CA2094874C - Non-antibacterial tetracycline compositons possessing antiplaque properties - Google Patents

Abstract

Methods of inhibiting plaque formation and caries on mammalian tooth surfaces are disclosed. The methods include contacting the tooth surfaces with an effective amount of a non-antibacterial tetracycline. In preferred embodiments, the tetracyclines are included in various oral hygiene products such as dentifrices, lozenges, chewing gums and the like to contact the tooth surfaces.

Description

a '"~ 294874 178-llo cIP

BACKGROUND OF THE INVENTION
The present application is a continuation-in-part Application of U.S. Patent Application Serial No.
07/654,073, filed February 1l, 1991.
The present invention relates to methods of inhibiting dental caries. In particular, the present invention relates to preventing dental caries using non-antibacterial tetracyclines.
For several decades now, there has been an increased , awareness of the relationship between plaque formation on tooth surfaces and dental cavities or caries. Dental plaque is generally regarded as a film of bacteria, bacterial polymers, salivary polymers, remnants of epithelial cells and leukocytes. The bacteria, principally Streptococcus mutans, is part of the naturally occurring microflora of the oral cavity. The bacteria use natural sugars such as sucrose and glucose included in the diet as a nutrition source and produce cement-like polymers which bind to the enamel tooth surface. Once bound, the bacteria cause demineralization of the enamel by secreting acids and ultimately enamel caries.
Although the roots of teeth lack enamel, plaque formation may also be found below the gingival margin. The roots of teeth contain cementin and dentin which are more bone-like than tooth enamel. In addition, the roots are also susceptible to breakdown by the collagenase produced by Bacteroides c,Lng~ivalis and some other bacteria, a common part of oral cavity microflora. Root plaque formation ultimately leads to root caries, a leading cause of tooth loss in adults. Root caries can be especially prevalent when, due to periodontal disease, the gums and alveolar bone both recede and expose the roots.

-, 2094874 1 In the past, most efforts aimed at reducing plaque formation and dental caries have included reducing sugar intake, regular brushing, flossing and periodic removal of the plaque by dental professionals.
In some cases, plaque formation on tooth surfaces may become excessive and even pathologic. In these situations, it is often necessary to institute prophylactic measures in addition to those described above.' In the past, broad spectrum antibiotics such as tetracyclines and metronidazole have been used in the treatment of periodontal disease to reduce oral cavity microflora, which is the most virulent aspect of plaque and caries formation.
Although antibiotic agents are effective in reducing the number and amount of bacteria responsible for plaque and caries formation, extended periods of antibiotic administration are avoided due to high incidences of side effects. Side effects most often associated with long-term antibacterial agent usage include intestinal disturbances, overgrowth of yeast and fungi, and most importantly, the development of antibiotic-resistant bacterial.
As stated above, tetracyclines are broad spectrum antibiotics and are active against most oral cavity microflora. The tetracycline compound exhibits the . following general structure:
t!0 ~ , C113' N(C(!3) z.
Utl :0N112 ~u ~ vu 1 The numbering system of the ring nucleus is as follows:
~ ~ 5a 4a a 5 4 12a The tetracycline molecule is amenable to substantial modification without losing its antibiotic properties.
Examples of modifications that may and may not be made to the basic tetracycline structure have been reviewed by Mitscher in the rhpmistry of Tetrac~clines, Chapter 6.
According to Mitscher, the substituents at positions 5-9 of the tetracycline ring may be modified without complete loss of antibiotic properties. Changes to the basic ring system or replacement of the substituents at positions 1-4 and 10-12, however, generally lead to synthetic tetracyclines having substantially less or effectively no antibacterial activity. For example, 4-dedimethylaminotetracycline is commonly considered to be a non-antibacterial tetracycline.
Various properties of antimicrobial and non-antimicrobial tetracyclines are known. For example, it is . known that antimicrobial and non-antimicrobial tetracyclines can bind to metal ions such as calcium.
. Tetracyclines are also known inhibitors of collagen destructive enzymes such as mammalian collagenase, a calcium dependent zinc-metalloproteinase. Collagen is a major component of connective tissue matrices such as those in the bone, synovium, eye, skin, tendons, gingiva, cementum and dentin of the tooth, but not tooth surface enamel.

