S. Patent 4,684,518, August 4, 1987 to Parran et al., which disclose toothpaste compositions containing particular dialkali metal and tetraalkali metal pyro-phosphate salts.
Mechanical removal of plaque and the minerals found which can collect near or underneath the gums which nourishes the bacteria which causes plaque is accomplished by conscientious oral care practitioners by brushing and flossing ~fter meals. Mechanical removal, unfortunately, is not always completely thorough or j~ 15 effective, especially when not performed correctly and regularly.
It is desirable to provid~ chemical compositions and methods which effectiYely inhibit plaque formation. These are preferably used in comhination with mechanical methods of removal.
The art contains numerous disclosures of phosphonate materials useful as bpth ant;calculus and anti-plaque/antigingivitis agents in oral compositions. For e~ample, U . S . Patent 3, 429, 963, i ssued February 25, 1969 to Shedlovsky, U.S. Patent 4,102,993, issued July 25, 1978 to Gaffer, U.S. Patent . , ;~ 2S 4,042,679, issued August 16, 1977 to Gaffer, U.S. Patent 4,100,270, issued July 11, 1978 to Gaffer, U.S. Patent 4,098,880, ~ssucd July 4, 1978 to Gaffer, U.S. Patent 4,123,512, issued `1 October 31, 1978 to Gaffer, U.S. Patent 4,133,477, issued February 6, 1979 to Gaffer, and U. K. Patent Application 2,151,478, pub--~ lished July 24, 1985, Gaffer, all disclose polyvinyl phosphonate polymers having monophosphonate monomeric units. U.S. Patent ~ 3,553,315, issued January 5, 1971 to Francis, discloses short '''~! chain carboxyphosphonic acid compounds. U.S. Patent 3,553,314, ;; issued January 5, 1971 to Francis, U.S. Patent 3,641,126, issued February 8, 1972 to Prentice, and U.S. Patent 3,737,522, issued .' :! 35 June 5, 1973 to Francis, d;sclose nonpolymeric compounds having ~i geminal diphosphonate groups.
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; , - 4 -U.S. Patent 4,208,401, issued June 17, 1980 to Bauman, dis-closes a quaternary ammonium alkylene diphosphonate anticalculus agent having a geminal diphosphonate carbon. U.S. Patent ; 3,678,154, issued July 189 1972 to ~idder et al., and U.S. Patent .~ 5 4,025,616, issued May 24, 1977 to Haefele, disclose polyphosphonate mater;als hav;ng one phosphonate group per carbon in the polymer backbone and phosphonate molecules having one geminal diphosphonate carbon atom.
,~ While numerous materials as described above have been dis-.; 10 closed for use in oral compositions as anticalculus and antiplaque :.~ agents, there still exists a need for improved anticalculus and , antiplaque agents.
It is an object of this invention to provide safe and effec-; tive anticalculus oral care compositions having good long term storage stability and high effectiveness.
' It is a further object of this invention to provide oral care compositions, as described above, that provide both anticalculus .', activity and antiplaque activity.
. It is another object of this invention to provide safe and ', Z effective anticalculus and antiplaque oral care compositions which, in addition to being stable and having high anticalculus and/or antiplaque effectiveness, can be made at ~ommercially j, viable economic cost.
'~ It is yet another object of this invention to provide a safe ~c and effective method for inhibiting the formation of calculus ,, in the oral cavity. It is still another object of this invention ;', to provide a s~fe and effective method for inhibiting the ',~ formation of both calculus and pl~que in the oral cavity.
,l It is still a further object of this invention to proYide a , 30 safe and effective method for inhibiting the formation of calculus '., and/or plaque which, in addition to providing antical~ulus and antiplaque efficacy, can be implemented at commercially viable ~, economic cost.
SummarY of the I,nvention It has surprisingly been found that the objects of the present invention can be met by oral care compositions comprising .`!, , '. ~

:'. . . ~ . . ~ .

,. ~' ,' ' ' : ' ;'`, '' ' ~ ' ;' , : ', ~ :

:

.
`- 1 328224 .
; - 5 -.~ geminal diphosphonate polymers and a pharmaceutically acceptable carrier. Specifically, such geminal diphosphonates include:
.. . Ra R1 Rb R2 " (i) (-CH - Cl~a -(CH - C- )b . 5 Q~
C-(P03H2J2 : R3 wherein each R1, R2, Ra~ and Rb can independently be H, ~.~ C02H or ester thereof, -P03H2, -C--N, substituted or : 10 unsubstituted aryl, substituted or unsubstituted C1-C1o alkyl, or substituted or unsubstituted C~-C20 oxyalkyl, each R3 can independently be -H9 -OH, amine, or . substituted or unsubstituted C1-C3 alkyl, each m can ,'.~'~f independently be O or 1, each Q can independently be a .; 15 substituted or unsubstituted aryl or a substituted or unsubstituted C1~Clo alkylene, and the ratio of a/b is ~ greater than or equal to C and less than about 30;
i'''j P03H2 P3H2 (ii) (-CH2 - CH )a ~ t-~H2 - C - )b , 20 P03H2 wherein a/b is greater than or equal to O and less than about 30; and (iii) polymerization products of , CH2-CH-cH=c(Po3x2)2 ~:^ 25 wherein each X can independently be -H or a C1-C10 . 1 alkyl, and when X is an alkyl, each -P03X2 group is ; ~ converted to a -P03H~ group subsequent to .l polymerization, and mixtures thereof;
said geminal diphosphonate polymer having an average molecular weight of between about 1,000 and about 20,000 and an average of at least three geminal diphosphonate units per polymer chain.
.~ Detailed Description of the Invention This invention pertains to geminal diphosphonate polymers, ; ~j' oral care compositions containing such geminal diphosphonate ;,'~.J,~ 35 polymers specifically formulated for administration to the oral `~ cavity without substantial ingestion, and methods for inhibiting .

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~ calculus and plaquP in the oral cavity. Applicable compositions ~ include, but are not limited to, mouth washes, tooth pastes, powders, dentifr;ce compositions, topical solutions, prophylaxis -~ pastes and gels, lozenges, gums, and the like.
: 5 Geminal Di~hosDhonatQ Polymers .~ Geminal diphosphonate polymers within the scope of the ~ inven~ion include the following three formulas:
.~ (1) Ra Rl Rb R2 .. i. (-CH - CHta~ ---t-CH - ~,C-)b ,: 10 Qm C-(P03H2)2 ~: R3 wherein: each Rl, R2, Ra~ and Rb can ;ndependently be -H, -CO?H or ~, ester thereof, -P03H2, -C--N, substituted or unsubstitutPd aryls, substituted or unsubstituted C1-Clo alky1s, or substituted or unsubstituted Cl-C20 oxyalkyl, preferably -H, -C02H, -P03H2, or unsubstituted C1-C3 alkyls; each R3 can independently be -H, -OH, -C3 substituted or unsubstituted alkyl, or amine (including, but not limited to alkyl amines), preferably -H, -OH, or unsubstituted l 20 Cl alkyl; each m can independently be O or 1, and each Q can inde-.,~ pendently be a substituted or unsubstituted aryl or a substituted ~x or unsubstituted Cl-Clo alkylene, preferably a Cl-C3 alkylene; and the mole ratio of a/b is greater or equal to O and less than about :~ 30, preferably less than about 20;
,:l 25 (2) P03H2 P03H2 CH2 - CH lhrt-C~2 - C )b ;
' PO H
.1 wherein a/b is greater or equal to O and less than about 30, , preferably less than about 20; and a geminal diphosphonate polymer ~ormed from the polymer;zat;on of `' the monom~r of Formula (3) as shown below:
' ~03X2 (3J CH2=CH-CH~C

;; 35 wherein each X can independently be -H or a Cl-CIo alkyl, ,t preferably a C~-Cs alkyl, m~re preferably a ~I-C3 al~yl, and most ,, ;, i .,~, preferably a C~ alkyl, and if X is not -H, each -P03X2 group ;s converted to a -P03H2 group subsequent to, or concurrent with, polymerization. This geminal diphosphonate polymerization of the Formula ~3) monomer includes homopolymerization as well as co-polymerization, terpolymerization, and the like, oP said monomer along with sther diphosphonate- or compatible nondiphosphonate-containing monomers. As used herein, "compatible nondiphos-phonate-containing monomers" means monomers which do not signi-ficantly interfere with the anticalculus efficacy, and preferably o the antiplaque efficacy, of the geminal diphosphonate groups.
As indicated by the above formulas, the geminal diphosphonate polymers of the present invention can have a geminal diphosphonate unit as part of the polymer backbone, as part of an alkyl or aryl group bonded to the polymer backbone~ or as a mixture thereof. As used herein, the term "geminal diphosphonate" shall refer to chemical functionalities or monomeric units having a carbon atom `- with two phosphonate groups, or salts thereof, attached to that carbnn atom.
As used herein, the term "polymer" with reference to the geminal diphosphonate polymer of the present invention shall include polymers, copolymers, terpolymers, and the like. The term "polymer" shall also include oligomers so long as the molecular ~- weight limitations of the present invention are met. The geminal diphosphonate polymers of the present invent;on shall include the phosphonic acid forms of the diphosphonate as well as pharmaceu-tically acceptable salts thereof, such as, but not llm;ted to, alkali metal salts (e.g., sod;um and potassium), alkali earth ~ metal (e.g., calcium and magnesium)1 and ammonium or low molecular :'i weight substituted ammon;um (e.g., mono-, di-, and triethanol-u 30 ammonium) salts. At least about 3%, on a molar basis, of the , monomeric units of the polymer should constitute or have substi-j tuted thereon a geminal carbon diphosphonate unit. Preferably at ~ least about 5% of the monomeric units of the polymeric chain -> constitute, or have substituted thereon, a geminal diphosphonate unit. The non-geminal diphosphonate monomeric units should be ; geminal diphosphonate-compatible monomers. By "geminal ,~ .

, :, ~ .
.... : ,,;, :

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1 3282~4 .

