WO1999038480A2

WO1999038480A2 - Antiplaque oral composition and method

Info

Publication number: WO1999038480A2
Application number: PCT/US1999/002022
Authority: WO
Inventors: John C. Brahms; Shirley A. Lucchesi; Frederick G. Saunders; Abdul Gaffar; Stuart Shapiro
Original assignee: Colgate Palmolive Co
Current assignee: Colgate Palmolive Co
Priority date: 1998-02-03
Filing date: 1999-01-28
Publication date: 1999-08-05
Anticipated expiration: 2000-08-03
Also published as: DE69902514D1; JP2002501878A; PL342663A1; ATE222088T1; WO1999038480A3; CN1168436C; EP1052967A2; US5851513A; AU740549B2; AU2486499A; EP1052967B1; BR9908556A; CN1289246A; CA2319753A1

Abstract

An oral composition comprising an orally acceptable vehicle and an effective antiplaque amount of at least one substantially water insoluble noncationic antibacterial agent of the formulae (1) and (2).

Description

ANTIPLAQUE ORAL COMPOSITION AND METHOD

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to an antibacterial antiplaque oral composition containing a substantially water insoluble, noncationic antibacterial phenolic compound which is more fully described below.

2. The Prior Art

Dental plaque is a soft deposit which forms on teeth as opposed to calculus which is a hard calcified deposit on teeth. Unlike calculus, plaque may form on any part of the tooth surface, particularly including at the gingival margin. Hence, beside being unsightly, it is implicated in the occurrence of gingivitis.

Cationic antibacterial materials such as chlorhexidine, benzthonium chloride and cetyl pyridinium chloride have been used by the art as antibacterial antiplaque agents in oral compositions. However, such agents are generally not effective when used with anionic materials ingredients such as anionic surfactants required for the effective performance of oral compositions such as toothpaste and mouthrinses. Noncationic antibacterial materials can be compatible with anionic components in an oral composition and noncationic halogenated hydroxydiphenyl ethers such as Triclosan have been effectively employed in oral compositions as antibacterial antiplaque agents when admixed with neutral materials such as humectants, abrasives and thickeners used in the formulation of oral compositions.

Phenol and alkyl substituted phenols are well known and widely used antimicrobials. However, it is difficult to predict the functionality of these antimicrobials as antiplaque agents when incorporated in oral composition vehicles. For example, thymol (2-isopropyl-5- methylphenol) is an active antimicrobial agent in commercial mouthrinse formulations, but its antibacterial activity is considered relatively low and possibly insufficient, its activity for example being only a small fraction of the activity of Triclosan . SUMMARY OF THE INVENTION

In accordance with the present invention there is provided an oral antiplaque composition comprising an orally acceptable vehicle and an effective antiplaque amount of at least one substantially water insoluble noncationic adamantyl-substituted phenolic antibacterial agent having the following formulae:

10 and mixtures thereof.

While adamantyl substituted phenolic compounds are known (Chemical Abstracts Registration Numbers 41031-50 and 29799-07-03) their use as antiplaque agents delivered in 15 an orally acceptable vehicle is not known to the prior art.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The adamantyl substituted phenolic compound is incorporated in the oral compositions 20 of the present invention in a non-toxic, effective antiplaque amount, typically in a range of about 0.003 to about 5%, preferably about 0.005 to about 3%, more preferably about 0.02 to about 1% by weight.

To enhance the antibacterial activity of the adamantyl-substituted phenolic antibacterial 25. agent, an antibacterial enhancing agent may be included in the oral composition. The use of such antibacterial enhancing agents in combination with water-insoluble noncationic antibacterial compounds is known to the art, as for example, U.S. Pat. No. 5,188,821 and 5,192,531.

