Oral compositions containing monoperoxy acids

Disclosed are oral compositions useful for reducing plaque and gingival or periodontal diseases comprising monoperoxyphthalic acids and having a pH of from about 3.0 to about 5.0.

TECHNICAL FIELD 
The present invention relates to compositions and methods for reducing 
dental plaque and gingival or periodontal diseases through the use of 
specific peroxy acid compositions. 
BACKGROUND OF THE INVENTION 
Peroxy compounds, including monoperoxyphthalic compounds, have been used in 
oral compositions for a variety of purposes such as stain reduction: U.S. 
Pat. Nos. 3,988,433 issued to Benedict on Oct. 26, 1976; 4,273,759 issued 
to Gaffar & Gaffar on Jun. 16, 1981; 4,490,269 issued to Gallopo on Dec. 
25, 1984; and European Patent Application No. 0,133,354 of Interox 
Chemicals, Ltd., published Feb. 20, 1985. Monoperoxyphthalic acid 
compounds have also been disclosed in antigingivitis compositions: U.S. 
Pat. Nos. 4,670,252 issued to Sampathkumar on Jun. 2, 1987; and 4,716,035 
issued Sampathkumar on Dec. 29, 1987. 
The present inventors have discovered that by maintaining the pH of the 
monoperoxy compositions within a certain range enhanced effectiveness of 
the monoperoxy compounds is achieved. 
It is an object of the present invention therefore to provide compositions 
and methods which provide for enhanced antiplaque and antigingivitis 
efficacy through the use of monoperoxy compositions. 
It is a further object of the present invention to provide compositions 
which have enhanced efficacy but also have very low levels of stain. 
These and other objects will become more apparent from the detailed 
description below. 
All percentages and ratios herein are by weight unless otherwise specified. 
Also, all measurements are made at 25.degree. C. unless otherwise 
specified. 
SUMMARY OF THE INVENTION 
The present invention relates to compositions and methods for treating or 
preventing plaque and gingival or periodontal diseases in humans and lower 
animals wherein such compositions comprise: 
(a) a safe and effective amount of a monoperoxyphthalate compound; 
(b) a suitable carrier; 
wherein the composition has a pH of from about 3.0 to about 5.0. 
A detailed description of the essential and optional components of the 
present invention are detailed below. 
Monoperoxyphthalate Compounds 
The present invention relates to monoperoxyphthalate compounds. As used 
herein, monoperoxyphthalate compounds have the structure: 
##STR1## 
or the pharmaceutically acceptable salts or esters thereof, wherein R" may 
be one or more substituents compatible with the peroxy acid functionality 
of the aromatic ring. 
By "substituents compatible with the peroxy acid functionality of the 
aromatic ring", as used, herein, is meant substituents on the ring which 
do not react with peroxy acids thereby reducing the stability and 
effectiveness of the compounds to treat diseases of the oral cavity. 
Nonlimiting examples of R" groups include hydrogen, hydroxy, substituted 
and unsubstituted saturated alkyl having from 1 to about 20 carbon atoms 
(e.g., methyl, ethyl), substituted and unsubstituted aryl (e.g., phenyl, 
naphthyl), substituted and unsubstituted benzyl, chloro, fluoro, nitro, 
sulphonate, trifluoromethyl, trialkylammonium (e.g., trimethylammonium, 
triethylammonium), cyano, carboxy, carboxylate (e.g., --COOCH.sub.3), 
percarboxyl (e.g., --CO.sub.3 H), and alkoxy (e.g., methoxy, ethoxy). 
Preferred R" groups are hydrogen, saturated alkyl having from 1 to about 
20 carbon atoms, aryl, benzyl, chloro, fluoro, carboxy, and alkoxy. 
Particularly preferred is R" being hydrogen. R" may also be an iodo, 
bromo, substituted or unsubstituted amino, or amido group, but such groups 
are generally not desirable since they can react with peroxy acid groups. 
Selection of substituents compatible with the peroxy acid functionality of 
the aromatic ring can easily be made by one skilled in the art. 
By "pharmaceutically-acceptable salts or esters", as used herein, is meant 
esters and salts of substituted or unsubstituted monoperoxyphthalic acid 
compounds which have the same general antibacterial properties as the 
preferred magnesium salt of monoperoxyphthalic acid, and which are 
acceptable from a toxicity viewpoint. Nonlimiting examples of 
pharmaceutically-acceptable salts include alkali metal (e.g., sodium, 
potassium), alkaline earth metal (e.g., calcium, magnesium), non-toxic 
heavy metal, and tetraalkylammonium (e.g., tetraethylammonium). Preferred 
compounds useful in the present invention are the substituted or 
unsubstituted monoperoxyphthalate compounds with 
pharmaceutically-acceptable divalent cation salts (e.g., magnesium, 
calcium), and the magnesium salt being the most preferred. 