'~' diphosphonatecompatible monomers" is meant monomers which do not signif;cantly interfere with the anticalculus, and preferably the Z antiplaque, efficacy of geminal diphosphonate groups.
~` As used herein, the symbols "a" and "b" shall refer to mole proportions and the ratio "a/b" shall therefore be a mole ratio.
The ratio of a/b can be determined by using phosphorus-31 Nuclear Magnetic Resonance Spectroscopy (P31NMR) techniques, said techniques being known to those skilled in the art.
~` The geminal diphosphonate polymers of the present invention are also characterized by having molecular weights of at least about 1,000, preferably between about 1~0ZOO and about 20,000, more ,.
preferably between about 1,000 and about 5,000, and mos~ prefer-ably between about Z,000 and about 5,000. As used herein, "molecular weight" shall refer to the weight average molecular ;l 15 weight as measured by the Low Angle Laser Light Scattering (LALLS) ~ technique, said technique being known to those skilled in the art.
; It is undesirable for the molecular weight to be substantially lower than about 1,000 for safety concerns related to absorption into the bloodstream and effects upon bone remineralization and ~, 20 desorption. Anticalculus eff;cacy ls believed to decrease as the i~ ability of the geminal diphosphonat~ polymer to adsorb onto tooth `i or plaque material decreases. Molecular weights below about 20~000 are desirab1e since diphosphonate adsorption generally ~1 decreases with increasing molecular weight. Especially high Z 25 anticalculus efficacy has be~n observed in the most preferred ran~Ze between about 2,000 and about 5,000. The polymers of Formulas (1)-(3) are further characterized by having at least three geminal diphosphonate units per individual polymer chain.
W;thin the scope of geminal diphosphonate polymers of Formula ~ ., !?Z 30 (1) are the following preferred polymers:

(la) (CH2 - CH-t-a--t-cH2 - Cl- )b P03H2 R4 - C - CH(P~Z3H2)2 ~1 Rs ~`Z 35 wherein a/b is greater than or equal to 0 and less than about 30, ~3 preferably less than about 20 and, for practical considerations.

.;,~Z ~

-` 1 328224 generally greater than about 0.5, each R4 can independently be H
or a substituted or unsubstituted Cl-Clo alkyl, pre~erably H o~ a , Cl-C3 unsubstitu~ed alkyl, more preferably H, each Rs can inde-.1 pendently be H or a substituted or unsubstituted Cl-Clo alkyl, . pre~erably H or a Cl-C3 unsubstituted alkyl, more preferably -H, s and most preferably, both R4 and Rs are H;
.. P03H2 (Ib) (CH2 - CH~t-d (-cH2 - C- )b ;i P03H2 Q
` ¢ - (P3H2)2 wherein a/b is greater than or equal to O and less than about 30, preferably less than about 20 and for practical considerations, `~ generally greater than about 0.5, each R6 can independently be H, substituted or unsubstituted Cl-Clo alkyl, preferably H or un-substituted Cl-C3 alkyl, more preferably H or CH3, and each Q can independently be substituted or unsubstituted aryl, substituted or - unsubstituted C1-CIo alkylene, preferably unsubstituted Cl-C3 .. alkylene; and :i H
(lc) (CH2 - CH-t-a--t-cH2 - C- lb R8 Qm C - (P03H2)2 ' wherein alb is greater than or equal to O and less than about 30, preferably less than about 20 and for practical considerations, generally greater than about 0.5, m can be O or 1, preferably 0, Q
~, can independently be substituted or unsubstituted aryl or a substituted or unsubstituted Cl-Clo alkylene, preferably an unsub-;1 stituted Cl-C3 alkylene, R7 is OH or NH2, preferably OH, or a salt ~. 30 thereo~, and R8 is C02H or CSN, preferably C02H. The geminal ;~ diphosphonate polymers of Formula l(c), wherein R7 is -OH or a salt thereof and R8 is -C02H, are esp cially preferred because it .. 3i is believed that the hydroxylated geminal diphosphonate polymer is .' an especially e~fective oral calculus inhibitor, additionally it ;;~ 35 has antiplaque activity, and it can be made at significant '~ 1 ` 1 32~224 :

econom~c savings rela~ive to most other gemlnal diphosphonate pol ymers .
SYnthesis of Geminal ~iphosphonate PolYm~rs Diphosphonate polymers of the type described by Formula (la) .; can be synthesized by dehydrogenation of polyvinylphosphonate followed by Michael addlt10n of a gem~nal diphosphonate group, or addition of an ester therof followed by conversion to the acid ; form. Polyvinylphosphonate can be made from vinylphosphonate, ~ which can be obta~ned commercially, for exampl~, from Aldr kh .. ~. Chemical Co. (M~lwaukee, W~sconsin), or can be made as described ; in the art (e.g., as described by Kosolapoff in J. Amer. Chem.
.`. Soc., Yol. 79, 1971-1972 (1948) and by Tavs and We~tkamp in ;. Tetrahedron, Vol. 26, 5529-5534 (1970).
~' , The polymerizat~on of unsaturated phosphonic acid and/or . phosphonates is described by Sander and Steininger in J.
Macromol. Sci. (Revs.3, C1, 7-89 (1967), incorporated by reference hereln. In general, the polymerization of vinylphosphonate can be carried out in accordance with the following description:
(i) CH2 ~ CH fre~ ra~ical~nitia~Qr~> (-CH2-C~~)n P03X2 neat solution P03X2 -- wher~in the react~on is preferably carried out at about 60-C to ; about 80-C in neat solution with about 0.1 mole % to about 10 mole :.l % (monomer basis) of a peroxide free radical such as benzoyl per-`;. 25 oxide, hydrogen perox~de, and the l~ke, and X is H or a Cl-Clo alkyl, preferably a C1-Cs alkyl, and most preferably a C2 alkyl;
: or `I (ii) C~2 - ~H aniQnic initiator, solvent? (CH2-CH~)n .. ,.~ P03X2 P03X2 ~: 30 wherein X is as defined above, the anionic initiator can be a `~ dialkyl amide, such as but not limit~d to lith~um diisopropyl-~, amide, a metal hydrideO suc~ as but not limi~ to potassiun hydride, or preferably, an organometallic base such as n-butyl-lithium, naphthalene-sodium, triethyl aluminum, and the like, and ~' 35 the reaction is carrisd out in a polar solvent such as THF, sulfolane, and the like, at low temperature, prcferably below ~: i .. ,~ .
.. ',' `

`:~
:`

~--. .

.. about -50CC, more preferably below about -70C. Generally, between about 0.1 mole % to about 20 mole % of the anionic ini-tiator ;s used (monomer basis). The molecular weight of the polymer formed from reaction (i) will generally be from about 1,000 to about 5,000. The molecular weight of the polymer formed from reaction (ii~ can vary depending upon reaction conditions, '.~ bUt will generally be from about 5,000 to about 20,000 at the preferred conditions. The geminal diphosphonate polymer can be formed by performing the following steps, which will also be ,- lo readily understood by those skilled in the art:
: strong base, solvent, CHz-CH~t~n low temp ~ -CH2C~
~: ¦ (a) : ~, PO~X2 /P03X2 ~; ^ ~
: 15 (b) /
;~ / Michael Addit;on , ~ . / RcH=c ( po3x2 ~ ?

j~ ~CH2-~H )d - (-CH2-CI -)b po3X2 RCH
CH(P03X2)2 1` \ strong mineral acid ,. \
( c ) \
~, ~1 P3H2 ;~ 25 -(CH2-CH J a -- ( CH2-lc)b ,~',r,,/ P03H2 RCH
CH(po3H2)2 . .
,,.~ ,~
';~. wherein, with respect to the Michael Addition reagent RCH =
C(P03X~2, X is a Cl-Clo alkyl, preferably a Cl-Cs alkyl, most ` 30 preferably a C2 alkyl, and each R can independently be H or a ,: .: ,, ,~, . .s : "

`;';

. , C1-C10. preferably a C1-C3 alkyl or H, most preferably H. The most preferred ~onomer, wherein X is C2 alkyl (i.e., ethyl), is hereafter alternately referred to as CH28C(PO3Et~2, tetraethyl : vinyldiphosphonate. The synthesis of preferred RCH3C(PO3X2)2 monomers is described in further detail by Degenhardt and Burdsall in "Synthesis of Ethenylldeneb~s (Phosphonic Acid) and Its Tetra-.. alkyl Esters,~ The Journal of Organic Chem~stry, 1986, 51, 3488.
Step (a) i~ performed u~ing ~
strong base, preferably an organometall ic base such as, but not limited to, n-butyllithium, naphthalene-sodium, and tetraethyl aluminum, or a dialkyl amide such as, but no~ limited to, lithi~m . diisopropylamide, or a metal hydride such as, but not 7imited to, potassium hydride, and a polar solv~nt such as, but not limited to, THF and 1,2 dimethoxyethane, and the like at a temperature pr~ferably below about -50-C, more preferably below about -70-C.
The step (c) conversion to the phosphonic acid form can b~ per-formed by treatment with a strong mineral acid solution, such as :~ HCl, H2S04, H3PO~, and the like. The step (b) Michael Addition : react~on can be performed by mixing the vinyl diphosphonate and ; 20 the base-treated polymer in THF solution.
The diphosphonate polymers of Formula (lb) can be synthcsized by the following reaction sequence which will readily be under-stood by those skil~ed in the art:
.strong base (CH2-CH)- >tCH2C-) ~, P03X2(d) / P03X2 ; (e) / YQmC(P03X2)2Z

, i~
" P03X2 P03H2 . (CH2-CH 3 d ~ CH2-C)b ~ stronq acid~ (cH2-cH-~a-4-cH2-c)b P03X2 Qm ~f3 P03H2 Qm C-(P03X2)2 C(P03H2)2 ~'' Z Z
,., ~,~1 .: :