30 Antibacterial enhancing agents preferred for use in the practice of the present invention include a natural or synthetic anionic polymeric polycarboxylate having a molecular weight of about 1,000 to about 5,000,000, preferably about 30,000 to about 500,000. Synthetic anionic polymeric polycarboxylates are generally employed in the form of their free acids or preferably partially or more preferably fully neutralized water soluble alkali metal (e g potassium and preferably sodium) or ammonium salts Preferred are 1 4 to 4 1 copolymers of maieic anhydride or acid with another polymeπzable ethylerucally unsaturated monomer, preferably methyl vinyl either/maleic anhydride having a molecular weight (M W ) of about 30,000 to about 1,000,000 most preferably about 30,000 to about 500,000 These copolymers are available, for example as Gantrez® AN 139 (M W 500,000), AN 1 19 (M W 250,000), and preferably S-97 Pharmaceutical Grade (M W 70,000), of GAF Corporation

Other polymeπc polycarboxylates useful in the practice of the present invention include the 1 1 copolymers of maieic anhydride with ethyl acrylate, hydroxyethyl methacrylate, N-vmyl- 2-pyrolhdone, or ethylene, the latter being available, for example, as Monsanto EMA® No 1 103, M W 10,000 and Grade 61, and 1 1 copolymers of acrylic acid with methyl or hydroxyethyl methacrylate methyl or ethyl acrylate, isobutvl methacrylate, isobutvl vinvl ether or N-vιnyl-2-pyrrolιdone

Additional operative useful polycarboxylate compounds include copolymers of maieic anhydride with styrene. isobutylene or ethyl vinyl either, polyacry c, polyitaconic and polvmaleic acids, and sulfonacry c ohgomers of M W as low as 1,000 available as Umroyal® ND-2

Also useful in the practice of the present invention are the so-called carboxyvinyl polymers, commercially available, for example, under the trademarks Carbopol® 934, 940 and 941 from B F Goodrich these polymers consisting of a colloidally water-soluble polymer of polyacryhc acid cross nked with from about 0 75% to about 2 0% of polyallyl sucrose or polyallyl pentaerythπtol as a cross linking agent, often with M W 's up to 4-5 million or more

The antibacterial enhancing agent, when employed, is incorporated in the compositions of the present invention in weight amounts of about 0 05 to about 5%, preferably about 0 1 to about 3%

Linear molecularly dehydrated polyphosphate salts can be optionally employed herein as anticalculus agents They are well known, being generally employed in the form of their whollv or partially neutralized water soluble alkali metal (e g potassium or preferably sodium) or ammonium salts, and any mixtures thereof Representative examples include sodium tπpolyphosphate, monosodium tπacid,-, disodium diacid-, tπsodium monoacid-, and tetrasodium-pyrophosphates, the corresponding potassium salts and the like In the present invention, they can be employed in the oral compositions in approximate weight amounts of about 0 1 to about 3%, typically about 1 to about 2 5%, more typically about 1 5 to about 2% especially about 2%. Particularly desirable anticalculus agents are tetraalkali metal pyrophosphates such as tetrasodium and tetrapotassium pyrophosphates. and mixtures thereof

Fluoride ions may desirably also be included in the oral compositions of the present invention to provide an anticaries effect.. Among these materials are inorganic fluoride salts, such as soluble alkali metal fluoride salts, for example, sodium fluoride, potassium fluoride, ammonium fluoride, sodium monofluorophosphate, and sodium hexafluorosilicate. Alkali metal and tin fluorides, such as sodium and stannous fluorides, sodium monofluorophosphate and mixtures thereof, are preferred.

The amount of fluorine-providing salt is generally present in the oral composition at a concentration of about 0.0005 to about 3.0% by weight. Any suitable minimum amount of such salt may be used, but it is preferable to employ sufficient fluoride salt to release about 300 to 2,000 ppm, more preferably about 800 to about 1,500 ppm, of fluoride ion.

The oral composition of the present invention may be a solution of ingredients such as a mouthrinse or it maybe a semi-solid such as a toothpaste or gel dentifrice or chewing gum or solid lozenge.

In the aspect of this invention wherein the oral composition is a gel or paste, an orally acceptable vehicle, including a water-phase with humectant which is preferably glycerine or sorbitol or an alkylene glycol such as polyethylene glycol or propylene glycol is present, wherein water is present typically in an amount of about 15-40% by weight and glycerine, sorbitol and/or the alkylene glycol (preferably propylene glycol) typically total about 20-75% by weight of the oral composition, more typically about 25-60% by weight.

When the oral composition is substantially semi-solid or pasty in character, such as a toothpaste or gel, the dentifrice vehicle may contain a dentally acceptable abrasive material such as sodium bicarbonate or water insoluble abrasive material such as sodium metaphosphate, potassium metaphosphate, tricalcium phosphate, dihydrated dicalcium phosphate, anhydrous dicalcium phosphate, calcium pyrophosphate, calcium carbonate, aluminum silicate, hydrated alumina, calcined alumina, silica, bentonite. and mixtures thereof.

