CA1272130A - Oral compositions comprising salicylamides and zinc salts for the synergistic inhibition of dental plaque - Google Patents

Abstract

ABSTRACT

The disclosure relates to oral compositions for retarding the formation of dental plaque comprising a mixture of a zinc-salt with certain salicylamides of the formula:

Description

- 1 - J.6007 ORAL COMPOSITIONS COMPRISING SALICYLAMIDES AND ZINC
SALTS FOR THE SYNERGISTIC INHIBITION OF DENTAL PLAQUE

BACKGROUND OF THE INVENTION

Field of the Invention __ This invention relates to oral compositions for controlling dental plaque.

The Prior Art Dental plaque forms as a film on teeth. It is a dense microbial layer formed as a product of microbial growth. The closely matted microorganisms in plaque are embedded in a proteinaceous matrix of uncertain origin that is generally considered to be at ].east partially salivary. The microorganisms involved are mainly coccoidal, this is especially true in early plaque which in the mouths of some persons change to filamentous organisms after a few days.

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- 2 - J.6007 It is believed that dental plaque precedes calculus.
Also, it is generally accepted by dental experts that clinical supra-gingival calculus (tartar) is a type of dental plaque which is mineralised with a formation of a calcium phosphate crystalline-structure. It will be apparent therefore that the incidence of calculus formation can be reduced by employing dental compositions which reduce or prevent the deposition of plaque.

Dental plaque has been observed to form following dental prophylaxis. This plaque was attributed to bacteria acquired from the saliva where they had resided and remained unaffected by the prophylaxis treatment.
Plaque may form on any part of the tooth surface. It is lS found particularly at the gingival margin, and on the surface of dental calculus. Plaque, like calculus, is considered to be a prime causative factor in peridontal disease. Gingivitis and other types of gingival disease arise when plaque is not controlled.
~0 A wide variety of chemical agents have been suggested to retard plaque formation and the resulting plaque diseases. Mechanical removal of plaque is attempted with oral hygiene measures, but average toothbrushing only ~5 partially results in plaque removal. Therefore, the addi~ional use of chemical antibacterials inhlbiting plaque formation in inaccessible dental areas is indicated. Germicides which have been proposed include phenolic compounds, halogenated bis-phenols (e.g.
hexachlorophene~, organic mercurials, hydroxyquinolines, iodine esters of hydroxyben~oic acids, chloramine T, and surface active compounds ~detergents) among others. These germicides are excellent laboratory disinfectants but are relatively poor in vivo plaque inhibitors.

~5~ 7~

- 3 - J.6007 The antiplaque properties of metal ions were mentioned as early as 1940 (Hanke, M.T.: "Studies on the local factors in dental caries. I. Destruction of plaque and retardation of bacterial growth in the oral cavity", JADA ~7, 379, 1940). US Patent 1,593,~85 refers to zinc phenolsulfonate as a bactericide. The use of zinc oxide or zinc pho~phate for the stabilisation of dental creams is desc~ibed in US Patent 3,622,662. Zinc oxide and zinc sulphate are described in US Patent 3,624,199 for the same purpose. Effervescent antiplaque tablets containing zinc chloride are described in US Patent 3,888,976.

Antiplaque and anticalculus effects have been claimed in US Patent 4,146,607 for zinc ions combined with 15 tetradecylamine. US Patent 4,339,432 discloses mouthwashes combining zinc and glycine. Combinations of zinc salts and enzymes are reported for their oral activity in US Patent 4,0~2,841.

~d Antiplaque effects of oral rinses containing zinc salts and antibacterials have been reported in US Patent ~,0~2,880. Among the antibacterials listed in this patent are halogenated bisphenols, alkylbenzoyl acrylates, quaternary ammonium compounds, thiuram sulfides, ~5 dithiocarbamates, antibiotics, halogenated diphenol ethers, halogenated anilides of thiophene carboxylic acids, and chlorhexidines. US Patent 4,522,806 discloses the antiplaque activity of zinc salts in combination with hexetidine.
As may be noted from the foregoing description of the prior art, zinc salts and combinations of these salts with antibacterials and other actives have been shown to be inhibitors of dental plaque. There are, however, taste, formulation and safety di~ficulties associated with zinc salts and many of their co-actives. It has also been 3l) _ 4 _ J.6007 found desirable to obtain antiplaque compositions with increased efficiency.