1 U.S. Patent No. 4,666,897 to Golub, et al. discloses tetracyclines, including commercially-available antimicrobial forms of the drug, inhibit excessive bone resorption and collagenolytic enzyme activity. U.S. Patent No. 4,704,383 to McNamara, et al. discloses tetracyclines having substantially no effective antibacterial activity inhibiting collagenolytic enzyme activity in rats.
Moreover, McNamara, et al. also disclose that ~non antimicrobial tetracyclines reduce bore resorptiori in organ culture.
Although some oral hygiene products such as dentifrices have been introduced to combat dental plaque and caries, a complete solution remains elusive.
In view of the desire to reduce caries and further in view of the desire to avoid using antimicrobial antibiotics to accomplish this result, it is an object of the present invention to provide an improved method of inhibiting the effect of caries on tooth surfaces.
It is a further object of the present invention to provide a method of inhibiting plaque and caries formation on tooth surfaces using non-antibacterial tetracyclines.
SUMMARY OF THE INVENTION
In accordance with the present invention, it has been surprisingly found that tetracyclines inhibit plaque and caries formation on tooth surfaces in a manner completely separate from antibacterial eradication of the oral_ cavity microflora. The method includes contacting the tooth surfaces with an effective amount of a non-antimicrobial tetracycline which results in the prevention of plaque and caries formation on tooth surfaces.

4a ~ 73802-25 The present invention also provides a use of an effective amount of a non-antimicrobial tetracycline to treat a mammalian tooth surface to prevent root caries.
The present invention further provides a confection for treating mammalian tooth surfaces to prevent root caries comprising an effective amount of a non-antimicrobial tetracycline in admixture with a suitable diluent or carrier.
The present invention yet also provides a confection for treating mammalian tooth surfaces to prevent adhesion of root plaque comprising an effective amount of a non-antimicrobial tetracycline in admixture with a suitable diluent or carrier.
The present invention also provides a use of a confection described above to treat a mammalian tooth surface to prevent root caries or to prevent the adhesion of root plaque.
The present invention further provides a commercial package containing as active ingredient a confection described above together with instructions for the use thereof to treat a mammalian tooth surface to prevent root caries or to prevent the adhesion of root p:Laque.

'~ ~Q9487~

1 The non-antimicrobial tetracyclines useful in the present invention are preferably chemically modified tetracyclines (CMT's) such as dedimethylaminotetra-cyclines. Examples of such preferred tetracyclines include 4-dedimethylaminotetracycline, 12a-deoxydedimethylamino-tetracycline and its derivatives, 4-dedimethylamino-5-oxytetracycline, 6-deoxy-6-demethyl-4-dedimethylamino-tetracycline, 7-chloro-6-demethyl-4-de.dimethylamino-tetracycline and 6-a-deoxy-5-hydroxy-4-dedimethylamino-tetracycline. Other suitable CMT's include, for example, 6-a-benzylthiomethylenetetracycline, the mono-N-alkylated amide of tetracycline, 6-fluoro-6-demethyltetracycline, tetracyclinonitrile, 4-hydroxy-4-dedimethylaminotetracy-cline and lia-chlortetracycline.
The amount of the non-antimicrobial tetracycline used in the methods of the present invention may be generally described as that amount which effectively inhibits plaque and/or caries formation on tooth surfaces. For example, a non-antimicrobial tetracycline, may be included in dentifrices, mouthwashes or similar oral hygiene preparations in amounts ranging from about 10 mg% to about 100 mg%. In a preferred embodiment, the non-antimicrobial tetracycline is included in amounts of from about 15 mg% to about 25 mg%, with concentrations of about 20 mg% being most preferred. When contacting tooth surfaces at these concentrations and for time periods typical for the oral hygiene product selected to contain the non-antimicrobial tetracycline, the non-antibacterial tetracyclines described herein prevent caries formation on tooth surfaces.
Naturally, the amount of the various tetracycline analogues will vary somewhat from each other and the ranges is set forth above are only illustrative of all possible dosage choices. Those skilled in the art will determine optimal concentrations for the desired non-antimicrobial tetracycline from clinical experience in order to carry out the present method.

