JPH01265013A - Oral cavity composition - Google Patents

Abstract

PURPOSE: To obtain a safe composition for oral cavity, comprising gem- diphosphonate polymer component, useful for inhibiting formation of tartar and plaque and having good long term preservation stability. CONSTITUTION: This composition for oral cavity includes 0.1-20wt.%, especially 1-5wt.% gem-diphosphonate polymer containing a combination of monomer units of formulas I [R1 , R2 , Ra and Rb are each H, CO2 H or its ester, CN, PO3 H2 , an aryl, a 1-10C alkyl or a 1-20C oxyalkyl; R3 is H, OH, NH2 , a 1-3C alkyl; (m) is 0 or 1; Q is an aryl or a 1-10C alkylene; mol ratio of (a/b) is 0-30, preferably 0-20], II and III (X is H or a 1-10C alkyl; when X is an alkyl, PO3 X2 is converted to PO3 H2 ), having 1,000-20,000, preferably 2,000-5,000 average molecular weight and further having at least three gem-diphosphonate unit per polymer chain, and a pharmaceutically permissible carrier.

Description

DETAILED DESCRIPTION OF THE INVENTION TECHNICAL FIELD The present invention relates to oral care compositions containing anti-calculus and anti-plaque agents and methods for inhibiting tartar and plaque formation in the oral cavity.

BACKGROUND OF THE INVENTION Tartar and plaque are two undesirable, but unfortunately common, dental conditions experienced during dental implants.

Tartar, or sometimes called LarLar, is a deposit that forms on the surface of teeth at the gingival margin. Supragingival calculus appears primarily in areas near the mouth of the salivary ducts, such as on the auspicious surfaces of the lower anterior teeth, the buccal surfaces of the upper first and second molars, and the distal surfaces of the posterior molars.

Mature dental calculus consists of an inorganic portion, mostly calcium phosphate, arranged in a hydroxyapatite crystal lattice similar to bone, enamel and dentin.

An organic portion is also present, consisting of desquamated epithelial cells, white blood cells, salivary deposits, food debris and various types of microorganisms.

As mature tartar grows, it becomes visually white or yellowish unless colored or bleached by some foreign substance. In addition to being aesthetically unsightly and undesirable, mature tartar deposits are a constant source of irritation to the gums.

Another source of irritation within the oral cavity is plaque. Plaque is a mixture of minerals and bacteria present in the mouth. Bacteria associated with plaque secrete enzymes and endotoxins that can irritate the gums and cause inflammatory gingivitis. As the gums become increasingly irritated by this process, they bleed and lose their toughness and resilience.
It has a tendency to lose its III ency and detach from the tooth, leaving a periodontal pocket in which debris, secretions, and even more bacteria and toxins can accumulate.

Food can also accumulate within these pockets, providing nutrients for high bacterial growth and producing endotoxins and destructive enzymes.

Periodic mechanical removal of tartar by a dentist is, of course, a routine dental procedure.

However, effective compositions and methods for inhibiting tartar formation during dental visits are desired to enhance oral hygiene. Various chemical agents have been shown in the art to either prevent tartar formation or remove tartar after it has formed.

Inhibition of calculus formation during a dental visit is usually accomplished with chemicals that prevent calcium formation and/or remove calcium and destroy mature calculus by chelating calcium ions and/or inhibiting crystal growth.

Several chelating agents have been disclosed in the art for this purpose. British Patent No. 490,384, published Feb. 15, 1937, discloses oral compositions containing ethylenediaminetetraacetic acid, nitrilotriacetic acid and similar compounds as anti-calculus agents. These anti-calculus agents have relatively low effectiveness.

Oral care compositions containing soluble pyrophosphates have also been disclosed in the art. Such disclosures include Salzmann et al., 1960, which discloses dental powders containing chlorophyll and pyrophosphate.
U.S. Pat. No. 2,941,926, June 21, 1964; to Schiraldl, June 1, 1964, disclosing a toothpaste containing pyrophosphate.
No. 6, U.S. Pat. No. 3,137,632;
U.S. Pat. Nos. 3,927,201 and 3,297,202 of December 16, 1975;
U.S. Pat. No. 4,2 dated January 13, 1981 to
No. 44,931 and U.S. Pat. Parr discloses tetraalkali metal salts in oral fluid compositions.
U.S. Pat. No. 4,333,551, issued April 6, 1982; Baran et al., 1985, 5 JJ7, which discloses toothpaste compositions containing certain dialkali metal and tetraalkali metal birophosphates. No. 4,515,772, dated May 20, 1986 to Baran et al.
No. 4,590,066 and Baran et al.
There is a specification of US Pat. No. 4,684,518 dated August 1987.

Mechanical removal of plaque and minerals that collect near or under the gums, which nourish plaque-producing bacteria, is accomplished by postprandial brushing and flossing by oral care practitioners. Unfortunately, however, mechanical removal is not always completely thorough or effective, especially if it is not performed accurately and regularly. Therefore, chemical compositions and methods that can effectively inhibit plaque formation! It is recommended that you serve 2 servings.

Preferably, these are used in conjunction with mechanical removal methods.

There are various disclosures in the art regarding phosphonate materials useful as both anti-calculus and anti-plaque/anti-gingivitis agents in oral compositions. See, for example, Shed Iovsky, U.S. Pat. No. 3,429,963, issued February 25, 1969, Gaff 7 (
U.S. Pat. No. 4,102,993 issued to Gafrer on July 251, 1978, U.S. Pat. U.S. Patent No. 4,
No. 100,270, U.S. Pat. No. 4,098,880, issued July 4, 1978, to Gaff 7-1
U.S. Patent No. 4.123,5, issued October 31, 1978.
No. 12, Gallafer, U.S. Pat. A polyvinylphosphonate polymer having monomer units is disclosed. U.S. Pat. No. 3,553,315 to Pranci, issued January 5, 1971, discloses short chain carboxyphosphonic acid compounds. Francis, U.S. Patent No. 3,641,126, issued February 8, 1972;
No. 3,737,522, issued May 5, discloses non-polymeric compounds having gem-diphosphonate groups.

Bauman, U.S. Pat. No. 4,208,401, issued June 17, 1980, describes the gem-
Disclosed are quaternary ammonium alkylene diphosphonate anti-calculus agents in which the diphosphonate carbon is changed. U.S. Patent Section 3.678,15 of Wjdder et al.
No. 4 and Ilacfele's 1977
U.S. Pat. No. 4,025,616, issued May 24, 2007, describes polyphosphonate materials having one phosphonate group per carbon in the polymer backbone and phosphonates having one gem-diphosphonate carbon atom. Discloses molecules.

Although a variety of materials have been disclosed for use in oral compositions as anti-calculus and anti-plaque agents as described above, there still exists a need for improved anti-calculus and anti-plaque agents. It is.

The object of the present invention is to provide a safe and effective anti-tartar oral care composition with good long-term storage stability and high efficacy.
"(It is to be.

Another object of the invention is to provide an oral care composition as described above having both anti-calculus and anti-plaque activity.

Another object of the present invention is to provide safe and effective anti-calculus and anti-plaque products that, in addition to having stable and high anti-calculus and/or anti-plaque efficacy, can be manufactured at commercially economical cost. An object of the present invention is to provide a composition for internal care.

Another object of the present invention is to provide a safe and effective method for inhibiting tartar formation in the oral cavity. Yet another object of the present invention is to provide a safe and effective method for inhibiting the formation of both tartar and plaque within the oral cavity.

Still other objects of the present invention, in addition to providing anti-calculus and anti-plaque capabilities, are commercially viable.

It is an object of the present invention to provide a safe and effective method for inhibiting the formation of tartar and/or plaque that can be carried out at economical cost.

SUMMARY OF THE INVENTION It has surprisingly been found that the objects of the present invention can be achieved by oral care compositions containing gem-diphosphonate polymers and a pharmaceutically acceptable carrier. Specifically, such gem-diphosphonates include: (In the above formula, each RRR and R6 are each independently -H, -Co2H or an ester thereof,
-C giant N, -P03H2, substituted or unsubstituted aryl, substituted or unsubstituted C1-C1o alkyl, or substituted or unsubstituted C1-C2o oxyalkyl; each R3 is independently -H1-0H1 amine or is substituted or unsubstituted Ct-03 alkyl;
Each m is independently 0 or 1; each Q is independently substituted or unsubstituted aryl or substituted or unsubstituted C□-〇 alkylene; and the a/b ratio is greater than OO or equal to 0 and less than or equal to about 30); (wherein a/b is greater than or equal to O and less than or equal to about 30); and (+N) CH
2-CH-CH-C(PO3X2) Polymerization product of 2 (in the above formula, each X is independently -H or C1-C
Io alkyl; and when X is alkyl,
each -PO3X2 group is converted to a -PO3H2 group after polymerization); and mixtures thereof; at least 3 g
It has em-diphosphonate units.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to gem-diphosphonate polymers, such gems specifically formulated for oral administration that are substantially non-ingestible.
- Oral care compositions containing diphosphonate polymers and methods for inhibiting tartar and plaque in the oral cavity. Usable compositions include, but are not limited to, mouthwashes, toothpastes, powders, dentifrice compositions, topical solutions, prophylactic pastes and gels, lozenges, gums, and the like.

