NZ206200A

NZ206200A - Oral compositions containing 1-imidazoyl-1(parachlorophenoxy)-3,3-dimethyl-butanone

Info

Publication number: NZ206200A
Application number: NZ206200A
Authority: NZ
Inventors: A Gaffar; C B Davis; M L Vasers
Original assignee: Colgate Palmolive Co
Priority date: 1982-11-17
Filing date: 1983-11-08
Publication date: 1985-11-08
Also published as: ZW24183A1; FR2535970A1; DE3340878A1; FI834194A0; FI78832B; IE832693L; GR79100B; GB8330671D0; FI834194A; SE8306305D0; AU550144B2; HK54491A; CH656528A5; ATA403183A; IT1206160B; GB2130089B; DE3340878C2; PH19311A; MX157553A; MY8700950A

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £06200 *0 ^ 7 NO Priority Date{$): .. J,7.7 iX r&fk- Complete Specification Filed: {t Class: M.t'Ky./J.k;.. ftMfejJkP * riBWigS? Publication Date: Iwr... P.O. Journal. Nx Z.... Patents Form No. 5 Number PATENTS ACT 1953 Dated COMPLETE SPECIFICATION ORAL PRODUCT FOR CONTROLLING GINGIVITIS J YlWe COLGATE-PALMOLIVE COMPANY a corporation organised under the laws of the State of Delaware, United States of America of 300 Park Avenue, New York, New York 10022, United States of America do hereby declare the invention for which //we pray that a Patent may be granted to>ree/us. and the method by which it is to be performed, to be particularly described in and by the following statement: 1 (Followed by page la) *°<*o0 Background of the Invention This invention relates to an antibacterial-containing oral composition which promotes oral hygiene, controls plaque formation, gingivitis and periodontitis, by the topical application to the oral cavity, of a mouthrinse or dentifrice containing an effective amount of the antigingivitis agent, 1-imidazoyl-l-(p-ohlorophenoxy) 3-3-dimethyl 2-butanone (Climbazol« by Bayer), eg Periodontitis,, or pyorrhea, is a disease affecting the supporting tissues of the teeth including the gingiva, the in membrane lining the sockets/which the teeth lie, and the bones surrounding the teeth* The disease may initially be associated with conditions of oonstant irritation of the gingiva by dental plaque, food impaction, poor dental restorations, traumatic occlusion, or chemical irritants. The gums may be seriously harmed by deposits of dental plaque, a combination of minerals and bacteria found in the mouth* The bacteria associated with plaque can secrete enzymes and endotoxins which can irritate the gums and cause an inflammatory gingivitis. As the gums become increasingly irritated by this process they have a tendency to bleed, lose their toughness and resiliency, and separate from the teeth, leaving periodontal pockets in which debris, secretions, more bacteria and toxins further accumulate. It is also possible for food to accumulate in these pockets, thereby providing nourishment for increased growth of bacteria and production of endotoxins and destructive enzymes. The pus that forms in this process is capable of destroying gum and bone tissue. Bacteria are generally found to be present during the active stages of periodontal disease* Such organisms as anaerobic gram negatives are usually present, and are found in the purulent discharge aa well as in the involved tissue, and may be absorbed into the general aystea through the lymphatics or venous blood stream. The progression of the pyorrheie process usually begins with gingivitis, initiating at the aargina of the guas, in which the gingiva become more tender and sensitive, and appear flabby, inflamed and swollen* Periodontal pockets become apparent, and infection takes place in these pockets* Effective control and prevention of gingivitis accordingly constitutes a desideratua for the prevention of further periodontal diseases* A nultitude of materials have been previously proposed and employed for controlling oral diseases and malfunctions suoh as plaque, calculus, tartar, caries, halitosis, and periodontal diseases such as gingivitis and pyorrhea, but none have been entirely satisfactory* For example, oral compositions containing anti-inflaauaatory agents which reduce the symptoms of swelling, bleeding and inflaanatlon associated with gingivitis, by preventing tartar formation and/or countering oral calculus, include an imidassole such as hlstadlne or histamine as disclosed in U* 3* Patent No* 3»497,591| a dichloro-2-guanidino benzixaidazole, as disclosed in U* 3* Patent No* 3*523,1541 carragheenln as -3- 206200 disclosed, in U. S« Patent No, 4»029j760} a mixture of tranoxamlc acid and folic acid, as disclosed in New Zealand Patent Specification No. 196,077 and tannic acid, as disclosed in U.S. Patent No. 4,273,7 58. All of aforesaid agents are non-antimicrobial. U, 3. Patent No. 3>577»520 also discloaes a dentifrice composition containing 5,5-dlaryl-2,iK-i»idaEolidinediones in the treatment of pyorrhea, by repairing the lesions of parodontosis, U» S. Patent No. 3»9H*133 discloses an antibacterial composition effective against both gram positive and grata negative bacteria, comprising an imidazole derivative, which la a bis(imi-daaollua quaternary salt), useful in mouthwashes, toothpastes and dental gels as a method of inhibiting the formation of dental plaque or in the prevention of gingivitis. U„ S. Patent No. 4,243*670 discloses imidaaolium derivatives having strong antimicrobial activity against dermatophytes, yeasts, molds, biphase fungi and gram positive ooccij and useful a3 an additive to oral hygiene products such as toothpastes and mouthwashes, to avoid miorobially caused infections of the jauQoaa of the mouth and aa a prophylactic against infection It Is also known in the art, that certain gram negative C~ .'*• 1 r -T* 1 ■"> 71 £T [ J,! gJU i t CO I -4- 2o organisms such as Baoteriodes asaccharolyticus or Baoteriodes gingivalis are associated with adult periodontitis* By eliminating these and other gram negative anaerobes fron the plaque accumulated on the gingival tissues, effective control and prevention of periodontal disease can be achieved. Accordingly, it has been shown by Listgarton et al in the J, Periodont. Res, 1^: 65-75 (1979)» that metronidasole, N02- CEjCHgOH \ \-CH. given systemically causes the elimination of said gram negative anaerobes from the plaque* This was substantiated by Heijl and Lindhe in the J« Clinical Periodontology 6, 197-209 (1979)* wherein is shown that metronidazole is effective in reducing plaque and gingivitis scores in doga} and by Loesche et al in the J, of Clinical Periodontology, fli 29-44 (1981)* wherein it is -5- . 2" shown that metronidazole is affective in reducing the anaerobic B. asaccharolyticus count in plaque removed from periodontal pockets, concommitantly, with a substantial reduction in pooket depth and considerable gain in apparent attachment* However, metronidazole, sold under the tradename of Flagyl, is carcinogen* ic (Physician Reference Handbook p« 1761) and cannot be used indiscriminately. It has now been found that another derivative of imidazole is effective against said gram negative anaerobic organisms, which is nonmutagenlo, noncarcinogenic and can be topically applied to the oral cavity in the treatment of gingivitis,' namely, l-imidazoyl-l-(p-chlorophenoxy)3-3-dimethyl 2-butanone. The imidazoyl ketones such as l-imidazoyl-l-(4 chlorophenoxy)-3,3-dimethyl 2-butanone, are disclosed in U.S. Patent Nos. 3f9l2,142 and 3»9Q3*287 an anti-aycotic agent, useful in pharmaceutical compositions Including pastes, gels, creams, aqueous and nonaqueous suspensions. Its action against pathogenic protozoa, gram positive and negative bacteria such as Staphlococoi and Escherichia ooli is also noted herein* -6— British Patent No. 1,502,144 discloses hair or skin treating compositions, effective against Pityrosporum ovale, containing the imidazoyl ketone antimycotic agents dispersed in a dermatologically acceptable carrier which contains a detergent-active compound. These compositions are in the form of creams, aerosols, powders and liquids. The prior art discloses the 1-imi-dazoyl-l-(4-chlorophenoxy)-3,3-dimethyl 2-butanone in a fungicidal composition, either in dry form, as a dispersion in water, water-in-oil or oil-in-water omulsion or a spray, useful for protecting plaster coatings, dispersion dyes, wall-paper, tiled surfaces, paints, glues, bitumina, furniture, leather, shower curtains, textiles, carpets, wood and paper, against a long list of pathogenic fungi, molds and bacteria. However, there is no mention of Bacteroides asaccharolyticus or gingivalis, the particular anaerobic gram negative organisms found in gingivitis. The prior art also discloses a mixture of the imidazoyl ketone fungicide and a quaternary ammonium bactericide useful for protecting materials such as paints, glues, bitumen, cellulose, paper, textiles, leather and wood. Although