As a result of the present invention, significant improvements in oral hygiene are realized. The present invention prevents plaque formation and reduces caries effects on the enamel portion of tooth surfaces and also on the root surfaces below the gingival margin. Thus, the present invention inhibits steps in the pathologic process of tooth decay. Moreover, the prophylaxis is achieved without using antimicrobial agents. Thus, the oral microflora remains intact. Antimicrobially=resistant strains of organisms, gastrointestinal disturbances,' yeast and fungi overgrowth which are associated. with antimicrobial therapy are also beneficially avoided.
For a better understanding of the present invention, together with other and further objects, references made to the following description and its scope will be pointed out in the appended claims.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a photograph showing the gum area, gingival margin and lower incisors of a non-diabetic control Osaka Dental University (ODU) rat.
Figure 2 is a photograph showing the gum area, gingival margin and lower incisors of an untreated diabetic ODU rat with extensive plaque formation on the incisors and on the gums.
Figure 3 is a photograph showing the gum area, gingival margin and lower incisors of a diabetic ODU rat after having been treated with oral daily doses of the antimicrobial agent, tetracycline hydrochloride.

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1 Figure 4 is a photograph showing the gum area, gingival margin and lower incisors of a diabetic ODU rat after having been treated with oral daily doses of the non-antimicrobial tetracycline, 4-dedimethylamino-tetracycline.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with the present invention, methods for preventing dental plaque and reducing caries are disclosed.
The method includes contacting tooth surfaces with an effective amount of a non-antimicrobial tetracycline which prevents plaque formation.
The non-antimicrobial tetracyclines useful in carrying out the method of the present invention may be described as chemically modified tetracyclines (CMT's). For purposes of the present invention, CMT designates a tetracycline molecule which has been modified to essentially eliminate antimicrobial efficacy. Methods for altering and eliminating the antimicrobial efficacy of a tetracycline are disclosed in the ~lhemistry of Tetracyclines, Chapter 6, Mitscher, Ed., at page 211. As pointed out by Mitscher, modifications of the tetracycline molecule at positions 1, 2, 3, 4, 10 and 12a can lead to loss of antimicrobial activity.
Examples of such preferable tetracyclines include those lacking the dimethylamino side chain at position 4.
Such chemically modified tetracyclines (or CMT's) include, for example, 4-dedimethylaminotetracycline, 4-dedimethylamino-5-oxytetracycline, 4-dedimethylamino-7-chlortetracycline, 4-hydroxy-4-dedimethylamino-tetracycline, 6-demethyl-6-deoxy-4-dedimethylamino-tetracycline, 6-a-deoxy-5-hydroxy-4-dedimethylamino-tetracycline, and 12a-deoxydedimethyl as described by Green, et al., J. me Chem. oc , 82, 3946-3953 (1960).

_8_ 1 Further examples of tetracyclines modified for reduced antimicrobial activity include 6-a-benzylthiomethylene tetracycline, the mono-N-alkylated amide of tetracycline, 6-fluoro-6-demethyltetracycline, ila-chlortetracycline and tetracyclinonitrile.
The amount of the tetracycline required to inhibit dental caries is an amount which is effectively ~non-antimicrobial yet is effective in inhibiting plaque and/or caries formation. The amount of non-antimicrobial tetracycline may also be described as a range. The highest amount is that amount which does not cause clinically detrimental side effects. For the purpose of the present invention, side effects would include any untoward reaction which would clinically warrant ceasing the tetracycline's administration. Such side effects include, for example, symptoms of toxicity. The lowest amount is that minimum amount which produces the desired anti-plaque and/or anti-caries result.
For illustrative purposes, non-antimicrobial tetracyclines can be included in vehicles such as dentifrices, mouthwashes, chewing gums, lozenges, confections or other suitable dental hygiene preparations.
In such embodiments, the tetracycline may be included in an amount of from about 10 mg% to about 100 mg%. In a preferred embodiment, the non-antimicrobial tetracycline may be present in amount of from about 15 mg% to about 25 mg%. In a most preferred embodiment, the non-antimicrobial tetracycline is present in an amount of about 20 mg%. The method of the present invention may then be carried out by using one of the dental hygiene products described above containing a non-antimicrobial tetracycline to contact the tooth surfaces for a sufficient time to inhibit plaque formation and/or dental caries.