Accordingly, it is an object of the present invention to provide an oral composition of improved effectiveness against dental plaque.

SUMMARY OF THE INVENTION

According to the present invention there is provided an oral composition comprising:

(i) from about 0.001 to 10~ by weight of a salicylamide selected from the group consisting of a compound of the formula (hereinafter referred to as formula I):

O H
/~
Rl ~ ~ C - N - R3 OH
~5 where (a) R1 is n-decanoyl and R3 is p-nitrophenyl (hereinafter called AN-10), (b) R1 is n-octanoyl and R3 iS p-trifluoromethyl-phenyl (hereinafter called APCF3-8), (c) R1 is n-octanoyl and R3 is m-trifluoromethyl-phenyl (hereinafter called AMCF3-8), (d) Rl is n-hexyl and R3 is p-nitrophenyl 7 (hereinafter called SAN-6)/
(e) Rl is n-butyl and R3 is m-trifluoromethyl-- 5 - J.6007 phenyl (hereinafter called S-4-F), (fj Rl is n-nonanoyl and R3 is m-carbethoxyphenyl (hereinafter called ACBXE-9~, (g) Rl is n-decanoyl and R3 is benzothiazol-2-yl (hereinafter called ABC-4), (h~ Rl is n-hexadecanoyl and R3 is thiazol-2-yl (hereinafter called RV-19), (i) R1 is n-decanoylJthe -OH group is replaced by acryloyloxy, and R3 is p-nitrophenyl (hereinafter called ACN-10)~

and (ii) from about 0.001 to about 10~ by weight of a physiologically acceptable zinc salt.

DETAILED DESCRIPTION OF THE INVENTION

It has now been discovered that dental plaque and calculus can be greatly reduced by contacting the teeth with a combination of zinc ions and certain salicylamides which are non-halogenated on their aromatic rings.
Salicylamides are known for their analgesic and anti-inflammatory properties and have been recognised as ~5 being effective antiplaque agents~see, Batista, A.J., "Salicylanilides: Design, Synthesis, and In Vitro Evaluation as Inhibitors of Dental Plaque-Forming Microoganisms", Ph.D. Dissertation, State University of New York at Buffalo, 1980; US Patent 4,358,443; and US
Patent 4,287,191. A combination of certain salicylamides identified by formula I when combined with zinc ions were surprisingly found to provide substantially more antiplaque activity than would be expected from the mere additive effects of both antiplaque agents individually~

- 6 - J.6007 The above salicylamides are known and described in existing literature. A representative, although not the only available or conceivable method of synthesis, is disclosed in US Patent 4,287,191 and US Patent No.4,560,549.

In general, salicylamides can be prepared by reacting a lower alkyl (Ra) salicylate ester with an acyl chloride (R~COCl) in the presence of a Lewis acid to form an ester 1~ of a 5-acylsalicylic acid. The 5-acylsalicylic acid ester is then hydrolyzed and the resulting free acid is reacted ~ith a substituted amine or aniline H2N-R3 to form the 5-acylsalicylamide. The term "lower alkyl" as used herein means alkyl of from 1 to 4 carbon atoms. Rx is n-C7 in the case of APCF3-8 and AMCF3-8. It is n-C9 in the case of AN-10. It is n-C8, n-C9 and n-C15 in the cases involving ACBXE-9, ABC-4 and RV-19 respectively. In the cases of SAN-6 and S-4-F, the Friedel-Crafts acylation step is replaced by a Friedel-Crafts alkylation process by substituting the acid chloride R -CO-C1 by a normal alkyl halide RxCl. In the cases of SAN-6 and S-4-F which are prepared by way of the Friedel-Crafts alkylation initial step, Rx is C6 and C4, respectively. R3 is a substituted benzene ring or a thiazole or a benzothia~ole ring. In the case of a substituted benzene ring, the substituents ma~ be -NO2 in a para position or -COOC2H5 in a meta position or -CF3 in either a para or a meta posi~ion.
When R3 is one of the two heterocyclic attachments mentioned above, the linking thereof to the secondary amido nitrogen atom occurs through the No.2 carbon atom of the heterocyclic attachment. ACN-10 is, as already noted above, an acrylic acid derivative of AN-10 wherein the 2-hydroxy group of AN-10 is replaced by the CH2=CH-COO-group. Such replacement is accomplished by the esterification of AN-10 in the manner generally employed for the esterification of phenols. Thus, esterification 3~3 - 7 - J.6007 o~ AN-10 with acryloyl chloride in pyridine or other base results in the esterified product, i.e. ACN-10.