~- 1 328224 wherein steps (d) and (f) are performed as defined above for steps (a) and (c3 respectively, and Y is a halogen, preferably C1, or ;; sulfonate ester, ~ is H or a Cl-Clo alkyl group, preferably H or a Cl-C3 alkyl group, most preferably H or CH3, X is as defined above - s with reference to reaction (ii), m is either O or 1, and Q is a substituted or unsubstituted aryl or a substituted or unsubsti-tuted Cl-Clo alkylene, preferably a Cl-C3 alkylene.
The preferred geminal diphosphonate polymers of Formula (lc) - wherein R7 is OH, or a salt thereof, can be synthesized by re-acting phosphorous acid or a precursor of phosphorous acid which is capable of generating phosphorous acid in aqueous solution, such as PC13, in a polar organic solYent with a water-soluble carboxyl polymer. Preferred organic solvents are those in which the carboxyl polymer and the phosphorouc acid or phosphorous acid precursor are essentially completely soluble so as to proYide a ~ homogeneous reaction mass. Typical preferred solvents are sulfo-;~ lane (tetrahydrothiophene-l,l-dioxide), di-n-propyl sul~one, tetrahydrofuran (THF), 2-methyl THF, 3-methyl THF, tetrahydropyran `-I and the like. The temperature of the reaetion mass should be above its freezing temperature. The reaction is preferably carried out at a temperature in the range from about O-C to about 200'C, more preferably from about 50'C to about 150-C.
The carboxyl polymer may be der;ved from an ~-~-olefinically unsaturated monomer having a carboxyl group. The carboxyl polymer can also be derived from an acid anhydride polymer derived from monomers readily converted to a carboxylic acid form. Preferred " carboxyl polymers are those with at least 50% by weight with ;` carboxylated or methyl-ester monomer units. Applicable polymers , include polyacrylic acid, polymethacrylic acid, copolymers of acrylic acid and methacrylic acid, such as are commercially available; and polymaleic acid or polymaleic anhydride prepared as .:"'rl described by Norman G. Gaylor in J. Macromol. Sci. Revsi. Macro-- mol. Chem., C13(2), 235-261 (1975); or copolymers of maleic anhydride with an olefin having from 2 to ~ carbon atoms; or a 1 35 copolymer of maleic anhydride with a vinyl ether or vinyl ester or -~ alkyl(meth)acrylate. The process for making such geminal , . ;~
. . - . . .
; ~, ,..... -:

-` 1 328224 ..

. . .
-`~ - 14 -d;phosphonat~ polymers is described in further d~tail by MaslQr : and Spauld1ng in U.S. Patent 49207,455, issued June 10, 1980.

Gemlnal dilphosph3nate polymer encompassed by Formula (lr) wherein R7 is an amine and R8 is -C~N can be made by reacting phosphorous aeid or a precursor thereof wiith (-CH2-CH~RCN)-)n as - described by Chai et al. in U.S. Paten~ 4,239,695, issued December 16, 1980, wherein, pre~erab1y ~ach ~1 independent1y is a : C1-c10 a1$phatic bridging radical.
.. 10 ~; Those skilled in the art will recosn1ze that the processes disclosed above for synthesis of certain polymers described by Formula (1), each of said processes involYlng a step of attach~ng :1 a geminal diphoisphonate-conta~n~ng group to a polymeric backbone, ::~ 15 will ordinarily result ~n products having an a/b ratio greater than 0, for th~ reason that th~ reaction involv~ng the 9eminal diphosphonate group, for example, the Michael addition during manufacture of a Formula (la) type polymer, the displacement ~ reaction during manufacture of a Formula (2b) ~ype polymer, and .~ ~ the carboxyl polymer-phosphorous acid reaction product of Formula (lc), will generally not occur at all of the potential reaction sites on the polymer. If ~t ~s desired So have the ratio atb by 0 or near zero, the pertinent reactlon ment~oned above can be designed to approach or, to the extent possible for the particular `~ 25 starting mater~als, achieve such goal, by, for example, increasing . reagent concentrat~on and/or reaction time, or by other methods which w1ll be understood by those skilled in the art.
Another approach to achieve an a/b rat10 of zero for the ~'~ Formula (1) polymers is to homopolymer ke a monomer having the ~ 30 following formula:
,`~i R2 ~~ (4) CH2=C
,! ~m Ç- (P3~2~2 , 35 R3 .,, (.
-'`', ~1 .. ~; -- . , 1 32822~
~ 15 ~
wherein R2, R3, m, and Q are as defined with respect to Formula (1)~ This homopolymerkat1On ~s prefer~bly carried out by an~onic or free radical polymer katlon techn;ques. Fre~ radical poly-merization can be carried out ut~ ing free radicals surh as benzoyl peroxide, hydrogen peroxide, and the liks ln neat solution or in a nonpolar solvent, preferably at about 60~C to about 80-C
with about 0.1 mole % to about lO mole Z of the free radical, .. caleulated on a monomer molar basis. Anionic polymer~zation is ~ preferably initiated with an organometallic base such as n-butyl-:' 10 lithium, naphthalene-sodium, triethyl aluminumjl and the like, and the reaction is carr~ed out in a polar solvent such as THF, .i sulfolane, and the like, at low temperature, preferably below about -50C, more preferably below about -70'C. Generally, - between about 0.1 mole % to about 20 mole X of the an~onic ini-~:, 15 tiator ls used (monomer basis).
:t Methods for synthesiz~ng geminal diphosphonate polymers of the type described by Formula 2 wherein a/b is zero are known to .~ those skilled in th~ art and have been disclosed, for example, by arroll and Crutchfield ~n U.S. Patent 3,544,509, issued December , 20 1, 1970. The~e di ,J, phosphonat~ polymers can be made by polymerlization of lower ~lkylene-l$l-diphosphonat~ ac~ds and metal salts thereof. Alter-`'. nately9 the diphosphonate polymers can be made from esters of ~ lower alkylene-l,l-diphosphonate acids. Preferably the diphos-.l 25 phonate salts are converted to the fr~e acid by treatment with a strong acid.
In addit10n to the diphosphonic acld and metal salt monomers of U~S. Patent 3,544,509, monomers of th~ formula RCH~C(P03X2)2 as ; described above with reference to Formula (la) synthesis can be ~ 30 used, and are in fact preferred.
.~ Once polymer ked, polymers formed from RCHYC(P03X2)2 can be converted to diphosphonic acid form by treatment with a strong . mineral acid, such as H2S04, HCl, H3P04, and the like9 as de-scribed by ~orms and Schmidt-Dunker in "Organic Phosphorus ~, 35 Compounds," Yolume 7, edited by Kosolapoff and Maier, pp 1-487 ( 1967 ) ~
`~!" Bl , ,~
,, .

..... . . , . . ~.. . . ~ . .. ~ , `` 1 328224 . .
`-,'' ; - 16 -Polymerization can be carried out by such methods as heating and/or using, as a catalys~, ultraviolet light, a free radical initiator, or an anionic initiator appropriate for use due to its solubility in the lower alkylene-1,1-diphosphonates and/or the medium used for polymerization, such as water and/or organic solvents. Free radical initiators include peroxides, including benzoyl peroxide, tolyl peroxide, hydrogen peroxide, and the like.
- Anionic ;nitiators include organometallic reagents such as n-~` butyllithium, naphthalene-sod;um, triethyl aluminum, and the like.
The free radical or anionic initiators can be used in varying ,~ amounts. Generally from about 0.1% to about 5% by weight of the lower alkylene-1,1-diphosphonate is sufficient.
~; The diphosphonate polymers of Formula 2, wherein a/b is zero or greater than zero can be synthesized according to the following reaction sequence which will readily be understood by those skilled in the art:
: .
- strong base, solvent -(-CH2-CH ~~-n low temQ. ~ (-CH2-C- -)n P03X2 ~ P03X2 s 20 .. , /
. / (h) / displacement reaction `.', / YP03X'2 .~'., L/
03X'2 ,P3H2 (CH2CH-t-a-~-CH2-C -)-b stron~ acid~ (cH2-cH-t-a-t-cH2 C-)b P03X2 P03X2 (j) P03H2 P03H2 wherein steps (g) and (j) are performed as defined above for steps (a) and (c), respectively, Y is a halogen, preferably Cl, and X' is an aryl or C1-C1o alkyl, preferably an aryl or C1-Cs alkyl, ~; 30 more preferably an aryl or C2 alkyl. The step (h) displacement ;~ reaction can be performed by adding the phosphoryl halide ~ ~YP03X'2) to the THF solution of tha base-treated polymer. In ; l practice, the ratio of a/b will generally be greater than zero ,, 1 ''l .
, ":s, . . . .. .

---` 1 32822~

since all of the potential reaction sites on the polymer backbone will not experience the displacement reaction.
Ge~inal diphosphonate polymers formed from the monomers of Formula (3) can be prepared, in general, by 1,4 polymerization, 2,3 polymerization, or a combinatlon thereof of the Formula (4) monomers.
~; Formula (3) monomer preparation and subsequent polymerization can be performed according to the exemplary method shown below.
strong base, P03X2 CH2(PO3X2)2CH2 = CHCH2Y~ CH2 = CHCH2CH
`` (k) -'f"'- P03X2 .`,:, .~; (mJ /
f'~strong base, P03X2 -S-Ph CH2=CHCH2C-S-Ph ~
P03X2 1 oxidizing agent P03X2 CH2=CH-CH=~
(n3 / P03X2 (o) /) anionic initiator; or / 2) free radical initiator ;~',i ~ .
, 3X2 l)strong acid; or P03H2 (-CH2-CH~CHC- )n 2) silyl halide ~ (-cH2-cH=cHc- )n :, Po3x2 (P) P03H2 Referring to the methyl d;phosphonate starting material, X
can be H or a Cl-Clo alkyl, preferably a Cl-Cs alkyl, more ' preferably a Cl-C3 alkyl, and most preferably a C2 alkyl.
: Referring to reaction step (k~, the strong base is preferably a metal hydride, such as, but not limited to, pot~ssium hydride, and Y is a halogen, such as, but not limited to, bromine and chlorin~.
Referring to reaction step (m), the strong base can be the same as , with respect to step (k), and -S-Ph represents a phenyl thiol leaving group which can be derived from compounds such as, but not ; :, ':'1 , . !

