Diphosphonic acid esters as tartar control agents

Polyphosphonic acid ester compounds with flavorant, coolant and/or sweetener components, and tartar, plaque and/or calculus control compositions with improved taste comprising one or more polyphosphonic acid ester compounds are described.

BACKGROUND OF THE INVENTION 
Dental calculus is a deposit which forms on the surfaces of teeth at the 
gingival margin. A wide variety of chemical and biological agents have 
been suggested to retard calculus formation or to remove calculus after it 
is formed. Polyphosphonates have been disclosed for use as anticalculus 
agents. U.S. Pat. Nos. 3,678,154, issued Jul. 18, 1972; 3,737,533, issued 
Jun. 5, 1973; and 3,941,772, issued Mar. 2, 1976 disclose such compounds. 
Dental plaque comprises an accumulation of bacteria and bacterial 
byproducts on teeth. Azacycloalkane-2,2-diphosphonic acids are described 
in U.S. Pat. No. 3,941,772, Ploger et at, issued Mar. 2, 1976 as novel 
compounds which are said to be useful in preparations such as mouthwashes 
and toothpastes in order to avoid the formation of tartar or plaque. 
In spite of such work, there continues to be a need for new compounds and 
compositions for oral use effective for retarding calculus and/or plaque 
formation. In the present invention, flavorant, sweetener and/or coolant 
components have been attached to diphosphonic acids via an ester linkage 
in order to provide a tartar control agent which has improved and/or 
longer lasting taste and/or efficacy. Thus, one compound is provided which 
has two functions: improved taste; and tartar, plaque, and/or calculus 
control. 
SUMMARY OF THE INVENTION 
The present invention relates to poly (preferably di) phosphonic acid ester 
compounds of flavorant, coolant and/or sweetener components, said 
diphosphonic acid ester compounds being especially useful as tartar, 
plaque and/or calculus control agents having improved taste. The present 
invention also relates to tartar, plaque and/or calculus control 
compositions comprising one or more of these polyphosphonic acid ester 
compounds. Methods of using the compositions are also included. 
DETAILED DESCRIPTION OF THE INVENTION 
The subject invention relates to a compound of the formula: 
##STR1## 
where R1 through R4 are independently selected from the group consisting 
of a coolant component, a sweetener component, a flavorant component; an 
adherent group, a physiologically active metal cation, an organic cation, 
and hydrogen; and at least one R1 through R4 is a coolant component, a 
sweetener component, or a flavorant component; 
R5 is selected from the group consisting of hydrogen, alkyl containing from 
1 to about 20 carbon atoms, alkenyl containing from 2 to about 20 carbon 
atoms, aryl (e.g., phenyl and naphthyl), phenylethenyl, benzyl, halogen 
(e.g. chlorine, bromine, and fluorine), amino, substituted amino (e.g. 
dimethyl amino, diethylamino, N-hydroxy-N-ethylamine, 
acetylamino),--CH2COOH, --CH2PO3H2, --CH(PO3H2)OH or--CH2CH(PO3H2)2, and 
salts thereof; 
R6 is selected from the group consisting of hydrogen, lower alkyl, (e.g. 
methyl, ethyl, propyl, and butyl), amino, benzyl, halogen (e.g., chlorine, 
bromine, and fluorine), hydroxy,--CH2COOH, --CH2PO3H2, or CH2CH2PO3H2; and 
salts thereof; such as alkali metal (e.g. sodium and potassium), alkaline 
earth metal (e.g. calcium and magnesium), and ammonium or low molecular 
weight substituted ammonium (e.g., mono-, di-, and triethanolammonium) 
salts thereof, 
R7 and R8 are independently hydrogen or CH2OH; and 
n is an integer of from 3 to 10, preferably from 3 to 5. 