As a usual procedure, the 5-acyl or 5-alkyl salicylic acid precursor is prepared in a medium or reaction solvent which is customarily considered suitable for the conductance of a Friedel-Crafts acylation or alkylation with optimal yield, minimal side reactions, non-onerous reactlon conditions and minimal reaction time. A
preferred reaction solvent is carbon disulfide. Anhydrous aluminum chloride or other Lewis acid is initially added to the carbon disulfide and the mixture is cooled, e.g.
with ice. A solution of the alkyl salicylate ester, e.g.
methyl salicylate, and an acyl halide, e.g. a chloride (or an alkyl halide as applicable) in carbon disulfide or other reaction solvent is then slowly added and the temperature is maintained below about 10C. After completion of reaction which may take as long as 24 hours, the reaction mass is poured into ice water and the mixture is then extracted with a suitable solvent such as ether.
The ether or other extract is washed with water and then dried over anhydrous sodium sulfate. ~hereafter, the ether or other solvent is evaporated in vacuo. The resulting solid residue is dissolved in a suitable solvent ~5 such as ethanol and treated with a solution of an alkali metal hydroxide, e.g. 2N NaOH solution. After heating to a temperature of between about 80 and 120C., e.g. on a steam bath, the mass is cooled and acidi~ied with a suitable acid such as HC1 to pH of about 1 to precipitate the product. Recrystallisation from ethanol gives purified 5-acylsalicylic acid or 5-alkylsalicylic acid, depending on whether an acid halide or an alkyl halide was the initial Friedel-Crafts reactant.

The 5-acyl or 5-alkyl salicylir acid is reacted with the appropriate subst`ituted aniline or other amine, e.g.

~ ~t7~ ~3~

- 8 - J.6007 p-nitroaniline in the case of AN-10, in a suitable reaction solvent such as chlorobenzene. Desirably the 5-acyl or 5-alkylsalicylic acid is pre-reacted with phosphorus trichloride in the solvent at a suitable temperature, e.g. between about 55C and about 80C. The reaction time is usually between about one and about five ours. The solution is then cooled and the appropriate substituted aniline or heterocyclic amine, e.g.
~-nitroaniline is then added and the solution is again heated to a suitable temperature, e.g. between about 55C
and about 80C as previously described for about one to about five hours and is then refluxed until the reaction is complete, e.g. for about 24 hours. The solvent is then removed ln vaco and the residue is purified by recrystallisation from a mixture of a suitable solvent such as a mixture of ethanol and water. The resultiny product is an amido compound of the invention.

Detailed descriptions of the methods of synthesis of ~0 5-n-decanoylsalicylic acid and of AN-10 therefrom are given in Examples 1 and 2 of US Paten~ No. 4,287,191.

Methods of synthesis of the other preferred compounds of the invention, namely APCF3-8, AMCF-8, SAN-6, S-4-F, ~5 ACB~E-9, ABC-4 and RV-l9 follow naturally from the method o synthesis described for AN-10 with appropriate substitution of the respective reactants. ACN-]0 i5 prepared, as already noted above, from AN-10 by esterification of the phenolic -OH group of AN-10 with acryloyl chloride in pyridine.