~0948'~4 -g-The time required for the non-antimicrobial tetracycline to contact the tooth surface and effectively inhibit plaque and/or caries formation is conveniently the same amount of time as one is accustomed to for using oral hygiene products. For example, if the non-antimicrobial tetracycline is included in a toothpaste, normal brushing one to three times daily is sufficient. Similarly, contacting the teeth with an oral rinse .containing the tetracycline far normal periods of around a minute followed by expectorating one to three times daily would achieve the same result.
Tests were conducted using the method of the present invention s prevention of plaque and caries formation on tooth surfaces. The tests demonstrate the effectiveness and unexpected ability of non-antimicrobial tetracyclines to prevent plaque adhesion which results in caries on tooth surfaces without antibiotic effect on oral flora.
EXAMPLES
The following Examples serve to provide further appreciation of the invention, but are not, in any way, to be considered restrictive of the effective scope of the invention.
EXAMPLE I
In this Example, the lack of antimicrobial effect of CMT on crevicular microflora was demonstrated using a group of six adult Osaka Dental University (ODU) rats. When rendered diabetic, these rats exhibit large plaque accumulations on their lower incisor teeth. Two rats were preserved as nondiabetic controls, while the remaining four c rats were made diabetic by injection of 70/mg/kg of the diabetogenic agent streptozotocin according the method set forth, for example, by Golub et al. in Infect. Immun..~7:
1013 (1982).
The diabetic rats were then further divided into two groups. One group was given 57 mg/kg/day of the CMT, 4-dedimethylaminotetracycline, which was incorporated into the rats daily food intake. The second diabeticgroup was left untreated.
After 21 days, the rats were sacrificed and samples of the crevicular microflora were removed from each of the rats in all groups and transferred to a brain-heart infusion-supplemented broth and incubated for 72 hours at 37°C.
At the end of this incubation period, the microflora from each group of rats was compared to determine if any changes in the microflora were attributable to 4-dedimethylaminotetracycline. The results are summarized in Table 1.
Table 1 shows the presence and/or absence of various bacteria found in the microflora of the oral cavity of the ODU rats. Changes in the makeup of the microflora found in each group are shown below.

2Q948'~~~

Non- Diabetic Diabetic 4-dedimethyl-Organisms Control Untreated aminotetracycline co i + + , ~ + .

Bacteroides + - -Fusobacterium + + +

Proteus + -Veillonella + + +

Leptotrichia + - -Streptococcus -alpha hemolytic - - -beta hemolytic - -gamma hemolytic + + +

Actinomyces + + +

Lactobacillus + - +

Staphylococcus - + +

Bifidobacterium + - -Candida - C) -+ = present - = not present Referring now to Table 1, the results of the isolation and identification of the organisms show that the untreated diabetic control animals and those treated with 4-dedimethylaminotetracycline had essentially the same oral flora. Moreaver, the bacterial composition and amount of growth obtained from both the diabetic control rats and the diabetic rats receiving 4-dedimethylaminotetracycline were ~u~4s~:~

1 essentially indistinguishable. These results, therefore, demonstrate the lack of antibacterial activity associated with 4-dedimethylaminotetracycline.
Thus, it can be seen that CMT's such as dedimethylaminotetracycline have essentially no antimicrobial effect on the crevicular microflora.
Moreover, CMT's also demonstrate essentially no microflora altering effects. Therefore, any prevention of plaque adhesion to tooth surfaces by CMT's cannot be attributed to antimicrobial or microflora altering properties of the CMT.
In this Example, the ~ v vo effect of non-antimicrobial tetracyclines on plaque accumulation on incisors was demonstrated. Thirty-two adult male ODU rats were distributed into four groups of eight. As was done in Example I, one group of rats was preserved as a non-diabetic control and the remaining rats were made diabetic by injection with streptozotocin. One group of diabetic rats was not treated further and designated the diabetic control. The second group of diabetic rats was given approximately 20 mg of the antimicrobial tetracycline hydrochloride in their daily meal. The last group of diabetic rats was treated by including approximately 20 mg of CMT as part of their daily meal.
After a 3-week protocol, the rats were anesthetized with halothane. The jaws of each rat were gently propped open, and the lower incisor teeth were flushed with distilled water to remove loose debris. The teeth were then stained with a plaque-disclosing solution (erythrocin R) to determine the presence of plaque on the incisor. The results are set forth below and in Figs. 1-4.