Included in the above formula are linear and cyclic structures. For 
example, R5 can be linked to R6 to create cyclic variants. Particularly 
preferred is the cyclic compound where R5 is (CH.sub.2).sub.n, where n is 
an integer from 3 to 5; and R6 is N-R9 wherein R9 is hydrogen or an alkyl 
having from 1 to 4 carbon atoms ("lower alkyl"). 
Mixed di (or poly) phosphonic acid esters are also included herein, such as 
where several R1-4 groups are flavorants, and several are coolants. The 
components within a category (coolants, flavorants, and sweeteners) can 
also vary in a single diphosphonic acid ester compound. For example, 
thymol may be R1 and eugenol may be R2 on the same compound. 
The present invention also relates to tartar, plaque and/or calculus 
control compositions with good or improved taste (versus currently 
available antitartar or antiplaque ingredients) comprising one or more of 
these diphosphonic acid ester compounds. 
The present invention also encompasses a method for retarding the 
development of plaque and/or gingivitis, tartar and/or calculus using 
these compositions. 
Flavor-containing di or poly phosphonite acid esters herein can be 
synthesized by coupling flavors with hydroxy groups with di or poly 
phosphonic acids. Similar reactions can be conducted with coolants or 
sweeteners which contain hydroxy functionality. 
Components 
The term "coolant component" as used herein refers to coolant compounds 
having a hydroxy functionality which is capable of forming an ester 
linkage with a phosphorus(V) atom. Preferred coolant components are 
selected from the group consisting of 1-menthol, d-menthol, 
3-1-menthoxypropane-1,2-diol ("TK-10"), menthone glycerol acetal ("MGA"), 
and 1-menthyl lactate. 
The term "flavorant component" as used herein refers to flavorant compounds 
having a hydroxy functionality which is capable of forming an ester 
linkage with a phosphorus(V) atom. Preferred flavorant compounds are 
selected from the group consisting of methyl salicylate, eugenol, 
vanillin, thymol, cinnamaldehyde glycerol acetal ("CGA"), and linalool. 
The term "sweetener component" as used herein refers to sweetener compounds 
having a hydroxy functionality which is capable of forming an ester 
linkage with a phosphorus(V) atom. Preferred sweetener components are 
saccharin, mannitol, sorbitol, glucose, sucrose, fructose, and 
neohesperidin dihydrochalcone. 
The term "adherent component" as used herein refers to either monomers, 
oligomers, or polymers having hydroxy functionalities which are capable of 
forming ester linkages with phosphorus(V) atoms. The monomers, oligomers, 
or polymers may also possess additional hydroxy groups which may either 
remain unsubstituted or be linked via ester linkage to a phosphorus(V) 
atom which is also attached to a coolant or flavor portion. Preferred 
adherents are selected from the group consisting of C12-C18 diacyl 
glycerol, partially hydrolyzed vinyl acetate/ethylene copolymer, 
cellulose, chitin, glucose, glucosamine, silica gel, glycerol, and methyl 
vinyl ethermaleic acid. 
Preferred "physiologically relevant metal cations" are sodium, potassium, 
calcium, zinc, copper, manganese, tin and magnesium. Most preferred are 
sodium and potassium. 
"Organic" cation as used herein refers to cations that contain positively 
charged nitrogen, phosphorous, oxygen, or sulfur atoms. Such cations may 
contain more than one positively-charged site and, in the case of 
oligomers or polymers containing nitrogen, phosphorous, oxygen, or sulfur 
atoms, many positively-charged centers may exit. Preferred organic cations 
include ammonium (most preferred), protonated amines such as protonated 
glucosamine, and partially or fully protonated amine-containing polymers 
such as protonated chitosan. 
Compounds 
Azacycloalkane diphosphonates are diphosphonates suitable for use in the 
practice of this invention. Reference can be made to U.S. Pat. No. 
3,941,772, to Ploger et al., Mar. 2, 1976, incorporated herein by 
reference, for syntheses of these materials. 