the prior art disclosed the specified i.) -7- 2q <0 ,»r ij Q imidazoyl ketone as an antimycotic agent, and its use in pharmaceutical formulations, particularly in hair and skin treating compositions, there is no disclosure of its use in dental preparations nor its effectiveness against the specific gram negative anaerobic organisms associated with gingivitis and periodontitis. Description of the Invention It has now been found that the water insoluble imidazoyl ketone, l~imidaaoyl-l-(p-chlorophenoxy)3-3-diraethyl 2-butanone, is selectively effective against the specific anaerobic gram negative organisms associated with gingivitis, when topically applied to the affected gingiva. Accordingly, it is a primary object of present invention to provide an oral fornmlation containing aforesaid water insoluble imidaaoyl ketone as the antigingivitis agent solubili-zed in an oral vehicle# Another object of this invention is to provide a raouthrinse or dentifrice effective in the control and treatment of plaque, gingivitis and periodontitis, 3till another object of this invention is to provide t Q an oral composition comprising aforesaid antigingivitis agent solubilized in an aqueous vehicle comprising a nonionic compound. Another object of this invention ia to provide an antibacterial-containing oral composition useful in the prevention and treatment of gingivitis in animals. Still another object of this invention ia to provide a method of improving oral hygiene by topically applying to the oral cavity the antibacterial-containing composition comprising aforesaid solubilized imidazoyl ketone. Additional objects, advantages and novel features of the invention will be set forth in part in the description which follows, and in part will become apparent to those skilled in the art upon examination of the following or may be learned by practice of the invention. The objects and advantages of ithe invention may be realized and attained by means of the instrumentalities and combinations particularly pointed out in the appended claims. To achieve the foregoing and other objects and in accordance with the present invention, as embodied and broadly described herein, this invention relates to an oral composition for controlling gingivitis comprising an oral vehicle and an effective amount of the water insoluble antigingivitis agent, l-imidazoyl-l-(p-chlorophenoxy) 3-3-dimethyl 2-butanone -9- ^0(c~ - . . • "■> , solubilized in a nonionic compound containing about 10 to hydrophilic units of polyoxyethylene per hydrophobic radical of sufficient length to aolubiliee said imidazoyl compound in an aqueous medium, and preferably in the $> ratio of 8:1 hydro-philic to hydrophobic radical* More specifically* the present invention relates to oral compositions comprising about 0.1 to 5# by weight of said antigingivitis agent solubilized in an aqueous oral vehicle comprising a nonionic compound containing a hydrophobic radical including a higher fatty acid radical containing 10-20 carbons, polyoxypropylene, hexitan mono-higher fatty acid esters* and fatty acid amides} and the hydrophilic group polyoxyethylene of sufficient length to effect solubilization. The oral vehicle may be liquid such as a mouthwash or rinse, solid such as chewing gum, or tooth powder, pasty or creamy such as a toothpaste or dental cream. These oral compositions are nontoxic and have a pH of about 5 to 7»5. The mouthwash which has a pH of about 5 to 7.5 is an aqueous-alcohol vehicle containing about 1-5# by weight of a nonionic surfactant selected from the group consisting of block polymers of ethylene oxide, mixed polymers of propylene oxide and ethylene oxide, polyoxyethylene hexitan mono-higher fatty acid esters containing 10-80 moles ethylene oxide per mol, -10- $2°a and higher fatty acid mono- and di-ethanolamides and mixtures thereof. The typical surfactant contains at least 10-80^ hydrophilic units of polyoxyethylene to the hydrophobic radical such as polyoxypropylene. The preferred i> ratio of hydrophilic to hydrophobic group is Si1 with a molecular weight of about 3250, as in the mixed polymers of propylene oxide and ethylene oxide* The ratio of solubilizer to imidazole compound is about ljl to 25»1 and preferably about 3>1 to 25«1. At ratios above 25si, gelation occurs. The toothpaste, which also has a pH of about 5-7.5 comprises a dentally acceptable polishing