WO1998020842A2 - Polymyxin compositions and methods for the treatment of periodontal disease and breath malodor - Google Patents

Abstract

The present invention relates to compositions for the topical treatment of periodontal disease and breath malodor, comprising: (a) a safe and effective amount of polymyxin A, B, C, D, E, and salts or mixtures thereof; and (b) a pharmaceutically-acceptable topical, oral carrier. The present invention also relates to a method of treating or preventing periodontal disease and/or breath malodor, in the oral cavity of a human or other animal by topically applying to the oral cavity tissues of the human or other animal, a safe and effective amount of the above composition. Such compositions include toothpastes, tooth gels, tooth powders, mouthwashes, mouth sprays, prophylaxis pastes, dental treatment solutions, lozenges, chewing gums, and the like.

Description

POLYMYXIN COMPOSITIONS AND METHODS FOR THE TREATMENT OF PERIODONTAL DISEASE AND BREATH MALODOR

TECHNICAL FIELD

The present invention relates to compositions and methods for the treatment and prevention of periodontal disease and breath malodor. In particular the present invention relates to compositions for the treatment and prevention of periodontal disease comprising (a) a safe and effective amount of polymyxin, and (b) a pharmaceutically-acceptable topical, oral carrier. The present invention also relates to a method of treating or preventing periodontal disease and/or breath malodor, in the oral cavity of a human or other animal by topically applying to the oral cavity tissues of the human or other animal, a safe and effective amount of the polymyxin composition. Such compositions include toothpastes, tooth gels, tooth powders, mouthwashes, mouth sprays, prophylaxis pastes, dental treatment solutions, lozenges, chewing gums, and the like.

CROSS REFERENCE

This application claims priority under Title 35, United States Code 1 19(e) from Provisional Application Serial No. 60/030,579, filed November 12, 1996.

BACKGROUND OF THE INVENTION "Periodontal disease", as used herein, is a broad term used to describe those diseases which attack the gingiva and the underlying alveolar bone supporting the teeth. Periodontal disease includes a series of diseases exhibiting various syndromes which vary from each other according to the stage or situation of the disease or the age of the patient, and have not been definitely subclassified. The term is used for any inflammatory disease which initially occurs at a marginal gingiva area and finally reaches the alveolar bone. Two common periodontal diseases are gingivitis (inflammation of the gingiva) and periodontitis (manifested by progressive resorption of alveolar bone, increasing mobility of the teeth, and loss of the teeth at advanced stage). Other terms used for various aspects of periodontal disease include "juvenile periodontitis", "acute necrotizing ulcerative gingivitis", and "alveolar pyorrhea." Periodontal disease is characterized by one or more of the following: inflammation of the gingiva, formation of periodontal pockets, bleeding and/or pus discharge from the periodontal pockets, resorption of alveolar bone, loose teeth and/or loss of teeth.

Periodontal disease is generally considered to be caused by or associated with bacteria which are generally present in dental plaque. This bacteria and plaque forms on the surface of the teeth and in the periodontal pocket. The treatment of periodontal disease has primarily focused on the use of broad spectrum antibiotics. For example, Suido et al., tested the antimicrobial activity of 102 antibiotics against 6 periodontopathic bacterial species. Penicillin G was the most effective antibiotic among Penicillins, minocycline among the Tetracyc lines, and clindamycin among Lincomycins. This reference indicates that minocycline is the "most" suitable antibiotic for the treatment of periodontitis due to its strong and broad antimicrobial effectiveness against periodontopathic bacteria. Suido, J. and Yamamoto, Y., Antimicrobial activities of various antibiotics against periodontopathic bacteria, Jpn. J. Oral. Biol, 30: 741-760, 1988.

Sutter et al. tested the susceptibilities of 193 bacterial strains associated with periodontal disease to 14 antimicrobial agents. Sutter indicates that various agents tested may be useful therapeutically. Sutter also indicates that some agents, as in the case of colistin, may be useful as selective agents in culture media. Sutter reports that almost 98% of all of the oral isolates tested were susceptible to 2U or less of pencillin G, indicating that this antibiotic should continue to provide adequate therapy for a variety of oral infections. Sutter, V.L., Jones, M.J., Ghoneim, A.T.M. (1983). Antibiotic Susceptibilities of Bacteria Associated with Periodontal Disease, Antimicrobial Agents and Chemotherapy, Vol. 23(3), p. 483-6.

Loe reports that local administration of antibiotics with a limited spectrum, like polymyxin B and vancomycin, may be useful for the study of the pathogenicity of the different components of the gingival microbial flora. Loe, H., Theilade, E., Jensen, S.B., and Schiott, C.R. (1967). Experimental gingivitis in man III. The influence of antibiotics on gingival plaque development. J. Periodont. Res. 2:282-289.