The salicylamides may be present from about 0.001% to about 10% by weight of the total oral composition.
Preferably, the concentration ranges from about 0.01 to about 2%, more preferably from about 0.05 to about 1.5%

. .

3~
- 9 J.6007 and most preferably from about 0.1 to about 1~ by weight of the total composition.

Zinc ions may be furnished by any pharmaceutically acceptable zinc salt having sufficient solubility in the solvent medium carrier to provide an effective level of 2inc ions, i.e. zinc cations, at the site of action of the ~inc ion. The remainder of the molecule of the zinc salt may be inert for antiplaque and anticalculus purposes.
By "zinc ion" is meant the zinc-atom portion of the molecule of a zinc compound in the solid or undissociated state, and capable of being dissociated into simple or complex zinc ions at temperatures of about 37C, as well as to simple or complex zinc ions formed in an aqueous medium such as a mouthwash or oral salivary secretions.

The term "pharmaceutically acceptable" used herein with reference to zinc compounds, is applicable to those compounds which, under the conditions of use and in the compositions set forth herein, are safe and organoleptically tolerable in the oral cavity, and have no significant side effects either orally or systemically.

In mouthwashes, it is preferred to use the more soluble ~inc salts, e.g. those having a solubility in water at 20C of the equivalent of at least about one gram of Zn per lOOml of water. A particularly preferred zinc compound is zinc phenolsulfonate, because it is virtually insensitive to pH change, for example to the adjustment of the pH of a mouthwash to near neutrality, with respect to hydrolysis and precipitation.

Zinc compounds having a solubility in water as low as the equivalent of about 1 x 10 ~ zinc may be used, as well as those having solubilities ranging from the ~7~
- 10 - J.6007 aforesaia level up to that of the most soluble zinc compounds, for example that of zinc bromide, which is about 447 grams (equivalent to abou-t 130 grams Zn~+) per lOOml at 29C.

The solubilities and zinc contents of zinc compounds having utility in accordance with the instant invention may be derived from data readily obtainable in the li~erature.
1~ , Examples of the compounds that may be employed are zinc salts of the following organic and inorganic anions:
acetate, benzoate, borate, bromide, carbonate, citrate, chloride, fluoride, glycinate, hexafluorosilicate, dl-lactate trihydrate, phenolsulfonate, silicate, alkanoates having 8 to 18 carbon atoms, sulfate, tannate and titanate.

The zinc salts, according to the instant invention, will generally be present in the oral composition in an amount of from about 0.001% to about 10~. Preferably, they will be present from about 0.01 to about 2~, more preferably from about 0.05 to about 2~, most preEerably from about 0.1 to about 1.5%. In the case of mouthwash products, the zinc salt may be added at a level of about 0.04~ to about 0.7% by weight of soluble zinc ion, with 0.0~% being the approximate minimum active concentration and 0.7% being the approximate concentration at which astringency becomes objectionable. The preferred concentration of zinc ion in a mouthwash is 0.1~-0.3~, and 0.2~ to 3~ in a toothpaste.

The balance of the oral composition in accordance with the present invention will consist of the usual carrier media and other desired substances consistent with the form it is in. For example, where the oral ~ J.6007 composition contemplated is a mouthwash, the balance of the preparation ~ill usually contain water, or water and a mono- or polyhydric alcohol such as ethanol, glycerol, or sorbitol, and optionally, flavourin~ substances and foaming agents. Glycerol and sorbitol are also useful as aids in sweetening the product. Surfactants and/or suspending agents are usually present in mouthwashes as solubilisers for essential flavouring oils. The customary solubilisers for this purpose are the sorbitan fatty acid ~0 esters, the polyoxyethylene deriva~ives thereof, and polyoxyethylene fatty acid ethers.