material, and a liquid vehicle containing water and about 20-40# by weight of a nonionic humectant including at least one humectant selected from the group consisting of polyethylene glycol and polypropylene glycol. Glycerine, sorbitol or mannitol may be substituted for part of the humectant content provided said antigingivitis agent has been solubilized. The antigingivitis agent utilised in present invention is l-iraidazoyl-(p-chlorophenoxy) 3-3-dimethyl 2-butanone having the structural formula1 *0 ->-o-ch-coc(ch7) / I 3 n which is prepared by reacting l-bromo-l~(4-chlorophenoxy)-3,3-dimethyl-2-butanone with imidazole dissolved in acetonitrile as disclosed in U. 3. Patent Nos. 3»812,142 and 3*903,287, which is made a part of this specification. This imidazoyl ketone is a water insoluble crystalline powder having a melting point of 94»5-97.8°c which may be obtained from the Bayer Company as Climbazole. JJue to the water insolubility of this imidazole compound, it must first be solubilized in a nonionic compound prior to the addition of ionic materials in an aqueous medium# It has been unexpectedly found that this antibacterial compound added to oral vehicles is not only effective against the specific anaerobic organisms involved in periodontal disease, but also reduces the disease significantly when applied topicallj, as well as reduces the symptoms of gingivitis associated with periodontitis. The minimum inhibitory concentration (MIC) needed to kill Bacteroides assaccharolyticus (Forsyth strain), determined according to the procedure of Walker et al (Antimicrobial and Chemotherapy, Vol. 16, p. 452-457, 1979)» is between 7.8 to 31.2 micrograms perfml. The MIC value for B. gingivalis is -12- Zu VQ 25 micrograms per ml. The MIC value for B. gracilis and Fuso-bacterium, other gram negative organisms is greater than 50 for eachj and the MIC value for the gram positive organism Actinomyces viscosus is 125 for the aerobic strain and 250 for the anaerobic strain. This is clearly indicative of the selectivity of the antibacterial activity of the specific imidazole compound utilised herein as the antigingivitis agent. using a 0.3# Climbazole-containing mouth rinse, made in a study on 30 beagle dogs for 10 weeks, clearly shows its superior effectiveness against gingivitis. The procedure used includes the complete removal of hard and soft dental deposits, after which the dogs are kept on a soft diet for six weeks to permit the developement of gingivitis. The dentitions are then treated with the test solutions twice a day, 5 days a week, for about 15 seconds on each side of the mouth. The animals are examined ana the degree of inflammation of the gingiva is scored according to a scale of 0 to 3* 0 = No inflammation. 1 » Mild, localized edema, and redness of gingival margin, no bleeding is elicited upon gentle finger pressure. 2 = Moderate edema, and redness of gingival margin with bleeding upon gentle finger pressure. 3 = Severe edema and ulceration of gingival margin and attached gingiva, and bleeding without gentle finger pressure, A placebo rinse and 0.5# metronidazole rinse were used as the negative and the positive controls respectfully. The data is Evaluation of oral compositions against gingivitis, -13- Jj j * ^^2 VQ summarised in Table 1. Initial Treatment gingival units 6 weeks 10 weeks Ratings t 0 1 2 3 0 1 2 3 Placebo 9 533 8 - - 569 31 - - 526 72 -Rinse 0,5# Metroni- 13 573 9 - - 572 26 - - 576 24 -dasole Rinse 0.3# Climbasole 11 589 - •- 579 21 - - 578 22 - Compared to the placebo, both Metronidazole and Cliaba-zole rinses significantly reduced the deirelopment of the gingival unitB of 2, However, a smaller amount (0.3#) of Climbazole exhibits the same effectiveness against gingivitis than greater amounts (0.5#) of Metronidazole. However, although metronidazole is effective against the specific gram negative micro-organisms involved in periodontal disease when used systeraically, as fully dlsoussed prior art, it does not work as well when topically applied. The reason for said poor results is due to the absence in its structural formula of an appropriate hydrophobic group which is necessary for penetration into the gingival tissues. On the —14— contrary, Climba&ole has a bulky hydrophobic group, (p-chloro-pherioxy) 3-3-dimethyl 2-butanone, which provides good penetration into the tissues where the