The abrasive material is generally present in the paste or gel composition in weight concentrations of about 10% to about 60% by weight, preferably about 10% to about 30% in a gel and about 25% to about 60% in a paste. Toothpastes as well as gel dentirπces tvpically contain a natural or synthetic thickener or gelling agent in proportions of about 0 1 to about 10% bv weight, preferably about 0 5 to about 5% bv weight Suitable thickeners or gelling agents include Irish moss lota-carrageenan kappa- carrageenan, gum tragacanth starch, polwinylpyrrohdone hydroxyethvl propyl cellulose, 5 hvdroxvbutvl ethvl cellulose hvdroxvpropyl methvl cellulose hvdroxvethvl cellulose and sodium carboxvmethvl cellulose

In the aspect of the present invention wherein the oral composition is substantially liquid in character such as a mouthwash or rinse the vehicle is typicallv a water-alcohol mixture 0 Generally, the weight ratio of water to alcohol is in the range of from about 3 1 to 10 1 and preferably about 4 1 to about 6 1 The alcohol is a non-toxic alcohol such as ethanol or isopropanol A humectant such as glycerine sorbitol or an alkylene glycol such as polyethylene glycol or preferably propylene glycol mav be present in amount of about 10-30% by weight Mouthπnses typically contain about 50-85% of water about 0 to 20% bv weight ot a non-toxic ^ alcohol and about 10-40% bv weight of the humectant

Organic surface-active agents are used in the compositions of the present invention to achieve increased prophylactic action and assist in achieving thorough and complete dispersion of the adamantyl substituted phenolic antibacterial agent throughout the oral cavity The organic 0 surface-active material is preferably anionic, suitable examples which include water-soluble salts of higher fatty acid monoglyceπde monosulfates, such as the sodium salt of the monosulfated monoglyceπde of hvdrogenated coconut oil fatty acids, higher alkyl sulfates such as sodium lauryl sulfate, alkyl aryl sulfonates such as sodium dodecvl benzene sulfonate, higher alkyl sulfoacetates, higher fattv acid esters of 1 2- dihvdroxy propane sulfonate and the substantially ^ saturated higher aliphatic acvl amides of lower aliphatic amino carboxvhc acid compounds, such as those having 12 to 16 carbons in the fatty acid, alkyl or acvl radicals and alkoyl tauπnes, and the like Examples of the last mentioned amides and taurates are N-laurovl sarcosine, and the sodium, potassium and ethanoiamine salts of N-lauroyl, N-myπstoyl, or N-palmitoyl sarcosine which should be substantially free from soap or similar higher fattv acid material as well as N- 0 methyl-N-cocoyl (or oleoyl or palmitoyl) tauπnes

Any suitable flavoring or sweetening material mav also be emploved Examples of suitable flavoring constituents are flavoring oils, e g oil of spearmint, peppermint, wintergreen sassafras clove, sage, eucalyptus, cinnamon, lemon, and orange, and methyl sa cylate Suitable 5 sweetening agents include sucrose, lactose, maltose xylitol sodium cvclamate, peπllartine aspartyl phenvl alanme methvl ester, saccharine and the like Suitably flavor and sweetening agents mav each or together comprise from about 0 1% to 5% or more of the preparation Agents used to αiminisn teeth sensitivity such as strontium chloride, potassium nitrate and potassium citrate can also be included in the oral compositions of the present invention at concentrations of about 0 1 about 10% bv weight

\ aπous other materials mav be incorporated in the oral compositions of this invention including whitening agents such as urea peroxide hydrogen peroxide preservatives such as sodium benzoate vitamins and chlorophyll compounds These adjuvants when present, are incorporated in the compositions in amounts which do not substantially adversely affect the properties and characteristics desired

The oral compositions of the present invention mav be prepared bv suitably mixing the ingredients For instance in the preparation of a mouthπnse the adamantyl substituted phenolic antibacterial agent is dispersed in a mixture of ingredients e g alcohol humectants surfactants and salts such as sodium fluoride and flavor are then added and mixed The ingredients are then mixed under vacuum tor about 15-30 minutes The resulting rinse product is then packaged

Dentifrices are prepared similarly additional thickener and polishing agents being included in the last or penultimate step