:`:

, 1 32~22l~

limited to, diphenyl disulfide (PhSSPh) and S-phenylbenzenethio-sulfonate (PHS02SPh). Referring to reaction step (n), such step can be carried out using conventional oxidizing agents. The polymerization reaction of reaction step (o) can be carried out with either anionic initiators, such as but not limited to organo-metallic bases, dialkyl amides, and metal hydrides as previously discussed herein or free radical initiators, such as but not l;mited to benzoyl peroxide and hydrogen peroxide, preferably free radical initiators. If X ;s not -H, convers;on of the produet of step (o) to the phosphonic acid form can be performed by treatment with a strong mineral acid or, preferably, with a silyl halide, such as but not limited to trialkyl silyl halides, e.g., trimethyl silyl bromide. Details of a preferred execution of this process can be found in Example IV.
` Molecular weight can be varied by a variety of techniques which will be readily known to those skilleJ in the art. Without limiting the invention to any particular method, s~ch molecular weight-varying techniques include choice of catalyst or free -~ radical, choice of monomer, temperature, concentration, rate of stirring, etc. Molecular weight can also be manipulated by ` separa~ion techniques, such as with a gel filtration ~olumn.
Oral Care Compositions , The oral care compositions include any composition containing : 25 a pharmaceutically safe and effective amount of one of the above geminal diphosphonate polymers for inhibiting the formation of calculus and a pharmaceutically-acceptable carrier suitable for use in conjunction with oral administration. The compositions of the present invention are preferably formuiated specif;cally for use in the oral cavity (ie. mouth) without being generally ingested, except as to any ingestion that may incidentally occur during usage. Thus, in the course of ordinary usage or treatment, the composition will be administered to the oral cavity and subsequently expunged after the usage or treatment. By "oral ~: administration" and "administered to the oral cavity," or other analogous terms used herein is meant any activity by which the compositions of the present invention are administered into the :1 ''.'~
:,., ; ,i :

`:
. . - 19 -..
~ mouth and contacted with the teeth and gums. As used herein, "oral administrat;on" and "administration to the oral cavity"
., .
shall include contact with teeth and gums areas, as well as with any calculus or plaque that may already be formed in the oral cavity. Contact may occur by such nonlimiting activities as . rinsing, brushing with a tooth brush, and directin~, a stream of water containing the composition toward the teeth and/or gum ; areas. The present invention embraces powders, pastes, gels, ; solutions, and the like, for rinsing, washing, or topical 10 application in the oral cavity. These compositions include dentifrices, such as powders, pastes, gels, and liquids for - cleaning teeth, prophylactic compositions, such as antigingivitis compositions and mouth rinses and other oral care compositions.
,., ! Alsu included are compositions conta~ning combinations of 15 dentifrice, prophylactic, and other oral care ingredients.
By "pharmaceutically acceptable carrier", as used herein, is . .
meant one or more diphosphonate-compatible solid or liquid diluents or encapsulating substances which are suitable for oral i administration, but which needn't be suitable for ingestion of - 20 substantial quantities on a regular basis. By "diphosphonate-compatible", as used herein, is meant components of the composition that do not interact with the diphosphonate ,i polymer , espe~ially during storage, in a manner which would ;. 3 substantially reduce the composition's ef~ectiveness for 25 inhibiting formation of calculus and/or plaque. By suitable for "oral administration", as used herein, is meant suitable for application to or rinsing of the interior, or cavity, of ones ~` mouth, or a part thereof.
The concentration of geminal diphosphonate polymer in the 30 oral care composition is at least an effective amount for pro-viding anticalculus efficacy (i.e., calculus-inhibiting utility).
Preferably the concentration of geminal diphosphonate polymer in the oral composit;on will be between about 0.1% and about ~0%, by weight. Generally the oral care composition will contain between 35 about 1% and 10%, most generally between about 1% and about 5%.
. ~
. .
., .
,.,:

` 1 3~8224 :

.
.~ By "safe and effective amount" as used herein is meant an amount of a geminal diphosphonate polymer high enough to provide anticalculus and/or antiplaque efficacy, preferably both, but not so high as to fall outside the scope of sound medical judgment.
The safe and effective amount of the geminal diphosphonate polymer can vary with the particular polymer chosen, the duration of treatment, and the particular carrier from which the geminal diphosphonate polymer is applied and other considerations as may ` be apparent to one skilled in the art. Generally an amount of at least about 0.025 grams of the geminal diphosphonate polymer administered on a rPgular basis, e.g., one or more times per day, to the oral cavity in such oral care products as des~ribed above `~ under the conditions and circumstances in which such products are ~; conventionally utilized effective for inhibiting formation of ; 15 calculus. Optionally, at least about 0.05P grams is administered in a regular basis. These same amounts can also be effective for inhibiting the formation of plaque in the oral cavity. Generally, the amount of geminal diphosphonate polymer administered orally is less than about 5 grams per oral administration.
The oral care compos;tions of the present invention prefer-ably have a pH of between about pH 5.0 and about pH 11Ø A
~, preferred pH range is from about pH 7.0 to about pH lO.O. The pH
I of the composition, of course, is determinative of the predominant , salt form of the diphosphonate polymers present therein. Prefer-":! 25 ably the composition is buffered, for example, by lncluding a :`, buffer in the carrier, such that a pH of between about pH 5.0 and about pH 11.0, more preferably betwe~n about pH 7.0 and about pH
10, is maintained in the oral cavity during use. Exemplary nonlimiting buffers include c~trate, citrate/bicarbonate, and phosphate buffers.
The carrier can additionally comprise the usual and optional components of the particular type of oral composition desired.
Such additional components can include abrasives, sudsing agents, `~ flavoring agents, sweetening agents, antiplaque agents, antitartar ;,,3 35 agents, antigingivitis agents, coloring agents, pigments, hu~ec-~ tant~, binders (thickening agents), fluoride anticar;es agents, ., , . s ~ ` 1 328224 .
,`,:

etc. The choice of carrier to be used is basically determined by - the way the composition is to be introduced to the oral cavity and ~: by the purposes, in addition to inhibiting formation of calculus, -`~ for which the composition is meant to bc effect1ve. For example, if a toothpaste is to be used, then a "toothpaste carrier" is chosen as disclosed in, e.g., U.S. Patent 3,98~,433, to Benedict, (e.g., abrasive materials, susding agents, binders, humec~ants, flavoring .; and sweeten1ng agents, etc.), or if a mouth rinse is to be used, . 10 then a "mouth rinse carrier" is chosen, also as disclosed in, ~; e.g., U.S. Patent 3,988,433 to Bened~ct (e.g., water, flavoring .~ and sweetening agents, possibly an organic solvent such as ethan-ol, etc.). Similarly, if a mouth spray is to be used, then a : "mouth spray carrier" which can be similar to mouth rinse carriers - 15 as described above, is chosen and, depending upon the type of . application chosen, a propellant may also be included; if a , chewing gum is to be used, then a "chewing gum carrier" is chosen, .~ as disclosed ~n, e.g., U~S. Patent 4,472,373, to Ryan, and in U.S.
~ Patent 4,083,955, to Grabenstett~r ~t al., :.~. 20 (e.g~, gum base, flavoring and sweetening agents); and if a sachet is to be used, thPn a ~sachet . carrier" is chosen (e.g., sachet bag, flavorlng and sweetening agents). Carriers suitable for the preparation of compositions of the present ~nvention are well known in the art. Their selection will also depend on secondary considerations like taste, cost9 :, shelf stability, which are not crltlcal for the purpose of the ^~1 present invention, and can be made without dlfflculty by a person , skilled in the art.
The abrasive polishing mater~al contemplated for use in the present invention can be any material which does not excessively .. 1 abrade dentin. These include, for example, silicas including gels and precipitates, calcium carbonate, dicalcium orthophosphate ~i dihydrate, calcium pyrophosphate, tricalcium phosphate, calcium ~'`t polymetaphosphatP? insoluble sodium polymetaphosphate, hydrated alumina, and resinous abrasive materials such as particulate Bl condensation products of urea and formaldehyds, and others such as ., . .. `
.....
` ~ ::! '' '~'1:.' '; , :` ~ ' ' ~ ' ' ' r~

.' ': . .. . ' : ~ , :
:'~

1 32822~

disclosed ln U.S. Patent 3,079,510, Cooley et al., December 25, 2. ~ixturQ~ of abras~ve~ ~ay also be used. Preferably, ~he abras~ves used are not large sources of solubl~ calcium such that the crystal growth ~nhibiting ~, capacity of the diphosphonate polymer 1S significantly depleted.
.l For this reason, conventional abrasives such as calclum carbonate ;-- and dicalcium orthophosphate are preferably not used, or are ,. present in sm~ll quantitles relative to the diphosphonate polymer such that significant anticalculus efficacy ls ma1nta~ned, or are . 10 not contacted with the diphosphonate polymer until shortly before or slmultaneously with delivery to the oral cavity. However, predominantly ~-phase calcium pyrophosphate such as that prepared . in accordance w~th Schweizer, U.S. Patent 3,112,247, issued : November 26, 1963, which contains relatively l~ttl~ soluble ~: 15 calcium, can be used and is a preferred abrasive. Other preferred `: abrasives include alumina insoluble ~etaphosphate, and the resin-:;, ous abrasives cf U.S. Patent 3,070,510.
Silica dental abrasives, of various types, can provide ~' exceptional dental cleaning and polishing performance without . unduly abrad~ng tooth enamel of dentin. Silica abrasive materials i are also believed to be exceptionally compatible w~th phosphate ~;,` materials as well as with sources of soluble fluoride. For ~hese reasons they are especially preferred for use herein.
~; The silica abrasive pol1shing materials useful herein, as well as the other abrasives, generally have an average part;cle s~ze ranging between about 0.1 and about 30 microns, pr~ferably ~ between about 5 and about 15 microns. The silica abrasive can be ,1 precipitated silica or silica gels such as the silica xerogels described in Pader et al., U.S. Patent 3,538,230, issued March 2, 1970 and DiGiu1io, U.S. Patent 3,862,307, June 21, 1~ 1975. Preferred are the ~ilica ~.i.' ~erogels marketed under th~ trademRrk "Sylo~d~ by the W. R. &race ; ! & Company, Davison Chemical ~ivision. Preferred precipitated -,: silica materials include those marketed by the J. M. Huber Corpo-~ 35 ration under the trad~mark "~eodent." These silica abrasives are . "
... .