Gem-Diphosphonate Polymers Gem-diphosphonate polymers within the scope of the present invention have the following three formulas = (in the above formula, each R1,
R2, Ra and R6 are each independently -H, -Co2
H or its ester, -PO3H2, -Cson1 substituted or unsubstituted aryl, substituted or unsubstituted Cl-
C10 alkyl or substituted or unsubstituted C1-020 oxyalkyl, preferably -H, -Co2H.

-PO3H2 or unsubstituted C1-C3 alkyl. Each R3 is independently -H1-〇H1 substituted or unsubstituted C1-C3 alkyl or amine (for example, alkylamines, but not limited to), preferably -H1-O
H or unsubstituted C alkyl; each m is independently 0 or 1; each Q is independently substituted or unsubstituted aryl or substituted or unsubstituted Cl-Cl
,0 alkylene, preferably C1-C3 alkylene; and the molar ratio of a/b is greater than or equal to 0 and less than or equal to about 30, preferably less than or equal to about 20. b is greater than or equal to 0 and less than or equal to about 30, preferably less than or equal to about 20)
and gem-diphosphonate polymers formed from the polymerization of monomers of formula (3) as shown below: (wherein each X is independently -H or c-
c alkyl, preferably cl-c5 alkyl, more preferably C1-C5 alkyl, most preferably C2 alkyl; if X is other than -H, each -P O3
The X2 groups are converted into -PO3H2 groups after or simultaneously with the polymerization). This gem-diphosphonate polymerization of monomers of formula (3) includes homopolymerizations of the monomers described above, as well as copolymerizations with other diphosphonates or compatible non-diphosphonate-containing monomers, terpolymerizations, and the like. “Compatible non-diphosphonate-containing monomer” as used herein
means a monomer that does not significantly interfere with the anti-calculus, preferably anti-plaque, ability of the gem-diphosphonate group.

As shown in the above formula, the gem-diphosphonate polymers of the present invention include gem-diphosphonates as part of the polymer backbone, as part of an alkyl or aryl group attached to the polymer backbone, or as a mixture thereof. It has units.

“Gem-diphosphonate” as used herein
The term relates to a chemical functional group or monomer unit having a carbon atom to which two phosphonate groups or salts thereof are attached.

As used herein, the term "polymer" with respect to the gem-diphosphonate polymers of the present invention refers to polymer, copolymer, terpolymer? -(terpo
lymer), etc. The term "polymer" also includes oligomers so long as they meet the molecular weight limitations of this invention.

The gem-diphosphonate polymers of the present invention include phosphonates of diphosphonates and pharmaceutically acceptable salts thereof, such as, but not limited to, alkali metal salts (e.g., sodium and potassium), alkaline earth metals (
e.g. calcium and magnesium) and ammonium or low molecular weight substituted ammonium (e.g. mono-
, di- and triethanolammonium) salts. At least about 3% on a molar basis of monomer units of the polymer
should be a gem-carbon diphosphonate unit or have said unit substituted therein. Preferably, at least about 5% of the monomer units of the polymer chain are
gem-diphosphonate units or have said units substituted therein. The non-gem-diphosphonate monomer units should be gem-diphosphonate compatible monomers. By "gern-diphosphonate compatible monomer" is meant a monomer that does not significantly interfere with the anti-calculus and preferably anti-plaque capabilities of the gem-diphosphonate group.

As used herein, the symbols "a" and "b" refer to molar proportions, thus the "a/b" ratio is a molar ratio. The a/b ratio is measured by using the phosphorus-31 nuclear magnetic resonance spectroscopy (P31 NMR) technique, which is known to those skilled in the art.

The gem-diphosphonate polymers of the present invention have a molecular weight of at least about 1,000, preferably from about 1,000 to about 20,0
00, more preferably about 1,000 to about 5,000. It is also most preferably characterized by having a molecular weight of about 2,000 to about 5,000. As used herein, "molecular weight" refers to small-angle laser light scattering (Low A
ngle La5erI, Light 5cacter+
ng, LALLS) technique, which is known to the person skilled in the art. From the viewpoint of safety issues due to absorption into the bloodstream and effects regarding bone remineralization and desorption, it is undesirable for the molecular weight to be substantially less than about 1,000. Anti-calculus ability is believed to decrease as the ability of the gem-diphosphonate polymer to adsorb to teeth or plaque material decreases. Approximately 2
A molecular weight of 0.000 or less is desirable because diphosphonate adsorption typically decreases as molecular weight increases. Particularly high anti-calculus ability is about 2.000 to about 5.00.
observed within the most favorable range of 0.000. Formula (1) ~
The polymers of (3) are further characterized by having at least three gem-diphosphonate units per individual polymer chain.

The following preferred polymers fall within the scope of gem-diphosphonate polymers of formula (1) = (wherein a
/ b is greater than 0 and C is equal to 0 and about 3
0 or less, preferably about 20 or less, and typically 0.5 or more in practice: each R is independently H or substituted or substituted C1-C1o alkyl, preferably H or unsubstituted C1- 03 alkyl, more preferably H; each R is independently H or substituted or unsubstituted C
-C alkyl, preferably H or valve lid 1t.

substituted C-C alkyl, more preferably -H; most preferably both R and R are H; where a/b is greater than or equal to 0 and less than or equal to about 30; , preferably about 20 or less, and typically 0.5 or more in practice; each R6 is independently H or substituted or unsubstituted C1-C10 alkyl, preferably H or unsubstituted CI-C3 alkyl, More preferably H or CH3: each Q is independently substituted or unsubstituted aryl, substituted or unsubstituted C1-
C alkylene, preferably unsubstituted C1-03 alkylene); and (wherein a/b is greater than or equal to 0 and less than or equal to about 30, preferably less than or equal to about 20;
In practice, it is usually 0.5 or more; m is 0 or 1, preferably 0; Q is each independently substituted or unsubstituted aryl or substituted or unsubstituted C□-C1o alkylene, preferably unsubstituted C-C alkylene; R
7 is OH or NH2, preferably OH, or a salt thereof; and R is C02H or -C, preferably Co
H). R7 is -OH or its salt and R is -C02
Gem-diphosphonate polymers of formula 1(C) where H is particularly preferred because hydroxylated gem-diphosphonate polymers
It is believed that diphosphonate polymers are particularly effective oral tartar inhibitors, and that they have antiplaque activity.
and because it can be produced with significant economic savings compared to most other gem-diphosphonate polymers.

Synthesis of gem-diphosphonate polymers Diphosphonate polymers of the type described in formula (1a) are prepared by dehydrogenation of polyvinylphosphonate, followed by Michael addition of the gem-diphosphonate group or addition of its ester, followed by addition of the gem-diphosphonate group to the acid form. Composed by transformation. Polyvinylphosphonates are manufactured from vinylphosphonates, such as those produced by Aldrich Chemical Co.
Chemical Co., Inc. (Milwaukee, Wis.) or as described in the art [e.g. Journal or American
Tetrahedron (Chemical 5ociety), Vol.
TeLral+edron), Volume 26, No. 552
Tavs, 1970, pp. 9-5534.
) and Wei tkamp].

The polymerization of unsaturated phosphonic acids and/or phosphonates is described in the Journal of Macromolecular Science (Rc
vs.) (Journal of Macromol
ccularScience (Revs, )], Volume 01, Page 789.