In general, azacycloalkane-2,2-diphosphonates useful for substitution have 
the formula 
##STR2## 
wherein R can be hydrogen or lower alkyl (C1-4), e.g., methyl, ethyl, 
propyl, and the like, and n is an integer from 3 to 5. Such materials are 
prepared by reaction of the corresponding cyclic lactam with, for example, 
H.sub.3 PO.sub.3. In this manner are prepared, for example, 
azacyclopentane-2,2-diphosphonic acid ("ACP"), 
N-methyl-azacyclopentane-2,2-diphosphonic acid ("NMAP") and 
azacyloheptane-2,2-diphosphonic acid, which is more properly named as 
1-azacycloheptylidene-2,2diphosphonic acid. Use of such materials as their 
acids or water-soluble salts, e.g., Na+, K+, NH.sub.4 +, salts, is 
contemplated by this invention. The sodium salts of 
1-azacycloheptylidene-2,2-diphosphonic acid are referred to herein, 
collectively, as "AHP". (It will be appreciated that, as long as the salt 
is water soluble, the particular salt form used herein, i.e., mono-, di-, 
tri- or tetra-salt, is of no particular consequence in the practice of 
this invention, since it is the anion that provides the anti calculus 
benefit.) By "effective amount" of such diphosphonates herein is meant an 
amount sufficient to provide an anti calculus benefit. 
Other polyphosphonates found useful in the present invention are those set 
forth in U.S. Pat. No. 3,488,419, to McCune et at., Jan. 6, 1970 
incorporated herein in its entirety by reference. Polyphosphonates useful 
for substitution herein are selected from the group consisting of those of 
the formulae: 
##STR3## 
wherein R7 and R8 are hydrogen or CH.sub.2 OH; n is an integer of from 3 
to 10; R5 is hydrogen, alkyl containing from 1 to about 20 carbon atoms, 
alkenyl containing from 2 to about 20 carbon atoms, aryl (e.g., phenyl and 
naphthyl), phenylethenyl, benzyl, halogen (e.g., dimethylamino, diethyl 
amino, N-hydroxy-N-ethylamino, acetyl amino), --CH.sub.2 COOH, --CH.sub.2 
PO.sub.3 H.sub.2, 
EQU --CH(PO.sub.3 H.sub.2) 
(OH) or --CH.sub.2 CH(PO.sub.3 H.sub.2).sub.2 ; R.sub.6 is hydrogen, alkyl 
of from 1 to 12 carbon atoms (e.g., methyl, ethyl, propyl, butyl, octyl 
and decyl), amino, benzyl, halogen (e.g., chlorine bromine and fluorine), 
hydroxyl, --CH.sub.2 COOH, --CH.sub.2 PO.sub.3 H.sub.2, or --CH.sub.2 
CH.sub.2 PO.sub.3 H.sub.2 ; or a pharmaceutically acceptable salt thereof 
such as alkali metal (e.g., sodium and potassium), alkaline earth metal 
(e.g., calcium and magnesium), and ammonium or low molecular weight 
substituted ammonium (e.g., mono-, di, and triethanolammonium) nits, and a 
carrier suitable for use in the oral cavity, the pH of the composition 
being within the range from about 5.0 to about 11.0. 
Operable phosphonates of the above Formula (I) include: 
propane-1,2,3-triphosphonic acid; 
butane-1,2,3,4-tetraphosphonic acid; 
hexane-1,2,3,4,5,6-hexaphosphonic acid; 
hexane-1-hydroxy-2,3,4,5,6-pentaphosphonic acid; 
hexane-1,6-dihydroxy-2,3,4,5-tetraphosphonic acid; 
pentane-1,2,3,4,5-pentaphosphonic acid; 
heptane-1,2,3,4,5,6,7-heptaphosphonic acid; 
octane-1,2,3,4,5,6,7,8-octaphosphonic acid; 
nonane-1,2,3,4,5,6,7,8,9-nonaphosphonic acid; 
decane-1,2,3,4,5,6,7,8,9,10-decaphosphonic acid; 
and the pharmaceutically acceptable salts of these acids, e.g., sodium, 
potassium, calcium, magnesium, ammonium, triethanolammonium, 
diethanolammonium, and monoethanolammonium salts. 