destructive process of periodontitis occurs, enabling this antibacterial to maintain an effective concentration to reduce the bacterial count of the gram negative anaerobic micro-organisms associated with this disease# In addition, metronidazole is, due to its nitro group, mutagenic, whereas Climbazola is not mutagenic in mutagenic tests, because it lacks the nitro group as can be seen by the structural formulae below: Climbazole Metronidazole K such as The oral composition of this invention may be liquid a mouthwash or rinse. In such a preparation the vehicle is typically a water-alcohol mixture. Generally, the ratio of water to alcohol is in the range of from about lsl to about 20:1 preferably from 3:1 to 20:1, by weight. The alcohol conten* preferably constitutes about 20-40by weight of the vehicle. The total amount of water-alcohol mixture in this type of preparation is typically in the range of from about 70 to about by weight of the preparation. The pH of such liquid and other preparations of the invention is generally in the range of from about 5 to about 7*5. An essential component of the liquid oral preparations is about l-5?« by weight of a nonionic surfactant containing 10-S0ji hydrophilic units of polyoxyethylene to hydrophobic polyoxypropylene or higher fatty acid, fatty ester or fatty amide. The preferred ratio of hydrophilic to hydrophobic is 8:1, in order to solubilize the water insoluble Climbazole in the aqueous-alcohol vehicle. Suitable nonionic surfactants include block polymers of ethylene oxide, mixed propylene oxide-ethylene oxide polymers polyoxyethylene hexitan mono-higher fatty acid esters having from 10-20 carbon atoms in the higher fatty acyl thereof and 4-100, preferably 10-80 mols of ethylene oxide per raol. Preferably, the hexitan is sorbitan, although mannitan and other -16- hexitans are also oftt;n useful, the :higher fatty acyl will be of 10-16 or 20 carbon atoms/ more preferably of 12-16 or 13 oarbor atoms and most preferably oi about 12 carbon atoms, and the number of ethoxies will be from 15-30, often preferably about 20, Especially useful Is an I.C.I, product sold under the tradename Tweon 20, also kncwn as Polysorbate 20 which is polyoxyethylene (20) sorbitan monolaurate. Similarly usti'ul products are sold under, similar, identifications, such aa Tweens 40, 60, 65 and B0f all of which are nonionic surface active agents wherein the higher fatty acyl is palmitoyl, stearoyl or oleyoyl and the number of the niols of ethylene oxide ]<er rr.ol is about 20. However, of these materials the polyoxyethylene sorbitan monolaurate is usually favored. Polyoxyethylene (30) sorbitan monolaurate may be used in place of said polysorbate 20. Other suitable nonionic surfactants include the mono- and di-ethanolamio.es of higher fatty acid having about 10-lS carbon atoms in the acyl group such a.-i cocomonoethanolamide, cocodiethanolanri.de, laurlc myristic diethanolamide, lauric mono-ethanolamide or combinations thereof. Present oral compositions may be substantially pasty -17- *0 V0 in character, such as a toothpaste or dental cream. The vehicle of such pasty oral preparations contains polishing material. Examples of polishing materials are water insoluble sodium metaphosphate, potassium metaphosphate, tricalcivun phosphate, calcium pyrophosphate, magnesium orthopnosphate, trimagnesium phosphate, calcium carbonate, alumina, hydrated alumina, aluminum silicate, sirconiur silicates, silica bentonite, crystalline silica having particle sizes of up to 5 microns, silica gel, complex amorphorus alkali metal aluminosilicate> hydrated alumina, dicalciura phosphate, and mixtures thereof. rfhen visually clear gels are employed, a polishing agent of colloidal silica, such as those sold under the trademark oILOID as Syloid 7~ and Syloid 74 or under the trademark 3ANT0CEL as Santocol 100 and alkali metal aluminosilicate complexes are particularly useful, since they have refractive indices close to the refractive indices of gelling agent-liquid (including water and/or humectant) systems commonly used In dentifrices. The polishing material is generally present in amounts ranging from about 10 to about 99# by weight of the oral preparation. Preferably, it is present in amounts ranging from about —18— 2°v2q0 10 to about 75/<> in toothpaste# . In a toothpaste, the liquid vehicle comprises water and humectant