WO2000074639A1

WO2000074639A1 - Composition and method for treating dental caries using inorganic metal salts

Info

Publication number: WO2000074639A1
Application number: PCT/US2000/011874
Authority: WO
Inventors: Gregory Mooser; Kumari S. Devulapalle
Original assignee: University Of Southern California
Priority date: 1999-06-07
Filing date: 2000-06-07
Publication date: 2000-12-14
Also published as: AU5439600A

Abstract

In accordance with the present invention there is provided an oral composition comprising an effective amount of an orally acceptable carrier and an anti-caries agent that can reduce the activity of the enzyme glucosyltransferase. Also provided are methods of treating dental caries using such oral compositions and methods of manufacturing such oral compositions.

Description

COMPOSITION AND METHOD FOR TREATING DENTAL CARIES USING INORGANIC METAL SALTS

FIELD OF THE INVENTION This invention relates to a composition and method for treating dental caries. In particular, the invention relates to oral compositions that comprise orally-acceptable carriers and effective amounts of agents that reduce the activity of the enzyme glucosyltransferase, and to the use of such agents in various forms to treat dental caries. The invention also relates to methods of manufacturing various oral compositions that can be used to treat dental caries.

BACKGROUND OF THE INVENTION

Dental caries is an undesirable condition of the oral cavity and, over the years, has remained an intractable disease. With advances in science and technology, newer methods have been introduced to combat this disease but the quest for an acceptable treatment continues.

Traditional approaches to counteracting dental caries mainly relied on removal of dental plaque by cleaning teeth, sometimes simply by rubbing the teeth with one's own fingers. In some cultures, sticks of neem plant were used as a brush to remove dental plaque. As technology advanced, bicarbonate powder and similar products were used to remove dental plaque.

More recent efforts toward the correction of dental caries revolve around the use of the standard tooth brush to remove dental plaque. Also in widespread use today are electric brushes, floss and adjuncts such as proxy brushes. In addition, numerous tooth pastes and mouth rinses containing various supplements are touted as aids to prevention of dental caries. For example, fluoride is commonly sold as a product for slowing the process of dental decay.

The efficacy of both the traditional and modern methods of treating or preventing dental caries is questionable. Dental plaque can only partially be removed from the oral cavity, and that too with a demanding regimen of oral hygiene that may include flossing, brushing and regular visits to a dentist. Further, some of the pastes and mouth rinses contain toxic supplements that must be kept out of reach of children. Fluoridated toothpaste and toothpastes containing triclosan can be toxic to very young children.

The present invention provides a safe and effective composition and method for treating dental caries. Dental caries is inhibited as soon as the composition is applied. Further, the compositions of the present invention are non-toxic. They can also be used in very small quantities and hence can be affordable and inexpensive.

SUMMARY OF THE INVENTION

In accordance with the present invention, there is provided an anti-caries oral composition comprising an effective amount of an orally acceptable carrier and an anti-caries agent that reduces the activity of the enzyme glucosyltransferase. Also provided are methods of treating dental caries using such oral compositions and methods of manufacturing such compositions. While some of the compounds suitable for use in this invention are known, their use as anti-caries agents delivered in an orally acceptable carrier is not known to the prior art.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a plot of the activity of glucosyltransferase as a function of the concentration of ferrous sulfate.

Figure 2 is a plot of the activity of glucosyltransferase as a function of the concentration of ferric chloride.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Devulapalle et al. in "Knowledge-Based Model of a Glucosyltransferase from the Oral