Most preferred for use in the present invention is the magnesium salt of 
monoperoxyphthalic acid. This magnesium salt is the salt of the carboxylic 
acid group only, having the structure: 
##STR2## 
(hereinafter referred to as "PAM"), as disclosed in European Patent 
Application No. 27,693, published Apr. 29, 1981, filed by Interox 
Chemicals, Ltd., the disclosure of which is incorporated herein by 
reference. The compound is a hydrate when in its solid form. Synthesis of 
the compound is also disclosed. This compound is also commercially 
available from Interox Chemicals Limited. 
Synthesis of substituted and unsubstituted monoperoxyphthalate compounds 
can be achieved by those skilled in the art using methods disclosed in, 
for example, in addition to European Patent Application No. 27,693, 
European Patent Application No. 66,992 to Interox Chemicals Ltd.; U.S. 
Pat. No. 3,075,921 to Brockelhurst, et al.; "Organic Peroxides", Daniel 
Swern, Editor, published 1970 by John Wiley & Sons, Inc.; and in British 
Patent Specification No. 1,378,671; the disclosures of all of which being 
incorporated herein by reference. 
Suitable Carriers 
Since the monoperoxy phthalate compounds are unstable in aqueous or polar 
solvent media or to exposure to oxidizing/reducing agents, care must be 
taken to avoid exposure of the compounds to such materials where it is 
desired to have the materials in the compositions in total. One way to 
accomplish this is to have two compositions which are combined just prior 
to insertion of the mixed composition into the mouth. Due to aesthetic 
reasons, the anhydrous monoperoxy phthalate part of a toothpaste 
composition would be less than the amount of a major phase which would be 
more like a conventional toothpaste. Of course single phase anhydrous 
systems or systems wherein the peroxy compound in powder form may be added 
to a composition containing potentially unstabilizing components 
immediately prior to use. 
Whatever form the compositions take the monoperoxy phthalate concentration 
in the final (mixed) formulation should be in the range of 0.01% to about 
10%, preferably in the range of 0.1% to about 7.5%, more preferably in the 
range of 0.25% to about 5%. 
Also the final formulation put into the mouth should have a pH of from 
about 3 to about 5, preferably from about 3.5 to about 5, more preferably 
from about 4.0 to about 4.7 and be safe to tooth enamel. The pH control 
agents can be any agents which buffer in the desired pH range. Such agents 
include organic agents such as mono-, di-, tri as well as higher 
polycarboxylates and amino carboxylates. Included among such agents are 
citric acid, malic acid, tartaric acid and gluconic acid among many 
others. 
Inorganic agents may also be used and include phosphates and polyphosphates 
such as pyrophosphate. Phosphonates such as ethylene hydroxy diphosphonate 
may also be used. 
Looking now at materials which may comprise the remainder of the peroxy 
acid minor portion of a toothpaste composition, for example, they include: 
Solvent 
Solvents that are compatible with the peroxy acid can be used. The 
preferred levels of the solvent are 1-95% of the minor, more preferred in 
the range of 5-90% and the most preferred range of 10-70%. In general 
terms, compatible solvents do not appreciably solubilize the proxy acid. 
In practice, solvents include (1) natural hydrocarbons of the general form 
(C.sub.n H.sub.2n+2), wherein n=1, (2) triacetin and other fully 
esterified glycerols, (3) vegetable oils, (4) some high molecular weight 
polyethylene glycols (likely also are polyacids such as polyphosphate, 
polysulfonic; these acids are unlikely to react since they are already 
highly oxidized). 
Thickening Agent 
Thickening agents in the range of 1-95% of the minor phase formulation, 
more preferably in the range of 5-90% and most preferred in the range of 
10-70%. These thickening agents must be substantially compatible with the 
peroxy acid and can thicken nonaqueous nonpolar systems. Thickening agents 
that are useful include (1) natural hydrocarbons (paraffin waxes, 
petroleum jellies), (2) high molecular weight synthetic alkanes (allied 
Signal-homopolymers Ac-x), (3) inert building/thickening agents including 
silicas (precipitated, fumed and silica gels), clays (Bentone gels, 
Veegums), diatomaceous earth, and synthetic silicates (Zeolites). 
Other Components 
Components of Major Phase 
The major, nonperoxy acid composition can contain any of the conventional 
components present in aqueous toothpaste compositions. Optional components 
include: aesthetic additives can be added such as oxidation stable colors, 
flavors, and sweeteners in the range of 0.1% to 20% of the major phase 
formulation. 
Dentifrices generally contain an abrasive polishing material and typically 
also contain sudsing agents, flavoring agents and sweetening agents. 
Toothpaste compositions additionally contain binders, humectants and 
water. 
