WO1992018091A1

WO1992018091A1 - Antimicrobial oral compositions

Info

Publication number: WO1992018091A1
Application number: PCT/US1992/002359
Authority: WO
Inventors: Michael Frederick Lukacovic; Satyanarayana Majeti; David Allen Weber
Original assignee: The Procter & Gamble Company
Priority date: 1991-04-19
Filing date: 1992-03-25
Publication date: 1992-10-29
Also published as: AU1890292A

Abstract

Disclosed are compositions and their use in methods for treating and/or preventing microbial infections in the oral cavity of humans and/or lower animals in need of such treatment, comprising a monoperphthalic acid compound and thymol.

Description

ANTIMICROBIAL ORAL COMPOSITIONS

RAΓKEROUND OF THF INVENTION

Many microbial infections arise endogenously. Bacteria and yeast are a part of the normal flora of the skin. They also exist prevalently on all mucous membrane surfaces as indigenous flora. Given the proper circumstances and opportunity to penetrate tissues, bacteria from the indigenous flora can set up infections, such as gas gangrene, vulvovaginal abscess,¹ chronic sinusitis, and

Vincent's disease.

While good oral hygiene, as achieved by brushing the teeth with a cleansing dentifrice, may help reduce the incidence of periodontal disease, it does not necessarily prevent or eliminate its occurrence. This is because microorganisms contribute to both the ini iation and progress of periodontal disease. Thus, in order to prevent or treat periodontal disease, these micoorganisms must be suppressed by some means other than simple mechanical scrubbing. Towards this end, there has been a great deal of research aimed at developing therapeutic dentifrices, mouthwashes, and methods of treating periodontal disease which are effective in suppressing these microorganisms. Treatment with monoperoxy acid compounds has been suggested in treating bacterial infections of the oral cavity. However, there is still a need for safe and effective methods for treating and preventing yeast overgrowth which occurs with the use of such monoperoxy acids.

Monoperoxy acids are known for treating microbial diseases of the oral cavity. U.S. Patent 4,990,329, issued February 5, 1991 to Sampathku ar discloses an oral hygiene composition comprising a monoperphthalic acid compound or its pharmaceutically-acceptable salts or esters. These compositions are used to treat or prevent anaerobic infections in humans and lower animals.

U.S. Patent 4,886,658, issued December 12, 1989 to Charbonneau discloses methods for treating or preventing dental plaque, caries, or gingival or periodontal diseases of the oral cavity in humans or lower animals, with reduced staining of teeth or dentures. Compositions suitable for use in this invention comprise a monoperoxyphthalate compound and an anti-plaque bis-biguanide compound. U.S. Patent 4,716,035, issued December 29, 1987 to Sampath- kumar discloses oral compositions comprising certain organic peroxy acid agents and a source of fluoride ions. These .compo¬ sitions are used as anticaries and antigingivitis agents.

Monoperoxy acids are also used for other disinfecting/ cleansing purposes. European Patent Application No. 0,133,354 published February 20, 1985 by Interox Chemicals Limited, discloses denture cleansing compositions comprising an organic peroxygen compound, especially in effervescent tablet form.

Great Britain Patent Specification No. 2,137,822A, published October 17, 1984 by Interox Chemicals Limited, discloses an alkanolic solution of a magnesium salt of an aryl, cycloaliphatic, or conjugated aliphatic carboxylic acid (substituted by one or more peroxycarboxylic acid groups). This invention is said «_* to be useful as a broad spectrum disinfectant/sterilizing agent for hard surfaces.

U.S. Patent 4, 917,815, issued April 17, 1990 to Beil fuss et a! . , discloses aqueous solutions of aromatic percarboxyl ic acids. Uses for this invention include acidic or neutral l iquid disin¬ fectants for surfaces with l ow to medium l oading of di rt for the skin, the mucous membranes or the hands .

U.S. Patent 4,490, 269 i ssued December 25, 1984 to Gallopo discloses a denture cl eansing composition compri sing an efferves¬ cent agent, and as a bleaching agent, a monoperphthal ate or a potassium monopersulfate and a monoperphthal ate. U .S . Patent 4, 221 ,660, issued September 9, 1980 to Eggens- perger et al . , discl oses a method for disinfecting an aqueous system with a sol id aromatic percarboxyl ic acid having sol ubil ity in water. Percarboxyl ic acids which may be empl oyed in this invention incl udes monoperphthal ic acid. U.S. Patent 3,988,433, i ssued October 26, 1976 to Benedict discloses compositions containing al kyl and aryl peroxy acids . These compositions are stated to be useful to remove stains from teeth.