,.~
.;.. ~ .

,' ' '. : !
',','' , ~ '; 1 , i described in U.S. Patent 4,340,583, July 29, 1982.
~' The abrasive in the compositions described herein ;s prefer-ably prcsent at a level of from about 6% to about 70X, more 5 preferably from abuut 15% to about 25X when the dentifrice is a toothpaste. Higher levels, as high as 90%, may be used if the ; composition is a tooth powder.
An ingrtdient preferably ~ncorporated ~nto dentifrice com-posit~ons such as toothpastes ~s a suds1ng agent. Suitable suds-1~ ing agents are those which are reasonably stable and form suds throughout a wlde pH range, ~.e., non-soap anionic, non;on~c, . cationic, zwitterionic and amphoteric organic synthetic deter-gents. Sudsing agents of these types are described more fully in Agricola et al, U.S. Patent 3,959,458, issued May 25, 1976, and in Haefele, U.S. Patent 3,937,807, ~ssued February 10, 1976.
.,;;
Anionic sudsing agents useful herein includt the watersoluble ~, salts of alkyl sulfates having from 10 to 18 carbon atoms ~n the alkyl radical and the water-soluble salts of sul~onated , 20 monoglycerides of fatty acids having from 10 to 18 carbon atoms.
-, Sodium lauryl sulfate and sodium coconut nmonoglycer~de sulfonates are examples of anionic ~urfactants of thls type. Mixtures of ' anionic surfactants can also be employed.
r~ The nonionic sudsing ag~nts which can be used in the compo-~i 25 sitions o~ the present invention can be broadly defined as com-pounds produced by the condensaticn of alkylene oxide groups .~, (hydrophil;c in nature) with an organic hydrophobic compound which may be aliphatic or alkylaromatic in nature. Examples of suitable ;, nonionic sudsing agents include the PluronicsTM (Wyandotte Chemi-cals Corp., Wyandotte, Michigan), polyethylene ox~de condensates :~ of ethylene oxide with the reaction produot of propylene oxide and ethylene diamine, ethylene oxide condensates of aliphatic '~ alcohols, long chain tertiary amine ox;des9 long chain tertiary ,`, phosphine oxides, long chain dialkyl sulfoxides and mixtures of such materials.
, . ~

.'t''~

~. . , ', .. , . .: , ` `;
; `
;~ - 24 -; The zwitterionic synthetic sudsing agents useful in the ;. compositions of the present invention can be broadly described as derivatives of aliphatic quaternary ammonium9 phosphonium, and sulfoniurn compounds, in which the aliphatic radicals can be straight chain or branched, and wherein one of the aliphatic substituents contains from about 8 to 18 carbon atoms and one contains an anionic water-solubil king group, e.g., carboxy, sulfonate, sulfate, phosphate, orphosphonate.
The cationic sudsing agents useful in the compositions of the present invention can be broadly defined as quaternary ammonium compounds having one long alkyl chain containing from about 8 to about 18 carbon atoms such as lauryl trimethylammonium chloride;
cetyl pyridinium chloride, cetyl trimethylammonium bromide, di-isotubylphenoxyethoxyethyl-dimethylbenzylammonium chloride;
coconutalkyltrimethylammonium nitrite; cetyl pyridinium fluoride;
, ~ .
etc.
The amphoteric sudsing a~ents useful in the present invention can be broadly described as derivatives of aliphatic secondary and tertiary amlnes in which the aliphatic radical can be straight ;. 20 chain or branched and wherein one of the aliphatic substituents contalns from about 8 to about 18 carbon atoms and one contains an anionic water-solubilizing group, e.g., carboxylate, sulfonate, sulfate, phosphate, or phosphonate.
The sudsing agent can be present in the compositions of this ~;~, 25 invention in an amount from about 0% to about 10% by weight of the `~ total composition.
I Flavoring agents can also be added to the instant composi-;~ tions. Suitable flavoring agents include oil of wintergreen, oil ¦ of peppermint, oil of spearmint, oil of sassafras, and oil of clove. Sweetening agents which can be used include saccharin, dextrose, levulose, aspartame, D-tryptophan, dihydrochalcones~
acesulfame and sodium cyclamate. Flavoring agents are generally ~1 used in the compositions at levels of from about 0.4% to about 2%
~1 by weight and sweetening agents at levels of from about 0.1% to ;- 35 about 5% by weight.
~;3 , .. .;
., .:;`1 ,, j :.
. ,~ . .

~ " 1 328224 :~ Binders can also be used with the toothpastes of the present inventions. Such binders inelude, for example, xanthan gum carrageenan? Irish moss, ViscarinR, and carboxyvinyl polymers.
-i These binders are generally present at a level of from about O~lYo . 5 to 1%.
Other antiplaque agents can also optionally be added to the compositions of thls invention. Suitable antiplaque agents may include bis-biguanide compounds such as chlorhex~dine (1,6-bis [N5 pchlorophenyl-Nl-biguanido]hexane), the soluble and insoluble salts thereof, and related materials such as 1,2-bis(N5-p-tri-fluoromethylphenyl-N1-blguanido)ethane. These compounds are de ssribed more fully in Haefele, U~S. Patent 3,923,002, issued January 20, 1976; Haefele, U.S. Patent 3,937,807, issued February 10, 1976; Procter ~ Gamble, Belgian Patent 843,244, published December 22, 1976 and Procter & Ga~ble, Belgian Patent 844,764, published January 31, 1977.
The cornpo~itions of the preE;ent inverltion can also ~. contain other anticalculus agents, or antitartar agents, such as .. the dialkali metal and mixtures of dialkali metal and tetraalkali metal pyrophosphate salts described by Parran~ Jr. et al. in U.S.
Patents 4,515,772, 4,59~,006, and 4,684,518, respectively issued March 19, 1984, February 19, 1985, and August 4, 1987. If pres-ent, the optional antiplaque agents generally comprise from about ~: 0% to about 5~ by weight of the compositlons herein.
:~. 25 Another optional component of the compositions herein is a ~i humectant. The humectant serves to keep the compositions such as ., toothpaste from hardening upon exposure to air and ~n mouthwashes glve a moist feel to the mouth. Certain humectants can also impart desirabl2 sweetness of flavor to mouthwash and toothpaste ~rl 30 compositions. The humectant, on a pure humectant basis, generally ~'~ comprises from ~XO to 70%, preferably from 0% to 55%, by weight of . the compositions herein.
, Suitable humectants for use in this invention include edible :;, polyhydric alcohols such as glycerine, sorbitol, xylitol and pro-.. , 35 pylene glycol. Sorbitol is ~requently employed as a 70% aqueous ':1 Bl`i .
.
r,~j solution. The humectant ranges in the above paragraph, hawever, are based upon the pure sorbitol component of such solutions.
The topical solutions an~ mouth rinses herein may also contain ethanol in an amount preferably of from about OX to about 30%.
Suitable coloring agents include any pharmaceutically accept-able ~ood or drug color;ng acceptable for topical application in the oral caYity.
Water can also be present in the composltions of this inven-tion~ Water employed in the preparation of commerc~ally suitable ~: dentifrices, prophylactlc compositions, and other oral care compositions should preferably be deion ked and free of organic impurities. ~ater generally comprises from about l0% tD 50~, preferably from about 20% to 40X, by weight of the toothpaste .. 15 compositions herein. Mouth rinses generally contain from about 45X to about 95% water. These amounts of water include the free , water whlch is added plus that which is introduced with other .~ materlals such as with sorbitol.
^ It is common to have a water-soluble fluoride compoundpresent in dentifr1ces in an amount sufficient to give a fluoride concentration of from about 0.0025X to about 5.0X by weight, preferably from about 0.005X to about 2.0% by weight, to provide ~: additional anticaries efficacy. Preferred fluorides are sodium :~ fluoride, stannous fluoride, indium fluoride, and sodium mono-fluorophosphate. Norris et al., U.S. Patent 2,946,735, issued July 26, 1960, and Widder et al., U.S. Patent 3,678,154, issued ~ Ju1y 18, 1972, disclose sueh salts, as well as ot~ers.

:, Rat Calculus Test i~ 30 The following test method is useful for obtaining in vivo ; data on the calculus inhibition properties of geminal diphos-phonate polymers of the present invention, and for compar~ng their .~ performance with other phosphonate anticalcu1us agents.
:l Two or more groups of 22 to 23-day old Wistar strain rats, ., 35 each group comprising one member of each of 30 litters, are.. employed in this test, one group serving as the control and the ``~'' dE3.~
~i ~- . - , , , , ~ .

., . ~ ,~ . . , -. ~. . : . . .
.~. .