Jensen et al. found that plaque accumulated more rapidly and appeared more voluminous with vancomycin than polymyxin B, but appeared with both. Jensen, S.B., Loe, H., Schiott, C.R., Theilade, E., and Mikkelsen, I. (1967). The effect of vancomycin and polymyxin B on experimental gingivitis in man. J. Periodont. Res. 2:242-244.

However, despite the teachings of a preference for broad spectrum antimicrobials for the treatment of periodontitis, applicants have surprisingly discovered that treatment with polymyxin, especially polymyxin E (colistin), is effective to reduce or prevent periodontal disease, including gingivitis, periodontitis, plaque, as well as breath odor.

Moreover, the polymyxins potentially avoid staining and the elimination/reduction of healthy flora because they act on gram negative bacteria selectively. Moreover, although polymyxins are known to be cationic, surprisingly the compositions of the present invention comprising polymyxins are stable. This is true for especially dentifrice compositions, despite the presence anionic components, such as surfactants, saccharides, fluorides, abrasives, etc. Lastly, applicants have unexpectantly recognized that despite the larger size of the polymyxin molecules, application above the gum line also provides efficacy below the gumline.

Therefore, an object of the present invention is to provide topical, stable oral compositions comprising polymyxin for the treatment of periodontal disease and/or breath malodor.

A further object of the present invention is to provide such compositions and treatment to minimize systemic (blood) concentration of polymyxins.

All of the above references are incorporated herein by reference. SUMMARY OF THE INVENTION

The present invention relates to compositions for the topical treatment and prevention of periodontal disease and breath malodor comprising: (a) a safe and effective amount of polymyxin A, B, C, D, E and pharmaceutically acceptable salts thereof, and mixtures thereof; and (b) a pharmaceutically-acceptable topical, oral carrier. The present invention also relates to a method of treating or preventing periodontal disease and/or breath malodor, in the oral cavity of a human or other animal by topically applying to the oral cavity tissues of the human or other animal, a safe and effective amount of the above composition. Such compositions include toothpastes, tooth gels, tooth powders, mouthwashes, mouth sprays, prophylaxis pastes, dental treatment solutions, lozenges, chewing gums, and the like.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to compositions for the topical treatment of periodontal disease comprising: (a) a safe and effective amount of polymyxin A, B, C, D, E and pharmaceutically acceptable salts thereof, and mixtures thereof; and (b) a pharmaceutically-acceptable topical, oral carrier. The present invention also relates to a method of treating or preventing periodontal disease and/or breath malodor, in the oral cavity of a human or other animal by topically applying to the oral cavity tissues of the human or other animal, a safe and effective amount of the above composition. Such compositions include toothpastes, tooth gels, tooth powders, mouthwashes, mouth sprays, prophylaxis pastes, dental treatment solutions, lozenges, chewing gums, and the like.

"Safe and effective amount", as used herein, means an amount of a substance high enough to provide a significant positive modification of the condition to be treated, but low enough to avoid serious side effects (at a reasonable benefit/risk ratio), within the scope of sound medical judgment. A safe and effective amount of the substance will vary with the particular condition being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, and like factors. "Treat" and "treatment", as used herein, mean to attempt to slow the progress of or to reverse the symptoms of the condition being addressed.

"Pharmaceutically-acceptable topical, oral carrier", as used herein, denotes a carrier for the polymyxin which results in a composition which is administered topically to the oral cavity, held therein for a period of time, and then is largely expectorated rather than being swallowed.

"Topical application", as used herein, means applied so as to contact exposed surfaces of the oral cavity with a composition administered to the exposed surfaces of the oral cavity, preferably by swishing around in the mouth or brushing onto the teeth and/or over gum surfaces. The composition or compound is then preferably largely expectorated.

Polymyxins are known nonabsorbable, cyclic polypeptide antimicrobials that bind to and damage the cell membrane of gram-negative bacteria specifically. In addition, polymyxins bind to the Lipid A portion of bacterial endotoxin and neutralize the biological effects of this endotoxin. Rogers, M.J., Cohen, J. Comparison of the binding of gram- negative bacterial endotoxin by polymyxin B sulphate, colistin sulphate and colistin sulphomethate sodium. Infection 1986, 14(2), p. 79-81. Woodall, I.R., Comprehensive Dental Hygiene Care. 4th edition, 1993, Mosbly. Fine, D.H., Mendieta, C, Barnett, M.L., Furgang, D. Naini, A., and Vincent, J.W. Endotoxin Levels in Periodontally Healthy and Diseased Sites: Correlation with Levels of Gram-Negative Bacteria. J. Perio. Nov 1992, p. 897-901. Jenkins, W.M., MacFarlane, T.W., Gilmour, W.H., Ramsay, I., and MacKenzie, D. Systemic metronidazole in the treatment of periodontitis. J Clin Perio. 1989, Aug, 16(7), p. 443-50. Gallay, P., Jongeneel, C.V., Burnier, M., Baumgartner, J.D., Glauser, M.P., and Heumann, D. Short time exposure to lipopolysaccharide is sufficient to activate human monocytes. J. Immuno. 150(1 1), p. 5086-5093. All of the above references are incorporated herein by reference.