5ander and Stclninger, 1967, which is incorporated herein by reference. Generally, the polymerization of vinylphosphonates is carried out according to the following description: In the above formula, the reaction is carried out in a neat manner containing from about 0.1 to about 10 mole percent (monomer basis) of peroxide radicals, such as benzoyl peroxide, hydrogen peroxide, etc. (neat) about 60 to about 8 in solution
Preferably carried out at 0°C; X is H or C1-C1
o alkyl, preferably C1-C alkyl, most preferably C2 alkyl; or in the above formula, X is as defined above; Metal halides such as but not limited to potassium hydride, or preferably n-
organometallic bases such as butyllithium, naphthalene-sodium, triethylaluminum, etc.; the reaction is T
HF.

in a polar solvent such as sulfolane etc. at low temperature, preferably about -
It is carried out at a temperature of 50°C or lower, more preferably about -70°C or lower. Generally, from about 0.1 to about 20 moles26 of anionic initiator are used (monomer basis). The molecular weight of the polymer formed from reaction (1) is usually about 1,000 to about 5
,000. The molecular weight of the polymer formed from reaction (11) will vary depending on the reaction conditions, but under preferred conditions is usually from about 5,000 to about 20,000.

Gem-diphosphonate polymers are formed by performing the following steps, which will also be readily understood by those skilled in the art: a1 0 where the Michael addition reagent RCH-C(PO3X2)2 , X is C1-010 alkyl, preferably C1-05 alkyl, most preferably C
2alkyl; each R is independently H or c-
c, preferably C1-C3 alkyl or H1 most preferably H. The most preferred monomer in which X is C2 alkyl (ie, ethyl), hereinafter referred to by the formula CH2-C(PO3Et2)2, is tetraethyl vinyl diphosphonate. Preferred RCH=C(P
The method for synthesizing the O3
51, p. 3488, 1986, vol. 51, p. 3488, which is incorporated herein by reference. Step (a) is a strong base, preferably an organometallic base such as, but not limited to, n-butyllithium, naphthalene-sodium and tetraethylaluminum, or a dialkylamide, such as, but not limited to, diisopropylamide lithium, or particularly Metal hydrides such as, but not limited to, potassium hydride, and polar compounds such as, but not limited to, THF and 1,2-dimethoxyethane.
The reaction is preferably carried out at a temperature of about -50°C or lower, more preferably about -70°C or lower, using a neutral solvent. The conversion step (c) into a phosphonic acid form includes HCI, H2S 04, H3PO4
This is done by treatment with a strong mineral acid solution such as The Michael addition reaction of step (b) is carried out by mixing the vinyl diphosphonate and base-treated polymer in a THF solution.

Diphosphonate polymers of formula (1b) are synthesized according to the following reaction sequence, which will be readily understood by those skilled in the art: to n where steps (d) and (f) are each Process (a)
and as described above for (C); Y is a halogen, preferably C1 or a sulfonic ester;
Z is H or a Cl-010 alkyl group, preferably H or a C1-C3 alkyl group, most preferably H or CH3; X has the same meaning as in reaction (H); m is either O or 1 and Q is substituted or unsubstituted aryl, substituted or unsubstituted C1-C1o alkylene,
Preferably it is C1-C5 alkylene.

Preferred ge of formula (1c) where R7 is OH or a salt thereof
m-diphosphonate polymers are synthesized by reacting phosphorous acid or a phosphorous acid precursor such as PCl3, which can form phosphorous acid in aqueous solution, with a water-soluble carboxyl polymer in a polar organic solvent. Preferred organic solvents are those in which the carboxyl polymer and the phosphorous acid or phosphorous acid precursor can be substantially completely dissolved so as to form a homogeneous reactant.

Representative preferred solvents include sulfolane (tetrahydrothiophene-1,1-dioxide), di-n-propylsulfone, tetrahydrofuran (THF), 2-methyl T
These include HF, 3-methylTHF, and tetrahydropyran. The temperature of the reactants should be above their freezing temperature. The reaction is preferably carried out at a temperature of about 0 to about 200°C, more preferably about 50 to about 150°C.

Carboxyl polymer has a carboxyl group α,
Derived from β-olefinically unsaturated monomers. Carboxyl polymers are also derived from acid anhydride polymers obtained from monomers that are easily converted to carboxylic acid forms. Preferred carboxyl polymers have at least 50
A polymer containing a heavy total amount of carboxylated or methyl ester monomer units. Available polymers include commercially available polyacrylic acid, polymethacrylic acid, copolymers of acrylic acid and methacrylic acid; Journal φ
Journal of Macromolecular Science renamed Macromolecular Chemistry
cromolecular 5science l? ev
si.

Macromolecular Chemistry)
, Vol. C13, No. 2, pp. 235-261, 197
Norman G. Gaynor in 5 years
Polymaleic anhydride or polymaleic acid produced by G., Gayloy);
There are copolymers of maleic anhydride and olefins having 2 to 4 carbon atoms; or copolymers of maleic anhydride and vinyl ethers, vinyl esters or alkyl (meth)acrylates. A method for making such gem-diphosphonate polymers is described in U.S. Pat. No. 4,207,455 issued June 10, 1980 (
ter) and Spaulding
), which is incorporated herein by reference.

Gem-diphosphonate polymers encompassed by formula (1c) in which R is an amine and R8 is -C-N are described in U.S. Pat. 239,695 by reacting phosphorous acid or its precursor with (-CH2-CH(RCN)-)n, in which case Preferably, each R1 is independently a C-C1o aliphatic bridging group.

Those skilled in the art will appreciate that the methods described above for the synthesis of certain polymers of formula (1) are
It will be appreciated that the step of adding m-diphosphonate-containing groups to the polymer backbone generally results in a product having an a/b ratio greater than O.

The reason for this is due to reactions involving gem-diphosphonate groups, such as Michael addition during the production of formula (1a) type polymers, formula (2)
This is because the substitution reaction during the production of type b) polymers and the carboxyl polymer-phosphorous acid reaction product of formula (IC) do not normally occur at all reactive sites on the polymer. If it is desired to have an a/b ratio close to or near 0, the directly relevant reactions of the above can be performed, for example by increasing the reagent concentration and/or reaction time, or by those skilled in the art. Other methods, as will be appreciated, can be used to approach such a target or to achieve it to the extent possible depending on the specific starting materials.

Another approach to achieve an a/b ratio of O in formula (1) polymers is to homopolymerize monomers having the following formula: 2 in the above formula, R2, R3
, m and Q have the same meanings as in formula (1). This homopolymerization is preferably carried out by anionic or radical polymerization techniques.

Radical polymerization is preferably carried out at about 60 to about 80° C. using benzoyl peroxide, hydrogen peroxide, etc., in a neat solution or nonpolar solvent containing about 0.1 to about 10 mole percent radicals, calculated on a monomer mole basis. This is done using radicals such as The anionic polymerization is preferably initiated with a metal base such as n-butyllithium, naphthalene-sodium, triethylaluminum, etc., and the reaction is carried out in a polar solvent such as THF, sulfolane, etc. at low temperature, preferably about -50°C. Hereinafter, it is more preferably carried out at about -70°C or lower. Usually about 0. 1 to about 20 mole percent anionic initiator is used (monomer basis).

Methods for the synthesis of gem-diphosphonate polymers of the type of formula 2 in which a/b is zero are known to those skilled in the art and are described, for example, in U.S. Pat. No. 3,544,509, issued December 1, 1970. In the specification, Carol
rol l) and Crutchfield (CruLchl)
'jeld), which is incorporated herein by reference. These diphosphonate polymers are produced by polymerization of lower alkylene-1,1-diphosphonic acids and their metal salts. On the other hand, diphosphonate polymers can also be prepared from esters of lower alkylene-1,1-diphosphonic acids. Preferably, the cyphosphonate salt is converted to the free acid by treatment with a strong acid.

In addition to the diphosphonic acid and metal salt monomers of U.S. Pat. No. 3,544,509, monomers of formula RCH-C(PO3X2)2 as described above are used in the synthesis of formula (1a); is actually preferred.

Once polymerized, the polymer formed from RCH-C(PO3X2)2 is referred to as “organophosphorus compound + (Or
Ganic Phosphorous Compoun
ds), Volume 7.

Kosolaporr and Maier (M.
aier), pp. 1-487, 1967.
Strong minerals such as HSOHCl1H3PO4, etc., as described by Hmidt-Dunker)24
It is converted to a diphosphonic acid by treatment with diphosphonic acid.

Polymerization is carried out by heating and/or lower alkylene-1,1,
~ using anionic initiators, radical initiators or UV light as catalysts suitable for use in terms of solubility with the diphosphonate, and/or using polymerization media such as water and/or organic solvents; done by method. Radical initiators include peroxides such as benzoyl peroxide, tolyl peroxide, hydrogen peroxide, and the like. Anionic initiators include organometallic reagents such as n-butyllithium, naphthalene-sodium, triethylaluminum, and the like. Radical or anionic initiators can be used in a variety of ways. Typically from 0.1 to about 5% by weight of lower alkylene-1,1-diphosphonate is sufficient.