1 32~224 :.:

other serving as the test group. Each group is balanced for '; weight and sex. The control group of animals i's placed on a calculus inducing diet consisting of 5079 cornstarch, 32% non-fat dry milk, 5% celluflour, 5X powdered sucrose, 3X liver powder, 2.7% NaH?PO4-H2O, 1X vegetable oil, 1% CaCl2-2H2O, and 0.3% MgS04.
' The animals are fed ad libitum. The animals are provided with deionized water only for fluid replenishment. Each animal in the ~ test group(s) is administered an anticalculus agent twice daily, .; five days per week by contacting their teeth with an anticalculus ,~ 10 agent-soaked cotton-tipped applicator.
Three weeks after the commencement of the test, the animals ; are sacrificed and their molars are graded for severity of cal-,; sulus by assessing the area and depth of accumulation on each of ''., 44 orally exposed tooth surfaces e~amined in each animal. Grading ~, 15 is made on a 0-3 scale for each surface, 0 being no detectable .,..................... calcified deposits, 0.5 being moderate to heavy accumulation on 10% or less of the tooth surface area or light accumulation on 25%
or less of the area, 1 being moderate to heavy accumulation on 10%
,. to 25% of the area, 2 being light to moderate accumulation on 25%
,:", 20 to 50% of the area or heavy accumulation on 25% to 50% of the area, and 3 be;ng moderate accumulation on greater than 75% of the .~
; area or heavy accumulation on 50% or more of the area. The total calculus score for each animal is determined by adding the grades ",, for each of the 44 surfaces.
~:' . 75 Crvstal GrQwth Inhibition Determinati,on ,,:.; The following test method is useful for obtaining in vitro .~',,' calculus inhibition data on the geminal diphosphonate polymers ~;.' compositions of the present invention9 and for comparing those results with the performance of other phosphonate anticalculus agents.
~, As hereinbefore stated, the geminal diphosphonate polymers .. inhibit the growth of calcium hydroxylapatite crystals and in this ,~1 way interfere with the normal formation of calcium hydroxylapatite .';,~ from solution. This test determines the effects of the geminal diphosphonate polymers on the calcium phosphonate formed on .',' ad~ition of calcium ion to orthophosphate ion at constant pH. The '' ' , ~ 7 , .
, ",, - ' : . , , .~ ., .

~ 1 328224 . .

,~
: test is described in detail by Nancollas, et al., Oral Biol. 15, 731 (1970)~

In this test, hydroxyapatite seed crystals are added to a calcium/phosphate solution supersaturated with respect to induced precipitation of calcium phosphates but meta-stable toward spon-; taneous precipitation. The seed crystals induce precipitation and crystal growth. Test chemicals are added to the meta-stable Ca/P
solution before seeding. The effect of these chemicals on for-mation of hydroxyapatite induced by seed crystals has been shown .' to correlate with in vivo effects of these chemicals on calcium m~tabolism.
Formation of calcium phosphate crystals results in the ~r release of hydrogen ions (i.e., pH change). The rate of crystal growth is monitored by observing the addition of base required to maintain a constant pH. Low levels (1 x 10-6M) geminal polydi-phosphonates are capable of tnhibiting the formatlon of calcium phosphat~ for 20 minutes or longer. Crystal growth inhibition depends on the propensity of the polyphosphonates or geminal ~i 20 polydiphosphonates to adsorb on calcium phosphate crystal nuclei.
~;~ Anti-Adherance Test The following test method is useful for obtaining in vitro antiplaque data on the geminal diphosphonate polymers of the present invention. The test measures bacterial adherence on hydroxyapatite beads.
25 mgs. of hydroxyapatite (HAP) beads are pre-coated with human saliva for 1.5 hours. The HAP beads are then washed three i times with a buffer solution of 0.05 M KCl, lmM PO~ (pH 6.0), lmM
CaCl2 and O.lmM MgCl2. The HAP beads are then equilibrated with 0 an aqueous solution of a geminal diphosphonats polymer (at a des;red concentration such as 5%~, at pH 7.0, for 5 minutes with agitation. The HAP beads are removed from the aqueous solution ' and then washed once with a buffer solution as described above.
For the adsorption studies bacteria 25 mg of the HAP beads prepared as described above are placed in 1.0 ml of a cell suspension comprising about 1.5 ~ 108 bacteria (S. sanguis) `l B;
!
.
,:, in a buffer solution as described above. The beads are equilibrated in the mixture for three hours, with agita~ion. The beads are allowed to settle for one minute and the supernatant, which contains unadsorbed cells, is removed. The HAP beads are washed three times with buffer solution (same composition as described above), collected by filtration, and dissolved in hydrochloric ac;d. Radioactivity of the dissolved HAP is then measured by liquid scintillation counts in order to determine the number of bound oells. These results are compared to the ~. . .
o radioactivity of dissolved HAP that was prepared as a control without anticalculus/antiplaque agents.
The following examples are included to illustrate the present ; invention; it is not intended to limit the scope of the invention .-, to the exemplified subject matter. The scope of the invention is defined by the c7aims which follow these examples.
- Example I
,,, ;, .
The example shows the synthesis of a polyvinyldiphosphonate polymer of the type described by Formula (lb). The following ~ steps were performed:
`~ 20a) Tetraethyl vinyldiphosphonate synthesis:

S(CH20),n + Et2NH + CH2(PO3Et2)2 ~ CH30CH2cH(Po3Et2)2 .,.," ~
;~ ~ toluene, TsOH
25CH2=c(po3Et2)2 . . :
~.
Specifically, 104.2 grams (3.47 moles) of paraformaldehyde and i 50.8 grams (0.69 moles) of diethylamine were combined in 2.0 ~ liters of dry methanol and the mixture was heated until clear.
; (As used above and hereafter, "Et" shall refer to an ethyl group.) ;~` 30 The heat was removed and 200.0 grams (0.69 moles) of tetraethyl methylenebisphosphonate was added. The mixture was refluxed for ! 24 hours, then an additional 2.0 liters of methanol were added and ' !

~:.`.
;"'.'' "~ . . . . .

` ' .. ::, . ' ' ' ' ~ ~

~ 1 328224 .~
.

the solution was concen~rated under vaCuUm at 30-C. Five hundred (500) milliliters of toluene was added and the solution was again concentrated under vacuum -at 30'C to ~nsure complete removal of methanol from the intermediate product which inter~ediate product s a clear liquid. Next, 1.0 liter of toluene and 50.0 milligrams p-toluenesulfonic acid monohydrate were added to the intermediate . product and the solution was refluxed overnight in a 2.0 liter flask equipped with a Soxhlet extractor having 4 Angstrom molec-ular sieves. Methanol was removed by adsorption into these molecular sieves. The solvent (toluene) was removed under vacuum after 14 hours of reflux to provide the crude product. The crude product was dissolved in 1.0 lit~r chloroform and tWiCQ washed with 150 milliliters of dis~illed water. The chloroform solution was dried over anhydrous M~ ~ , concentrated, and then distilled to r~ 15 product 134.2 grams of the desired product, tetraethyl vinyldi-~1' phosphonate. The boiling point at 0.07 mm Hg was 121C.
.. , b) Polyvinyldiphosphonate polymer synthesis:
-~ CH2-CHY benzoYl peroxide~ CH2-CH-t-,.,1" P03Et2 P03Et2 .~, ~
. 20 / n Butyllithium, ' ~ THF
:.~ Li+
.. .
~CH2-C-~
:, ` I CH25C (PO3Et2)2 ~' 25 PD3Et2 \
,.`~ \~ ,P03Et2 -~-CH2CH-t-~-t-CH2c)b . P03Et2 CIH2 '"~1 ~ CH(po3Et2)2 `1 30 / nnc. HCl '" 1 P03H2 -CH ) d ( CH2-C )b `'. P03H2 CH2 ! CH(P03H2)2 : ~.

~ 1 328224 - 3l -To begin the diphosphonate polymer synthesis, 96.8 grams (0.59 moles) of polydiethylvinylphosphonate and 2.0 liters tetrahydro-furan (THF), freshly distilled from LiAlH4, were added to a 5.0 liter, three-neck, round-bottom flask equipped with a mechanical S
stirrer, a 500 milliliter- addition funnel, and an inlet. The solution was stirred at room temperature until the polymer was essentially comp1etely dissolved. The solution was then chilled to -78-C and stirred for one hour with 192.9 milliliters of 1.55 N
~; (in hexane) of n-butyllithium (0.30 moles). Next, 89.7 grams of CH2-C(P03Et2)2 (0.30 moles) were added and the temperature of the ; solution was maintained at -78'C for one hour with stirring. The solution was then allowed to warn to room temperature with stir-ring. Seventy-five (75) milliliters of d~stilled water were added and the solution was eoncentrated to provide a residue. The " residue was dissolved in 1~00 mill il iters concentrated HCl (12 molar), refluxed for four hours, and reconcentrated to provide crude polyvinyldiphosphonate polymer product. The crude product was chromatographed on SephadexTM 6-25 resin (availab1e from Pharmacia Inc., Piscataway) having a 5,000 molecular weight cutoff to provide 41 grams of a purified product having an average molecular weight of about 9500, as determined by low angle laser j`l light scattering (LALLS). The rat~o of a/b, as determined by ;i P31NMR analysis, was about 2.5.
~` 25 ~3~
,j This example shows the synthesis of a geminal polydiphos-phonate polymer of the type described by Formula (2) wherein the ~, ratio of a/b is greater than zero. The following steps were performed:
, . ..
~ 30 .~
.~
., :3 i 35 ~ .

....

~ 328224 ;, .<;

, n-butyllithium, Li~
"~ CH2-CH)n ~ ~CH2-C~)n P3Et2 PO3Et~
'~i', ,~ o ~ ClP(OEt)2 ~''......................... ~ P03Et2 ~. ~CH2-CH ) i ( CH2-C )b ''i,~i P03Et2 P03E~2 . ~
~, conc. HCl ~ PO3H2 o ~CH2-CH J d --( CH2-C )b , ....
`." P3~12 P~3H2 - -, ~. Specifically, 114.42 grams of polyvinyldiethylphosphonate (0.70 ` moles) and 1.9 liters THF (freshly distilled from LiAlH4) were ,` mixed in a S liter, 3-neck, round-bottom flask equipped with a mechanical stirrer, a 500 milliliter addition funnel, and Ar inlet ~; at room temper~ture until the polymer was essentially completely ;~ dissolved. After chilling the solution to -78-C, 225 milliliters of 1.55 N (in hexane) n-butyllithium (0.35 moles) were added ~ dropwise and the solution was mixed for one hour at -78DC. Next, ''"''~1 20 60.1 grams of diethyl chlorophosphate (0.35 moles) were added and the solution W2S allowed to warm to room temperature with stir-.~ ring. The solution was then cooled to -78C, treated with n-butyllithium and diethyl chlorophosphate, and warmed to room ` temperature as described above. Fifty (50) milliliters of dis-tilled water were added and the solution was concentrated to provide a residue of the product. The res;due was refluxed with ; j 750 milliliters concentrated HCl (12 molar) for three hours and reconcentrated to provide the crude product. The crude product ~j was chromatographed on SephadexTM G-25 resin ~5000 molecular weight cutoff), available from Pharmacia Inc., to provide 33.1 ~ grams of the desired diphosphonate polymer. The ratio of a/b, as .~! dPterm;ned by P31NMR analysis was about 2.6.
Example III
This example shows the synthesis of a preferred geminal diphosphonate polymer of the type described by Formula (1c).
. ~ .