The dentifrice abrasive, generally has a particle size of from about 0.1 to 
about 10 microns in diameter and can be any abrasive polishing materials 
which does not excessively abrade tooth dentin. These include,, for 
example, silica, both precipitated and gels, calcium carbonate, dicalcium 
orthophosphate dihydrate, calcium pyrophosphate, calcium 
polymethaphosphate and insoluble sodium polymetaphosphate. Preferably, 
however, the abrasive is one which has a high degree of compatibility at 
low pH's with the peroxy compounds and fluoride ions. These include, for 
example silica xerogels such as those described in U.S. Pat. No. 3,538,230 
to Pader et al., issued Nov. 3, 1970; hydrofluoric acid-treated amorphous 
silica abrasives such as those disclosed in U.S. pat. No. 3,862,307 to 
DiGiulio, issued Jan. 21, 1975; mineral abrasives coated with cationic 
polymers such as those disclosed by J. J. Benedict in U.S. Pat. No. 
4,157,387, issued Jun. 5, 1979; and condensation products of urea and 
formaldehyde such as those disclosed in Cooley et al., in U.S. Pat. No. 
3,070,510, issued Dec. 24, 1972. All of these patents are incorporated 
herein by reference. 
The total amount of abrasive materials in the dentifrice embodiments of 
this invention can range from about 0.5% to about 95% by weight of the 
dentifrice. Preferably toothpastes contain from about 6% to about 60% by 
weight and toothpowders contain from about 20% to about 95% by weight 
abrasives. 
Dentifrice compositions can also contain emulsifying agents. Suitable 
emulsifying agents are those which are reasonably stable and foam 
throughout a wide pH range, including nonsoap nonionic, cationic, 
zwitterionic and amphoteric organic synthetic detergents. Many of these 
suitable surfactants are disclosed by Gieske et al. in U.S. Pat. No. 
4,051,234, Sep. 27, 1977, incorporated herein by reference. 
It is common to have a water-soluble fluoride compound present in 
dentifrices in an amount sufficient to give a fluoride concentration of 
from about 0.0025% to about 5.0% by weight, preferably from about 0.005% 
to about 2.0% by weight, to provide anticaries effectiveness. The fluoride 
compounds are believed to provide protection against demineralization as 
well as aid in remineralization of dental enamel. Preferred fluorides are 
sodium fluoride, stannous fluoride, indium fluoride, and sodium 
monofluorophosphate. Norris et al., U.S. Pat. No. 2,946,725, issued Jul. 
26, 1960 and Widder et al., U.S. Pat. No. 3,678,154, issued Jul. 18, 1972 
disclose such salts as well as others. 
In preparing toothpastes, it is necessary to add some thickening material 
to provide a desirable consistency. Preferred thickening agents re 
carboxyvinyl polymers, hydroxyethyl 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 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 an amount from 0.5% 
to 5.0% by weight of the total composition can be used. 
It is also desirable to include some humectant material in a toothpaste to 
keep it from hardening. Suitable humectants include glycerin, sorbitol, 
and other edible polyhydric alcohols. 
The humectant can comprise up to about 65% by weight of the toothpaste 
composition. 
With both humectants and binders, care must be taken if these are combined 
with the peroxy compound that they do not activate the compound before the 
product is used. 
Flavoring agents can also be added to dentifrice compositions. Suitable 
flavoring agents include oil of wintergreen, oil of peppermint, menthol, 
oil of spearmint, oil of sassafras, and oil of clove. Sweetening agents 
which can be used include aspartame, magna sweet, acesulfame, saccharin, 
dextrose, levulose and sodium cyclamate. Flavoring and sweetening agents 
are generally used in dentifrices at levels of from about 0.005% to about 
2% by weight. 
Another preferred embodiment of the major portion present invention is a 
mouthwash composition. Mouthwashes generally comprise about 20:1 to about 
2:1 of a water/ethyl alcohol solution and preferably other ingredients 
such as fluoride ion sources, flavor, sweeteners, humectants, and sudsing 
agents such as those mentioned above for dentifrices. 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 humectant, 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 
about 1.67% fluoride ions (preferably from about 0.0017% to about 0.67%), 
0% to 0.3% (preferably 0.03% to 0.3%) flavoring agent, and the balance 
water. 
The minor portion if in mouthwash form would contain only anhydrous 
materials such as glycerin or similar materials. 
The compositions of the present invention may also include tartar control 
agents and antidemineralization agents. 
Tartar control agents can be added to this formulation to provide 
additional consumer benefits. Agents which can chelate calcium or prevent 
the crystallization/crystal growth of calcium phosphates are useful. 