The compositions of this invention can be incorporated in lozenges or in chewing gum or other products e g bv stirring into a warm gum base or coating the outer surface of a gum base illustrative of which may be mentioned jelutone rubber latex and vinv te resins desirably with conventional plasticizers or softeners sugar or other sweeteners or carbohydrates such as glucose, sorbitol and the like

The vehicle or carrier in a tablet or lozenge is a non-caπogenic solid water-soluble polyhvdπc alcohol (polvol) such as mannitol xy tol sorbitol, mahtol a hvdrogenated starch hydrolvsate hvdrogenated glucose hydrogenated disacchaπdes or hydrogenated polysacchaπdes, in an amount of about 90 to 98% by weight of the total composition Salts such as sodium bicarbonate, sodium chloride potassium bicarbonate or potassium chloride mav totally or partially replace the polvol carrier Tableting lubricants in minor amounts of about 0 1 to 5% bv weight, may be incorporated into the tablet or lozenge formulation to facilitate the preparation of both the tablets and lozenges Suitable lubricants include vegetable oils such as coconut oil magnesium stearate, aluminum stearate talc starch and Carbowax®

Lozenge formulations contain about 2% gum as a barrier agent to provide a shiny surface as opposed to a tablet which has a smooth finish Suitable non-caπogenic gums include kappa carrageenan carboxymethvl cellulose hvdroxvethyl cellulose Gantrez®, and the like The lozenge or tablet may optionally be coated with a coating mateπal such as waxes, shellac, carboxymethyl cellulose, polyethylene/maleic anhydride copolymer or kappa- carrageenan to further increase the time it takes the tablet or lozenge to dissolve in the mouth The uncoated tablet or lozenge is slow dissolving, providing a sustained release rate of active ingredients of about 3 to 5 minutes Accordingly, the solid dose tablet and lozenge composition of this invention affords a relatively longer time peπod of contact of the teeth in the oral cavity with the active ingredients

The following example further illustrates the present invention, but it is understood that the invention is not limited thereto All amounts and proportions referred to herein and in the appended claims are by weight unless otherwise indicated

EXAMPLE

A mouthπnse was prepared using the following ingredients

Ingredients Composition A (grams) Composition B (grams)

Glvceπn (99 7% stock) 10 0 10 000

Sorbitol (70% stock) 10 0 10 000

Ethanol 15 0 15 0

Propvlene glvcol 15 0 15 0

Sodium laurvl sulfate 0 3 0 3

Tauranol 0 3 0 300

Sodium fluoride 0 243 0 243 ρ-( 1 -adamantvl)phenol 0 03 -

2-( 1 -adamantvl)-p-cresol - 0 03

The antibacterial efficacy of mouthπnse compositions A and B was evaluated in accordance with a MIC (Minimum Inhibitory Concentration ) test which measures the minimum concentration in ppm of the mouthπnse at which the growth of the bacteria is completely inhibited The smaller the MIC, the greater the antibacterial activity of the mouthπnse being tested Water is used as a control These MIC test is more fully descπbed in U S Patent No 5,275,805 at column 1 1, lines 54-68, which descπption is herewith incorporated herein The results of the MIC tests are recorded in the table below

TABLE

A. viscosus (MIC in ppm)

Mouthπnse A 15.6

Mouthπnse B 15.6

Control (water) <125

The results recorded in the Table demonstrate that mouthrinses containing an adamantyl substituted phenol are effective as antiplaque oral compositions

Claims

What is claimed is

1 An oral composition comprising an orally acceptable vehicle and an effective antiplaque amount of at least one substantially water insoluble noncationic antibacterial agent of the formulae

and mixtures thereof

2 The composition of claim 1 wherein the antibacterial agent is present in the oral composition in a amount in the range of about 0 003 to about 5 0% by weight

3 The composition of claim 1 wherein an anionic polycarboxylate antibacterial enhancing agent is incorporated in the composition

4 The composition of claim 3 wherein the anionic polycarboxylate is a maieic anhydride copolymer

5. A composition according to claim 1 wherein the composition is in the form of a mouthrinse.

6 A composition according to claim 1 in the form of a dentifrice containing a dentally acceptable polishing agent and a vehicle comprising water and humectant

7 A method of promoting oral hygiene comprising applying to dental surface an effective amount of a composition as defined in claim 1