Polymyxins are generally described in Hoeprich, P.D., The Polymyxins, Medical Clinics of North America, p. 1257, 54 (5), Sept. 1970, which is herein incorporated by reference in its entirety. All of the polymyxins are branched cyclic decapeptides that are cationic and appear to be antibiotic through surfactant activity. They are not qualitatively distinct from one another with respect to either spectrum or toxicity. For example, all polymyxins have no clinically useful activity against gram-positive bacteria. They do exhibit, however, definite but clinically insignificant antifungal activity, and selective activity against gram-negative bacilli such as Pseudomonas aeruginosa, Escherichia coli, Klebsiella sp., Enterobacter sp., Salmonella sp., Shigella sp., Vibrio sp., Pasteurella sp., Hemophilus sp., and Bordetella sp.

The polymyxins are a group of closely related antibiotics including substances known as circulins and colistins. They are all cyclic polypeptide products of bateria, namely Bacillus sp. Minor, R.W., ed.: Antibiotics derived from Bacillus polymyxin. Ann. N. Y. Acad. Sci., 51 :853, 1949, which is herein incorporated by reference. The chemical characteristics include a fatty acid, L-threonine, and α,γ-diaminobutyric acid residues. The polymyxins can be distinguished from each other by the presence of the amino acids D- leucine, L-leucine, L-isoleucine, D-phenylalanine, D-valine, and D-serine.

The antibiotic activity is related to ring size. The two analogs of polymyxin B with eight amino acid residues in the ring have about one-tenth the activity of the corresponding cyclic analog with seven amino acid residues. The antimicrobial activity is also related to the basic amino acid groups. Acetylation and carbobenzoxylation of polymyxins can lead to totally inactive material. Principles of Medicinal Chemistry, 2nd ed. 1981, pp. 778-779.

Polymyxin structures are disclosed in The Merck Index, 10th Ed. (1976), No. 2438; colistin (Merck Index, No. 2442); Principles of Medicinal Chemistry, 2nd Ed. 1981, p. 779, all of which are herein incorporated by reference in their entirety. The term "polymyxin" includes Ai , A2, Bj , B2, D1 , D2, E_j (colistin A), E2 (colistin B), circulin A, and pharmaceutically acceptable salts thereof, and mixtures thereof. For convenience, these polymyxins will be referred to herein as A (A\ and/or A2), B (Bj and/or B2), C (circulin), D (Dj and/or D2), and E (E\ and/or E2; colistin A and/or colistin B). (It is reported that polymyxin M is identical to polymyxin A. Wilkinson, S. and Lowe, L.A., Structure of the polymyxin A and the question of identity with polymyxin M. Nature, 212:31 1, 1966, which is herein incorporated by reference.)

Polymyxin salts include but are not limited to the sulfate salt, (i.e. polymyxin B sulfate, colistin sulfate, etc.), sulfomethyl derivatives such as colistin sulphomethate sodium, colistimethate sodium, sold under the tradename of Coly-Mycin® M, Parke-Davis, etc. Colistin sulfate is sold under the tradename of Coly-Mycin® S, Parke-Davis.

One aspect of the present invention is compositions comprising polymyxin. "Safe and effective amount" of polymyxin, as used herein, means that the compositions of the present invention comprise from about 0.001% to about 20% by weight, preferably from about 0.02% to about 4%, more preferably from about 0.04% to about 2%, even more preferably from about 0.1% to about 1%, by weight of the composition, of polymyxin.

For mouthrinse, mouthwash and dental solutions, preferably these compositions comprise from about 0.001% to about 5% by weight, preferably from about 0.005% to about 1%, more preferably from about 0.01% to about 0.5%, still more preferably from about 0.5%) to about 0.2% by weight of the composition, of polymyxin.

