WO1992010991A1

WO1992010991A1 - Methods for making oral compositions

Info

Publication number: WO1992010991A1
Application number: PCT/US1991/009376
Authority: WO
Inventors: Nigel John Leeves
Original assignee: The Procter & Gamble Company
Priority date: 1990-12-19
Filing date: 1991-12-13
Publication date: 1992-07-09
Also published as: IE914419A1; AU9164491A; MX9102617A

Abstract

Disclosed is a method for making oral compositions which are effective against plaque and gingivitis and contain a noncationic water insoluble antibacterial agent. The process comprises mixing said antibacterial agent with a solvent and adding this combination to the composition at the same time as a surfactant or just after said surfactant is added.

Description

METHODS FOR MAKING ORAL COMPOSITIONS

TECHNICAL FIELD The present invention relates to a method for making oral compositions which provide antiplaque and antigingivitis benefits as well as being effective against other anaerobic infections of the mouth.

Plaque induced diseases, including periodontitis and gin¬ givitis, are believed to involve anaerobic bacterial infections. Periodontal disease affects the periodontium, which is the investing and supporting tissue surrounding a tooth (i.e., the periodontal ligament, the gingiva, and the alveolar bone). Gingivitis and periodontitis are inflammatory disorders of the gingiva and the periodontal ligament, respectively. Gingivosis and periodontosis are more severe conditions involving degener¬ ative disorders of the tissue. Combinations of inflammatory and degenerative conditions are termed periodontitis complex.

Periodontal disease is a major cause of tooth loss in adults.

Tooth loss from periodontal disease is a significant problem beginning at age 35, but even by age 15 it is estimated that about

4 out of 5 persons already have gingivitis and 4 out of 10 have periodontitis.

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 initiation and progress of periodontal disease. Thus, in order to prevent or treat periodontal disease, these micro¬ organisms 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.

The use of noncationic, water-insoluble antibacterial agents in oral products is disclosed in a number of references. One such reference is U.S. Patent 4.022.889 to Vinson et al . Vinson describes compositions containing zinc salts and antibacterial agents such as halogenated salicylanilides and halogenated hydroxydipheny1 ethers.

Another reference disclosing noncationic water-insoluble antibacterial agents is U.K. Patent Application GB 2.200.551. published August 10, 1988. In addition to the antibacterial, the compositions contain a molecularly dehydrated polyphosphate salt. The salt is stated to improve the effectiveness of the anti¬ bacterial. All prior art references are included herein in total by reference.

It has now been found that the bioavailability and effective¬ ness of the antibacterial can be improved significantly by putting the antibacterial into the composition at the same time or after a surfactant has been put into the composition. This allows for the antibacterial to be better dissolved in the composition.

It is therefore an object of the present invention to provide an improved method for making products containing antibacterial agents.

It is a further object of the present invention to provide more effective products for treating diseases of the oral cavity. It is still a further objective to provide methods for treating diseases of the oral cavity.

These and other objects will become readily apparent from the disclosure which follows. All percentages and ratios used herein are by weight unless otherwise specified. Also, all measurements referred to herein— are made at 25'C in the composition unless otherwise specified.

SUMMARY OF THE INVENTION The present invention, in certain aspects, embraces a method for enhancing the effectiveness of water-insoluble, noncationic antibacterial agents involving dissolving the antibacterial agent in a solvent and putting this solution into the composition at the same time or after a surfactant has been put into the composition, preferably at the same time. The present invention also encompasses a method for treating diseases of the oral cavity using the compositions prepared by the stated process. By "oral compositions" . as used herein means a product which in the ordinary course of usage is not intentionally swallowed for purposes of systemic administration of particular therapeutic agents, but is rather retained in the oral cavity- for a time sufficient to contact substantially all of the dental surfaces and/or oral tissues for purposes of oral activity.

By "safe and effective amount" as used herein means suffi¬ cient amount of material to provide the desired benefit while being safe to the hard and soft tissues of the oral cavity. By the term "comprising", as used herein, is meant that various additional components can be conjointly employed in the compositions of this invention as long as the listed materials perform their intended functions.