Bacterial Group of Mutans Streptococci", Protein Science, 6, 2489-2493 (1997), which is incorporated here by reference, describe the mechanism of dental caries, an undesirable condition of the oral cavity. The oral cavity contains a well-balanced community of a multitude of microorganisms. Dental caries is a bacterial infection predominantly caused by one of these common oral bacterium, Streptococcus mutans, present in nearly all individuals. Streptococcus mutans derives its potential to initiate dental caries on smooth dental enamel and root surfaces, in large measure, from the production of an extracellular enzyme, glucosyltransferase. Accordingly, the enzyme glucosyltransferase is arguably the most significant virulence factor in dental caries. Bacterial colonization is promoted by long chain sticky polysaccharides (chains of sugar molecules), which adhere to tooth enamel surfaces and form a scaffolding for bacterial colonization. In the protected environment of the polysaccharides, Streptococcus mutans and other oral microorganisms form a stable community (dental plaque) and release sufficient quantities of metabolic acids to demineralize tooth enamel and initiate dental caries. For example, many of the microorganisms in dental plaque proceed by anaerobic metabolism, the end product of which is lactic acid. The acidic conditions created by the lactic acid demineralize a crystal called hydroxyapatite, a component of tooth enamel. The demineralization of hydroxyapatite is the initial event in dental caries.

The long chain polysaccharides that play an important role in bacterial colonization, are formed from sugar molecules. The conversion of sugar molecules to polysaccharides is catalyzed by the extracellular enzyme, glucosyltransferase. Thus, glucosyltransferase is the key pathogenic component in dental caries.

In the present invention, dental caries are treated by reducing the activity of glucosyltransferase, the enzyme that catalyzes the synthesis of sticky polysaccharides. Methods of manufacturing anti-caries oral compositions are also described. The anti-caries oral compositions of the present invention are useful in inhibiting dental caries and comprise: (a) an orally acceptable carrier and (b) an effective amount of an anti-caries agent that reduces the activity of glucosyltransferase.

"Anti-caries agents" as used herein means compounds and mixtures thereof that can reduce the activity of the enzyme glucosyltransferase. "The activity of glucosyltransferase" as used herein refers to the ability of the enzyme glucosyltransferase to catalyze the synthesis of polysaccharides from sugar or similar molecules.

"Anti-caries oral composition" as used herein means a product that in the ordinary course of usage is not intentionally swallowed for purposes of systemic administration of particular therapeutic agents, but is rather retained in the oral cavity for a time sufficient to contact substantially all of the dental surfaces and/or oral tissues for purposes of oral activity.

"Effective amount" as used herein means sufficient amount of material to provide the desired benefit.

The terms "carrier" or "orally acceptable carrier" as used herein, refers to a vehicle that is pharmaceutically acceptable and can be used to apply the present compositions in the oral cavity.

Anti-caries agents for Reducing the Activity of Glucosyltransferase

As the examples below illustrate, a number of anti-caries agents can be used to reduce the activity of glucosyltransferase. Ferrous sulfate and ferric chloride can reduce the activity of glucosyltransferase at low concentrations, and almost completely inactivate the enzyme at concentrations of about 6mM. A number of other agents can also be used to reduce the activity of glucosyltransferase and hence used in anti-caries oral compositions. Examples include ferrous sulfate (FeSO₄), ferrous chloride (FeCl₂), cupric chloride (CuCl₂), cobalt chloride (CoCl₂), cadmium sulfate (CdSO₄), manganese sulfate (MnSO₄), and zinc sulfate (ZnSO₄) which can be used to inactivate glucosyltransferase at very low concentrations.

Some of the preceding anti-caries agents are Fenton reactants. As example 3 shows, the reduction in activity of glucosyltransferase by a Fenton reactant such as ferrous sulfate proceeds by binding at the catalytic site of glucosyltransferase. Many Fenton reactants yield a hydroxyl radical when reacted with hydrogen peroxide. Thus, anti-caries oral compositions can be made with metal salts that yield hydroxyl ions when reacted with hydrogen peroxide.