When mouthwashes and dental solutions having the above concentrations of polymyxin are used in the oral cavity, the effective concentrations of polymyxin solutions which contact the mucosal surfaces are essentially the same as given above, because dilution of the mouthwash or dental solution with saliva is minimal. On the other hand, it is known that dentifrices, when used in the mouth, are mixed with substantial amounts of saliva; the dilution amount is about 3: 1 saliva to dentifrice. (See U.S. Pat. No. 4,358,437, issued November 9, 1982 to Duke, and U.S. Pat. No. 3,956,480, issued May 1 1, 1976 to Dichter et al.)

Therefore, preferred concentrations of polymyxin in a dentifrice are about four times the above preferred mouthwash concentrations: from about 0.004% to about 20% by weight, preferably from about 0.02% to about 4%, more preferably from about 0.04% to about 2%, still more preferably from about 0.2% to about 0.8%) of polymyxin by weight of the composition.

The pH of the compositions of the present invention for which pH can be measured is preferably from about 2 to about 10, more preferably from about 4 to about 7, more preferably still from about 5 to about 6.

Pharmaceuticallv-Acceptable Topical. Oral Carrier

Components of the pharmaceutically-acceptable topical, oral carrier are suitable for administration to the oral cavity of a human or lower animal and are compatible with one another and the other components, especially polymyxin, used in the oral compositions of the present invention.

The term "compatible" as used herein, means that the components of the compositions are capable of being commingled with one another, in a manner such that there is no interaction which would substantially reduce the efficacy of the oral composition under ordinary use conditions.

Surprisingly, although polymyxins are known to be cationic, the compositions of the present invention, comprising polymyxins, are stable. This is true, especially for dentifrice compositions, despite the presence anionic components, such as surfactants, saccharides, fluorides, abrasives, etc.

Preferred pharmaceutically-acceptable, topical, oral carriers thus provide the desired characteristics for toothpaste, tooth gels, tooth powders, mouthwashes, mouth sprays, prophylaxis pastes, dental treatment solutions, lozenges, chewing gums, and the like. The pharmaceutically-acceptable topical, oral carriers of the present invention comprise components typically used in such compositions which are well known to a skilled practitioner. Such components include, but are not limited to anticaries agents, antiplaque agents, anticalculus agents, dental abrasives, surfactants, flavoring agents, sweetening agents, binders, humectants, thickening agents, buffering agents, preservatives, coloring agents and pigments, ethanol and water.

Water is an optional component of the pharmaceutically-acceptable topical, oral carriers of the compositions of the present invention. Water employed in the preparation of the commercially suitable compositions should preferably be of low ion content and free of organic impurities. Water preferably comprises from about 2% to about 99%, more preferably from about 20% to about 95%> of the compositions of the present invention. When in the form of toothpaste, the compositions preferably are from about 2% to about 45%, more preferably from about 30% to about 40%, water, while mouthwashes are preferably from about 45% to about 95%, more preferably from about 75% to about 90%, water.

Dental abrasives useful in the pharmaceutically-acceptable topical, oral carriers of the compositions of the present invention include many different materials. The material selected must be one which is compatible within the composition of interest and does not excessively abrade dentin. Suitable abrasives include, for example, silicas including gels and precipitates, insoluble sodium polymetaphosphate, hydrated alumina, and resinous abrasive materials.

A class of preferred abrasives for use in the subject compositions is the particulate thermo-setting polymerized resins as described in U.S. Patent No. 3,070,510 issued to Cooley & Grabenstetter on December 25, 1962. Suitable resins include, for example, melamines, phenolics, ureas, melamine-ureas, melamine-formaldehydes, urea- formaldehydes, melamine-urea-formaldehydes, cross-linked epoxides, and cross-linked polyesters.

Silica dental abrasives are also preferred in the compositions of the present invention. The silica abrasive polishing material generally has an average particle size ranging between about 0.1 and about 30 microns, preferably between 5 and 15 microns. The abrasive can be precipitated silica or silica gels such as the silica xerogels described in U.S. Patent No. 3,538,230 issued to Pader & Wiesner on March 2, 1970, and in U.S. Patent No. 3,862,307 issued to DiGuilio on January 21, 1975. Preferred are the silica xerogels marketed under the tradename Syloid® by the W. R. Grace & Co., Davison Chemical Division. Preferred precipitated silica materials are those marketed by the J.M. Huber Corporation under the tradename Zeodent®, particularly the silica carrying the designation Zeodent 119®. These silica abrasives are described in U.S. Patent No. 4,340,583 issued to Wason on July 29, 1982.

Mixtures of abrasives can be used. All of the above patents regarding dental abrasives are incorporated herein by reference.