Among the operable polyphosphonates encompassed by the above Formula (II) 
are 
ethane-1-hydroxy-1,1-diphosphonic acid; 
methanediphosphonic acid; 
methanehydroxydiphosphonic acid; 
ethane-1,1,2-triphosphonic acid; 
propane-1,1,3,3-tetraphosphonic acid; 
ethane-2-phenyl-1,1-diphosphonic acid; 
ethane-2-naphthyl-1,1-diphosphonic acid; 
methanephenyldiphosphonic acid; 
ethane-1-amino-1,1-diphosphonic acid; 
methanedichlorodiphosphonic acid; 
nonane-5,5-diphosphonic acid; 
n-pentane-1,1-diphosphonic acid; 
methanedifluorodiphosphonic acid; 
methanedibromodiphosphonic acid; 
propane-2,2-diphosphonic acid; 
ethane-2-carboxy-1, 
1-diphosphonic acid; 
propane-1-hydroxy-1,1,3-triphosphonic acid; 
ethane-2-hydroxy-1,1,2-triphosphonic acid; 
propane-1,3-diphenyl-2,2-diphosphonic acid; 
nonane-1,1-diphosphonic acid; 
decane-1-hydroxy-1,1-diphosphonic acid; 
hexadecane-1,1-diphosphonic acid; 
pent-4-ene-1-hydroxy-1,1-diphosphonic acid; 
octadec-9-ene-1-hydroxy-1,1-diphosphonic acid; 
3-phenyl-1,1-diphosphonoprop-2-ene; 
octane-1,1-diphosphonic acid; 
dodecane-1,1-diphosphonic acid; 
phenylaminomethanediphosphonic acid; 
naphthylaminomethanediphosphonic acid; 
N,N-dimethylaminomethanediphosphonic acid; 
N-(2-hydroxyethyl)-aminomethanediphosphonic acid; 
N-acetylaminomethanediphosphonic acid; 
aminomethanediphosphonic acid; 
and the pharmaceutically acceptable salts of these acids, e.g., sodium, 
potassium, calcium, magnesium ammonium, triethanolammonium, 
diethanolammonium and mono-ethanolammonium salts. 
Mixtures of any of the foregoing and/or their salts can be used in the 
compositions of this invention. 
Ethane-1-hydroxy-1,1-diphosponic acid, a preferred di (or poly) 
phosphonate, has the molecular formula CH.sub.3 C(OH)(PO.sub.3 
H.sub.2).sub.2. (According to nomenclature by radicals, the acid might 
also be named 1-hydroxyethylidene diphosphonic acid). The most readily 
crystallizable salt of this acid is obtained when three of the acid 
hydrogens are replaced by sodium. Preferred salts for the purpose of this 
invention are the trisodium hydrogen salt, which has the formula: 
##STR4## 
and the disodium salt. 
A highly preferred diphosphonic acid ester is tetramenthyl 
aminohexanediphosphonate (AHP). 
Without meaning to be bound by theory, it is believed that the desired 
coolant, sweetener or flavorant can be delivered through the action of the 
polyphonate derivative itself. The compositions may also provide a 
sustained effect by cleavage of the coolant, flavorant and or sweetener 
component to the molecule after cleavage of the polyphonic acid from the 
coolant, flavorant and/or sweetener by acid, alkaline, neutral or 
pyrophosphatase enzymes. 
Levels 
The compound of the present invention is used in the present compositions 
at levels of from about 0.001% to about 25%, preferably from about 0.01% 
to about 15%, most preferably from about 0.1% to about 5%, by weight of 
the composition. 
Preferrably, compositions herein include from about 85% to about 99.99%, 
more preferably from about 90% to about 99.05%, most preferably from about 
95% to about 99.5%, by weight of the composition, of carrier material. 