When the oral composition is in the form of a toothpaste, there may be present polishing agen~s, humectants, bodying agents, flavouring substances, sweetening substances, foaming agents, etc. It will be understood that the polishing agents and other components suitable for use in the toothpastes of the invention must be compatible with the zinc compounds and salicylamides.
2n Among the suitable inorganic polishing agents useful in accordance with the invention are the silica xerogels and silica aerogels manufactured by the Davison Chemical Division of W.R. Grace and Company, for example those ~5 available under the trade names of Syloid 63 and Syloid 65 (xexogels), and Syloid 244 (aerogels~. The xerogels are synthetic, aggregated, amorphous, highly porous silicas having generally a mean particle diameter of about 4 to 10 microns. The aerogel Syloid 244 has a mean particle diameter of about 3 microns and is more porous than the xerogels. Also useful are other polishing agents disclosed hereinafter.

The polishing agent should be in the form of fine particles, as is well known in the art. Preferably, the particles should be of such size that at least 40% pass 3~3 12 - J.6007 through a 325 mesh screen, and at least 90~ pass through a 20 mesh screen. The finer particles within this size range are preferred, particularly a size distribution such that all the particles pass through a 20 mesh screen; more than 90% pass through a 100 mesh screen; more than 80%
pass through a 200 mesh screen; and more than 40~ pass through a 325 mesh screen. Especially preferred are the finer particles having a mean particle diameter of about 3 to about 44 microns.
Other substances proposed as dental abrasives include various abrasive materials such as silica embedded in protective plastic particles, chalks, metaphosphates, pyrophosphates, and dicalcium phosphate dihydrate.
Polishing agents will be present in the toothpastes of the invention over the broad range of about 1~ to 70%, preferably 10% to 60%, and typically from about 20% to 50~. In a tooth powder~ the polishing agent will be ~0 present over the range of about 50% to 99%, preferably from about 70% to 95~, and typically from about 90% to about 95%.

The toothpastes will usually contain compatible ~5 bodying agents such as gum Karaya, gum Tragacanth, starch, sodium carboxymethylcellulose, Irish moss, gum arabic, sodium carboxymethylhydroxyethylcellulose, polyvinylpyrrolidone, etc. When present, these will usually be at levels of from about 0.5~ to about 3%, preferably from about 0.8~ to about 1.5%.

Humectants are desirable in a toothpaste to provide smooth texture and flowability. These will usually be such compounds as glucose, honey, glycerol, propylene glycol, sorbitol, polyethylene glycol 400, and other ~7~3V

- 13 - J.6007 polyhydric alcohols, and ma~ be present in the composition in amounts of up to about 80% by weight.

Other adjuvants may be present, such as fluorides, chlorophyll compounds, flavouring substances, saccharin, aspartame, urea, ammonium compounds, alcohol, mineral oil, and foaming agents or detergents, such as sodium lauryl sulfate, dodecanesulfonate, acyl taurines, acyl isethionates, etc, depending upon the form of the product.
n Chewing gum compositions are also within the scope of this invention. A chewing gum medium normally comprises a gum base and common flavouring materials used in the field. The flavouring materials are present at a level of about 0.01-2.0% of ~he final chewing gum composition. The base is a chewable plastic gum material such as natural rubber, chickle, polyvinyl acetatet ester gum, coumarone resin and paraffin wax. The gum base is typically made fxom a mixture of two or more plastic gum materials to ~0 achieve a preferred degree of plasticity for chewing.
Optionally, a binder or a softener may be used as well as sweetening agents. Lozenges may also be made containing the synergistic combination of this invention.

~5 TEST PROCEDURE FOR DETERMINING ANTIPLAQUE ACTIVITY

The in vitro test used for examining the effects of chemotherapeutic agents on plaque was reported in the "Journal of Dental Research", Vol. 55, February 1976, page B286, by R.T. Evans, P.J. Baker, R.A. Coburn and R.J. Genco. This assay system for producing artificial plaque was developed to rapidly screen antiplaque agents under conditions which simulate those found in the oral cavity. Evans et al ~ound that effective dosages in the in vitro assay correlated with results of previously - 14 - J.6007 published clinical studies. The assay gives reproducible, quantitative results and has the ability to distinguish between antibacterial agents which are clinically effective or non-effective as plaque inhibitors.