Many other anti-caries agents can be used to reduce the activity of glucosyltransferase. For instance, anti-caries oral compositions can be made wherein the anti-caries agent for reducing the activity of glucosyltransferase is a metal salt comprising a metal and an anionic group. Similarly, transition metals or near transition metals can be used to make anti-caries oral compositions with metal salts wherein the metal is selected from the group consisting of iron, copper, zinc, cadmium, cobalt, chromium, manganese, mercury, nickel, silver, gold, titanium, tin, lead and bismuth.

These anti-caries agents can be used to reduce the activity of glucosyltransferase at very low concentrations. Therefore, anti-caries oral compositions can be made with metal salts wherein the compositions comprise as little as about 0.0001 weight percent metal salt.

Further, using these anti-caries agents at higher concentrations would also reduce the activity of glucosyltransferase. For example, glucosyltransferase activity can be reduced by using anti-caries oral compositions wherein the metal salt concentration is from about 0.0005 weight percent to about 99 weight percent. Similarly, glucosyltransferase activity can be reduced by using anti-caries oral compositions wherein the metal salt concentration is from about 0.005 weight percent to about 10 weight percent.

Example 1

The reduction in activity of purified glucosyltransferase enzyme was measured using dextran synthesis assay based on C-isotope transfer from uniformly labeled sucrose to glucan.

The dextran synthesis assay is as follows.

Equilibrium Equilibrium

Enzyme + *sucrose + dextran_(n) =≠ dextran_(n) 'Enzyme-Glucose* + *Fructose ≠ Enzyme +

*Dextran_(n+ι_}

Uniformly labeled sucrose is used as a substrate for dextransucrase. The labeled glucose is transferred to a dextran chain. The dextran product is then separated from other reactants by washing an aliquot of the reaction mixture, spotted on filter paper (Whatmann #1), in methanol. The reaction of glucosyltransferase with ferrous sulfate follows a first order reaction. Ferrous sulfate concentrations used in this example were 0, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0 mM. Fifty-μl reaction mixtures were buffered in 0.1M MES ( 2-(N-morpholino) ethanesulfonic acid) buffer at pH 6.0 Data were analyzed using GraphPad Prism software (GraphPad Software, Inc. San Diego).

The results of this example are shown in Figure 1. The inhibition of glucosyltransferase is a classical first order reaction that progressively loses activity with time - Figure 1 shows that, as the ferrous sulfate concentration is increased, the enzyme loses its activity. When the ferrous sulfate concentration is 6.0 mM, the enzyme is almost completely inactivated.

Example 2

A procedure similar to that of Example 1 was used to measure the reduction in activity of glucosyltransferase by ferric chloride. The results are shown in Figure 2, which is similar to Figure

1. The reduction in activity of glucosyltransferase by ferric chloride also follows first order kinetics

- Figure 2 shows that, as the ferric chloride concentration is increased, the enzyme loses its activity. When the ferric chloride concentration is 6 mM, the enzyme is almost completely inactivated.

Example 3

The inhibition constant for glucosyltransferase was determined by standard kinetic procedures. Fifty-μl reaction mixtures were buffered in 0.1 M MES at pH 6.0. The inhibition constants were determined using a number of different concentrations of sucrose and metal salts. For example, four ferrous sulfate concentrations (0, 4, 8, and 12 mM) and four sucrose concentrations (2.5, 3.3, 5.0, and 10.0 mM) were used to determine the inhibition constant of ferrous sulfate. Dextran synthesis assay conditions were the same as described in Example 1.

Kinetic data were resolved by nonlinear regression based on the algorithm described by Cleland,

W. W., Methods Enzymol 63, 103-138.. Kinetic data were graphed in reciprocal form to establish a linear relationship before resolving the data by nonlinear regression.

Linear competitive inhibition data were resolved according to the following equation. v = VA/(_T(1 + _VK_t) + A) where v is the initial velocity, V is the maximum velocity, K is the Michaelis constant, Kj is the inhibition constant for inhibitor /, and A is the substrate concentration. The inhibition constant of ferrous sulfate for glucosyltransferase was determined to be

4.62± 1.15 mM. This value of the inhibition constant is sufficient to inhibit glucosyltransferase.