Diphosphonate polymers of formula 2 where a/b is zero or greater than zero are synthesized according to the following reaction sequence, which will be readily understood by those skilled in the art: (g)
Ql Country D Kuniyama-Q-Mountain Work 1 x Work Oel
Co Q-
B.

0-low-04
Ikkoku Kogyo OOQ
-B.

I
c+Q ヱwherein steps (g) and (j) are carried out as described above for steps (a) and (c) respectively; Y is halogen, preferably CI; X' is aryl or C1-C
1o alkyl, preferably aryl or CI-Cs alkyl, more preferably aryl or C2 alkyl. In the substitution reaction of step (h), TH of the base-treated polymer is
This can be done by adding phosphoryl halide (YP03X2) to the F solution. In practice, the a/b ratio is usually greater than zero because not all reactive sites on the polymer backbone undergo substitution reactions.

Gem-diphosphonate polymers formed from monomers of formula (3) are formed by 1.4 polymerizations of monomers of formula (4), 2
, tripolymerization or a combination thereof.

Formula (3) monomer preparation and subsequent polymerization can be carried out according to the following exemplary method: or C
1-C10 alkyl, preferably C1-C5 alkyl,
More preferably C1-03 alkyl, most preferably C
2 alkyl. In reaction step (k), the strong base is preferably a metal hydride such as, but not limited to, potassium hydride, and Y is a halogen such as, but not limited to, bromine and chlorine. In reaction step (m), the strong base is the same as in step (k), and -5-p
Although h is not particularly limited, diphenyl disulfide (Ph
SSPh) and S-phenylbenzenethiosulfonate (PhS02SPh). Reaction”-
In step (m), such steps are carried out using conventional oxidizing agents. The polymerization reaction of reaction step (o) may be carried out using anionic initiators such as, but not limited to, organometallic bases, dialkylamides, and metal hydrides, as described herein above, or benzoyl peroxide and hydrogen peroxide. It is carried out using any of the radical initiators such as, preferably, a radical initiator. If X is other than -H,
The conversion of the product of step (0) to the phosphonate is carried out by treatment with a strong mineral acid or preferably by treatment with a silyl halide such as, but not limited to, a trialkylsilyl halide, for example trimethylsilyl bromide. I can do it. Details of the preferred operation of this method are found in Example 4.

Molecular weights vary according to a variety of techniques readily known to those skilled in the art. The present invention is not limited to any specific method, and techniques for changing the entire molecule include catalyst or radical selection, monomer, temperature, concentration,
There are options such as stirring speed. Molecular weight can also be manipulated by separation techniques such as gel filtration columns.

Composition for Oral Care Composition for oral care includes a composition for inhibiting tartar formation.
Any composition containing a pharmaceutically safe and effective amount of em-diphosphonate polymer and a pharmaceutically acceptable carrier suitable for buccal administration may be used. The compositions of the present invention are preferably formulated for intraoral (ie oral) use, which is not normally ingested other than by any ingestion that may occur incidentally during use. As a result, during normal use or treatment, the compositions are administered into the oral cavity and then discharged after use or treatment. As used herein, "buccal administration" and "buccally administered" or other similar terms refer to any situation in which the compositions of the invention are administered into the mouth and come into contact with the teeth and gums. means operational activity.

As used herein, "buccal administration" and "administration into the oral cavity" also refer to contact with the teeth and gingival areas, as well as with tartar or plaque that has already formed within the oral cavity. Contact occurs by non-limiting movements such as rinsing, brushing with a toothbrush, and directing a stream of composition-containing water toward the teeth and/or gum area. The present invention includes powders, pastes, gels, solutions, etc. for intraoral rinses, washes or topical applications. These compositions include dentifrices such as tooth cleaning powders, pastes, gels and liquids, prophylactic compositions such as anti-gingivitis compositions, mouth rinses and other oral care compositions. . Also included are compositions containing combinations of dentifrice, prophylactic and other oral care ingredients.

As used herein, "pharmaceutically acceptable carrier" means
Refers to one or more diphosphonate-compatible solid or liquid diluents or encapsulating materials suitable for oral administration, provided that they need not be suitable for substantial ingestion on a regular basis.

"Diphosphonate compatibility" as used herein means
It refers to components of the composition that do not interact with the diphosphonate polymer in such a way as to substantially reduce the effectiveness of the composition in inhibiting tartar and/or plaque formation, particularly during storage.

As used herein, "suitable for buccal administration" means suitable for application or rinsing to the inside of a person's mouth, ie the oral cavity or a part thereof.

The concentration of gem-diphosphonate polymer in the oral care composition is at least as high as is effective to provide anti-calculus capability (ie, tartar inhibiting efficacy). Preferably, the concentration of gem-diphosphonate polymer in the oral composition is from about 0.1 to about 20% by weight. Oral care compositions typically contain about 1% to about 10%, most commonly about 1%
Contains ~5%.

As used herein, a "safe and effective amount" means sufficiently high to exhibit anti-calculus and/or anti-plaque capabilities, preferably both, but so high as to be outside the range of normal medical judgment. means the amount of gem-diphosphonate polymer that is not present. The safety effectiveness of gem-diphosphonate polymers depends on the specific polymer chosen, the duration of treatment, the gem
- will vary depending on the specific carrier from which the diphosphonate polymer is released and other considerations that will be apparent to those skilled in the art. Generally, in oral care products such as those described above, under conditions and environments in which such products are conventionally used to be effective in inhibiting tartar formation, at least about 0.0.
An amount of 0.25 grams of gem-diphosphonate polymer is administered intraorally on a regular basis, eg, once or more times a day.

Optionally, at least about 0.050 grams is administered on a regular basis. Amounts similar to these are also effective in inhibiting plaque formation in the oral cavity. Typically, the amount of gem-diphosphonate polymer administered orally is about 5 grams or less per buccal administration.

The oral care composition of the present invention has a pH of about 5.0 to about pH 1.
Preferably it has a pH of 1.0.

A preferred pH range is about pH 7.0 to about pH 10.0. The pH of the composition will, of course, be determined by the predominant salt form of the diphosphonate polymer present therein.

Preferably, the composition has a pH of about 5.0 to about pH 11.
0, more preferably from about pH 7.0 to about pH 10, is buffered, for example by incorporating a buffer into the carrier, such that a pH of from about pH 7.0 to about pH 10 is maintained in the oral cavity during use. Non-limiting examples of buffers include citric acid, citric acid/bicarbonate and phosphate buffers.

The carrier may further contain conventional and optional ingredients for the particular type of oral composition desired. Such additional ingredients include abrasives, foaming agents, flavoring agents,
Sweeteners, anti-plaque agents, anti-tartar agents, anti-gingivitis agents, colorants, pigments, humectants, binders (thickeners), fluoride anti-caries agents, etc.

The choice of carrier used is fundamentally determined by the manner in which the composition is to be applied in the oral cavity and the purpose for which the composition is desired to be effective in addition to inhibiting tartar formation. for example,
“Toothpaste carrier” when toothpaste is used
See, for example, Baned jet U.S. Pat.
No. 88,433 (e.g., abrasive materials, foaming agents, binders, humectants, flavorings and sweeteners, etc.) or when a mouthrinse is used. The rinsing liquid carrier'' is also chosen, for example as disclosed in Benedict U.S. Pat. ), similarly, when a mouth spray is used, the same "oral spray carrier" as the mouthrinse carrier described above is selected, although a propellant may be present depending on the application type chosen. .

In the case where chewing gum is used, the "713 body for chewing gum" is described, for example, in U.S. Pat. No. 4,472,373 to Ryan and Grabenstetter et al. US Patent No. 4
, 083,955 (eg, gum base, flavoring agents, and sweetening agents).

If sachets are used, a "sachet carrier" is also selected (eg, sachet bag, flavoring agent, and sweetener). Carriers suitable for preparing compositions of the invention are well known in the art. Their selection also depends on secondary considerations such as taste, cost, and storage stability, which are not important for the purposes of the present invention, but can be easily made by one skilled in the art.

The abrasive polish contemplated for this invention may be any material that does not excessively abrade the dentin.