~0948'~4 Referring now to Fig: 1, it can be seen that the non-diabetic control ODU rats showed no detectable plaque accumulation on their lower incisors at or near the gingival margin. As can be seen in Fig. 2, the untreated diabetic ODU rats showed large accumulations of dental plaque on the incisors extending to and. including the gingiva. In Figs. 3-4, it can be seen that the rats in both the antimicrobial and non-antimicrobial tetracyaline-treated groups showed significant reductions in plaque accumulation on the lower incisors when compared to the untreated diabetic group. It was also observed that the lower incisors of the rats in the dedimethylamino-tetracycline-treated group greatly resembled those of the non-diabetic control rats which normally do not develop excessive plaque formation on their tooth surfaces.
It can be seen, therefore, that non-antimicrobial tetracyclines inhibit microbially-mediated dental plaque accumulation on teeth ~ yivo by a mechanism independent of antimicrobial properties of tetracyclines.
In this Example, further evidence of non-antimicrobial tetracyclines ability to inhibit plaque formation was demonstrated. Tiles made of polymethylmethacrylate, which is used for dentures, and has a surface which approximates the enamel of teeth for plaque adherence purposes were selected. Ten tiles were incubated in test tubes with a plaque-forming solution containing sucrose, fresh saliva, K+, Ca++, Na+, C1' and F' ions, a buffer containing Na2 HP04 7H20 NaHC03, and a culture of oral cavity microflora obtained from a patient at the University of New York Dental School Clinic at Stony Brook, New York which had been incubated for three days at 37 °C. Half of the test 1 tubes were incubated with 20 mg% or 0.02% by weight of 4-dedimethylamino-tetracycline to demonstrate its effectiveness against plaque formation, while the other half were maintained as untreated controls. After the 3-day incubation, each tile was removed from the test tube and all non-adherent material was rinsed away with distilled water. The tiles were then air-dried and any bacterial plaque adhering to the tiles was stained by dipping the tiles into a solution of Basic Fuchsin. The amount of stain on the tile provides a direct, correlation to plaque formation. Each tile was then destained in a solution of 5% EDTA in 50% 2-propanol. An aliquot of the destaining solution was then measured for light absorbence at 550 nm in a Spect. 70 colorimeter and compared to an aliquot from the untreated tiles. The results are set forth below in Table 2.

Spect. 70 colorimeter Absorbance Untreated 0.513 Tiles Treated 0.330 Tiles (0.02% CMT) Difference 36%
As can be seen from the above Example, the method of the present invention provides significant advantages and improvements in the inhibition of plaque formation on tooth surfaces. Furthermore, by contacting tooth surfaces with an effective amount of a non-antimicrobial tetracycline, bacterial plaque formation can be significantly inhibited in the oral cavity.

20948' EXAMPLE IV
In this Example, the ~ vo effect of non antimicrobial tetracycl'nes 'n r venting dental root ~:'~~~
caries was demonstrated.~~:e~~~a~p cif is pathogen-free , adult rats were distributed in four rou s. As was done irf g P
the previous examples, one group of rats was preserved as ~l a control group (normal control). The second group of rats was an untreated infected control group. A third group of rats was given 5 milligrams of the antimiarobial tetracycline, doxycycline, in their daily meal. The.fourth and final group was treated by including 5 milligrams of the chemically-modified tetracycline, (CMT), 4-dedimethyl-aminotetracycline. Prior to treatment, all of the animals in the group were infected with ]Bacteriodes aingivalis, a commonly-found oral bacterium responsible for caries.
After 42 days, the rats were examined for the presence of root caries. The jaws were stained, examined and inspected.

'~ 209484 1 Darker staining areas indicate greater demineralization of the cementum, which represents root caries. The results are set forth in Table 3, below.

ging~ivalis induced root caries: Effect of doxycycline and 4-dedimethylaminotetracycline.
Root Surfaces Root Surfaces Root Caries as Group with Recession with Caries % of Recession Normal Control 0 0 0 Untreated Control 42 18 42.8 Doxycycline 3 0 0.0 CMT 4 0 0.0 Both the antimicrobial and non-antimicrobial tetracyclines prevented the development of root caries.
The doxycycline eliminated the ~. g~givalis and caries by antibacterial action. More dramatic, however, was the fact that CMT was equally effective in preventing caries in spite of the lack of antibacterial activity. Thus, it can be seen that. non-antimicrobial tetracyclines not only inhibit dental plaque accumulation on teeth, but also can prevent dental caries. The non-antibacterial action, therefore, affords the artisan with a valuable alternative to antimicrobial therapy.