typically in an amount ranging from about 10 to about 90$ by weight of the preparation# An essential component of the toothpaste and dental cream is about 20-40/4 by weight of a nonionic humectant including at least one humectant selected from the group consisting of polyethylene glycol and polypropylene glycol in order to solubilize the water insoluble Climbazole in the aqueous vehicle. Glycerine, sorbitol or mannitol may be substituted for part; of the humectant content, provided said imidazole compound is solubilized in the polyoxyethylene or polyoxypropylene glycol, which contains at least 10-80# and preferably 80:10 polyoxyethylene or polyoxypropylene groups. A gelling agent, such as natural or synthetic gums or gum-like materials, typically Irish moss, sodium carboxy-methylcellulose, methyl cellulose, hydroxyethyl cellulose, gum tragacanth, polyvinylpyrrolidone, starch and hydroxypropyl methyl cellulose is usually present in toothpaste in an amount up to about by weight, preferably in the range of from about 0.5 to about 5#. In a toothpaste or gel, the liquids and solids are proportioned to form a creamy or gelled mass which is extrudable from a pressurized container or from a collapsible, e.g., aluminum or lead, tube. The oral compositions of this invention may contain a non-soap synthetic sufficiently water soluble organic anionic or nonionic surfactant in concentrations generally ranging from about 1-5 weight percent, to promote wetting, detersive and foaming properties. U. 3. Patent No. 4,041,149 discloses 3uch suitable anionic surfactants in col. 4».lines 31-36, and such suitable nonionic surfactants in col. 8, lines 30-68 and col. 9, lines 1-12, which passages are incorporated herein by reference thereto. The antibacterial-containing oral compositions of this invention may optionally contain a fluorine-providing compound including inorganic fluoride salts, such as soluble alkali metal, alkaline earth metal and heavy metal 3alts, for example, sodium fluoride, potassium fluoride, ammonium fluoride, calcium fluoride, a copper fluoride such as cuprous fluoride, zinc fluoride, a tin fluoride such as stannic fluoride or stannous chlorofluoride, barium fluoride, sodium fluorosilicate, ammonium fluorosilicate, sodium fluorozirconate, sodium mono-fluorophosphate, aluminum mono- and di-fluorophosphate, and fluor-inated sodium calcium pyrophosphate. Alkali metal and tin -20- *°620o fluorides, such as sodium and stannous fluorides, sodium mono-fluorophosphate and mixtures thereof, are preferred. The amount of the fluorine-providing compound is dependent to some extent upon the type of compound, its solubility, and the type or oral preparation, but it must be a nontoxic amount. In a solid oral preparation, such as toothpaste or chewing gum, an amount of such compound which releases a maximum of about 1# by weight of the preparation is considered satisfactory. Any suitable minimum amount of such compound may be used, but it is preferable to employ sufficient compound to release about 0.005 to 1#, and preferably about 0.1# of fluoride ion. Typically, in the cases of alkali metal fluorides and stannous fluoride, this component is present in an amount up to about 2# by weight, based on the weight of the preparation, and preferably in the range of about 0.05 to 1#. In the case of sodium monofluorophosphate, the compound may be present in an amount up to 7.6# by weight, more typically about 0.76#. Various other materials may be incorporated in the oral preparations of this invention which do not adversely affect the properties of the composition, such as sweetening agents (e.g., saccharin, sucrose, lactose, maltose, sorbitol, etc.); flavoring oils (e.g., oils of spearmint, peppermint, wintergreen, sassafras, clove, sage, eucalyptus, marjoram, cinnamon, lemon, orange, etc.), coloring or whitening agents (e.g., titanium dioxide), preservatives (e.g., sodium benzoate) and the like. Minor amounts, up to about 5# in total, and preferably 0.01 to 3# by weight of these materials may be added to the oral composition. The present oral compositions are readily prepared by simple mixing methods from readily available components. However, it is essential that the imidazoyl compound be first mixed with the nonionic component prior to its addition to the oral vehicle which typically includes water. For instance, a raouthrinse or