By the term "carrier", as used herein, is meant a suitable vehicle which is pharmaceutically acceptable and can be used to apply the present compositions in the oral cavity.

DETAILED DESCRIPTION OF THE INVENTION The present invention in certain aspects involves mixing water-insoluble, noncationic antibacterials with a solvent and a surfactant(s) prior to adding to the remainder of the composition or adding the antibacterial and solvent after the surfactant. The essential and optional components of the compositions are made using the process described in detail below.

Antibacterial Aoents Given below are examples of antibacterial agents useful in the process of the present invention which are water insoluble and noncationic.

Halooenated Diohenvl Ethers 2',4,4'-trichloro-2-hydroxy-diphenyl ether (Triclosan) 2,2'-dihydroxy-5,5'-dibromo-diphenyl ether.

Phenolic Compounds (including phenol and its homologs, mono- and poly-alkyl and aromatic halophenols, resorcinol and its derivatives, bisphenolic compounds and halogenated salicylani- lides).

tert-Amyl o-Chlorophenol n-Hexyl o-Chlorophenol n-Heptyl o-Chlorophenol o- Benzyl - p-Chlorophenol o-Benxyl -m-methyl - p-Chlorophenol o-Benzyl -m, m-dimethyl - p-Chlorophenol o-Phenylethyl - p-Chlorophenol o-Phenylethyl-m-methyl - p-Chlorophenol

3-Methyl - p-Chlorophenol

3,5-Dimethyl - p-Chlorophenol

6-Ethyl-3-methyl - p-Chlorophenol

6-n-Propyl-3-methyl - p-Chlorophenol

6-iso-Propyl-3-methyl - p-Chlorophenol

2-Ethyl-3,5-dimethyl - p-Chlorophenol

6-sec-Butyl-3-methyl - p-Chlorophenol

2-iso-Propyl-3,5-dimethyl - p-Chlorophenol

6-Diethylmethyl-3-methyl - p-Chlorophenol

6-iso-Propyl-2-ethyl-3-methyl - p-Chlorophenol

2-sec-Amyl-3,5-dimethyl - p-Chlorophenol

2-Diethylmethyl-3,5-dimethyl - p-Chlorophenol

6-sec-0ctyl-3-methyl - p-Chlorophenol p-Bromophenol

Methyl p-Bromophenol

Ethyl p-Bromophenol n-Propyl p-Bromophenol n-Butyl p-Bromophenol n-Amyl p-Bromophenol sec-Amyl p-Bromophenol n-Hexyl p-Bromophenol cyclohexyl p-Bromophenol o-Bromophenol tert-Amyl o-Bromophenol n-Hexyl o-Bromophenol n-Propyl-m,mDimethyl o-Bromophenol

2-Phenyl Phenol 4-Chloro-2-methyl phenol 4-Chloro-3-methyl phenol 4-Chloro-3,5-dimethyl phenol 2,4-dichloro-3,5-dimethylphenol 3,4,5,6-terabromo-2-methylphenol 5-methyl-2-pentylphenol 4-isopropyl-3-methylphenol 5-Chloro-2-hydroxydiphenylmethane R or in l its erivatives

Halogenated Salicylanilides

4' ,5-dibromosalicylanilide

3,4',5-trichlorosalcylanilide

3,4' ,5-tribromosalicylanilide 2,3,3' ,5-tetrachlorosalicylanil ide

3,3',5-trichlorosalicylanilide

3,5-dibromo-3'-trif1uoromethyl salicylani1ide

5-n-octanoyl-3'-trifluoromethyl salicylani1ide

3,5-dibromo-4'-trif1uoromethyl salicylani1ide 3,5-dibromo-3'-trifluoromethyl salicylanilide (Fluorophene) Benzoic Esters p-Hydroxybenzoic Acid