Baldry, M.G. "The Antimicrobial Properties of Magnesium Monoperoxyphthalate Hexahydrate," Journal of Applied Bacteriology, Vol. 57, pages 499-503 (1984), investigated the antimicrobial properties of magnesium monoperoxyphthalate hexahydrate (herein¬ after referred to as "MMPP hexahydrate") against yeasts, vegetative bacteria and bacterial endospores. The results of this investigation suggest that 1-2% MMPP hexahydrate produces a total kill of L. albicans when used for at least 10 minutes.

In spite of such disclosures, it has been observed that when monoperphthalic acid is used as an antimicrobial agent in oral compositions, some humans and lower animals exhibit an overgrowth of yeast. A possible explanation for such yeast overgrowth is that oral compositions containing monoperphthalic acids are not present in the oral cavity for a period of time necessary to kill the yeast flora. Therefore, it is necessary to reduce the number of viable yeast in the oral cavity during the limited contact time available with the use of these oral monoperphthalic acid compo- sitions. Surprisingly, it has been discovered that incorporation of thymol into the oral monoperphthalate compositions lessens the amount of time necessary to reduce the viable yeast flora in the oral cavity.

Thymol, a phenolic compound useful in the present invention, is known to have some antibacterial properties. Listerine® antiseptic mouthrinse, sold by Warner-Lambert Company is a thymol- containing product currently on the market.

It is the object of the present invention to provide oral compositions comprising a monoperphthalic acid and thymol useful for treating or preventing microbial infections of the oral cavity. It is a further object of the present invention to provide methods for treating or preventing microbial infections of the oral cavity by administering to humans or lower animals in need of such treatment a composition comprising a monoperphthalic acid and thymol. An additional object of this invention is to provide such treatment without causing in the humans or lower animals an overgrowth of yeast in the oral cavity. These and other objects of the present invention will be apparent from the detailed description of the invention contained hereinafter.

All percentages and ratios herein are by weight and all measurements are made at 250C unless otherwise specified.

CMMMΔPV ΠF THF INVENTION The present invention provides oral compositions useful for treating or preventing microbial infection of the oral cavity, said oral compositions comprising: _(a) from about 0.25% to about 5% of a monoperphthalic acid compound; and (b) from about 0.025% to about 0.1% thymol.

The present invention further relates to methods of treating or preventing microbial infections of the oral cavity, such methods comprising administering to a human or lower animal in need of such treatment, and possibly exhibiting an overgrowth of yeast, an oral composition comprising a monoperphthalic acid and thymol as described hereinafter.

A detailed description of the essential and optional compo- nents of the present invention are detailed below. nFTΔTtm INSCRIPTION OF THE INVENTION

Mnnoper_Dhthalic Acid Com^pounds:

The present invention relates to compositions and methods for treating or preventing microbial diseases of the oral cavity by administering to humans or lower animals a composition comprising a safe and effective amount of a monoperphthalic acid and thymol. By "diseases of the oral cavity", as used herein, is meant diseases which are initiated and/or perpetuated by bacteria in the oral cavity, and includes such diseases as, for example, perio- dontal disease, gingivitis, periodontitis, gingivosis, perio- dontosis, periodontitis complex, and other inflammatory and/or degenerative conditions of the tissues within the oral cavity, plus caries, Vincent's disease, trench mouth, malodor, and yeast overgrowth. Also specifically included are dentoalveolar infectious, dental abscesses (e.g., cellulitis of the jaw; osteomyelitis of the jaw), acute necrotizing ulcerative gingivitis (i.e., Vincent's infection), infectious stomatitis (i.e., acute inflammation of the buccal mucosa), and Noma (i.e., gangrenous stomatitis or cancrum oris). Oral and dental infections are more fully disclosed in Fingold, Anaerobic Bacteria in Human Diseases, chapter 4, pp 78-104, and chapter 6, pp 115-154 (Academic Press, Inc., NY, 1977), the disclosures of which are incorporated herein by reference. The method of treatment of the present invention is particularly effective for treating or preventing periodontal disease, gingivitis and/or periodontitis, while lessening the potential for an overgrowth of yeast to occur in the oral cavity.