The total amount of abrasive in dentifrice compositions of the present invention preferably range from about 10% to about 70% by weight; toothpaste preferably contain from about 10% to about 50%, more preferably from about 10% to about 30%, by weight. Solution, mouth spray and mouthwash compositions of the present invention may contain quantities of abrasive as low as 0%. Flavoring agents are preferred in the pharmaceutically-acceptable topical, oral carriers of the compositions of the present invention in order to make them more palatable. Typical flavoring agents include methanol, oil of wintergreen, oil of peppermint, oil of spearmint, oil of sassafras, and oil of clove. If present, flavoring agents are generally included in the subject compositions in amounts of from about 0.04% to about 2% by weight.

Sweetening agents are also preferred in the pharmaceutically-acceptable topical, oral carriers of the compositions of the present invention in order to make them more palatable. Typical sweetening agents include saccharin salts, dextrose, laevulose, thaumatin, aspartame, D-tryptophane, dihydrochalcones, acesulfame and cyclamate salts, especially sodium cyclamate and sodium saccharin. If present, sweetening agents are generally included in the subject compositions in amounts of from about 0.01% to about 5% by weight.

Another optional component of the pharmaceutically-acceptable topical, oral carriers of the compositions of the present invention is a humectant. The humectant serves to keep toothpaste compositions from hardening upon exposure to air, and to give mouthwash and toothpaste compositions a moist feel to the mouth. Certain humectants can also impart desirable sweetness of flavor to mouthwash and toothpaste compositions. The humectant, on a pure humectant basis, generally comprises from about 0% to about 70%, preferably from about 0% to about 55%, by weight of the compositions herein. Suitable humectants for use in compositions of the present invention include edible polyhydric alcohols such as glycerin, sorbitol, xylitol, polyethylene glycol, and propylene glycol, especially sorbitol and glycerin.

Buffering agents are another optional component of the pharmaceutically-acceptable topical, oral carrier of the compositions of the present invention. The buffering agents serve to retain the pH of the compositions within the preferred range. The buffering agent generally comprises from about 0% to about 10%, preferably from about 0.2% to about 5%, by weight of the compositions herein. Suitable buffering agents for use in compositions of the present invention include soluble phosphate salts.

Other optional components of the pharmaceutically-acceptable topical, oral carriers of the compositions of the present invention are preservatives. The preservatives prevent microbial growth in the compositions. Suitable preservatives include methylparaben, propylparaben, benzoates and ethanol. If the preservative is ethanol, it generally comprises from 0%) to about 35%, preferably from about 5%> to about 15%, of the compositions herein. Other preservatives generally comprise from about 0%> to about 5%, preferably from about 0.1% to about 2%, by weight of the compositions herein.

Binders and thickening agents may be used in the pharmaceutically-acceptable topical, oral carriers of the compositions of the present invention, particularly in toothpaste compositions. Preferred binders and thickening agents include, for example, carrageenan (e.g., Irish moss, Viscarin TP-5 which is an iota carrageenan), cellulose derivatives (e.g., hydroxyethyl cellulose, sodium carboxymethyl cellulose, sodium carboxymethyl hydroxypropyl cellulose), carboxyvinyl polymers (carbomers), natural gums (e.g., gum karaya, gum arabic, gum tragcanth), polysaccharide gums (e.g., xanthan gum), fumed silica, and colloidal magnesium aluminum silicate. If present, these binders and thickening agents are generally present in the compositions of the present invention in amounts of from about 0.1% to about 5% by weight.

Compositions of the present invention may also contain a surfactant. Suitable surfactants are those which are reasonably stable and preferably form suds through the pH range of the compositions. Surfactants useful as sudsing agents may be soaps, and anionic, nonionic, cationic, zwitterionic and amphoteric organic synthetic detergents, and compatible mixtures thereof. Surfactants of these types are described more fully in U.S. Patent No. 3,959,458 issued to Agricola, Briner, Granger & Widder on May 25, 1976, which is incorporated herein by reference. Such surfactants are generally present in the compositions of the present invention at a level of from about 0% to about 10%> by weight. Surfactants may also be used as solubilizing agents to help retain sparingly soluble components, e.g., some flavoring agents, in solutions. Surfactants suitable for this purpose include polysorbates and poloxamers.

The compositions of the present invention may also comprise an anticaries agent. Preferred anticaries agents are water-soluble fluoride ion sources. Fluoride ions also generally help stabilize pyrophosphate (generally an anticalculus agent) in the oral cavity, thus enhancing the benefits provided by any soluble pyrophosphate included in the compositions. The number of such fluoride ion sources is great and includes those disclosed in U.S. Patent No. 3,535,421 issued October 20, 1970 to Briner & Widder, incorporated herein by reference. Preferred fluoride ion source materials include: sodium fluoride, potassium fluoride, and sodium monofluorophosphate and mixtures thereof. Sodium fluoride is the preferred fluoride source. The amount of the fluoride ion source in the oral compositions of the present invention, if present, is preferably sufficient to provide from about 0.005%) to about 0.35%, more preferably from about 0.05% to about 0.3% of fluoride ions in the compositions.