Methyl - p-Hydroxybenzoic Acid Ethyl - p-Hydroxybenzoic Acid

Propyl - p-Hydroxybenzoic Acid

Butyl - p-Hydroxybenzoic Acid

Halogenated Carbanilides

3,4,4'-trichlorocarbani1ide 3-trifluoromethyl-4,4'-dichlorocarbani1ide

3,3',4-trichlorocarbanilide

The antibacterial agent is present in the oral composition prepared using the claimed method in an effective antiplaque amount, typically about 0.01-5% by weight, preferably about 0.03-1%. The antibacterial agent is substantially water- insoluble, meaning that its solubility is less than about 1% by weight in water at 25'C and may be even less than about 0.1%. If an ionizable group is present solubility is determined at a pH at which ionization does not occur. Surfactants

The surfactants useful in the process of this invention include many different surfactants. Suitable surfactants include any which are reasonably stable and function over a wide pH range.

Included are non-soap anionic, nonionic, cationic, zwitterionic and a photeric organic synthetic surfactants. Many of these are disclosed by Gieseke et al . in U.S. Patent 4,051,234, September 27, 1988 incorporated herein in total by reference.

Preferred surfactants include alkyl sulfates. The surfactant is generally present at a level of from about 0.2% to about 7% preferably from about 0.6% to about 4.0%. Water

Water is also present in the compositions made using the process of this invention. Water employed in the preparation of commercially suitable compositions should preferably be deionized and free of organic impurities. Water generally comprises from about 10% to 50%, preferably from about 20% to 40%, by weight of the toothpaste compositions herein while mouthwashes contain from about 40% to about 95%, preferably 50-80%. These amounts of water include the free water which is added plus that which is introduced with other materials as with sorbitol.

Solvent

A solvent is present in the compositions made using the process of the present invention. The solvent is used to solu- bilize the antibacterial and can be any number of agents.

Preferred agents include flavor oils such as those mentioned subsequently or agents such as polyethylene glycols, preferably those having molecular weights of from about 200 to about 600, propylene glycol, dipropylene glycol, methyl cellosolve, ethyl cellosolve, olive oil, castor oil, amylacetate, ethyl acetate, glyceryl tristearate, benzyl benzoate and mixtures thereof. The solvent is used generally in an amount of from about 1 to about

10%, preferably from about 2 to about 6%.

Optional Components The compositions made using the process of the present invention may contain in addition to the above-listed components many others which will be somewhat dependent on the type of composition (mouthwashes, toothpastes, topical gels, prophylaxis pastes and the like). Toothpastes and mouthwashes are the preferred systems with toothpastes being the most preferred. Toothpastes contain as a major component an abrasive. The abrasive polishing material contemplated for use in the present invention can be any material which does not excessively abrade dentin. These include, for example, silicas including gels and precipitates, calcium carbonate, dicalcium orthophosphate dihy- drate, calcium pyrophosphate, tricalcium phosphate, calcium polymetaphosphate, insoluble sodium polymetaphosphate, hydrated alumina, and resinous abrasive materials such as particulate condensation products of urea and formaldehyde, and others such as disclosed by Cooley et al . in U.S. Patent 3.070.510. December 25, 1962, incorporated herein by reference. Mixtures of abrasives may also be used.

Silica dental abrasives, of various types, can provide the unique benefits of exceptional dental cleaning and polishing performance without unduly abrading tooth enamel or dentin. Silica abrasive materials are also exceptionally compatible with sources of soluble fluoride and other ion sources. For these reasons they are preferred for use herein.

The silica abrasive polishing materials useful herein, as well as the other abrasives, generally have an average particle size ranging between about 0.1 and 30 microns, preferably 5 and 15 microns. The silica abrasive can be precipitated silica or silica gels such as the silica xerogels described in Pader et al., U.S. Patent 3.538.230. issued March 2, 1970 and DiGiulio, U.S. Patent 3.862.307. June 21, 1975, both incorporated herein by reference. Preferred are the silica xerogels marketed under the tradename "Syloid" by the W.R. Grace & Company, Davlson Chemical Division. Preferred precipitated silica materials include those marketed by the J.M. Huber Corporation under the tradename, "Zeodent", parti- cularly the silica carrying the designation "Zeodent 119". These silica abrasive are described in U.S. Patent 4.340.583. July 29, 1982, incorporated herein by reference.