By "safe and effective amount" as used herein is meant an amount of a monoperphthalic acid compound, or its pharmaceuti- cally-acceptable salt or ester, high enough to significantly positively modify the infection to be treated, but low enough to avoid serious side effects (at a reasonable benefit/risk ratio), within the scope of sound medical judgment. The safe and effective amount of a monoperphthalic acid compound or its pharmaceutically-acceptable salt or ester will vary with the particular infection (e.g., disease of the oral cavity) being treated, the age and physical condition of the patient being treated, the severity of the infection, the duration of treatment, the nature of concurrent therapy, the specific form (i.e., acid, salt, and/or ester) of the monoperphthalic acid employed, and the particular vehicle from which the monoperphthalic acid is applied. The monoperphthalic acid compounds, useful in this invention are substituted monoperphthalic acids having the general structure:

or its pharmaceutically acceptable salts or esters, wherein R may be one or more substituents compatible with the peroxy acid functionality of the aromatic ring.

By "substituents compatible with the peroxy acid function- al ty of the aromatic ring", as used herein, is meant substituents on the ring which do not react with peroxy acids thereby reducing the stability and effectiveness of the compounds to treat diseases of the oral cavity. Non-limiting examples of R groups include hydrogen, substituted and unsubstituted saturated alky! having from 1 to about 20 carbon atoms (e.g., methyl, ethyl), substituted and unsubstituted aryl (e.g., phenyl, naphthyl), substituted and unsubstituted benzyl, chloro, fluoro, nitro, sulphonate, tri- f1uoromethyl, trialkylammonium (e.g., trimethylammonium; trethylammonium), cyano, carboxy, carboxylate (e.g.,--0C0CH3), percarboxylate (e.g.,--C03H), and alkoxy (e.g., methoxy, ethoxy). Preferred R groups are hydrogen, saturated alkyl having from 1 to about 20 carbon atoms, aryl, benzyl, chloro, fluoro, carboxy, and alkoxy. Particularly preferred for use in the above method for treating or preventing diseases of the oral cavity is monoper- phthalic acid (i.e., R=H), or its pha aceutically-acceptable salts or esters. R may also be an iodo, bromo, substituted or unsub¬ stituted amino, or amido group, but such groups are generally not desirable since they can react with peroxy acid groups. Selection of substituents compatible with the peroxy acid functionality of the aromatic ring can easily be made by one skilled in the art.

By "pharmaceutically-acceptable salts or esters", as used herein, is meant esters and salts of the substituted or unsub¬ stituted monoperphthalic acid compounds which have the same general antibacterial properties as the preferred magnesium salt of monoperphthalic acid, and which are acceptable from a toxicity viewpoint. Nonlimiting examples of pharmaceutically-acceptable salts include alkali metal (e.g., sodium, potassium), alkaline earth metal (e.g., calcium, magnesium), non-toxic heavy metal, and trialkyl ammonium (e.g., trimethylammonium). Preferred compounds for treating or preventing diseases of the oral cavity are pharmaceutically-acceptable salts of the substituted or unsub¬ stituted monoperphthalic acid compounds, with the pharmaceu- tically-acceptable salts of divalent cations more preferred (e.g., magnesium, calcium) and the magnesium salt being the most preferred.

Most preferred for use in the above method of treating or preventing surface tissue infections caused by or involving microbial organisms, and particularly preferred for diseases of the oral cavity, is the magnesium salt of monoperphthalic acid. This magnesium salt is the salt of the carboxylic acid group only, having the formula:

as disclosed in European Patent Application No. 27,693, published Apr. 29, 1981, filed by Interox Chemicals, Ltd., the disclosures of which are incorporated herein by reference. This compound is a hexahydrate when in its solid form.