;3 '.` ' . ~ : ~ - , ~ 3~8224 .
~ - 33 -; Specifically, 125.0 grams of polyacrylic acid (1.44 moles, ;~ average molecular weight of 2100 as determined by LALLS~, 25.9 grams of distilled water (1.44 moles), and 300.0 grams of sulfolane (tetramethylene sulfone) were mixed in a two (2) liter, .~ round-bottom flask. This solution was stirred at 45lC until the polyacrylic acid was dissolved. Next, 125.6 milliliters of PC13 , (197.76 grams9 1.44 moles) were dripped ;nto the solution with continual stirring over a period of appro~imately one (1) hour.
,; Liberated HCl was removed from the flask with an argon purge. The solution was heated to lOO-C by placing the flask in an oil bath and maintained at that temperature for two (2) hours before ,j allowing the solution to cool to room temperature. Once at room temperature, 600 milliliters of CH~13 were poured into the flask ;~ which caused a yellow solid precipitate to fall out of solution.
~ 15 The precipitate was collected by vacuum filtration and washed with t'~ CHC13 five times, with 250 milliliter of CHC13 per wash. Residual ~ CHC13 was removed in vacuum, the precipitate was redissolved in ,' 500 milliliters of distilled water, and the aqueous solution was refluxed at lOO-C for 18 hours to produce crude geminal diphos-i~, 20 phonate polymer product. The aqueous solution containing the ~`, J' ' crude product was concentrated to about 200 milllliters under vacuum at 50-C, then 1.2 llters of acetone were added. The oily ~; geminal diphosphonate polymer was recovered by deeantation.
~;~i The precipitation procedure was carrled out an additional four times, to produce 72 grams of geminal diphosphonate polymer product. Exa~ination of the product by p31 NMR analysis indicated that 43 mole X of the phosphorus in the product was present as ~;~ hydroxydiphosphonic acid. The product contained 12.28 wt. % total phosphorus. Th~ mole ratio of a/b was calculated to be about 1 30 4Ø

, This example shows the synthesis of a geminal polydiphos-; phonate polymer formed by polymerization of a monomer of the type described by Formula (3). The following steps were performed:

..~
i ~

, ...

... , ., . . , . ~ ~ .

` 1 328~24 ,'~.

1) KH, 2) cH2=cHlr-H2Br P03Et2 ,, CH2(P03Et2)2 -' ~ CH2=CHCH2CH
,"-, /~ P3Et2 ~ 1) KH
` ~ 2) PhS02SPh P03Et2 P03Et~
`' CH2=CHCH2C-S-Ph ~ 3` CH2=CHCH=C
, Im-chloroperbenzoic acid_",- ¦
.. 10 P03Et2 ~ P03Et2 .,. / .
~ enzoyl peroxide ~, P03Et2 ~ P03H2 (-CH2-CH=CHC-~n - ~ - > (-CH2CH=CHC-)n f Itrimethylsilyl bromide P03Et2 P03H2 ~,~
, Specifically, to an oven-dried flask under argon was added 11.93 grams of 35% potassium hydride (KH) in mineral oil (0.104 moles). The KH was washed several times with dry toluene to ~, remove the mineral oil. Toluene was added, the mixture waschilled in an ice bath and 30.00 grams of freshly-distilled Z~ tZeZtraethyl methylenediphosphonate (0.104 moles) in 100 milliliters ~l toluene was added dropwise. The mixture was then stirred for 1 :, hour at room temperature. This solution was then placed ;n a drop 1 funnel and was added dropwise over a 2.5 hour period to a stirred ;Z 25 solution of allyl bromide (12.58 grams, 0.104 moles) in 250 m~lliliters toluene at C0-C. The solution was stirred at room ~i temperature for an additional 1~ hours. The reaction mixture was `;; whtn stripped of toluene and redissolved in 600 milliliters of , ethyl ether. The ether solution was washed with water (three ;j 30 times with IC0 milliliters per wash~, with brine (two times with 100 milliliters per wash3, and dried over anhydrous MgS04. The solids were filtered and the filtrate concentrated at 30C to ~ afford 35.12 grams of product (a clear liquid). The crude product `Z was purified on silica gel with 1:1 hexane:acetone as the eluant '`''`Z
, ~;
; i i '~Z

` --` 1 328224 ;.

to give ~.5 grams of tetraethyl 3-butene-1,I-diphosphonate prod-uct, as determined by 31P NMR analysis.
Next, to a dry flask was added 2.85 grams of 35% potassium hydr;de (KH) in mineral oil (0.0286 moles KH) and washed clean of the m;neral o;l w;th 10 m;ll;liter portions of dry toluene.
Toluene (75 m;ll;l;ters) was then added and the m;xtur@ ch;lled in an ;ce bath wh;le 9.40 grams of tetraethyl 3-butene-1,1-diphos-; phonate (0.0286 moles) ;n 25 millil;ters of toluene was added dropw;se under argon. The solution was stirred at room tempera-ture For 1 hour and then recooled in an ice bath. A solut;on of r:' 7.16 grams of S-phenylbenzeneth;osulfonate (0.0286 moles) dis-~/ solved in 50 milliliters of toluene was added dropw; se to the j, ;,~ stirred solution. The mixture was stirred for 18 hours at room ~ t~mperature, concentrated, then redissolved ;n 250 millil;ters ,~ 1S ethyl ether. The ether solution was washed with water (three times with 50 milliliters per wash), brine (one t~me with 50 m;llilit~rs), and dr;ed over anhydrous MgS04. The m;xture was filtered and the solut;on concentrated to g;ve 13 grams crude ~, product. The product was purified by chromatography on s;l;ca gel w;th 2:1 hexane:acetone as the eluant to afford 9.85 grams of f tetraethyl l-phenylthio-3-butene-1,1-d;phosphonate product9 as determ;ned by 31p NMR analysis.
In a 250 milliliter flask was placed 3.0Q grams of tetraethyl l-phenylth;o-3-butene-1,1-d;phosphonate (0.00687 moles~ in 50 milliliters of (ethanol-free) CHC13 and stirred at 0C under , .
;~ ar~on. To the st~rred solution was added dropwise 1.56 grams of meta-chloroperbenzo;c acid in 25 milliliters of CHC13. Stirring ~I was continued at 0C for 1 hour and then for 18 hours at room temperature. The reaction mlxture was coo1ed to 0C and 50 l 3~ mill;l;ters of 10% sod;um thiosulfate solut;on were added. The cold solution was placed ;n a separatory funnel and the C~C13 layer ;solated. The CHC13 solution was then washed with saturated sodium bicarbonate solution (2 x 20 milliliters), water (2 x 25 `;~ milliliters~, and dr;~d over anhydrous MgS04. After f;ltering, ~,'! 35 the solut;on was concentrated to g;ve 3 0 grams of crude product.
The crude product was pur;f;ed by chromatography on s;lica gel .~ .
''`';`' ;..

,..:.

`~

``:

with 2:1 hexane:acetone as the eluant. The chromatography af-forded 1.35 grams (60%) of tetraethyl 1,3-butadiene-1,1-diphos-; phonate product, as determined by 31p NMR analysis.
In a 25 milliliter round-bottom flask was placed 1.35 grams of tetraethyl 1~3-butadiene-1~1-diphosphonatS (4.14 millimoles) and ; 15 milliliters of benzene and the solution was degassed to remove ; oxygen. Benzoyl perox;de (10 milligrams, 0.04 millimoles) was added and the solution heated under argon to 60'C in an oil bath.
The reaction was monitored by 31p NMR. An additional 10 milligram increments of benzoyl peroxide were added after 26, 50, and 74 hours of reaction time. After 74 hours, the solvent was removed under vacuum at 30-C to provide 1.37 grams of a solid tetraethyl 1,3-butadiene-1,1-diphosphonate polymer product, as determined by 31P NMR analysis.
The tetraethyl 1,3-butadiene-1,1-diphosphonate polymer was placed in a 25 milliliter flask with 15 milliliters of CHC13 and I 4.90 grams (0.032 moles) of trimethylsilyl bromide. The mixture was stirred at 60'C for 18 hours, then concentrated at room . temperature under vacuum. , The product was stirred in 10J 20 milliliters of methanol for several minutes, then the solution was ;i concentrated. This was repeated three timeSs to afford 1.15 grams of crude 1,3-bu~adiene-1,1-diphosphonate polymer as determined by p31 NMR analysis. This polymer was further purified by chromatography on a column of "Sepha~ex G-25" (MW cutoff 5,000) packing.

~ The following is a representative example o~ a toothpaste of m the present invention.
j Compo~ent %
`'5 30 Distilled ~ater 16.50 Sorbitol (70X Aqueous Solution) 4~.56 .~: Sodium Saccharin 0.30 .. ~ Dye Solution 0.35 t~l Precipitated Silica 20.00 ~ 35 Sodium Fluoride 0.25 ;~ Flavor 1.30 . ., , *l~ad~nark ~ ~ ~ , . . . . , -'"1 . .
.