These include, for example, silicas including gels and precipitates, calcium carbonate, dicalcium orthophosphate dihydrate, calcium pyrophosphate, tricalcium phosphate, calcium polymetaphosphate, insoluble sodium polymetaphosphate, hydrated alumina, urea and formaldehyde. 12 of Coolcy et al., 1962, which is incorporated herein by reference.
There are other materials, such as those disclosed in U.S. Pat. Mixtures of abrasives can also be used. Preferably, the abrasive used is not a source of soluble calcium so large that its ability to inhibit crystal growth of the diphosphonate polymer is significantly lost. For such reasons, conventional abrasives such as carbonate and dicarmine orthophosphate are preferably not used, or are present in small amounts compared to the diphosphonate polymer so that significant rock-rocking ability is maintained, or Do not contact the diphosphonate polymer immediately prior to or concurrently with release into the oral cavity. However, Schweitzy −(Sc
Predominantly phase calcium pyrophosphate containing relatively little soluble calcium, such as that prepared in accordance with U.S. Pat. It is a preferred abrasive. Other preferred abrasives include alumina, insoluble metaphosphates and US Pat.
There is a resin-based polishing agent No. 070,510.

Various types of silica dental abrasives can provide exceptional tooth cleaning and polishing without overly abrasive the southern enamel of the dentin. Silica abrasive materials are believed to have exceptional compatibility with phosphate materials and soluble fluoride sources. For these reasons, they are particularly preferred for use in the present invention.

The silica abrasive polishes and other abrasives useful in the present invention are typically 0.05 mm. 1 to about 30 microns, preferably about 5
It has an average particle size of ~15 microns. Silica abrasives include Pader et al., U.S. Pat. No. 3,538,230, issued March 2, 1970, and DiGiul io, U.S. Pat. There are precipitated silicas or silica gels, such as silica xerogels, which are described in each of the patents of this patent, both of which are incorporated herein by reference. Double Earl Grace & Company (W
,I? , Grace &(?company)'s Davison Chemical Relay Division (Davison Chca+
Preferred is the silica xerogel commercially available under the trade name "Syloid" from Jcal Division. A preferred precipitated silica material is manufactured by J.M.Huber Corporation (J.M.
(Huber Corporation). These silica abrasives are described in US Pat. No. 4,340,583, dated July 29, 1982, which is incorporated herein by reference.

The abrasive in the compositions described herein, when the dentifrice is a toothpaste, preferably ranges from about 6 to about 7
0%, more preferably at a level of about 15% to about 25%. If the composition is a toothpaste, higher levels such as 90% can be used.

A preferred ingredient incorporated into dentifrice compositions, such as toothpastes, is a foaming agent. Suitable foaming agents include foaming agents that are reasonably stable and produce foam over a wide pH range, i.e. non-soap anionic, nonionic, cationic, zwitterionic and amphoteric organic synthetic surfactants. It is. These types of foaming agents include Agrleola
) et al., U.S. Patent No. 3,95, issued May 250, 1976.
No. 9,458 and U.S. Pat. No. 3,937 to Ilaerele, issued February 10, 1976.
, 807, both of which are incorporated herein by reference.

Anionic foaming agents useful in the present invention include water-soluble salts of alkyl sulfates having 10 to 18 carbon atoms in the alkyl group and water-soluble salts of sulfonated monoglycerides of fatty acids having 10 to 18 carbon atoms. be. Sodium lauryl sulfate and sodium coconut monoglyceride sulfonate are examples of this type of anionic surfactant.

Mixtures of anionic surfactants can also be used.

Nonionic foaming agents that can be used in the composition of the present invention are compounds produced by condensation of alkylene oxides (hydrophilic in nature) and organic hydrophobic compounds that are aliphatic or alkyl aromatic in nature. Can be broadly defined. Examples of suitable nonionic foaming agents include Pluronics (Pl
uronjcsTM) C WyandotLe Chemi-cals
Corp.), Wyandotte, Michigan],
a polyethylene oxide condensate of ethylene oxide and a reaction product of propylene oxide and ethylene diamine;
These include ethylene oxide condensates of aliphatic alcohols, long chain tertiary amine oxides, long chain tertiary phosphine oxides, long chain dialkyl sulfoxides, and mixtures of such materials.

The zwitterionic synthetic blowing agents useful in the compositions of the present invention can be broadly described as derivatives of aliphatic quaternary ammonium, phosphonium and sulfonium compounds, in which case the aliphatic groups may be linear or It may be branched and one of the aliphatic substituents has a carbon atom reservation of 8 to 18 and one carries an anionic water-solubilizing group such as carboxy, sulfonate, sulfate, phosphate, orthophosphate. have

Cationic foaming agents useful in the compositions of the present invention include lauryltrimethylammonium chloride, cetylpyridinium chloride, cetyltrimethylammonium bromide, diisobutylphenoxyethquinethyl-dimethylbenzylammonium chloride, coconut alkyltrimethylammonium nitrite, cetylpyridinium It can be broadly defined as a quaternary ammonium compound having one long alkyl chain of about 8 to about 18 carbon atoms, such as chloride and the like.

The amphoteric blowing agents useful in the present invention can be broadly described as derivatives of aliphatic secondary and tertiary amines, in which case the aliphatic groups may be linear or branched;
and one of the aliphatic substituents has about 8 to about 18 carbon atoms and one has an anionic water solubilizing group such as carboxylate, sulfonate, sulfate, phosphate or phosphonate.

Foaming agents can be present in the compositions of the present invention in amounts ranging from about 0 to about 10% by weight of the total composition.

Flavoring agents can also be added to the composition. Suitable flavoring agents include oil of wintergreen, oil of peppermint, oil of spearmint,
There are Satsafrasura and Ojiura.

Sweeteners that can be used include saccharin, dextrose, lebulose, aspartame, D-tryptophan, dihydrochalcones, acesulfneem and sodium cyclamate. Flavoring agents are typically used in the compositions at levels of from 0.4% to about 2% by weight, and seasoning agents from about 0.1% to about 2% by weight.
It is used at a level of about 5% by weight.

Binders can also be used in the toothpastes of the present invention. Such binders include, for example, xanthan gum, carrageenan, Irish moss, Viscarin.
inR) and carboxyvinyl polymers. These binders are usually about 0. Present at levels of 1-1%.

Other antiplaque agents may also optionally be added to the compositions of the invention. Suitable anti-plaque agents include chlorhexidine [1,6-bis(N5-p-chlorophenyl-
Bisbiguanide compounds such as Nl-biguanido)hexane], their soluble and insoluble salts, and similar substances such as 1,2-bis(N''-p-trifluoromethylphenyl-Nl-biguanido)ethane. The compound is disclosed in U.S. Pat.
Belgian Patent No. 843,244 dated December 22, 1976 and Brocter & Gamble No. 197
Further details are given in Belgian Patent No. 844,764, published January 31, 1997. These patent specifications are incorporated herein by reference. The compositions of the present invention are dated 3J119/1984 and 2/1985, respectively.
Parran φ Jr. in U.S. Pat.

It may also contain other anti-tartar agents, such as dialkali metals, mixtures of dialkali metals and tetra-alkali metal pyrophosphates, ie anti-tartar agents, as described by J. D. Jr. et al. If present, the optional anti-plaque agent usually represents from about 0 to about 5% by weight of the composition.

Another optional component of the composition is a humectant. Humectants help prevent compositions such as toothpastes from hardening upon exposure to air and provide a moist feel to the mouth in the case of mouthwashes. Certain humectants can also impart desirable flavor tastiness to mouthwash and toothpaste compositions. The humectant is a pure humectant based and typically contains 0 in the composition.
It accounts for ~70% by weight, preferably 0-55% by weight.

Humectants suitable for use in the present invention include glycerin,
There are edible polyhydric alcohols such as sorbitol, xylitol and propylene glycol. Sorbitol is often used as a 70% aqueous solution. However, the moisturizer range in the previous paragraph is based on the pure sorbitol component of such solutions.The topical solutions and mouthrinses of the present invention may also contain ethanol, preferably in an amount of about 0 to about 30%. good.

Suitable colorants may be any pharmaceutically acceptable food or drug colorants that are acceptable for topical application in the oral cavity.

Water may also be present in the compositions of the invention.

Water used in the manufacture of commercial dentifrices, prophylactic compositions and other oral care compositions should preferably be deionized and free of organic impurities. Water is typically 10-50% by weight of the main dentifrice composition, preferably about 2% by weight of the main dentifrice composition.
It accounts for 0 to 40% by weight. Mouth rinse solution is usually about 45
Contains ~95% water. These amounts of water include water added f'ree in addition to water mixed in with other substances such as sorbitol.