Antimicrobial antiplaque agents can also optionally be present in the oral compositions of the present invention, on the condition that they are compatible with the polymyxin. Such agents may include Triclosan, 5-chloro-2-(2,4-dichlorophenoxy)-phenol, as described in The Merck Index. 10th ed. (1976), p. 1381; U.S. Patent No. 3,506,720; and European Patent Application No. 0,251,591 of Beecham Group, PLC, published January 7, 1988, chlorhexidine, (Merck Index. No. 2090), alexidine (Merck Index. No. 222); hexetidine (Merck Index. No. 4624); sanguinarin (Merck Index. No. 8320); benzalkonium chloride (Merck Index. No. 1066); salicylanilid (Merck Index. No. 8299); domiphen bromide (Merck Index. No. 341 1); cetylpyridinium chloride, (CPC) (Merck Index. No. 2024); tetradecylpyridinium chloride, (TPC); N-tetradecyl-4-ethylpyridinium chloride (TDEPC); octenidine; delmopinol, octapinol, and other piperidino derivatives; nicin preparations; zinc/stannous ion agents; antibiotics such as augmentin, amoxicillin, tetracycline, doxycycline, minocycline, and metronidazole; and peroxides, such as cylium peroxide, hydrogen peroxide, and magnesium monoperthalate and its analogs as described in U.S. Patent No. 4,670,252; and analogs and salts of the above antimicrobial antiplaque agents. If present, the antimicrobial antiplaque agents generally comprise from about 0.1% to about 5%> by weight of the compositions of the present invention. Preferably, for ease of processing, to lower formulation complexity, and to reduce cost of formulation, the compositions of the present invention do not contain additional antimicrobial antiplaque agents, other than polymyxin as disclosed herein.

Nutrients can also be present in oral compositions of the present invention, on condition that they are compatible with the polymyxin. Such agents may include folate, retinoids (Vitamin A), Vitamin C, Vitamin E and zinc. If present, the nutrients generally comprise from about 0.001%) to about 10%> by weight of the compositions of the present invention.

Compositions of the present invention may also include one or more anticalculus agents, on the condition that they are compatible with the polymyxin. Anticalculus agents which may be useful in the compositions of the present invention include pyrophosphates or poly phosphates such as those disclosed in U.S. Patent No. 4,590,066 issued to Parran & Sakkab on May 20, 1986; polyacrylates and other polycarboxylates such as those disclosed in U.S. Patent No. 3,429,963 issued to Shedlovsky on February 25, 1969 and U.S. Patent No. 4,304,766 issued to Chang on December 8, 1981 ; and U.S. Patent No. 4,661,341 issued to Benedict & Sunberg on April 28, 1987; polyepoxysuccinates such as those disclosed in U.S. Patent No. 4,846,650 issued to Benedict, Bush & Sunberg on July 1 1, 1989; ethylenediaminetetraacetic acid as disclosed in British Patent No. 490,384 dated February 15, 1937; nitrilotriacetic acid and related compounds as disclosed in U.S. Patent No. 3,678,154 issued to Widder & Briner on July 18, 1972; polyphosphonates as disclosed in U.S. Patent No. 3,737,533 issued to Francis on June 5, 1973, U.S. Patent No. 3,988,443 issued to Ploger, Schmidt-Dunker & Gloxhuber on October 26, 1976 and U.S. Patent No. 4,877,603 issued to Degenhardt & Kozikowski on October 31, 1989; all of these patents are incorporated herein by reference. If present, the anticalculus agents generally comprise from about 0.2% to about 13%, preferably from about 0.4%) to about 6% by weight of the compositions of the present invention.

Preferred compositions of the present invention are in the form of toothpaste. Components of such toothpaste generally include a dental abrasive (from about 10%_> to about 50%>), a surfactant (from about 0.5% to about 10%o), a thickening agent (from about 0.1% to about 5%), a humectant (from about 10% to about 55%>), a flavoring agent (from about 0.04% to about 2%), a sweetening agent (from about 0.1% to about 3%), a coloring agent (from about 0.01% to about 0.5%>) and water (from about 2%> to about 45%). Such . toothpaste may also include one or more of an anticaries agent (from about 0.05% to about 0.3%) as fluoride ion), an anticalculus agent (from about 0.1% to about 13%), and an antiplaque agent (from about 0.1% to about 5%).