The abrasive in the dentifrice compositions described herein is present at a level of from about 6% to about 70%, preferably from about 15% to about 30% when the dentifrice is a toothpaste. Flavoring agents, as was noted earlier, can also be added to the dentifrice and other compositions made using the process of the present invention. Suitable flavoring agents include oil of wintergreen, oil of peppermint, oi.l of spearmint, oil of sassa- fras, and oil of clove. Sweetening agents are also useful and include aspartame, acesulfame, saccharin, dextrose, levulose and sodium cyclamate. Flavoring and sweetening agents are generally used in the compositions herein at levels of from about 0.005% to about 2% by weight and may be used as a solvent for the anti- bacterials hereinbefore indicated.

In preparing toothpastes, it is necessary to add some thickening material to provide a desirable consistency. Preferred thickening agents are carboxyvinyl polymers, carrageenan, hydroxy- ethyl cellulose and water soluble salts of cellulose ethers such as sodium carboxymethyl cellulose and sodium carboxymethyl hydroxyethyl cellulose. Natural gums such as gum karaya, gum arabic, and gum tragacanth and polysaccharide gums such as xanthan gum can also be used. Colloidal magnesium aluminum silicate or finely divided silica can be used as part of the thickening agent to further improve texture. Thickening agents in a combined amount from 0.5% to 5.0% by weight of the total composition may be used.

It is also desirable to include a humectant in a toothpaste to keep it from hardening. Suitable humectants include glycerin, sorbitol, and other edible polyhydric alcohols at a level of from about 10% to about 70%.

Another preferred embodiment of the present invention is a mouthwash composition made using the process of this invention. Mouthwashes generally comprise from about 20:1 to about 2:1 of a water/ethyl alcohol solution and preferably other ingredients such as flavor, sweeteners, humectants and sudsing agents such as those described above. The humectants, such as glycerin and sorbitol give a moist feel to the mouth. Generally, on a weight basis the mouthwashes of the invention comprise 5% to 60% (preferably 10% to 25%) ethyl alcohol, 0% to 20% (preferably 5% to 20%) of a humec¬ tant, 0% to 2% (preferably 0.01% to 0.15%) emulsifying agent, 0% to 0.5% (preferably 0.005%- to 0.06%) sweetening agent such as saccharin, 0% to 0.3% (preferably from 0.03% to 0.3%) flavoring agent, and the balance water.

The pH of the present compositions and/or its pH in the mouth can be any pH which is safe for the mouth's hard and soft tissues. Such pH's are generally from about 3 to about 10, preferably from about 4 to about 9.

Another optional component is an anionic polycarboxylate. The anionic polymeric polycarboxylates optionally but preferably employed herein are well known, being employed in the form of their free acids or partially or 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 maleic anhydride or acid with another polymerizable ethylenically unsaturated monomer, preferably methyl vinyl ether (methoxyethylene) having a molecular weight (M.W.) of about 30,000 to about 1,000,000. These copolymers are available for example as Gantrez (AN 139(M.W. 500,000), A.N. 119 (M.W. 250,000) and preferably S-97 Pharmaceutical Grade (M.W. 70,000), of GAF Corporation.

Other operative polymeric polycarboxylates include those such as the 1:1 copolymers of maleic anhydride with ethyl acrylate, hydroxyethyl methacrylate, N-vinyl-2-pyrollidone, or ethylene, the latter being available for example as Monsanto EMA No. 1103, M.W. 10,000 and EMA Grade 61, and 1:1 copolymers of acrylic acid with methyl or hydroxyethyl methacrylate, methyl or ethyl acrylate, isobutyl vinyl ether or N-vinyl-2-pyrrolidone.