,~,XAMPLES V-IX
In these Examples, various oral hygiene products containing non-antimicrobial tetracyclines are set forth.
In each of the products, the term "CMT" is used to designate a chemically modified tetracycline such as a dedimethylamino- tetracycline which essentially lacks antimicrobiah activity. Each of the following illustrative products is useful in providing a vehicle for allowing an effective amount of the tetracycline to contact the tooth surface and thereby inhibit plaque formation.

. . , . ;, 20948'4\' Tooth Powder ;ngredient wt %

Silica hydrogel 96.10 Zinc chloride 0.50 Sodium fluoride 0.22 Sodium gluconate . 0.27 Synthetic sweetener (saccharin/aspartame) 0.50 Sodium methyl cocoyltaurate 1.50 .

Flavoring 0.80 C~ 0.01-0.10 EXAMPLE VI
j~o z eng~e Ingredient Sorbitol powder 74.50 Corn syrup 15.00 Zinc chloride 0.50 Sodium fluoride 0.22 Flavor and color 1.15 Sodium gluconate 0.30 Synthetic sweeteners 0.20 Tableting lubricant 5.00 Deionized water 3.00 0.01-0.10 20948'4 EXAMPLE VII

ChewiHg Gum Ingredient wt %

Gum base 30.00 Sorbitol 48.85 Corn syrup 15.00 Flavor 1.50 Zinc chloride . 0.50 Sodium fluoride ' 0.22 Sodium gluconate 0:30 Gum tragacanth 0.50 Deionized water 3.00 0.01-0.10 EXAMPLE VIII

Dentifrice Compositio n ingredient wt %

Glycerin 25.00 Zeo 498 (Silicone Dioxide) 21.50 HMP (Hexaphos) 6.00 Syloid 244 (synthetic silica) 3.00 Sodium Lauryl Sulfate 1.20 Flavor 1.00 Sodium Hydroxide (50% Solution) 1.00 Xanthan Gum 1.00 Sodium Benzoate 0.50 Titanium Dioxide 0.50 Sodium Saccharin 0.30 Sodium Fluoride 0.22 CMT 0.01-0.10 Deionized water to Q.S. 100 z~~~s7~

Mouthwash Incrredient wt %

Ethyl Alcohol 15.0 Glycerol 10.0 Flavor 0.4 Sodium saccharin , 0.03 Sodium Fluoride ' 0.05 pluronic F 108 2.0 0.01-0.10 Deionized Water to Q.S. 100 Other formulations for self-treatment as well as professional treatment can be provided by skilled artisans.
The present invention provides a highly effective and reliable anti-plaque and anti-caries agents and treatments which can be used without the side effects associated with antibacterial tetracyclines.
While there have been described what are presently believed to be the preferred embodiments of the present invention, those skilled in the art will realize that changes and modifications may be made thereto without departing from the spirit of the invention, and it is intended to claim all such changes and modifications as fall within the true scope of the invention.

Claims (27)

1. A use of an effective amount of a non-antimicrobial tetracycline to treat a mammalian tooth surface to prevent root caries.

2. The use according to Claim 1, wherein said non-antimicrobial tetracycline is a dedimethylaminotetracycline.

3. The use according to Claim 2, wherein said dedimethylaminotetracycline is selected from the group consisting of 4-de(dimethylamino)-tetracycline, 4-de(dimethylamino)-5-oxytetracycline, 4-de(dimethylamino)-7-chlortetracycline, 4-hydroxy-4-dedimethylaminotetracycline, 6-demethyl-6-deoxy-4-dedimethylaminotetracycline, 6-.alpha.-deoxy-5-hydroxy-4-dedimethylaminotetracycline, and 12a-deoxydedimethylaminotetracycline and its derivatives.