Other preferred compositions of the present invention are mouthwashes and mouth sprays. Components of such mouthwashes and mouth sprays include water (from about 45% to about 95%), ethanol (from about 0%> to about 25%), a humectant (from about 0%> to about 50%>), a surfactant agent (from about 0.01% to about 7%), an flavoring agent (from about 0.04%) to about 2%>), a sweetening agent (from about 0.1% to about 3%), and a coloring agent (from about 0.001% to about 0.5%). Such mouthwashes and mouth sprays may also include one or more of an anticaries agent (from about 0.05%) to about 0.3%> as fluoride ion), an anticalculus agent (from about 0.1% to about 3%), and an antiplaque agent (from about 0.1 %> to about 5%).

Other preferred compositions of the present invention are dental solutions. Components of such dental solutions generally include water (from about 90% to about 99%), preservative (from about 0.01% to about 0.5%), thickening agent (from about 0%> to about 5%), flavoring agent (from about 0.04% to about 2%>), sweetening agent (from about 0.1% to about 3%), and surfactant (from 0% to about 5%).

Another aspect of the present invention involves methods of treating periodontal disease including gingivitis, periodontitis, plaque, and breath malodor, by the topical application of the compositions described above, comprising a safe and effective amount of polymyxin, to the mucosal tissues of the oral cavity, especially the gingival mucosa. Preferred are methods for treating periodontal disease and breath malodor by topical application of a safe and effective amount of polymyxin to gingival mucosa.

The topical application of polymyxin to the oral cavity tissues avoids the adverse side effects associated with systemic concentrations of polymyxins.

The methods of the present invention preferably comprise contacting a composition of the present invention with oral cavity tissue afflicted for at least about 10 seconds, preferably from about 15 seconds to about 10 minutes, more preferably from about 20 seconds to about 5 minutes, more preferably from about 30 seconds to about 60 seconds The composition is then preferably expectorated. Typically, this is achieved by conventional methods of tooth brushing, rinsing the mouth with mouthwash or dental solution, etc. The composition is placed in the mouth, swished around or brushed on the teeth and outer gum surfaces and largely expectorated.

All percentages listed herein, are by weight of the composition, unless otherwise indicated.

Preferably, the compositions of the present invention are essentially free of morpholinoamino alcohols and corticosteroids.

The following examples are provided as illustrations of the composition and methods of the present invention, but are not limitations of the scope of the present invention.

Examples 1 to 3

Examples of toothpaste and tooth gel compositions of the present invention are made by conventional processes by mixing the following:

Example 1 Example 2

(Wt. %) (Wt. %)

Sorbitol 42.00 35.00

Saccharin Sodium 0.13 0.20

FD&C Blue (l% soln) 0.05 0.05

Precipitated Silica 20.00 25.00

Sodium Fluoride — 0.24

Flavor 0.90 1.50

Purified Water qs qs

Sodium Alkyl Sulfate 1.00 1.20

Phosphoric Acid 0.40 —

Carbomer 940 0.25 0.25

Xanthan Gum 0.50 0.65

Titanium Dioxide 0.50 0.50

Colistin 0.05 0.10

Example 3

(Wt. %)

Water qs

Sorbitol (70%) 59.237

Colistin 2.00 Sodium Fluoride 0.243 Trisodium phosphate 1.45

Monosodium phosphate 0.59

Sodium Saccharin 0.13

Sodium Alkyl Sulfate 4.00

Flavor 0.10

Silica 20.00

Natrosol 250 1.20

Titanium Dioxide 1.00

FD&D Blue #l 1% Soln. 0.05

Examples 4 to 6

Examples of mouthwash and dental solution compositions of the present invention are made by conventional processes by mixing the following:

Example 4 Example 5

(Wt. %) (Wt. %)

Colistin 0.10 0.01

Ethanol 12.00 15.00

Glycerin 10.00 12.00

Dibasic Sodium Phosphate

Heptahydrate 0.07 0.48

Saccharin Sodium 0.08 0.08

Monobasic Sodium Phosphate

Monohydrate 2.03 1.82

Polysorbate 80 0.33 0.33

FD&C Blue (1% Soln) 0.02 0.02

Flavor 0.15 0.15

Purified Water qs qs

Example 6 (Wt. %)

Colistin 0.20

Saccharin Sodium 0.05 Polysorbate 80 0.3 Methyl Paraben 0.2 Propyl Paraben 0.10

Flavor 0.10

Purified Water qs

Example 7

An example of a dental solution of the present invention is made by conventional processes by mixing the following:

(Wt. %)