Additional operative polymeric polycarboxyVates disclosed in above referred to U.S. Patent Nos. 4.138.477 and 4.183.914. incorporated herein by reference, include copolymers of maleic anhydride with styrene, isobutylene or ethyl vinyl ether, poly- acrylic, polyitaconic and polymaleic acids, and sulfoacrylic oligomers of M.W. as low as 1,000 available as Uniroyal ND-2,

Suitable generally are polymerized olefinically or ethylen- ically unsaturated carboxylic acids containing an activated carbon-to-carbon olefinic double bond and at least one carboxyl group, that is, an acid containing an olefinic double bond which readily functions in polymerization because of its presence in the monomer molecule either in the alpha-beta position with respect to a carboxyl group or as part of a terminal methyleήe grouping. Illustrative of such acids are acrylic, ethacrylic, ethacrylic, alpha-chloroacrylic, crotonic, beta-acryloxy propionic, sorbic, alpha-chlorsorbic, cinnamic, beta-styrylacrylic, muconic, ita- conic, citraconic, mesaconic, glutaconic, aconitic, alpha-phenyl- acrylic, 2-benzyl acrylic, 2-cyclohexylacrylic, angelic, umbellic, fumaric, maleic acids and anhydrides. Other different olefinic monomers copolymerizable with such carboxylic monomers include vinylacetate, vinyl chloride, dimethyl maleate and the like. Copolymers contain sufficient carboxylic salt groups for water- solubility. Also useful herein are carboxyvinyl polymers, referred to herein earlier as suitable binders, disclosed as toothpaste components in U.S. Patent No. 3.980.767 issued Sept. 14, 1976 to Choun et al., U.S. Patent No. 3.935.306 issued Jan. 27, 1976 to Roberts et al., U.S. Patent No. 3.919.409 issued Nov. 11, 1975 to Peria et al., U.S. Patent No. 3.911.904 issued Oct. 7, 1975 to Harrison, and U.S. Patent No. 3.711.604 issued January 16, 1973 to Colodney et al . They are commercially available for example under the trademarks Carbopol 934, 940, 941 and 956 of B.F. Goodrich, these products consisting essentially of a colloidally water-soluble polymer of polyacrylic acid crosslinked with from about 0.75% to about 2.0% of polyallyl sucrose or polyallyl pentaerythritol as crosslinking agent.

The synthetic anionic polymeric polycarboxylate component is mainly a hydrocarbon with optional halogen and 0-containing substituents and linkages as present in for example ester, ether and OH groups, and when present is generally employed in the instant compositions in approximate weight amounts of 0.05 to 3%, preferably 0.05 to 2%, more preferably 0.1 to 2%.

Another optional component is a fluoride ion source. The sources of fluoride ions, or fluoride-providing compounds, required according to this invention as an essential acid phos- phatase and pyrophosphatase enzyme inhibitor component are well known in the art as anticaries agents and also act as such agents in the practice of this invention. These compounds may be slightly soluble in water or may be fully water-soluble. They are characterized by their ability to release fluoride ions in water and by freedom from undesired reaction with other compounds of the oral preparation. Among these materials are inorganic fluoride salts, such as soluble alkali metal, alkaline earth metal salts, for example, sodium fluoride, barium fluoride, sodium fluor- silicate, ammonium fluorosilicate, sodium fluorozirconate, sodium monofluorophosphate, aluminum mono- and di-fluorophosphate, and fluorinated sodium calcium pyrophosphate. Alkali metal and tin fluorides, such as sodium and stannous fluorides, sodium mono¬ fluorophosphate (MFP) and mixtures thereof, are preferred. The amount of fluoride-providing compound is dependent to some extent upon the type of compound, its solubility, and the type of oral preparation, but it must be a nontoxic amount, generally about 0.005 to about 3.0% in the preparation. In a dentifrice preparation, e.g. dental gel, toothpaste (including cream), an amount of such compound which releases up to about 5,000 ppm of F ion 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 300 to 2,000 ppm, more preferably about 800 to about 1,500 ppm 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 of about 0.1-3%, more typically about 0.76%.

Still another optional component for use in the compositions made using the present process is an anticalculus agent. These agents include any which are effective against calculus such as pyrophosphate salts as disclosed in U.S. Patent 4.515.772. May 7, 1985 incorporated herein by reference. The preferred agents are mono, di, tri and tetra alkali metal and ammonium pyrophosphate. Such agents- are used in amounts sufficient to reduce calculus. These amounts are preferably in an amount of at least about 1% O7. most preferably at least about 1.3%, most preferably at least about 1.5%. .