Included in this group are chelating agents (EDTA, NTA, other 
carboxylates, aminocarboxylates), and agents which prevent crystal growth 
of natural calcium phosphates in the mouth. Such agents include (1) 
polyphosphates (including pyrophosphate and phosphocitrate, at least at 
0.5%, preferably in the range of 1-10% and most preferably in the range of 
2-6%), (2) phosphonates (including linear and cyclic alkyl diphosphonates 
at least at levels of 0.25%, more preferably in the range of 0.5-10% and 
the most preferred range of 1-6%), and (3) zinc containing components in 
the range of 0.1% to 10%, more preferably in the range of 0.25% to 7.5% 
and most preferred in the range of 0.5-5% on a zinc basis. The zinc should 
be complexed to allow for efficacious soluble levels of zinc. Chelators 
are effective complexing agents and carboxyl based chelating agents are 
preferred, especially citrate. 
Materials that can prevent/slow down the dimineralization of enamel and 
dentin are useful in this range of pH's below 4. Included are fluorides, 
phosphates, pyrophosphates, stannous ion, indium ion, titanium ion, zinc 
ion. Levels that effectively protect the enamel surface range from 0.01% 
to 10%. 
In addition to toothpaste and mouthwash compositions, the peroxy acid 
component can be formulated as a dry powder or tablet or capsule with dry 
flavoring, sweetening agents and mixed with an aqueous solution just prior 
to use in the mouth. 
METHOD OF MANUFACTURE 
Minor Phase 
A method for manufacturing the minor phase of Example VI is as follows: the 
mineral oil is heated to approximately 55.degree. C. with agitation. The 
petrolatum is then added, again with agitation. The combination is mixed 
vigorously for about two minutes. The heat source is removed and the 
peroxy acid is slowly dispersed in the mixture. The mixing of these 
materials is such to produce a smooth and creamy texture. The material is 
then milled, deaerated and packed into appropriate packages. 
In addition to the oil/wax formulations described above, silica (such as 
the high oil absorbency silicas, Zeodent 163, Zeothix 265 manufactured by 
Humber Chemical Co.) can replace the wax. Other high oil absorbency 
silicas (fumed, precipitated and silica gels) can also replace the wax. 
Typically the manufacturing of this phase is accomplished by adding the oil 
(all acceptable grade mineral oils as differentiated by viscosity) to an 
appropriate mixing system, such as a double planetary mixer or other 
appropriate bath processing system, and then adding the silica. This is 
mixed at ambient temperature to achieve a stable gel. The active 
ingredient, PAM, is then added to the system at ambient temperature. Other 
acceptable excipients, sweeteners (such as monoammonium glycerrhyzinate, 
saccharin, cyclamates) or inert, unreactive components are added at this 
time. The system is mixed to achieve a homogeneous suspension. 
The physical stability of these systems depends on the PAM concentration 
and the silica/oil (w/w) ratio. For high total solids levels (40-60% (w/w) 
determined as the sum of the PAM and the excipients, but not including the 
silica), a silica/oil ratio of 0 to 0.2 is preferred. At lower solids 
levels (less than 40%), higher silica/oil ratios are needed to achieve 
homogeneous, physically stable formulations. These formulations are 
designed to attain a balance between physical stability and acceptable 
rheology. 
These systems (mineral oil/wax/PAM and mineral oil/silica/PAM) described 
above are amenable to continuous processing as well as batch processing. 
Major Phase 
The manufacturing of the major phase parallels typical dentifrice 
manufacturing. The water is added to an appropriate mix tank and heated. 
An adequate amount of humectant is added to the mix tank and agitated for 
2-5 minutes. The basic form of the buffer is added and dissolved in the 
mix tank. The components are agitated in the tank to ensure complete 
dissolution of this material. The acidic form of the buffer is then added 
followed by the sweetener. All components are agitated to ensure complete 
dissolution and mixing. The abrasive is slowly added to the mix tank with 
agitation. This is agitated for approximately 10 minutes, increasing speed 
of mixer as appropriate. The fluoride is added to the mix tank as is the 
opaquing agent (if any). The foaming agent is then added and mixed slowly 
to fully disperse the components. In a separate mix tank, the remaining 
humectant is added and the binder(s) are dispersed into the humectant. 
This mixture is agitated to an appropriate consistency. The binder slurry 
is added to the main mix tank and agitated. Any color and flavor 
components are added and the mixture is agitated to an appropriate 
consistency. The mixture is milled, dearated and packed into appropriate 
packages. 
A process for manufacturing powders of the type disclosed in Examples 
XII-XV can be as follows. The peroxy acid, the buffers and the sweetener 
are mixed in a blender and mixed for two minutes. The flavor and dyes, if 
present, are then added and the entire mixture is mixed for ten minutes. 
COMPOSITION USE 
The compositions of the present invention are used by combining the two 
phases, if present, just prior to use and used by the user for a period of 
normal use (e.g., 10 seconds to 5 minutes).