The in vitro plaque was formed at 37C on uniformly si~ed aluminum plummets which were first coated with saliva. The plummets were then placed in a growth medium inoculated with clinical plaque samples. After seven hours the plummets were suspended overnight in a 25~
saliva mixture. On the second day, the plummets were immersed in a 50% saliva -- 50% test compound mixture for one minute, placed in the growth medium for seven hours, retreated with the test mixture and suspended in 25%
saliva overnight. The plummets were treated again on the third day and incubated in the growth medium for three hours. the plaques were removed from the plummets by sonication into approximately six millilitres of buffer and quantitated by optical density (O.D.) in a Beckman DU
~0 at 570mm.

A test compound showed antiplaque activity if the O,D. (plaque mass) was reduced from the control plaques treated with water. Positive controls were included to ~5 determine relative activity. Comparisons of antiplaque activity were then made within a given experiment. At least five replicas per compound were examined.

The following Examples will more fully illustrate the embodiments of this invention. All parts and proportions referred to herein are by weight unless otherwise noted.

The following Example illustrates the interactive effective of three different types of salicylamide (i.e.

3~
- 15 - J.6007 AN-lO, APCF3-8 and ACN-lO) with zinc salts in an aqueous media. Samples 1-4 and 5-12 of the Table are separated into Sets A and B because the comparative placebos and test conditions were slightly varied. As a result, each of the two placebos exhibited a different response.
Samples within each group were compared to their respective placebo values. In Table I, the placebo of set B consisted of 25~ ethanol, 25~ propylene glycol, 0.5~
~Pluronic 84 (an ethylene ~xide-propylene o~ide polymer sold by Rohm & Haas Company) and 0.4% glycine with the balance water. The placebo of set A did not contain glycine and the Pluronic 84 was substituted with 1.5 *Tween 20, a trademark of ICI, Americas, representing sorbitan monolaurate ethoxylated with 20 moles ethylene oxide.

It was found that both zinc chloride and zinc phenol sulfonate provided about 5~ plaque reduction. This finding is supported by the results of clinicals reported in the scientific literature.

0 In set A, the salicylamide AN-10 reduced plaque by about 21%. The combination of AN-lO and zinc phenolsulfonate, however, reduced plaque by S0~. It should be noted that the halogenated congener of AN-lO, 3,4', 5 tribromo salicylanilide (TBS) can reduce plaque by about 20~ but the combination of zinc phenol sulfonate and TBS reduces plaque by only about 35~.

Set B of Table I compares various salicylamides in combination with zinc chloride. Relative to the placebo of set B, ~N-10 alone appeared to have a greater plaque reduction effect than relative to the placebo of set B.
Nonetheless, the combination of AN-10 with zinc chloride gave a plaque reduction of 68~, which is greater than the sum of the separate active. Combinations of zinc chloride * DenotQs trade mark ~7~130 - 16 - J.6007 with APCF3-8 and ACN-10 provided significantly more plaque reduction than would have been expected from a merely additive combination of salicylamide and zinc salt.

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- 18 - J.6007 The following Example illustrates a typical mouthwash composition incorporating the salicylamide known as ~MCF3-8 and zinc glycinate.

Mouthwash Ingredient % Weight Glycerol 35.00 Ethanol 27.00 Polyethylene glycol 10.00 Flavour, colour 0.90 Zinc glycinate 0.25 ~Polyoxyethylene (20) sorbitan monolaurate 0.20 AMCF3-8 0.2 Water Balance to 100 3~

- 19 - J.6007 i The following Example illustrates a further mouthwash composition using the salicylamide known as AN-10 and zinc sulfate.

Mouthwash Ingredient ~ Weight Glycerol 8.00 Flavour 0.15 Saccharin 0.02 FD~C Yellow No. 6 (0.7~ solution) 0.10 FD&C Red No. 2 (0.2~ solution) 0.12 AN-10 0.10 Zinc sulfate 0.40 Sodium lauryl sulfate 0.33 Polyoxyethylene (20) sorbitan 0.30 monolaurate Water Balance to 100 ~'7~3~
- 20 - J.6007 The fQllowing Example illustrates a ~ypical gel dentifrice containing zinc phenolsulfonate and the salicylamide AMCF3-8.