Synthesis of substituted and unsubstituted monoperphthalic acid compounds can be achieved by those skilled in the art using methods disclosed in, for example, European Patent Application No. 27,693, published Apr. 29, 1981, filed by Interox Chemicals Limited; European Patent Application 66,992, to Interox Chemicals Limited; U.S. Pat. No. 3,075,921, to Brockelhurst et al . ; "Organic Peroxides", Daniel Swern, Editor, published 1970 by John Wiley & Sons, Inc.; and in British Patent Specification No. 1,378,671; the disclosures of all of which being incorporated herein by reference. Synthesis of the magnesium salt of monoperphthalic acid is disclosed in the European Patent Application No. 27,693, cited above. This compound is also commercially available from Interox Chemicals Limited. For the compositions and methods of treatment and prevention of diseases of the oral cavity, as defined by the present invention hereinabove, the amount of monoperphthalic acid or its pharmaceutically-acceptable salts or esters is from about 0.01% to about 55%; a more preferred amount is from about 0.25% to about 22.1%. The most preferred amount of monoperphthalic acid or its pharmaceutically-acceptable salts or esters useful in the present invention is from about 0.5% to about 17.7%. Thymol Thymol is a phenolic compound necessary in the oral compo¬ sitions of the present invention to extend the antimicrobial spectrum of the monoperphthalic acid to include yeast. Thymol aids in reducing viable yeast in the oral cavity, thereby decreasing the potential for an overgrowth of yeast to occur when a patient is undergoing treatment with the use of a monoper¬ phthalic acid composition.

Thymol is obtained from the essential oil of the plants Thymus vulgaris L. and Monarada punctata L., Labiatae. Thymol is a phenolic compound having the general structure: CH₃

/ \

H3C CH3

It is stated that thymol has use for destroying mold and herbarium parasites. Thymol has been recommended for the prevention of mildew growth. Merck, Tenth Edition, Number 9246, page 1347, published in 1983 by Merck & Co., Inc., incorporated herein by reference in its entirety. Thymol is available commercially from Sigma Chemical Company, St. Louis, Missouri. The amount of thymol present in the oral compositions of the present invention is from about 0.01% to about 12.37%; more preferably from about 0.025% to about 6.19%; and most preferably from about 0.05% to about 2.65%. Suitable Carripr Materials:

Suitable carrier materials for the oral compositions of the present invention are preferably in the form of any of a number of conventional oral care products, for example, a solution (e.g., mouthrinse, a dentifrice (e.g., toothpaste, gel or tooth powder), chewing gum, chewable tablets, lozenge or sachet. Preferred compositions useful in the methods of the present invention are solutions and dentifrices

These suitable carrier materials should be compatible with the monoperphthalic acid and thymol present in the oral co po- sitions of the present invention. By "compatible", as used herein, is meant that the components of the composition are capable of being commingled without interaction in a manner which would substantially reduce the compositions efficacy for treating or preventing microbial diseases of the oral cavity, according to the method of the present invention.

Examples of suitable pharmaceutically-acceptable carrier materials useful in oral care formulations of the present invention include, but are not limited to the group consisting of flavoring agents, sweetening agents (e.g. saccharin, aspartame, magnasweet), coloring agents, humectants, emulsifying agents, buffering agents, suitable aqueous carriers and mixtures thereof. The term "suitable aqueous carriers" as used herein, means water or a mixture of water and any alcohol that is proven to be safe for human use. A buffering agent is useful in the present invention to maintain a desirable pH of the monoperphthalic acid/thymol containing compositions of from about 5 to about 7, and preferably from about 5 to about 5.5. Examples of suitable buffering agents for the present invention include sodium bicarbonate, citric acid, malic acid, tartaric acid, gluconic acid and monosodium phosphate. Preferred buffering agents for the present invention are sodium bicarbonate, citric acid, and monosodium phosphate. Dptionally, the oral compositions of the present invention may contain a water-soluble fluoride compound in an amount sufficient to give a fluoride concentration of from about 0.0025% to about 5.0% by weight, preferably from about 0.005% to about 2.0% by weight, to provide anticaries effectiveness. The fluoride compounds are believed to provide protection against deminerali- zation as well as aid in re ineralization of dental enamel. Preferred fluorides are sodium fluoride, stannous fluoride, indium fluoride, and sodium onofluorophosphate. Norris et a!., U.S. Patent 2,946,725, issued July 26, 1960 and Widder et al., U.S. Patent 3,678,154, issued July 18, 1972 disclose such salts as well as others.