mouthwash may be prepared by first solubilizing the imidazole compound by emulsifying in a nonionic surfactant, prior to addition to the aqueous or alcoholic aqueous vehicle. The other ingredients such as flavor, sweetener, etc. may be added to the aqueous vehicle either prior to or subsequent to the addition of the solubilized imidazole to the aqueous vehicle. The toothpaste may be prepared by first mixing the imidazole compound with the humectant which is nonionic, wherein it is solubilized, and then adding the thickener such as carboxy- *0 67 methyl cellulose to form a gel, followed by the addition of polishing agent, water and other ingredients* The sequence of the addition of the various ingredients can be varied, provided the imidazole compound is first solubilized in the nonionic humectant prior to addition to the water component. In the practice of this invention an oral composition according to this invention such as a mouthwash or toothpaste containing l-imidaaoyl-l- (p-chlorophenoxy) 3-3-dioethyl 2-butanonf antigingivitis agent in an amount effective to promote oral hygiene, is applied regularly to dental enamel, preferably from about 1 to about 3 times dally at a pH of about 5 to about 7.5. Detailed Description of the Invention The following specific examples are further illustrative of the nature of the present invention, but it is understood that the invention is not limited thereto. All amounts and proportions referred to herein and the appended claims are by weight unless otherwise indicated. 206200 example 1 Mouthrinse Mouthrinae solution; Alcohol = 25# Climbazole - 0.3# Flavor (K-91-3U63) 0.22 *Pluronic i''10$ 3 3,0 Glycerine =» 25 Sodium Saccharin « 0.03# Water to make 100# ♦•Block polymer of polyoxyethylene and polyoxypropylene in 8:1 ratio with a molecular weight of 3250, obtained from BASF Wyandotte Company. The Climbazole is mixed with Fluronic until homogeneous and clear, prior to addition to the aqueous-alcoholic vehicle containing glycerin, flavor and sodium saccharin. The resultant product is effective in controlling gingivitis and treating periodontitis, and provides a simple means of improving oral hygiene, when used on a regular regime 20620q of 1 to 3 applications to the oral cavity per day. The unexpected superior antigingival activity of this product is shown in Table 1, wherein the mouthrinse of Example 1 was used as the test solution. This product also possesses antibacterial properties against Bacteroides assaccharolyticus and B. gingivalis. EXAMPLE 2 Dental Paste Ingredients Percent Grams *2° 31.3 156.5 Na - Benzoate 0.5 2.5 Na - Saccharin 0.2 1.0 Polyethylene glycol 600"1" 25.0 125 Climbazole 1.0 5.0 Carboxymetliyl. cellulose 1.5 7.5 oyloid-2442 3.0 15.0 2eo-49^ 35.0 175 Sodium lauryl sulfate 1.5 7.5 Flavor 1.0 5.0 H(0CJH?CH9) OH where n is an integer between 10-14, preferably < n 12.5 to 14 and having a mol weight of 570-630 2 colloidal silica 3 . sodium aluminosilicate (silica with 1 i» combined alumina) by Huber Co. -25- </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 2062 qQ The Climbazole is premlxed with the polyethylene glycol prior to the addition of the carboxymethyl cellulose, whereby a gel is formed. To this gel is added, with agitation, the Syloid, Zeo, sodium lauryl sulfate, flavor, water, benaoate and saccharin. The benzoate and saccharin may be dissolved in ■ the water prior to mixing with the rest of the ingredients. Similarly, the Zeo, flavor and sodium lauryl sulfate may be premixed prior to addition to the gel* This product also possesses similarly good antimicrobial and antigingivitis properties* Other conventional components may be substituted or added, as disclosed hereinbefore. For example, hydrated alumina or water insoluble metaphosphate or dloaloium phosphate dlhydrate and other polishing agents may be substituted for the alkali metal aluminosilicate (Zeo) or the oolloidal silica (Syloid) in total or in part. Similarly, other nonionic surfaotants may be substituted for the block polymer of ethylene oxide (Pluronic) such as the polyoxyethylene hexitan mono-higher fatty acid esters* It is understood that the foregoing detailed description ie given merely by way of illustration and that variations may be made therein without departing from the spirit or scope of the invention as defined in the appendant claims. -26- 206200 WHAT WE CLAIM IS:

1. An oral composition for treating gingivitis and periodontitis comprising an oral vehicle and em effective amount of the water insoluble antigingivitis agent, l-imidazoyl-l-(p-chloro-phenoxy)-3,3-diraethyl 2-butanone, solubilized in a nonionic compound, in the weight ratio of 3:1 to 25:1 nonionic:antigingivitis agent.

2. The oral composition according to Claim 1, wherein 0*1-555 by weight of said antigingivitis agent is solubilized in an aqueous oral vehicle comprising a nonionic compound containing 10-80% hydrophilic units of polyoxyethylene per hydrophobic radical of sufficient length to effect solubilization.

3« An oral composition according to Claim 1, wherein the water insoluble antigingivitis agent is solubilized in a nonionic compound containing a mixture of hydrophilic and hydrophobic radicals of sufficient length to effect solubilization in an aqueous vehicle, the weight ratio of hydrophilic:hydrophobic radicals in the nonionic compound being 8:1.

4. The oral composition according to Claim 3» which 1b a mouthwash having a pH of 5 to 7.5 and an aqueous-alcohol vehicle containing 1 to 5% by weight of a nonionic surfactant

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206200

> selected, fro:.: uha group consisting of block polymers of ethylene oxide, mixed polymers of propylene! oxldo and ethylene oxide, polyoxyethylene hexitan mono-higher fatty acid esters containing 10-00 moles ethylene oxide per mol, and higher fatty acid mono-and di-ethanolamidea and mixtures thereof,

5, The oral composition according to Claim 1, which is a toothpaste having a pH Of 5-7.5 containing a dentally acceptable polishing material, and a liquid vehicle comprising water, and 20-40% by weight of a nonionic humectant including at least one humectant selected from the group consisting of polyethylene glycol, and polypropylene glycol.

6, The oral composition according to Claim 5» wherein glycerin, sorbitol or mannitol may be substituted for part of the humectant content, provided said antigingivitis agent has been solubilized.

WEiCT-WAlKEH, McCADE

ar- ^

ATTORNEYS FOR Tt+f. KPf-UCANl

^ t \ .J vj J i CjO |

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