Ingredient % Weight Silica polishing agent (1)15.00 Silica polishing agent (2)8.00 Sodium carboxymethylcellulose 0.84 Sorbitol 36.00 Saccharin 0.20 Zn phenolsulfonate 1.00 ~MCF3-8 0.25 Flavour 1.30 i2 0.50 FD&C Blue No. 1 colourant (1% soln.) 0.02 Sodium Hydroxide 0.10 Sodium lauryl sulfate-glycerine (3) 7.00 Water Balance to 100 (1) Syloid 63, a silica xerogel having an average particle diameter of 4-10 microns.
~5 (2) Syloid 244, a silica aerogel having an average particle diameter of 3 microns.

(3) A solution of 21 parts sodium lauryl sulfate in 79 parts glycerol.

Syloid 63 and Syloid 244 are trademarks of the Davison Chemical Division of the W.R. Grace Company.

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- 21 - J.6007 The following Example illustrates a high abrasive containing toothpaste utilizing zince acetate and the.
salicylamide AN-10.

Ingredient ~ Weiyht Dicalcium phosphate dihydrate40.0 Calcium pyrophosphate 5.0 Sodium carboxymethylcellulose1.0 Glycerol 20.0 Sorbitol 10.0 Zinc acetate 1.5 AN-10 0.1 Sodium lauryl sulfate 1.5 Water 20.9 The foregoing description and Examples illustrate selected embodiments of the present invention and in light thereof various modifications will be suggested to one skilled in the art, all of which are within the spirit and purview of this invention.

Claims (7)

- 22 - J.6007 THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. An oral composition comprising:

(i) from about 0.001 to 10% by weight of a salicylamide selected from the group consisting of a compound of the formula:

where (a) R1 is n-decanoyl and R3 is p-nitrophenyl;
(b) R1 is n-octanoyl and R3 is p-trifluoromethyl-phenyl;
(c) R1 is n-octanoyl and R3 is m-trifluoromethyl-phenyl;
(d) R1 is n-hexyl and R3 is p-nitrophenyl;
(e) R1 is n-butyl and R3 is m-trifluoromethyl-phenyl;
(f) R1 is n-nonanoyl and R3 is m-carbethoxyphenyl;
(g) R1 is n-decanoyl and R3 is benzothiazol-2-yl;
(h) R1 is n-hexadecanoyl and R3 is thiazol-2-yl;
(i) R1 is n-decanoyl, the -OH group is replaced by acryloyloxy, and R3 is p-nitrophenyl;

and (ii) from about 0.001 to about 10% by weight of a physiologically acceptable zinc salt.

- 23 - J.6007

2. A composition according to claim 1 wherein the salicylamide is present in a concentration from about 0.01 to about 2%.

3. A composition according to claim 1 wherein the salicylamide is present in a concentration from about 0.05 to about 1.5%.

4. A composition according to claim 1 wherein the salicylamide is present in a concentration from about 0.1 to about 1%.

5. A composition according to claims 1, 2 or 3 wherein said zinc salt is selected from the group consisting of zinc sulfate, zinc chloride, zinc acetate, zinc phenolsulfonate, zinc borate, zinc bromide, zinc nitrate, zinc glycerophosphate, zinc benzoate, zinc carbonate, zinc citrate, zinc hexafluorosilicate, zinc dl-lactate trihydrate, zinc oxide, zinc peroxide, zinc salicylate, zinc silicate, zinc soaps of fatty acids having 8-18 carbon atoms, zinc stannate, zinc tannate, zinc tartrate, zinc titanate, zinc tetrafluoroborate, zinc glycinate and mixtures thereof.

6. A composition according to claims 1, 2 or 3 wherein the concentration of the zinc salt ranges from about 0.05% to about 2%.

7. A composition according to claims 1, 2 or 3 further comprising a carrier vehicle selected from the group consisting of water, glycerol, sorbitol and mixtures thereof.