In order to further demonstrate the anti-caries ability, approximately 0.0025 ~
It is common to have enough water-soluble fluoride compounds present in the dentifrice to provide a fluoride concentration of about 5.0% by weight, preferably from about 0.005 to about 2.0% by weight. .

Sodium fluoride, stannous fluoride, indium fluoride and sodium monofluorophosphate are the preferred fluorides. Norris et al., July 2, 1960
No. 6, issued U.S. Pat. No. 2,946,735 and Wldder et al., U.S. Pat. No. 3,678,154, issued July 18, 1972, disclose such salts and others. , the disclosures of which are incorporated herein by reference.

Rat Tartar Test The following test method is useful for generating in vivo data regarding the tartar inhibiting properties of the gem-diphosphonate polymers of the present invention and for comparing their effectiveness with other phosphonate anti-calculus agents.

22 or more groups of 2 or more, each group consisting of 30 mass production groups.
~23 day old Wistar rats are used in this study, one group is used as control and the other as test group.

Each group is averaged with respect to body weight and sex.

Control group of animals: 50% cornstarch, 32%
Nonfat dry milk, 5% cellulose, 5% powdered sucrose, 3% liver powder, 2.7% NaH2PO4/H2O
, 1% vegetable oil, 196CaC1.2HO and 0.3% M
They are fed a tartar-inducing diet consisting of gSO4. Animals are allowed to feed ad libitum. Animals are given deionized water for fluid replenishment only. Each animal in the test group receives the anti-calculus agent twice a day for 5 days/week by contacting their teeth with an anti-calculus agent-impregnated cotton-tipped applicator.

Animals were killed in the mouth three weeks after the start of the study, and their molars were graded according to the degree of tartar by assessing the area and depth of accumulation on each of the 44 exposed oral tooth surfaces tested in each animal. be done. Grading is done on a scale of 0 to 3 for each surface, where 0 is undetectable amount of calcification and 0.5 is moderate to severe accumulation on less than 10% of the surface area or 25% of the area. Mild accumulation in: 1 is moderate to 10% to 25% of the area
Severe accumulation, 2 is mild to moderate accumulation in 25-50% of the area or severe accumulation in 25-50% of the area, and 3 is moderate accumulation in 75% or more of the area or area Severe accumulation in more than 50% of patients.

The total calculus score for each animal is determined by adding the grades on each of the 44 surfaces.

Crystal Growth Inhibition Measurement The following test method manually generates in vitro tartar inhibition data for the gem-diphosphonate polymer compositions of the present invention.
and useful for comparing their results with the effectiveness of other phosphonate anti-calculus agents.

As mentioned above, gem-diphosphonate polymers inhibit the growth of calcium hydroxyapatite crystals, thereby preventing the normal formation of calcium hydroxyapatite from solution. This test allows investigating the effect of gem-diphosphonate polymers on calcium phosphonate formed upon addition of calcium and orthophosphate ions at constant pH. This study is based on Nancolas et al., Oral Biology, Vol. 15.
Vol. 731, 1970 [: Nanco I l
as.

at at, 0ral Biology, 15.
731 (1970)), the disclosure of which is incorporated herein by reference.

In this test, hydroxyapatite seed crystals are added to a calcium/phosphate supersaturated solution in induced precipitation of metastable calcium phosphate for spontaneous precipitation. Seed crystals induce precipitation and crystal growth. Test compounds are added to the metastable Ca/P solution prior to seeding. The effects of these compounds on seed crystal-induced hydroxyapatite formation have been shown to be correlated with their in vivo effects on calcium metabolism.

Formation of calcium phosphate crystals causes hydrogen ion release (ie, pH change). The crystal growth rate is constant p
This is monitored by observing the amount of base added to maintain H.

Low levels (I x 10'M) of gem-polydiphosphone-1 can inhibit calcium phosphate formation for over 20 minutes. Crystal growth inhibition is dependent on the nature of the polyphosphonate or gem-polydiphosphonate that can be adsorbed onto the calcium phosphate crystal nuclei.

Anti-Adherence Test The following test method is useful for obtaining in vitro anti-plaque data for the gem-diphosphonate polymers of the present invention. This test measures bacterial adhesion onto hydroxyapatite beads.

25 mg of hydroquine apatite (HAP) is pre-coated with human saliva for 1.5 hours. Then,
HAP beads are 0.05MK Cl -1mM P
04 (pH 6,0), 1 mM CaC1 and 0-1
Washed three times with buffer of m M M g CI 2. The HAP beads are then equilibrated with an aqueous gem-diphosphonate polymer solution (at a desired concentration, eg, 5%) at pH 7.0 for 5 minutes under stirring. The HAP beads are removed from the aqueous solution and then washed once with a buffer as described above.

In the bacterial adsorption test, HAP prepared as above
25IIIg beads are placed in 1.0 ml of the above buffer solution containing approximately 1.5 x 108 bacteria [S, sangujs].

The beads are equilibrated in the mixture for 3 hours under stirring.

The beads are left undisturbed for 1 minute and the supernatant containing untubed cells is removed. HAP beads were washed with buffer (same composition as above) for 3.
Washed twice, filtered and dissolved in hydrochloric acid. The radioactivity of the lysed HAP is then determined by liquid scintillation counting to determine the number of bound cells. These results are compared to the radioactivity of dissolved HAP prepared as a control without anti-calculus/anti-plaque agents.

The following examples are presented to illustrate the invention and are not intended to limit the scope of the invention to the illustrative headings. The scope of the invention is defined by the claims.

Example 1 This example illustrates the synthesis of a polyvinyl diphosphonate polymer of the type described by formula (1b). The following steps were carried out: a) Synthesis of tetraethyl vinyl diphosphonate: C]
13011 5 (CII20), +EL2NII +C112 (PO
3EL2)2->C1130C112CII(PO3E
L2)2C]12-C(PO3Et2)2 Specifically, 104.2 grams of paraformaldehyde (3
, 47 mol) and diethylamine 50.8 grams (0,
69 mol) in 2.0 liters of dry methanol and the mixture was heated until clear. (“Et” as used above and below refers to the ethyl group.) Excluding the heat source, tetraethyl methylene bisphosphonate 200
．． 0 grams (0.69 mol) were added. The mixture was refluxed for 24 hours, then 2.0 liters of methanol was added and the solution was concentrated under vacuum at 30°C. 500 milliliters of toluene was added and the solution was concentrated again under vacuum at 30° C. to completely remove methanol from the intermediate product. However, the intermediate product is a clear liquid.

1.0 liters of toluene and 50.0 milligrams of p-)toluenesulfonic acid hydrate were then added to the intermediate product, and the solution was poured into a 2.0 liter flask equipped with a Soxhlet extractor containing 4 angstrom molecular sieves. It refluxed inside overnight. Methanol was removed by adsorption onto these molecular sieves. solvent(
Toluene) was removed under vacuum after refluxing for 14 hours to obtain the crude product.

The crude product was dissolved in 1.0 liter of chloroform and washed twice with 150 ml of distilled water. The chloroform solution was dried over anhydrous MgSO4, concentrated, and then distilled to give the desired product, tetraethyl vinyl diphosphonate 1.
34.2 grams were obtained.

The boiling point at 1 g of 0.07 munl was 121°C.

b) Synthesis of polyvinyl diphosphonate polymer: C'
1 Cn -〇Country 1 > Cn (t) Engineering 96.8 grams (0,59
2.0 liters of freshly distilled tetrahydrofuran (THF) from L t A I H4 was added to a 5.0 liter three-necked round bottom flask equipped with a mechanical Starcy, 500 ml dropping funnel and inlet. The solution was stirred at room temperature until the polymer was substantially completely dissolved. The solution was then cooled to -78°C and 1.55N n-butyllithium (0.30 mol) (in hexane) 19
The mixture was stirred with 2.9 ml for 1 hour.

Then 89.7 grams (0.30 mol) of CH-C(PO3Et2)2 were added and the temperature of the solution was maintained at -78 DEG C. for 1 hour under stirring. The solution was then heated to room temperature under stirring. 75 ml of distilled water was added, the solution was concentrated, and the residue was purified. The residue was dissolved in 1500 milliliters of concentrated HCI (12 molar), refluxed for 4 hours, and condensed to give a crude polyvinyl diphosphonate polymer product. The crude product has a molecular weight of 5.0
Sephadex to cut off with 00
xTM) G-25 resin [Pharmacia (Phar)
macia Inc.).

chromatography using Plscataway) and small-angle laser light scattering (
average molecular weight of 950 as determined from
41 grams of purified product of 0.0 was obtained. The a/b ratio determined from P31 NMR analysis was approximately 2.5.