Compositions 
The present invention also encompasses an antitartar, antiplaque, or 
anticalculus composition, comprising, by weight of the composition, from 
about 0.001% to about 25%, by weight of the composition, of one or more of 
the present compounds. 
Oral compositions herein are preferably not, in the ordinary course of 
usage, intentionally swallowed for purposes of systemic administration of 
particular therapeutic agents, but are rather retained in the oral cavity 
for a time sufficient to contact substantially all or most of the dental 
surfaces and/or oral tissues. 
The phrase "a safe and effective amount", as used herein, means a 
sufficient amount of material to provide the desired benefit without undue 
adverse side effects (such as toxicity, irritation or allergic response) 
commensurate with a reasonable benefit/risk ratio when used in the manner 
of this invention. The specific safe and effective amount will vary with 
such factors as the particular condition that is being treated, the 
severity of the condition, the duration of the treatment, the physical 
condition of the patient, the nature of concurrent therapy (if any), and 
the specific formulation and optional components employed. 
The compositions herein are preferably toothpaste (most preferred), 
mouthrinse, or liquid dentifrice. Sodium fluoride is preferably included 
in dentifrice compositions herein. Components to be added should be safe 
for oral use. By "safe" is meant without undue adverse side effects (such 
as toxicity, irritation or allergic response) commensurate with a 
reasonable benefit/risk ratio when used in the manner of this invention. 
Carrier Materials 
In formulating the compositions of this invention the phosphate derivative 
will preferably be incorporated into a carrier which may be completely 
inert or which may be or contain other active ingredients. The term 
"carrier materials", as used herein, means one or more compatible 
substances suitable for administration to a human or lower animal. The 
term "compatible", as used herein means that the components of the 
compositions are capable of being commingled with phosphate derivatives, 
actives, and with each other, in a manner such that there is no 
interaction which would substantially reduce the efficacy of the present 
compositions under ordinary use situations. Carrier materials must also be 
of sufficiently high purity and sufficiently low toxicity to render them 
suitable for administration to the human or lower animal being treated. 
A wide variety of carders will be suitable depending upon the end use of 
the compositions. The phosphate derivatives can be incorporated into a 
range of topical compositions. Topical compositions include compositions 
applied to, or which in normal usage come in contact with, the internal 
membranes of the body such as those of the mouth, whether by direct or 
indirect application. Such compositions include (but are not limited to) 
dentifrices, oral rinses, lozenges, foams, and gels. Preferred 
compositions of the present invention are dentifrices and oral rinses. 
Suitable carrier materials herein, depending on intended end use, are 
selected from the group consisting of solvents, suspending agents, 
solubilizing agents, diluents, surfactants, buffers, lubricants, 
thickeners, emulsifiers, flavoring agents, colorants, humectants, 
sweeteners, co-solvents, binders, disintegrating agents, flow-inducing 
agents, coolants, wetting agents, antioxidants, stabilizers, and tableting 
agents. 
Dentifrices 
Dentifrice compositions may be of the liquid, paste, powder or gel type. 
These compositions will usually comprise a finely divided abrasive or 
polishing material, e.g. precipitated chalk, silica, magnesium silicate, 
calcium polymetaphosphate, aluminum hydroxide or other similar materials 
well known in the art. Abrasive materials are more fully described in U.S. 
Pat. No. 3,070,510, Cooley et at., Dec. 25, 1962, which is incorporated 
herein by reference. Toothpaste compositions additionally contain a 
surfactant or foaming agent. Suitable surfactants are those which are 
reasonably stable and foam throughout a wide pH range, including non-soap 
anionic, nonionic, cationic, zwitterionic and amphoteric organic synthetic 
detergents. These surfactants are disclosed by Gieske et at. in U.S. Pat. 
No. 4,051,234, issued Sep. 27, 1977, also incorporated herein by 
reference. 