The pharmaceutically-acceptable carrier materials in the oral monoperphthalic acid/thymol-containing compositions of the present invention are present in a range of from about 32.63% to about

99.89%; more preferably from about 71.71% to about 99.725%; and most preferably from about 79.65% to about 99.45%.

The preferred dentifrice compositions useful in the methods of the present invention for treating or preventing microbial infections, including overgrowth of yeast, in the oral cavity comprise a monoperphthalic acid or its pharmaceutically-acceptable salts or esters in an amount of from about 0.01% to about 10%; more preferably from about 1.0% to about 7.5%; most preferably from about 2.5% to about 5%; thymol in an amount of from about 0.025% to about 1.5%; more preferably from about 0.25% to about 1.25%; most preferably from about 0.25% to about 1.0%; and suitable carrier materials in an amount of from about 88.5% to about 99.97%; more preferably from about 91.25% to about 98.75%; most preferably from about 94% to about 97.25%. Other preferred compositions useful in the methods of the present invention are in the form of granules which may then be dissolved in a suitable aqueous carrier for use as a mouthrinse or mouth spray. Granular compositions useful in the methods of the present invention comprise a monoperphthalic acid or its pharmaceutically-acceptable salts or esters in an amount of from about 1.76% to about 55%; more preferably from about 4.4% to about 22.1%; most preferably from about 8.8% to about 17.7%; and thymol in an amount of from about 0.17% to about 12.37%; more preferably from about 0.44% to about 6.19%; most preferably from about 0.88% to about 2.65%; and suitable carrier materials .in an amount of from about 32.63% to about 98.07%; more preferably from about 71.71% to about 95.16%; most preferably from about 79.65% to about 90.32%. Method of Treatment:

The method of this invention to treat or prevent microbial diseases of the oral cavity said method comprising administering to humans or lower animals in need of such treatment or prevention an oral composition comprising a monoperphthalic acid compound and thymol as described in detail hereinabove.

In the methods of the present invention, such oral compo- sitions are preferably used from about once to about four times, more preferably once or twice daily, most preferably twice daily. The methods of the present invention comprise contacting such monoperphthalic acid/thymol-containing compositions with the dental surfaces in the oral cavity for from about one second to about 300 seconds during each use, more preferably for from about 10 seconds to about 120 seconds, during each use, and most preferably for from about 30 seconds to about 60 seconds during each use.

The granule compositions useful in the methods of the present invention, as described in detail hereinabove may be used in preparing aqueous compositions that may then be used to treat or prevent microbial infections of the oral cavity, including an overgrowth of yeast, in humans or lower animals in need of such treatment. The aqueous solution of monoperphthalic acid or its pharmaceutically-acceptable salts or esters and thymol are prepared by dissolving the granule compositions, as described in detail hereinabove, in a suitable aqueous carrier such that the resulting solutions provide monoperphthalic acid or its pharmaceutically-acceptable salts or esters in a range of from about 0.1% to about 5%; more preferably from about 0.25% to about 1.25%; most preferably from about 0.5% to about 1%; and thymol in a range of fro_*-, about 0.0» to about 0.7%; more preferably from about 0.025* to about 0.35%; most preferably from about 0.05% to about 0.15%. .

These monoperphthalic acid/thymol-containing solutⁱons are used in the methods of the present invention to treat or prevent microbial infections, of the oral cavity, including an overgrowth of yeast, said methods comprising having a human or lower anⁱmal in need of such treatment swish or otherwise retain and move around in the oral cavity from about 5 ml to about 30 ml; more preferably from about 10 ml to about 20 ml ; most preferably from about 12 ml to about 18 ml of said solutions.

The monoperphthalic acid/thymol containing dentifrice compo^¬ sitions are used in the methods of the present invention to treat or prevent microbial infections in the oral cavity, including an overgrowth of yeast, said methods comprising having a human or lower animal in need of such treatment brush their teeth or have their teeth brushed with preferably 0.2gms to about 2.5gms; more preferably O.δgms to about 2.0gms; most preferably lgm to about l.δgms of said dentifrice compositions. The following examples further describe and demonstrate preferred embodiments within the scope of the present invention. The examples are given solely for illustration and are not to be construed as limitations of this invention, as many variation thereof are possible without departing from the spirit and scope thereof.

Fxample I

A toothpaste is made using the procedure taught in U.S.