The measured values of the inhibition constants for some other metal salts are listed in the Table 1. Table 1 shows that many different metal salts can be used to reduce the activity of glucosyltransferase. Further, it would be obvious to a person of ordinary skill in the art that similar reduction in activity of glucosyltransferase can be accomplished by numerous metal salts that are analogous to those in Table 1. For example, similar reduction in activity of glucosyltransferase may be obtained by substituting the anions of the metal salts in Table 1 with other anions, or by substituting the metals of the metal salts in Table 1 with other transition or near-transition metals or redox-active divalent metal ions.

Table 1

Metal Salt Inhibition Constant (Ki, mM)

_____ 4.62 ± 1.15

FeCl₂ 0.49 ± 0.16

Fe₂(SO₄)₃ 1.69 ± 0.35

CuCl₂ 0.07 ± 0.06

CoCl₂ 9.74 ± 1.79

CdSO₄ 0.54 ± 0.15

MnSO₄ 5.12 ± 1.45

ZnSO₄ 1.05 ± 0.31

Example 4

The binding of ferrous sulfate at the catalytic site of glucosyltransferase was confirmed.

Glucose transition-state analogue 1-deoxynojirimycin (dNJ) is a strong ligand that binds at the glucose subsite of the glucosyltransferase. When glucosyltransferase is preincubated with dNJ, the ferrous sulfate reaction does not take place. The active site of glucosyltransferase is blocked by the ligand dNJ. When the active site is thus protected, the reaction with ferrous sulfate does not occur. Enzyme protection was carried out by preincubating the enzyme (137 μg) with dNJ (20 mM) in MES buffer pH 6.0 for 5 minutes at room temperature. After incubation, 8 mM ferrous sulfate was added, and the reaction mixture was further incubated for 2.5 minutes at room temperature. A 5 μl aliquot was removed and assayed for glucan synthesis activity after diluting the reaction mixture. The dilution reduced all inhibitor concentrations to low levels.

The results, shown in Table 2, demonstrate that dNJ protects the enzyme active site. When the active site is protected with dNJ, the enzyme activity is almost equal to the control. Ferrous sulfate completely inactivates the enzyme when the active site is not protected. Table 2

Reaction conditions Percent activity

Glucosyltransferase 100

Glucosyltransferase, dNJ, ferrous sulfate 90.94 ± 0.36

Glucosyltransferase, ferrous sulfate 0

Example 5

Streptococcus mutans bacterial growth was assessed on Brain Heart Infusion agar medium, with and without ferrous sulfate in varying concentrations, in Petri dishes. A loopfiil of

Streptococcus mutans bacterial suspension was streaked on the surface of the agar media and the plates were incubated for bacterial growth.

When ferrous sulfate was not present in the medium, bacteria grew along the streak. Four bacterial colonies were observed on media amended with 5mM to 7mM ferrous sulfate. No bacterial growth was observed with 8-20 mM ferrous sulfate. Similar results were obtained with feric chloride and ferric sulfate. Bacteria did not grow in media amended with 5mM ferric sulfate or lOmM ferric chloride.

Example 6

Glucosyltransferase activity in human plaque was assessed. Fresh dental plaque from dental hygiene human patients was collected in distilled water. Plaque in water was vortexed and spunned down to separate the supernatant. The supernatant was assayed for glucosyltransferase activity with and without ferrous sulfate. The example was repeated up to five times.

Glucosyltransferase activity was detected in human dental plaque. It was observed that when ferrous sulfate was added to the supernatant, the enzyme was almost totally inactivated. As can be seen from Table 3, experiments with human dental plaque indicate that human dental plaque exhibits glucosyltransferase activity and that ferrous sulfate reduces that activity.