Optional ingredients in dentifrice compositions include flavoring agents, 
colorants, buffers, lubricants, thickeners, emulsifiers or plasticizers, 
and humectants. Dentifrice carder materials typically comprise from about 
50% to about 94%, and preferably from about 60% to about 80%, by weight of 
the dentifrice compositions. 
Oral Rinses 
Oral rinses usually comprise an aqueous, alcoholic, or aqueous-alcoholic 
solution of an antiseptic which is often colored or flavored for 
palatability. Optional ingredients include humectants, surfactants, 
sweeteners, emulsifying agents, fluoride ion sources, tartar control, and 
anti-plaque agents. Oral rinse products may also be formed by dissolving a 
powder or tablet containing stannous gluconate in water just prior to use. 
Conventional oral rinse compositions generally comprise from about 0% to 
60% ethyl alcohol, 0% to 20% of a humectant, 0% to 2% emulsifying agents, 
0% to 0.5% sweetening agents, 0% to 0.3% flavoring agents and the balance 
water. 
Although water itself may make up the entire carder, typical oral 
formulations also contain a co-solvent including but not limited to 
alcohol, propylene glycol, glycerin, sorbitol solution, and the like, to 
assist solubilization and incorporation of water-insoluble ingredients, 
flavoring oils and the like into the composition. In general, the 
compositions preferably contain from about 5 to about 25 volume/volume 
percent of the co-solvent, most preferably from about 10 to about 20 
volume/volume percent of the co-solvent. 
Oral compositions herein are preferably toothpaste (most preferred), 
mouthrinse, or liquid dentifrice. Sodium fluoride is preferably included 
in dentifrice compositions herein. Components to be added should be safe 
for oral use. 
Other Carriers 
Coolant materials may also be included as carder materials in the invention 
compositions. Preferred coolants in the present compositions are the 
paramenthane carboxyamide agents such as N-ethyl-p-menthane-3-carboxamide 
(known commercially as "WS-3"), and 3-1-menthoxypropane-1,2-diol (known 
commercially as "TK-10"), and mixtures thereof. These coolants are 
described in PCT Patent Application Publication WO 92-17164, to Upson et 
at., published Oct. 15, 1992. TK-10 is also described in U.S. Pat. No. 
4,459,425 to Amano et at., issued Jul. 10, 1984; and WS-3 and the 
paramenthane carboxyamide agents are also described in U.S. Pat. No. 
4,136,163 to Watson et at., issued Jan. 23, 1979. The disclosures of all 
three of these patent publications are incorporated by reference herein in 
their entirety. 
Active 
The invention compositions may also contain a safe and effective mount of 
one or more additional actives. Some additional actives that are useful in 
these compositions include (but are not limited to) antimicrobial agents 
such as bisbiguanides or phenolics; antibiotics such as metronidazole, or 
clindamycin; dentinal desensitizing agents such as potassium nitrate, 
strontium chloride or sodium fluoride; odor masking agents such as 
peppermint oil or chlorophyll; local anesthetic agents such as lidocaine 
or benzocaine; antioxidants such as thymol, alphatocopherol and butylated 
hydroxy toluene; lipopolysaccharide complexing agents such as polymyxin; 
quaternary ammonium compounds such as benzalkonium chloride and cetyl 
pyridinium chloride; aromatics such as camphor, eucalyptus oil, and 
aldehyde derivatives such as benzaldehyde; denture adhesives such as lower 
alkyl vinyl ethermaleic acid or anhydride copolymers and their salts; 
coolants having therapeutic efficacy such as menthol; or peroxides such as 
urea peroxide. 
Preferred formulations for the present compositions are dental care 
preparations such as dentifrices and oral rinses. Dental care preparations 
may comprise a soluble fluoride ion source as one of the actives. The 
soluble fluoride ion source is used in an amount sufficient to provide 
from about 10 to about 5000 ppm of the fluoride ion. Preferred fluorides 
are sodium fluoride, stannous fluoride, inidium fluoride, and sodium 
monofluorophosphate. Norris et at., U.S. Pat. No. 2,946735, issued Jul. 