Patent No. 3,988,433 issued to Benedict on October 26, 1976, which is herein incorporated by reference herein. Componen ₊t Weig^aht %

A. Aqueous

1. Sodium Fl uoride °- ²⁷

2. Sorbitol ²⁶ - ⁵²

3. SASSa) 6.00 4. Peppermint Fl avor -⁶¹ B.

100.00 *PAM Dentifrice is a combination product consisting of 90% aqueous phase and 10% nonaqueous phase. ^a)SASS is a 28% aqueous solution of sodium alkyl sulfate, sold by Sigma Chemical Company, St. Louis, Missouri.

•-^■ PAM is 87% magnesium monoperphthalate, and 13% magnesium bis (hydrogen phthalate), sold by Interox Chemicals, Ltd.,

Warrington, Cheshire, England.

Example II A mouthrinse solution is made by dissolving the following components in water and mixing. The composition of the mouthrinse is as follows:

Citri.c AAci -dΛ 0υ.1ⁱ5o7^/5a 1.000%

Peppermint 0.0522 0.356%

Sodium lauryl sulfateb) 0.0394 0.250%

Saccharin 0.0120 0.076%

Thymol 0.0078 0.050%

Magnasweet 100 0.0038 0.024%

FD&C Blue Dye 0.0001 0.000%

_Water 15.0000 95.238%

_Total 15.7500 100.000% a)PAM is 87% magnesium monoperphthalace, and 13% magnesium bis (hydrogen phthalate), sold by Interox Chemicals, Ltd., Warrington, Cheshire, England. b)sodium lauryl sulfate is sold by Fisher Scientifⁱc, Pittsburgh, Pennsylvania.

A human or lower animal in need of a method of treatment or prevention of microbial diseases of the oral cavity swishes the above mouthrinse composition around the oral cavity twice daily for 30 to 60 seconds during each use.

WHAT IS CLAIMED IS:

Claims

15

1. An oral composition, for treating or preventing microbia diseases of the oral cavity comprising:

(a) a safe and effective amount of a monoperphthalic aci compound; and

(b) a safe and effective amount of thymol; and

(c) a suitable carrier material.

2. An oral composition according to Claim 1, wherein the monoper phthalic acid compound is the magnesium salt of monoperphthali acid.

3. An oral composition according to either of Claims 1 or 2 wherei the pH of the oral composition ranges from about 5 to about 7.

4. An oral composition according to any of Claims 1-3, wherein th pharmaceutically acceptable carrier materials are selected fro the group consisting of flavoring agent, sweetening agent coloring agent, humectant, emulsifying agent, surfactant, abrasive, a buffering agent, and a suitable liquid carrier(s) o mixtures thereof.

5. Oral composition according to Claim 1, wherein said compositio comprises:

(a) from about 0.01% to about 55% of a monoperphthalic aci compound; and

(b) from about 0.025% to about 12.37% thymol; and

(c) a suitable carrier material.

6. An oral composition according to Claim 5, wherein the monoper¬ phthalic acid compound is the magnesium salt of monoperphthalic acid.

7. An oral composition according to either of Claims 5 or 6, wherein the pH of said oral composition is from about 5 to about 6.

S. Dentifrice oral compositions. for treating or preventin microbial diseases of the oral cavity comprising:

(a) from about 0.01% to about 10% of a monoperphthali aci compound; and

(b) from about 0.025% to about 1.5% thymol: and

(c) a suitable carrier material.

9. Dentifrice oral compositions according to Claim 8, wherein the monoperphthal c acid is the magnesium salt of monoperphthalic acid.

10. Dentifrice oral compositions according to either of Claims 8 or 9, wnerein the pharmaceutically acceptable carrier materials are selected from the group consisting of flavoring agent, sweetening agent, coloring agent, humectant, emulsifying agent, surfactant, abrasive, a buffering agent, and a suitable liquid carrier(s) or mixtures thereof.

11. The use of monoperphthali acid for the manufacture of a composition for treating or preventing microbial infections of the oral cavity, said method comprising orally administering to a human or lower animal in need of such treatment or prevention an oral composition accorαing to Claim I; wherein said treatment is from about one second to about 300 seconds.

12. The use of monoperphthalic acid according to Claim 11, wherein said treatment is from about 10 seconds to about 120 seconds.