Table 3

Reaction conditions Glucosyltransferase activity CPM /min i π m IV V

Dental plaque supernatant 631 824 587 333 293

Dental plaque supernatant with ferrous sulfate 0 0 0 0 0

CPM: Counts Per Minute Example 7

The ability of ferrous sulfate solutions to reduce the activity of glucosyltransferase over time was assessed. The ferrous sulfate solution was initially prepared and stored at ambient temperature. Periodically, its effect on glucosyltransferase inactivation was monitored for up to four months.

The results indicate that ferrous sulfate maintained its efficacy over the four month period of the example.

Orally Acceptable Carrier Suitable orally acceptable vehicles that can be employed with the anti-caries agents to prepare the anti-caries oral compositions of this invention may comprise water, ethanol; such humectants as polypropylene glycol, glycerol and sorbitol; gelling agents such as cellulose derivatives, for example, Methocel, carboxymethylcellulose (CMC 7MF) and Klucel HF, polyoxypropylene/polyoxyethylene block copolymers, for example, Pluronic F-127, Pluronic F- 108, Pluronic P-103, Pluronic P-104, Pluronic P-105 and Pluronic P-123; colloidal magnesium aluminosilicate complexes such as Neegum, and mucoprotein thickening agents such as Carbopol 934; gel stabilizers such as the silicon dioxides, for example, Cab-O-Sil M5, and polyvinylpyrrolidone; sweeteners such as sodium saccharin; preservatives such as citric acid, sodium benzoate, cetylpyridinium chloride, potassium sorbate, methyl and ethyl parabens; detergents such as sodium lauryl sulfate, sodium cocomonoglyceride sulfonate, sodium lauryl sarcosinate and polyoxyethylene isohexadecyl ether (Arlasolve 200) and approved colors and flavors.

The following specific examples will serve further to illustrate the compositions of this invention.

Example A Mouthwash Solution

Anti-caries Agent 0.5-2.0 % w/w

Glycerol (humectant) 6.0 Pluronic F-108 1.0 Sodium saccharin (sweetener)

0.3

Deionized Water q.s.

Flavors 1.0

100.0

Example B

Mouthwash Solution

Anti-caries Agent 0.5-3.0 % w/w

Ethanol, USP 15.0

Pluronic F-108 (foaming agent)

2.0 Glycerol (humectant) 10.0 Sorbitol (humectant) 10.0 Sodium saccharin (sweetener)

0.2 Deionized Water q.s.

Flavors 0.2 100.0

Example C

Abrasive Dentrifice Gel

Anti-caries Agent 2.0-10.0 % w/w Fumed Silica (abrasive)

55.0 Sodium Lauryl Sulfate (detergent)

1.5 Glycerol (humectant) 10.0 Carboxymethylcellulose (gelling agent)

2.0 Sodium saccharin (sweetener)

0.2 Sorbitol (humectant) 10.0 Flavors 1.0

Deionized Water q.s.

Preservative 0.05

100.0

Example D

Chewing Gum

Anti-caries Agent 1.0-11.0 % w/w

Gum Base 21.3

Sugar 48.5-58.5

Corn Syrup (Baume 45)

18.2 Flavors 1.0

Example E

Nonabrasive Gel Dentifrice

Anti-caries Agent 0.05-30.0

% w/w

Sorbistat (preservative)

0.15

Deionized Water q.s.

Silicon Dioxide (gel stabilizer)

1.0

Pluromc F-127 (gelling agent)

20.0

Sodium Saccharin 0.2

Flavors 1.5

100.0

Example F

Nonabrasive gel composition

Ingredients % w/w

Distilled Water q.s.