Example 2 This example illustrates the synthesis of gem-polydiphosphonate polymers of the type described by formula (2) with an a/b ratio greater than zero. The following steps were carried out:
2 grams (0,70 mol) and (L i A I H4
9 liters of THFl (freshly distilled from ) were mixed at room temperature in a 5 liter 36 round bottom flask equipped with a mechanical stirrer, a 500 milliliter dropping funnel and an Ar inlet until the polymer was substantially completely dissolved. After cooling the solution to -78°C, 225 ml of 1.55N n-butyllithium (0.35 mol) (in hexane) were added dropwise and the solution was mixed at -78°C for 1 hour.

Then diethyl chlorophosphate (0.35 mol) 60.1
gram was added and the solution was allowed to warm to room temperature under stirring. The solution was then cooled to -78°C, treated with n-butyllithium and diethyl chlorinate, and warmed to room temperature as above. Fifty milliliters of distilled water was added and the solution was concentrated to obtain a residue of product. Incubate the residue with concentrated MCI for 3 hours.
Reflux with 750 milliliters (12 molar) and recondensation gave the crude product. The crude product was treated with Sephadex G-25 resin (molecular weight 5000, commercially available from Pharmacia).
33.1 grams of the desired diphosphonate polymer was obtained. P3'
The a/b ratio determined from NMR analysis was approximately 2.6.

Example 3 This example shows a preferred g of the type described by formula (IC)
The synthesis of em-diphosphonate polymers is shown.

Specifically, 125.0 grams of polyacrylic acid (1,44
mole, average molecular weight measured from LALLS 2100)
, 25.9 grams of distilled water (1.44 moles), and 300.0 grams of sulfolane (tetramethylene sulfone) were mixed in a 2 liter round bottom flask. This solution was stirred at 45° C. until the polyacrylic acid was dissolved. Then p
c+3125.6 milliliters (197.76 grams, 1.44 moles) was added dropwise into the solution over about an hour with continuous stirring. 1ilH
Cl was removed from the flask under argon purge. The solution was heated to 100° C. by immersing the flask in an oil bath and maintained at that temperature for 2 hours before the solution was allowed to cool to room temperature. After reaching room temperature, CHCl36
00 milliliters was poured into the flask and a yellow solid precipitate formed from the solution. The precipitate was collected by vacuum filtration, and C
Washed 5 times with HCl and 3250 milliliters of CHCl per wash. The remaining CHCl3 was removed under vacuum, the precipitate was redissolved in 500 milliliters of distilled water, and the aqueous solution was refluxed at 100 DEG C. for 18 hours to produce a crude gem-diphosphonate polymer product. Concentrating the crude product-containing aqueous solution under vacuum at 50° C. to about 200 milliliters;
Then 1.2 liters of acetone was added. oily gem
- The diphosphonate polymer was recovered by decantation.

Four additional precipitation operations yielded 72 grams of gem-diphosphonate polymer product. Testing of the product by P'' NMR analysis showed that 43 mole percent phosphorus in the product was present as hydroxydiphosphonic acid. The product contained a total of 12.28 percent phosphorus by weight. a /
The molar ratio of b was calculated to be approximately 4.0.

Example 4 This example demonstrates the synthesis of gem-polydiphosphonate polymers formed by polymerization of monomers of the type described by formula (3). 3 in mineral oil (0,104 mol) under argon in an oven-dried flask.
11.93 grams of 5% hydrogen potassium (KH) was added. The KH was washed several times with dry toluene to remove mineral oil.

Toluene was added, the mixture was cooled in a water bath and toluene 1
30.00 grams (0.104 moles) of freshly distilled tetraethyl methylene diphosphonate in 0.00 milliliters was added dropwise. The mixture was then stirred at room temperature for 1 hour.

This solution was then placed in an addition funnel and added dropwise over 2.5 hours to a stirred solution of allyl bromide (12.58 grams, 0.104 mole) in 250 milliliters of toluene at 60.degree. The solution was stirred for a further 18 hours at room temperature.

Toluene was removed from the reaction mixture and ethyl ether 60
Reconstituted to 0 ml. The ether solution was diluted with water (10
0 ml/wash 3 times) and brine (100 ml/wash 2 times) and dried over anhydrous MgSO4. The solids were filtered and the filtrate was concentrated at 30° C. to yield 35.12 grams of product (clear liquid). The crude product was purified on silica gel with 1:1 hexane:acetone as eluent and purified with tetraethyl 3 as determined by 3'P NMR analysis.
9.5 grams of -butene-1,1-diphosphonate product were obtained.

The dry flask was then charged with 35% potassium hydride in mineral oil (
2.85 grams (0,0286 moles KH) of KH) were added and the mineral oil was washed away with 10 milliliters of dry toluene. Tetraethyl 3-butene-1,1-diphosphonate 9. in 25 ml of toluene was then added while toluene (75 ml) was added and the mixture was cooled in a water bath.
40 grams (0,0286 moles) were added dropwise under argon. The solution was stirred at room temperature for 1 hour and then recooled in a water bath. 7.16 grams of S-phenylbenzenethiosulfonate dissolved in 50 milliliters of toluene (0.0
286 mol) was added dropwise to the stirred solution. The mixture was stirred at room temperature for 18 hours, concentrated and then redissolved in 250 milliliters of ethyl ether. Add ether solution to water (
50 milliliters/wash (three times) and brine (one time of 50 milliliters) and dried over anhydrous MgSO4.

The mixture was filtered and the solution was concentrated to yield 13 grams of crude product. The product was purified by silica gel chromatography, eluent 2:1 hexane:acetone,
9.85 grams of tetraethyl 1-phenylthio-3-butene-1,1-diphosphonate product was obtained as determined by 'P NMR analysis.

A 250 milliliter flask was charged with 3.00 grams (0,00687 moles) of tetraethyl 1-phenylthio-3-butene-1,1-diphosphonate in 50 milliliters of CHCl3 (ethanol free) and stirred at 0 DEG C. under argon. m- in 325 ml of CHCl in a stirred solution.
1.56 grams of chloroperbenzoic acid was added dropwise. Stirring to 0
C. for 1 hour and then at room temperature for 18 hours. The reaction mixture was cooled to 0° C. and 50 ml of sodium 1026 thiosulfate solution was added. The cold solution was placed in a branched funnel and the 68013 layer was separated. The CH013 solution was then added to a saturated sodium bicarbonate solution (2 x 20 ml),
Wash with water (2 x 25 ml) and anhydrous M g S
Dry with O4.

After filtration, the solution was concentrated to obtain 3.0 grams of crude product.

The crude product was purified by silica gel chromatography with 2:1 hexane:acetone as eluent. Chromatography yielded 1.35 grams (60%) of tetraethyl 1,3-butadiene-1,1-diphosphonate product as determined by 31PN MR analysis.

Tetraethyl 1.3- in a 25 ml round bottom flask
1.35 grams of butadiene-1,1-diphosphonate (
4.14 mmol) and 15 ml of benzene were added, and the solution was degassed to remove oxygen. Benzoyl peroxide (10 milligrams, 0.04 mmol) was added and the solution was heated to 60° C. under argon in an oil bath. The reaction is 3'P
Monitored by NMR. An additional 10 milligrams of benzoyl peroxide were added at 26.50 and 74 hours after the start of the reaction. After 74 hours, the solvent was removed under vacuum at 30°C and the 3'P
Solid tetraethyl 1.3- determined by NMR analysis
Butadiene-1,1-diphosphonate polymer product 1
．． 37 grams were obtained.

Tetraethyl 1,3-butadiene-1,1-diphosphonate polymer was mixed with 315 milliliters of CHCl and 4.90 grams (0,032 moles) of trimethylsilyl bromide.
25 ml flask. 60% of the mixture
Stirred at °C for 18 hours, then concentrated under vacuum at room temperature. The product was stirred in IO milliliters of methanol for several minutes, then the solution was concentrated. Repeat this 3 times, p3
tl, 3-butadiene-1 determined by 1NMR at 31℃
, 1.15 grams of 1-diphosphonate polymer were obtained.

The polymer was further purified by chromatography on a column packed with Sephadex G-25 (MW cutoff 5,000).

Example 5 The following are representative examples of toothpastes of the present invention.