26, 1960 and Widder et al., U.S. Pat. No. 3,678,154, issued Jul. 18, 1972, 
disclose such salts as well as others. Both patents are incorporated 
herein by reference in their entirety. 
Various polymers and mixtures thereof are also useful in dental care 
preparations. These polymers may be synthetic anionic polymeric 
polycarboxylates and their complexes and/or carboxyvinyl polymers. 
Polymers useful in the present compositions are disclosed in U.S. Pat. No. 
4,906,456 to Gaffer et al., issued Mar. 6, 1990, incorporated herein by 
reference in its entirety. 
Pyrophosphate salts are pharmaceutical actives that may also be included in 
dental care preparations. Any of the alkali metal pyrophosphate salts may 
be used in either their hydrated or unhydrated forms. Pyrophosphate salts 
are described in more detail in Kirk & Othmer, Encyclopedia of Chemical 
Technology, Second Edition, Volume 15, Interscience Publishers (1968), 
incorporated herein by reference in its entirety. 
Additional anti-plaque and anti-gingivitis pharmaceutical actives may also 
be included in the dental preparations. These actives include quaternary 
ammonium compounds or bis-biguanides. Oral compositions comprising 
stannous ion are described fully in U.S. Pat. No. 5,004,597 to Majeti et 
al., issued Apr. 2, 1991, incorporated herein by reference in its 
entirety. Disinfectant agents like triclosan and antiseptic agents like 
thymol may also be included in the dental preparations. 
Methods 
Included is a method comprising contacting dental enamel surfaces with an 
effective mount of a composition according to the above to reduce or 
prevent calculus or gingivitis, or tartar or plaque. 
All percentages and ratios used herein are by weight, and all measurements 
are made at 25.degree. C., unless otherwise specified.

The following examples further describe and demonstrate embodiments within 
the scope of the present invention. These examples are given solely for 
the purpose of illustration and are not to be construed as limitations of 
the present invention as many variations thereof are possible without 
departing from the spirit and scope of the present invention. 
Example I 
Toothpaste Composition 
A toothpaste composition according to the present invention is prepared 
having the following components: 
______________________________________ 
Component Weight % 
______________________________________ 
Tetramenthyl AHP 1.5 
Purified Water Balance 
Sorbitol 60.565 
Sodium Fluoride (1100 ppm F.sup.-) 
0.243 
Saccharin 0.130 
Colorant 0.500 
Silica 20.000 
Flavor 0.500 
Carboxymethyl cellulose 
0.300 
Xanthan Gum 0.475 
Trisodium Phosphate 1.450 
Monosodium Phosphate 0.590 
Sodium Alkyl Sulfate Solution 
4.000 
(27.9% in H2O) 
Titanium Dioxide 0.525 
______________________________________ 
*= tetramenthyl aminohexanediphosphonate 
Add sorbitol to water and mix. Dissolve salts, tetramenthyl AHP, sodium 
fluoride, saccharin, trisodium phosphate, and monosodium phosphate. Adjust 
the pH to 7.0 and then add colorant. Separately combine silica, 
carboxymethyl cellulose, and xanthan gum and then slowly add this mixture 
to the composition while mixing continuously. Add sodium alkyl sulfate. 
Add the flavor (eg, spearmint, peppermint, wintergreen, fruit) to the 
composition and mix for ten more minutes. 
Other compounds of the present invention can be substituted for the 
tetramenthyl AHP, such as tetramenthyl 1-hydroxyethylidene diphosphonate 
("EHDP"). The amount employed in the composition can vary within the 
limits described herein. 