Sodium Saccharin (sweetener) 0.20

Sodium Benzoate (preservative)

0.30 FD&C Blue #1 (0.1% aq. soln.)

0.27 D&C Yellow #10 (0.5% aq. soln.)

0.50 Gelling agent 18.00

Glycerol (Humectant) 20.00 Cab-O-Sil M5 (Silicon Dioxide) 1.00

Anti-caries Agent 5.00 (dry basis)

Flavor 0.80

100.0 Method of Using Anti-caries Oral Compositions for Treating Dental Caries

As described herein, glucosyltransferase from oral bacteria form sticky polysaccharides using sugar molecules. Dental caries may be treated by avoiding this initial event. According to this invention, the formation of sticky polysaccharides is inhibited by using a composition comprising orally acceptable carriers and anti-caries agents that reduces the activity of glucosyltransferase. An orally acceptable composition as described herein comprising a carrier and an effective amount of an anti-caries agent is applied to the oral cavity and the agent, directly or indirectly, reduces the activity of glucosyltransferase.

The anti-caries oral compositions should preferably be applied to the oral cavity every time that the subject eats foods containing sucrose. Therefore, since, generally, people eat foods with sucrose from one to three times a day, these compositions are preferably employed from one to three times daily in a routine oral hygiene program to inhibit dental caries.

Method of Manufacturing Anti-caries Oral Compositions for Treating Dental Caries

The details of preparing the above formulations are well within the skill of the art. In essence, methods of manufacturing anti-caries oral compositions comprise combining an orally acceptable carrier and an effective amount of an anti-caries agent that can reduce the activity of glucosyltransferase. A suggested procedure for preparing an anti-caries oral composition in a gel formulation will be described for completeness.

In a first container water, sodium saccharin, sodium benzoate and dyes are mixed. Then the container is put into an ice bath. When the temperature reaches 6 degrees C, the gelling agent is added and the contents mixed slowly until the gelling agent is dissolved. Then the solution is heated to 70 degrees C.

Into a second container is added the glycerin. Then Cab-O-Sil M5 is sprinkled in with mixing. Then the anti-caries agent is added and mixing continued to a smooth paste. The paste is then heated in a water bath with mixing to a temperature of 70 degrees C.

The contents of the first container are added to the second container and blended together until the batch is homogenous while maintaining a 70 degrees C temperature. Then a flavoring agent is added, mixing is stopped, and the formulation allowed to settle for approximately one hour. If necessary to remove air bubbles, overnight refrigeration may be employed.

It is also to be appreciated that the foregoing description of the invention has been presented for purposes of illustrations and explanation and is not intended to limit the invention to the precise compositions and manner of practice herein. It is to be appreciated therefore, that changes may be made by those skilled in the art without departing from the spirit of the invention.

Claims

WHAT IS CLAIMED IS:

1. An anti-caries oral composition comprising: an orally acceptable carrier; and an effective amount of an anti-caries agent, the anti-caries agent being capable of directly or indirectly reducing the activity of glucosyltransferase.

2. The anti-caries oral composition of Claim 1 wherein the anti-caries agent is a metal salt comprising a metal and an anionic group.

3. The anti-caries oral composition of Claim 2 wherein the metal salt yields hydroxyl ions when reacted with hydrogen peroxide.

4 The anti-caries oral composition of Claim 2 wherein the metal is selected from the group consisting of iron, copper, zinc, cadmium, cobalt, chromium, manganese, mercury, nickel, silver, gold, titanium, tin, lead and bismuth.

5 The anti-caries oral composition of Claim 2 wherein the composition comprises at least about 0.0001 weight percent metal salt.

6 The anti-caries oral composition of Claim 2 wherein the composition comprises about 0.0005 weight percent metal salt to about 99 weight percent metal salt.

7 The anti-caries oral composition of Claim 2 wherein the composition comprises about 0.005 weight percent metal salt to about 10 weight percent metal salt.

8 The anti-caries oral composition of Claim 2 wherein the metal salt is selected from the group consisting of FeSO₄, FeCl₂, Fe₂(SO₄)₃, CuCl₂, CoCl₂, CdSO₄, MnSO₄, ZnSO₄ and mixtures thereof.