Water qs

Colistin 0.15

Flavor 0.10

Polysorbate 80 0.25

Saccharin Sodium 0.05

Methylparaben 0.20

Propylparaben 0.10

Examples 8 and 9

Examples of toothpaste compositions of the present invention are made by conventional processes by mixing the following:

Example 8 Exampl

Ingredients (Wt. %) (Wt. %)

Sorbitol 37.20 37.20

Glycerine 19.00 19.00

Polyethylene Glycol 600 3.00 3.00

Sodium Saccharin 0.17 0.17

Precipitated Silica 20.00 20.00

Sodium Fluoride 0.24 0.24

Flavor 0.90 0.90

Purified Water qs qs

Sodium Alkyl Sulfate 1.00 1.00

Monobasic Sodium

Phosphate, Monohydrate 5.00 5.00

Fumed Silica 2.00 2.00 Carboxymethylcellulose 0.30 0.30

Titanium Dioxide 0.50 0.50

Colistin 0.15 1.00

Example 10

An example of a lozenge composition of the present invention is made by conventional processes by mixing the following:

Ingredients (Wt. %>)

Colistin 1.20

Sorbitol 90.50

Hydroxypropyl Cellulose 5.00

Flavor 0.80

Magnesium Stearate 2.5

Example 11

An example of a chewing gum composition of the present invention is made by conventional processes by mixing the following:

Component (Wt. %) Colistin 1.00

Gum Base 20.00 Plasticizer 2.00

Glycerin 10.00 Sweetener 1.00

Flavor 1.00

Sorbitol Solution 20.00 Sorbitol Powder qs

The Colistin of examples 1 to 1 1 can be substituted with any one of the following: Polymyxin A, B, C, D, and salts thereof.

While particular embodiments of the present invention have been described, it will be obvious to those skilled in the art that various changes and modifications to the present invention can be made without departing from the spirit and scope of the invention. It is intended to cover, in the appended claims, all such modifications that are within the scope of this invention.

Claims

What is claimed is;

1. A topical oral care composition for the prevention or treatment of periodontal disease and oral malodor comprising:

(a) a safe and effective amount of polymyxin E and pharmaceutically acceptable salts thereof, and mixtures thereof; and

(b) a pharmaceutically-acceptable topical, oral carrier.

2. A dentifrice composition for the prevention or treatment of periodontal disease and oral malodor comprising:

(a) from 0.02% to 4% by weight of the composition of polymyxin E and pharmaceutically acceptable salts thereof, and mixtures thereof; and

(b) from 10% to 30% by weight of the composition of an abrasive.

3. A mouthrinse, mouthwash, mouth spray or dental solution composition for the prevention or treatment of periodontal disease and oral malodor comprising:

(a) from 0.005% to 1% by weight of the composition of polymyxin E and pharmaceutically acceptable salts thereof, and mixtures thereof; and

(b) from 0.01% to 5% by weight of the composition of a flavoring or sweetening agent.

4. A topical oral care composition for the prevention or treatment of periodontal disease and oral malodor comprising:

(a) a safe and effective amount of a polymyxin selected from the group consisting of polymyxin A, polymyxin B, polymyxin C, polymyxin D and pharmaceutically acceptable salts thereof, and mixtures thereof; and

(b) a pharmaceutically-acceptable topical, oral carrier.

5. The composition of claim 1, 4 wherein the composition comprises from 0.01%) to 1% by weight of the composition of polymyxin.

6. A dentifrice composition for the prevention or treatment of periodontal disease and oral malodor comprising:

(a) from 0.02% to 4% by weight of the composition of a polymyxin selected from the group consisting of polymyxin A, polymyxin B, polymyxin C, polymyxin D and pharmaceutically acceptable salts thereof, and mixtures thereof; and (b) from 10%) to 30% by weight of the composition of an abrasive.

7. The composition of claim 2 or 6 wherein the composition comprises from 0.2% to 0.8% by weight of the composition of polymyxin.

8. A mouthrinse, mouthwash, mouth spray or dental solution composition for the prevention or treatment of periodontal disease and oral malodor comprising:

(a) from 0.005%> to 1% by weight of the composition of a polymyxin selected from the group consisting of polymyxin A, polymyxin B, polymyxin C, polymyxin D and pharmaceutically acceptable salts thereof, and mixtures thereof; and

(b) from 0.01% to 5% by weight of the composition of a flavoring or sweetening agent.

9. The composition of claim 3 or 8 wherein the composition comprises from 0.01%) to 0.5%) by weight of the composition of polymyxin.

10. The composition of claim 1, 2, 3, 4, 6 or 8 wherein the composition has a pH of from 4 to 7.