Ingredients %
Distilled water 16.
50 turbitol (70% aqueous solution)
49. 56 Saccharin Sodium
0.30 dye solution
0.35 precipitated silica
20. 00 Sodium Fluoride
0,257, -bar
1,3° Sodium alkyl sulfate (27,9% aqueous solution) 5.00 Carbopol 94
0s* 0.20 xanthan rubber 0.60 g of example 1
em-diphosphonate polymer 6.0010
0.00 *BF Gutdrich Company (B.

F. Goodrjch Con+pany) Commercially available carboxyl vinyl polymer The above composition is prepared by mixing water and some sorbitol in a stirred mixture and heating the mixture to 140'F (approximately 60°C).
It is produced by heating to

The gem-diphosphonate polymer, saccharin, sodium fluoride and precipitated silica are then added sequentially and the entire mixture is mixed for 5-10 minutes. Flavors, colors and surfactants are then added.

In a separate container, slurry the remaining sorbitol, Carbopol, and xanthan gum together and then add to the main mix tank. The complete batch is mixed for about 0.5 hours, then ground and degassed.

Gem-diphosphonate polymers can also be prepared as described in Examples 2.3 or 4.

Example 6 The following is another representative toothpaste of the present invention.

Ingredients?
6 Sorbitol (70% aqueous solution) 5
0.75 distilled water
16. 50 Saccharin Sodium
0.30 dye solution
0.35 precipitated silica
20. 00 thorium
0125 flavor
1.30 Sodium alkyl sulfate (27.9% aqueous solution) 5.00 Carbopol 940S O,20 Xanthan gum 0.60 Gem-diphosphonate polymer of Example 1 4.1
5100.00 On the other hand, g e m ~ diphosphonate polymer is Example 2.3
Alternatively, it can also be produced as described in 4.

In addition to the levels and tn combinations of ingredients shown in these examples, other ingredients consistent with the disclosed invention can also be used.

Example 7 This example illustrates a mouthrinse composition containing a gem-diphosphonate polymer of the present invention.

Mouth rinse is manufactured as follows:
Minutes %Example 1
gem-diphosphonate polymer 4.00
Distilled water 69.1
9 ethanol 1
6.25 Glycerin 1
0.00 nonionic surfactant
0.12 benzoic acid
0.05 Satucalin Sodium
0.05 flavor
0.15 colorant
0.04NaOH (10% solution)
0.15100.00 Mouth rinse is manufactured by adding each component to distilled water and stirring. On the other hand, gem-diphosphonate polymers can also be prepared as described in Examples 2.3 or 4.

Applicant's agent: Satoshi Fuji Manual Continuation Supplementary Book (Method) % Formula % 2 Name of the invention Oral composition 3 Person making the amendment Relationship to the incident Patent applicant Starting gate March 28, 1999 6 Target of correction Applicant column of application, power of attorney and specification

Claims (1)

[Scope of Claims] 1. An oral care composition, preferably formulated for intraoral administration that is not substantially ingested as a dentifrice or prophylactic composition, comprising: (a) a gem-diphosphonate polymer component [this The component contains one or more gem-diphosphonate polymers selected from the group consisting of polymers containing the following monomer unit combinations; Each R_1, R_2, R_a and R_b is each independently -H, -CO_2H or its ester, -C≡N, -PO_3H_2, substituted or unsubstituted aryl, substituted or unsubstituted C_1-C_1_0 alkyl, or substituted or unsubstituted C_1 -C_2_0oxyalkyl; each R_3 is independently -H, -
each m is independently 0 or 1; each Q is independently substituted or unsubstituted aryl or substituted or unsubstituted C_1-C_1_0 alkylene; (and the molar ratio of a/b is greater than or equal to 0 and less than or equal to 30, preferably less than or equal to 20); (ii) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the above formula, a /b molar ratio is greater than or equal to 0 and less than or equal to 30, preferably less than or equal to 20)
; and (iii) CH_2=CH-CH=C(PO_3X_2
)_2 polymerization product (in the above formula, each X is independently -H or C_1-
C_1_0 alkyl; and when X is alkyl, each -PO_3X_2 group is -PO_3H_
2 groups); the gem-diphosphonate polymer component has 1,00
average molecular weight of 0 to 20,000, preferably 1,000 to 5,000, more preferably 2,000 to 5,000, an average of at least 3 gem-diphosphonate units per polymer chain, and no more than 30 gems. - a molar ratio of diphosphonate-free monomer units to gem-diphosphonate-containing monomer units] and (b) a pharmaceutically acceptable carrier; 0.1-20 wt%, preferably 1-10%
, more preferably 1 to 5% of the above gem-diphosphonate polymer component. 2. The gem-diphosphonate polymer component is a gem-diphosphonate polymer of formula (i), preferably; Each independently -
H or substituted or unsubstituted C_1-C_1_0 alkyl, preferably -H or unsubstituted C_1-C_3 alkyl); (i-b) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (In the above formula, each R_6 is independently -H, substituted or unsubstituted C_1-C_1_0 alkyl, preferably -H or unsubstituted C_1-C_3 alkyl; m is 1
and each Q is independently substituted or unsubstituted aryl or substituted or unsubstituted C_1-C_1_
(in the above formula, each m is independently 0 or 1;
Each Q is independently substituted or unsubstituted aryl or substituted or unsubstituted C_1-C_1_0 alkylene,
Preferably C_1-C_3 alkylene; each R_7
are each independently -OH, -NH_2 or a salt thereof, preferably -OH or a salt thereof; and each R_8
2. Oral care composition according to claim 1, wherein each is independently selected from -CO_2H or -C≡N, preferably -CO_2H. 3. The gem-diphosphonate polymer component comprises one or more gem-diphosphonate polymers of formula (ic), and preferably further m is 0, or m is 1, in which case Q The oral care composition according to claim 2, wherein is unsubstituted C_1-C_3 alkylene and the a/b ratio is from 0.5 to 20. 4. A method for inhibiting dental calculus formation, comprising the step of administering a pharmaceutically safe and effective amount of an anti-calculus agent into the oral cavity, wherein the anti-calculus agent is selected from the group consisting of polymers containing the following monomer unit combinations: (i) ▲ Numerical formula, chemical formula, table, etc. ▼ (In the above formula, each R_1, R_2, R_a and R_b each independently represents -H, -CO_2H or The ester is -C≡N, -PO_3H_2, substituted or unsubstituted aryl, substituted or unsubstituted C_1-C_1_0 alkyl or substituted or unsubstituted C_1-C_2_0 oxyalkyl; each R_3 is independently -H, -
each m is independently 0 or 1; each Q is independently substituted or unsubstituted aryl or substituted or unsubstituted C_1-C_1_0 alkylene;
and the molar ratio of a/b is greater than or equal to 0 and less than or equal to 30, preferably less than or equal to 20); (ii) ▲ Numerical formulas, chemical formulas, tables, etc.▼ (In the above formula, a/b is greater than or equal to 0 and less than or equal to 30, preferably less than or equal to 20)
; and (iii) CH_2=CH-CH=C(PO_3X_2
)_2 polymerization product (in the above formula, each X is independently -H or C_1-
C_1_0 alkyl; and when X is alkyl, each -PO_3X_2 group is -PO_3H_
2 groups); the gem-diphosphonate polymer component has 1,00
average molecular weight of 0 to 20,000, an average of at least 3 gem-diphosphonate units per polymer chain, and no more than 30, preferably no more than 20 gem-diphosphonate-free monomer units to gem-diphosphonate-containing monomer units. A method characterized in that having a molar ratio. 5. The gem-diphosphonate polymer is selected from the group consisting of polymers containing the following monomer unit combinations; Each independently -
H or substituted or unsubstituted C_1-C_1_0 alkyl); (i-b) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (In the above formula, each R_6 is independently -H, substituted or unsubstituted C_1- C_1_0 alkyl; m is 1; and each Q is independently substituted or unsubstituted aryl or substituted or unsubstituted C_2-C_1
_0 alkylene); and (i-c) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (In the above formula, each m is independently 0 or 1, preferably 0; each Q is independently substituted or unsubstituted aryl or substituted or unsubstituted C_1-C_1_
0 alkylene; each R_7 is independently -O
H, -NH_2 or a salt thereof; and each R_8
are each independently -CO_2H or -C≡N) (in the above formula, the ratio of a/b is 30 or less, preferably 20 or less), the method for inhibiting tartar formation according to claim 4. 6. This method is also effective in inhibiting plaque.
The method for inhibiting dental calculus formation according to claim 4 or 5.