Example II 
Oral Mouth Rinse Composition 
An oral mouth rinse composition according to the present invention is 
prepared having the following components: 
______________________________________ 
Component Weight % 
______________________________________ 
Tetramenthyl EHDP* 0.5 
Ethanol (190 proof) 
16.250 
Polysorbate 80 0.120 
Glycerin 10.000 
Purified Water Balance 
Benzoic Acid 0.0045 
Cetylpyridinium Chloride 
0.045 
Domiphen Bromide 0.005 
Sodium Saccharin 0.060 
Colorant 0.040 
Sodium Benzoate 0.0537 
______________________________________ 
*= tetramenthyl 1hydroxyethylidene diphosphonate 
To ethanol, add all ingredients except tetramenthyl EHDP and mix for 5 
minutes. Add tetramenthyl EHDP first and then adjust the pH of the 
composition to pH 6.0. 
Other compounds of the present invention can be substituted for the 
tetramenthyl EHDP such as tetramenthyl AHP. The amount of the 
diphosphonate employed in the composition can vary within the limits 
described herein. 
Preparation of Tetramenthyl AHP 
The following is a method for synthesizing Tetramenthyl 
Azacycloheptane-2,2-diphosphonate (Tetramenthyl AHP). 
Step 1. Preparation of Azacycloheptane-2,2-diphosphonic Acid Chloride: 
Add azacycloheptane-2,2-diphosphonic acid (32.4g, 0.125 mol) to oxalyl 
chloride (400g, 3.2 mol) portionwise so as to allow gas to be evolved at a 
moderate rate and maintain the temperature at about 30.degree. C. Warm the 
mixture for 30 minutes at 35.degree. C. once gas production ceases and 
then concentrate it under vacuum at 50.degree. C. Repeatedly add methylene 
chloride (3.times.50 mL) to the remaining liquid and remove it under 
vacuum. Use the crude azacycloheptane-2,2-diphosphonic acid chloride so 
obtained directly in the next step. 
Step 2. Reaction with 1-Menthol: 
Add a solution of azacyloheptane-2,2-diphosphonic acid chloride (33.3 g, 
0.1 mol) in 50 mL of methylene chloride dropwise to a stirred, ice cooled 
solution of 1-menthol (68.8 g, 0.44 mol) and triethylamine (61.3 mL, 0.44 
mol) in 100 mL of methylene chloride. Once the addition is complete, heat 
the mixture at reflux for 2 hours. Cool the solution to room temperature 
and wash it, first with a 5% aqueous solution of hydrochloric acid 
(3.times.50 mL) and then with water (2.times.50 mL). Dry the solution over 
sodium sulfate and remove the solvent under vacuum. 
Preparation of Tetramenthyl EHDP 
The following is a method for synthesizing 1-Hydroxyethylidenediphosphonate 
(Tetramenthyl EHDP). 
Step 1. Preparation of Dimenthyl Acetylphosphonate: 
React 1-menthol and methyldichlorophosphite to give 
methyldimenthylphosphite (MDP). Add MDP (186.3 g, 0.5 mol) dropwise with 
stirring to acetyl chloride (39.2 g, 0.5 mol) over a period of about 30 
minutes while maintaining the temperature of the reaction mixture below 
30.degree. C. by cooling in an ice-bath. After the addition is complete, 
stir the mixture at 25.degree. C. for 1 hour and then heat it gently on a 
steam bath until the evolution of methyl chloride ceases. Use the crude 
dimenthylacetylphosphonate obtained directly in the next step. 
Step 2. Coupling with Dimenthylhydrogenphosphite: 
Mix dimenthylhydrogenphosphite (35.9 g, 0.1 mol) and diethylamine (7.3 g, 
0.1 mol) in a round-bottom flask and add dimenthyl acetylphosphonate (40 
g, 0.1 mol) dropwise with stirring. Stir the mixture for 2 hours and then 
partition it between water and diethyl ether. After washing the ether 
layer with a 5% aqueous solution of hydrochloric acid, dry it over sodium 
sulfate and remove the ether under reduced pressure. Triturate the product 
with n-hexane.