5 Other anticalculus agents are metal ions such as zinc disclosed in U.S. Patent 4.022.880. May 10, 1977 to Vinson incorporated herein by reference. Still others are polymers such as those described in U.S. Patent 4.661.341. April 28, 1987 to

Benedict and U.S. Patent 3.429.963. February 25, 1969 to

10 Shedlovsky, both of which are incorporated herein by reference.

Such metals are used in an amount of from about 0.01% to about 5%, preferably about 0.1% to about 2%, while such polymers are used in amounts of from about 0.1% to about 10%, preferably from about

0.5% to about 5%.

15 Given below are non-limiting examples which illustrate the processes of the present invention, compositions made using such processes and the use of such compositions.

EXAMPLES I - IV

Given below are four examples of compositions which are made

20 using the processes of the present invention.

Component (I) (II) (III) (IV) (V)

Water 20.518 20.518 14.069 11.165 20.618

Sorbitol (70%) 26.600 26.583 32.000 57.652 26.600

Glycerin 8.000 8.000 8.000 - 8.000

Sodium fluoride 0.243 0.243 0.321 0.243 0.243

Sodium acid pyrophosphate 1.650 1.650 1.650 - 1.650

25 Tetrasodium pyrophosphate 2.160 2.160 2.160 - 2.160

Tetrapotassium 7.379 7.379 6.800 - 7.379 pyrophosphate (60-65%)

Monosodiu phosphate . . . 0.590

Trisodium phosphate - - - 1.450 -

Saccharin 0.470 0.470 0.300 0.300 0.470

FD&C Blue No. 1 - - - 0.050 0.400 _n Titanium dioxide 0.500 0.500 0.700 0.525

^JU Flavor 1.100 1.100 0.970 0.970 1.100

PEG-300 4.000 4.000 4.000 - 4.000

Triclosan 0.280 0.450 0.280 0.280 0.280

Sodium alkyl 6.000 6.000 6.000 6.000 6.000 sulfate (27.9%)

Silica 20.300 20.300 22.000 20.000 20.300

Xanthan gum 0.600 0.600 0.500 0.475 0.600 5 Carbomer 956 0.200 0.200 0.250 0.300 0.200

100.000 100.000 100.000 100.000 100.000 The above compositions are made in a conventional manner for toothpastes except that triclosan, flavor and/or polyethylene glycol (if present) are mixed together and then mixed with the aqueous surfactant solution. This mixture is then added to the remainder of the compositions.

The performance of the above compositions made using the processes of this present invention are superior due to the improved bioavailability of the triclosan antibacterial.

WHAT IS CLAIMED:

Claims

1. A process for making an oral composition containing a non-cationic, water-insoluble antibacterial agent comprising mixing said agent with a solvent for said agent and adding this combination to said composition at the same time as a surfactant or just after said surfactant is added.

2. A process according to Claim 1 wherein said surfactant is an aqueous solution and is mixed with said solvent and said antibacterial prior to all three components being added to said composition.

3. A process according to either of Claims 1 or 2 wherein said solvent is a flavor oil .

4. A process according to either of Claims 1 or 2 wherein said solvent is a glycol .

5. A process according to either of Claims 1 or 2 wherein said solvent is a combination of flavoring oils and glycols.

6. A process according to any of Claims 1-5 wherein said composition is either a toothpaste or mouthwash.

7. A process according to any of Claims 1-6 wherein said composition is a toothpaste.

8. A process according to any of Claims 1-7 wherein said toothpaste contains an abrasive.

9. A process according to any of Claims 1-8 wherein said toothpaste also contains triclosan as the antibacterial agent.

10. A process according to any of Claims 1-9 wherein said toothpaste contains a soluble fluoride ion -source.

11. A process according to any of Claims 1-10 wherein said toothpaste contains an anticalculus agent.

12. A process according to any of Claims 1-11 wherein said anticalculus agent is a soluble pyrophosphate salt.

13. A process according to any of Claims 1-12 wherein said toothpaste contains a binder.