4. The use according to Claim 3, wherein said tetracycline is selected from the group consisting of 6.alpha.-benzylthiomethylenetetracycline, the mono-N-alkylated amide of tetracycline, 6-fluoro-6-demethyltetracycline, 11.alpha.a-chlortetracycline and tetracyclinonitrile.

5. The use of Claim 4, wherein said non-antimicrobial tetracycline is present in an amount of from about 10 mg% to about 100 mg% by weight.

6. The use of Claim 5, wherein said non-antimicrobial tetracycline is present in an amount of from about 15 mg% to about 25 mg%.

7. The use of Claim 6, wherein said non-antimicrobial tetracycline is present in an amount of about 20 mg%.

8. The use of Claim 4, wherein said non-antimicrobial tetracycline is incorporated into a dentifrice.

9. The use of Claim 4, wherein said non-antimicrobial tetracycline is incorporated into a lozenge.

10. The use of Claim 4, wherein said non-antimicrobial tetracycline is incorporated into a chewing gum.

11. The use of Claim 4, wherein the non-antimicrobial tetracycline is contained in a mouthwash or oral rinse product.

12. A confection for treating mammalian tooth surfaces to prevent root caries comprising an effective amount of a non-antimicrobial tetracycline in admixture with a suitable diluent or carrier.

13. The confection of Claim 12, wherein said non-antimicrobial tetracycline is a dedimethylaminotetracycline.

14. The confection of Claim 13, wherein said dedimethylaminotetracycline is selected from the group consisting of 4-de(dimethylamino)-tetracycline, 4-de(dimethylamino)-5-oxytetracycline, 4-de(dimethylamino)-7-chlortetracycline, 4-hydroxy-4-dedimethylaminotetracycline, 6-demethyl-6-deoxy-4-dedimethylaminotetracycline, and 6-.alpha.-deoxy-5-hydroxy-4-dedimethylaminotetracycline.

15. The confection of Claim 14, wherein said tetracycline is selected from the group consisting of 6.alpha.-benzylthiomethylenetetracycline, the mono-N-alkylated amide of tetracycline, 6-fluoro-6-demethyltetracycline, 11.alpha.a-chlortetracycline and tetracyclinonitrile.

16. The confection of Claim 15, wherein said non-antimicrobial tetracycline is present in an amount of from about mg% to about 100 mg%.

17. The confection of Claim 16, wherein said non-antimicrobial tetracycline is present in an amount of from about mg% to about 25 mg%.

18. The confection of Claim 17, wherein said non-antimicrobial tetracycline is present in an amount of about 20 mg%.

19. A confection for treating mammalian tooth surfaces to prevent adhesion of root plaque comprising an effective amount of a non-antimicrobial tetracycline in admixture with a suitable diluent or carrier.

20. The confection of Claim 19, wherein said non-antimicrobial tetracycline is a dedimethylaminotetracycline.

21. The confection of Claim 20, wherein said dedimethylaminotetracycline is selected from the group consisting of 4-de(dimethylamino)-tetracycline, 4-de(dimethylamino)-5-oxytetracycline, 4-de(dimethylamino)-7-chlortetracycline, 4-hydroxy-4-dedimethylaminotetracycline, 6-demethyl-6-deoxy-4-dedimethylaminotetracycline, and 6-.alpha.-deoxy-5-hydroxy-4-dedimethylaminotetracycline.

22. The confection of Claim 21, wherein said tetracycline is selected from the group consisting of 6.alpha.-benzylthiomethylenetetracycline, the mono-N-alkylated amide of tetracycline, 6-fluoro-6-demethyltetracycline, 11.alpha.a-chlortetracycline and tetracyclinonitrile.

23. The confection of Claim 22, wherein said non-antimicrobial tetracycline is present in an amount of from about mg% to about 100 mg%.

24. The confection of Claim 23, wherein said non-antimicrobial tetracycline is present in an amount of from about mg% to about 25 mg%.

25 25. The confection of Claim 24, wherein said non-antimicrobial tetracycline is present in an amount of about 20 mg%.

26. A use of a confection according to any one of Claims 12 to 25 to treat a mammalian tooth surface to prevent root caries or to prevent the adhesion of root plaque.

27. A commercial package containing as active ingredient a confection according to any one of Claims 12 to 25 together with instructions for the use thereof to treat a mammalian tooth surface to prevent root caries or to prevent the adhesion of root plaque.