9 The anti-caries oral composition of Claim 1 wherein the orally acceptable carrier is selected from the group consisting of orally acceptable mouthrinses, mouthwashes, irrigating solutions, abrasive gel dentifrices, non-abrasive gel dentifrices, denture cleansers, coated dental floss, coated interdental stimulators, toothpastes, gel dentifrices, breath fresheners, foams, sprays, chewing gums and lozenges.

10 A method of inhibiting dental caries comprising: applying to the oral cavity a composition comprising an orally acceptable carrier; and an effective amount of an anti-caries agent, the anti-caries agent directly or indirectly reducing the activity of glucosyltransferase.

11 The method of Claim 10 wherein the anti-caries oral composition is applied from about 1 to about 3 times per day.

12. The method of Claim 10 wherein the anti-caries agent is a metal salt comprising a metal and an anionic group.

13. The method of Claim 12 wherein the metal salt yields hydroxyl ions when reacted with hydrogen peroxide.

14 The method of Claim 12 wherein the metal is selected from the group consisting of iron, copper, zinc, cadmium, cobalt, chromium, manganese, mercury, nickel, silver, gold, titanium, tin, lead and bismuth.

15 The method of Claim 12 wherein the composition comprises at least about 0.0001 weight percent metal salt.

16 The method of Claim 12 wherein the composition comprises about 0.0005 weight percent metal salt to about 99 weight percent metal salt.

17 The method of Claim 12 wherein the composition comprises about 0.005 weight percent metal salt to about 10 weight percent metal salt.

18 The method of Claim 12 wherein the metal salt is selected from the group consisting of FeSO₄, FeCl₂, Fe₂(SO₄)₃, CuCl₂, CoCl₂, CdSO₄, MnSO₄, ZnSO₄ and mixtures thereof.

19 The method of Claim 10 wherein the orally acceptable carrier is selected from the group consisting of orally acceptable mouthrinses, mouthwashes, irrigating solutions, abrasive gel dentifrices, non-abrasive gel dentifrices, denture cleansers, coated dental floss, coated interdental stimulators, toothpastes, gel dentifrices, breath fresheners, foams, sprays, chewing gums and lozenges.

20. A method of manufacturing an anti-caries oral composition comprising: combining an orally acceptable carrier and an effective amount of an anti-caries agent, the anti-caries agent being capable of directly or indirectly reducing the activity of glucosyltransferase.

21. The method of Claim 20 wherein the anti-caries agent is a metal salt comprising a metal and an anionic group.

22. The method of Claim 21 wherein the metal salt yields hydroxyl ions when reacted with hydrogen peroxide.

23 The method of Claim 21 wherein the metal is selected from the group consisting of iron, copper, zinc, cadmium, cobalt, chromium, manganese, mercury, nickel, silver, gold, titanium, tin, lead and bismuth.

24 The method of Claim 21 wherein the anti-caries oral composition comprises at least about 0.0001 weight percent metal salt.

25 The method of Claim 21 wherein the anti-caries oral composition comprises about 0.0005 weight percent metal salt to 99 weight percent metal salt.

26 The method of Claim 21 wherein the anti-caries oral composition comprises about 0.005 weight percent metal salt to 10 weight percent metal salt.

27 The method of Claim 21 wherein the metal salt is selected from the group consisting of FeSO₄, FeCl₂, Fe₂(SO₄)₃, CuCl₂, CoCl₂, CdSO₄, MnSO₄, ZnSO₄ and mixtures thereof.

28. The method of Claim 20 wherein the orally acceptable carrier is selected from the group consisting of orally acceptable mouthrinses, mouthwashes, irrigating solutions, abrasive gel dentifrices, non-abrasive gel dentifrices, denture cleansers, coated dental floss, coated interdental stimulators, toothpastes, gel dentifrices, breath fresheners, foams, sprays, chewing gums and lozenge vehicles.