Sodium Alkyl Sulfate (27.9Y. Aqueous Solution) 5.00 "Carbopol 940S"(Trademark) 9.20 ;;~ Xanthan Gum 0.60 .~ Geminal Diphosphonate Polymer of Example I6.00;
`"'i ~ 100.0~
.; *A carboxyl vinyl polymer offered by B. F. Goodrich Company . The above composition is made by combining the water and part of the sorbitol in an agitated mixture and heating this mixture to 140-F. The geminal diphosphonate polymer9 saccharin, sodium ., 10 fluoride and precipitated silica are then added ~n order and the total mi%ture is mixed for from 5 to 10 minutes. The flavor, dye .~ and surfactant are then added. In a separate vessel the remainder .;; of the sorbitol, the "Carbopol"l and the xanthan gum are slurried nJ together and then added to the main mix tank. The complete batch ls mixed for about one-half hour and subsequently milled and . . .
. ~ deaerated.
Alternately, the geminal diphosphonate polymer can be pre-pared as described in Examples II, III, or IV.
ampl~ YT
, 20 The following is another representative toothpaste of the `.~ present invention.
~; C~mponen~ X
. Sorbitol (70% Aqueous Solution) 50.75 ~', Distilled ~ater 16.50 ;i~ 25 Sodium Saccharin 0.30 :.1 Dye Solut~on 0.35 ;~ Precipttated Silica 20.00 ~` Sodlum Fluoride 0.25 n ' Flavor - 1.30 Sodium Alkyl Sulfate (27.97o Aqueous Solution) 5.00 ~;j "Carbopol 940S" (Trademark) O.20 .~ Xanthan Gum 0.60 Geminal Diphosphonate Polymer of Example I 4.15 100.00 ~ 35 Alternately, the geminal diphosphonate polymer can be pre-:~, pared as described in Examples II, III, or IV.
....
:~ ~ 7 ~ ademark " ~

--` 1 328224 .

In addition to the levels and combinations of ingredients : shown in these examples, others can be used which are cons;stent ~ w;th the invention disclosed.
; Example VII
. 5 This example shows a mouth rinse composition containing a geminal diphosphonate polymer of the present invention.
:.- The mouth rinse is prepared as follows:
"" ~mP~ ~c ,~ Geminal Diphosphonate Polymer of Example I 4.00 Distilled H20 69.19 , Ethanol 16.25 :;~ Glycerin 10-00 -: Nonionic Surfactant 0.12 ::, Benzoic Acid 0.05 15 Na Saccharin 0.05 Flavor 0.15 ., Oolor 0.04 NaOH (10% Sol.) 0.15 100.00 The mouth rinse is prepared by adding each of the ingredients to the distilled water and stirring. Alternately the geminal diphosphonate polymer can be prepared as described in E~amples II, III, or IV.
`3, 2 '~
1.', ' .
:3 30 .~
'. 'l ..
, . . A
' '. ''~
'..~'..,i ;"''`,J

:-'.' , . . . ' ' ' ' ' ` ' : . ~
.'~" . ";

Claims (27)

1. An oral care composition formulated for administration to the oral cavity without substantial ingestion, said composition comprising:
(a) a geminal diphosphonate polymer component wherein said component contains one or more geminal diphosphonate polymers selected from the group consisting of polymers containing the following monomeric unit combinations:

(i) wherein each R1, R2, Ra, and Rb can independently be -H, -CO2H or ester thereof, -PO3H2, -C?N, substituted or unsubstituted aryl, substituted or unsubstituted C1-C10 alkyl, or substituted or unsubstituted C1-C20 oxyalkyl, each R3 can independently be -H, -OH, amine, or substituted or unsubstituted C1-C3 alkyl, each m can independently be 0 or 1, each Q can independently be a substituted or unsubstituted aryl or a substituted or unsubstituted C1-C10 alkylene, and the molar ratio of a/b is greater than or equal to 0 and less than about 30;

(ii) wherein the molar ratio of a/b is greater than or equal to 0 and less than about 30; and (iii) polymerization products of CH2=CH-CH=C(PO3X2)2 wherein each X can independently be -H or a C1-C10 alkyl, and when X is an alkyl, each -PO3X2 group is converted to a -PO3H2 group subsequent to polymeri-zation;

said geminal diphosphonate polymer component having an average molecular weight of between about 1,000 and about 20,000, an average of at least three geminal diphosphonate units per polymer chain, and a molar ratio of monomeric units not containing a geminal diphosphonate to monomeric units containing a geminal diphosphonate of less than about 30; and (b) a pharmaceutically acceptable carrier;
said composition containing between about 0.1 wt. % and about 20 wt. % of said geminal diphosphonate polymer component.

2. An oral care composition as in Claim 1, wherein said composition is a dentifrice or prophylactic composition.

3. The oral care composition of Claim 2, wherein the average molecular weight of said geminal diphosphonate polymer has an average molecular weight of between about 1,000 and about 5,000.

4. The oral care composition of Claim 3, wherein said average molecular weight is between about 2,000 and about 5,000.

5. The oral care composition of Claim 2, wherein said composition contains between about 1% and about 10%, by weight of the composition, of said geminal diphosphonate polymer component.

6. The oral care composition of Claim 4, wherein said composition contains between about 1% and about 5%, by weight of the composition, of said geminal diphosphonate polymer component.

7. The oral care composition of Claim 2, wherein the molar ratio of a/b for Formula (i) and (ii) geminal diphosphonate polymers is less than about 20.

8. The oral care composition of Claim 3, wherein the molar ratio of a/b for Formula (i) and (ii) geminal diphosphonate polymers is less than about 20.

9. The oral care composition of Claim 6, wherein the molar ratio of a/b for Formula (i) and (ii) geminal diphosphonate polymers is less than about 20.

10. The oral care composition of Claim 2, wherein said geminal diphosphonate polymer component is selected from the group consisting of the Formula (i) geminal diphosphonate polymers.

11. The oral care composition of Claim 7, wherein said geminal diphosphonate polymer component is selected from the group consisting of polymers containing the following monomeric unit combinations:

(i-a) wherein each R4 and R5 can independently be -H, or a sub-stituted or unsubstituted C1-C10 alkyl;

(i-b) wherein each R6 can independently be -H, substituted or unsubstituted C1-C10 alkyl, m is 1, and each Q can indepen-dently be substituted or unsubstituted aryl, or substituted or unsubstituted C2-C10 alkylene; and (i-c) wherein each m can independently be 0 or 1, each Q can independently be substituted or unsubstituted aryl or sub-stituted or unsubstituted C1-C10 alkylene, each R7 can in-dependently be -OH, -NH2, or a salt thereof, and each R8 can independently be -CO2H or -C?N.

12. The oral composition of Claim 11, wherein each R4 and R5 of the Formula (i-a) polymers independently is -H or an unsubsti-tuted C1-C3 alkyl, each R6 of the Formula (i-b) polymers indepen-dently is -H or an unsubstituted C1-C3 alkyl, and for the Formula (i-c) polymers, each R7 is -OH or a salt thereof, each R8 is -CO2H, and m is 0 or each Q independently is a C1-C3 alkylene.

13. The oral care composition of Claim 12, wherein said geminal diphosphonate polymer component is selected from the group consisting of the Formula (i-c) geminal diphosphonate polymers.

14. The oral care composition of Claim 13, wherein the average molecular weight of said Formula (i-c) geminal diphos-phonate polymer is between about 1,000 and about 5,000.

15. The oral care composition of Claim 14, wherein the molecular weight of said Formula (i-c) geminal diphosphonate polymer is between about 2,000 and about 5,000.

16. The oral care composition of Claim 15, wherein m is 0, or when m is 0 or Q is an unsubstituted C1-C3 alkylene, and the ratio of a/b is between about 0.5 and about 20.

17. The oral care composition of Claim 13, wherein said composition comprises between about 1% and about 10% of said geminal diphosphonate polymer component.

18. The oral care composition of Claim 16, wherein said composition comprises between about 1% and about 10% of said geminal diphosphonate polymer component.

19. The oral composition of Claim 2 formulated as a denti-frice paste, powder, or gel.

20. The oral composition of Claim 11 formulated as a denti-frice paste, powder, or gel.

21. The oral composition of Claim 18 formulated as a denti-frice paste, powder, or gel.

22. The oral composition of claim 2 formulated as a mouth rinse composition.

23. The oral composition of claim 11 formulated as a mouth rinse composition.

24. The oral composition of claim 18 formulated as a mouth rinse composition.

25. A use of a pharmaceutically safe and effective amount of one or more geminal diphosphonate polymers selected from the group consisting of polymers containing the following monomeric unit combinations:

(i) for inhibiting the formation of calculus;
wherein each R1, R2, Ra, and Rb can independently be -H, -CO2H or ester thereof, -PO3H2, -C?N, substituted or unsubstituted aryl, or substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C20 oxyalkyl, each R3 can independently be -H, -OH, or substituted or unsubstituted C1-C3 alkyl, each m can independently be 0 or 1, each Q can independently be a substituted or unsubstituted aryl or a substituted or unsubstituted C1-C10 alkylene, and the molar ratio of a/b is greater than or equal to 0 and less than about 30;

(ii) wherein the molar ratio of a/b is greater than or equal to 0 and less than about 30; and (iii) polymerization products of CH2=CH-CH=C(PO3X2)2 wherein each X can independently be -H or a C1-C10 alkyl, and when X is an alkyl, each -PO3X2 group is converted to a -PO3H2 group subsequent to polymerizations;
said geminal diphosphonate polmer component having an average molecular weight of between about 1,000 and about 20,000, an average of at least three geminal diphosphonate units per polymer chain, and a molar ratio of monomeric units not containing a geminal diphosphonate to monomeric units containing a geminal diphosphonate of less than about 30.

26. The use of Claim 25, wherein said geminal diphosphonate polymer is selected from the group consisting of polymers containing the following monomeric unit combinations:

(i-a) wherein each R4 and R5 can independently be -H, or a substituted or unsubstituted C1-C10 alkyl;

wherein each R6 can independently be -H, substituted or unsubstituted C1-C10 alkyl, m is 1, and each Q can independently be substituted or unsubstituted aryl, or substituted or unsubstituted C2-C10 alkylene; and wherein each m can independently be 0 or 1, each Q can independently be substituted or unsubstituted aryl or substituted or unsubstituted C1-C10 alkylene, each R7 can independently be -OH, -NH2, or a salt thereof, and each R8 can independently be -CO2H or -C?N, and wherein the ratio of a/b is less than about 20.

27. The use of Claim 26, wherein said use also is effective for inhibiting plaque.