CA2006716C - Antibacterial antiplaque oral composition - Google Patents
Antibacterial antiplaque oral composition Download PDFInfo
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- CA2006716C CA2006716C CA 2006716 CA2006716A CA2006716C CA 2006716 C CA2006716 C CA 2006716C CA 2006716 CA2006716 CA 2006716 CA 2006716 A CA2006716 A CA 2006716A CA 2006716 C CA2006716 C CA 2006716C
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Abstract
An oral composition dentifrice containing an orally acceptable vehicle, about 30-75 % by weight of a dentally acceptable water-insoluble polishing agent, a substantially water-insoluble noncationic antibacterial antiplaque agent, such as 2,4,4'-trichloro-2 1-hydroxy-diphenyl ether (triclosan) an antibacterial enhancing agent which enhances the delivery of said antibacterial agent to, and retention thereof on, oral surfaces, and a surface active agent and/or a flavoring oil.
Description
~~E~'~~~E~
This invention relates to an antibacterial antiplaque oral composition dentifrice. More particularly, it relates to an oxal composition dentifrice containing a substantially water-insoluble noncationic antibacterial agent effective to inhibit plaque.
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, besides being unsightly, it is implicated in the occurrence of gingivitis.
Accordingly, it is highly desirable to include antimicrobial agents which have been known to reduce plaque in oral compositions. Frequently, cationic antibacterial agents have been suggested. Moreover, in U.S. Patent 4,022,880 to Vinson et al, a compound providing zinc ions as an anticalculus agent is admixed with an antibacterial agent effective to retard the growth of plaque bacteria. A wide variety of antibacterial agents are described with the zinc compounds including cationic materials such as guanides and quaternary ammonium compounds as well as non-cationic compounds such as halogenated salicylanilides and halogenated hydroxydiphenyl ethers. The noncationic antibacterial antiplaque halogenated hydroxydiphenyl ether, triclosan, has also been described in combination with zinc citrate trihydrate in European Patent Publication 0161,899 to Saxton et al.
Triclosan is also disclosed in European Patent Publication 0271,332 to Davis as a toothpaste component in a carrier system containing a solubilizing agent such as propylene glycol.
The cationic antibacterial materials such as chlorhexidine, benzathonium chloride and cetyl pyridinium chloride have been the subject of greatest investigation as antibacterial antiplaque agents. However, they are generally not effective when used with anionic materials. ldoncationic antibacterial materials, on the other hand, can be compatible with anionic components in an oral composition.
This invention relates to an antibacterial antiplaque oral composition dentifrice. More particularly, it relates to an oxal composition dentifrice containing a substantially water-insoluble noncationic antibacterial agent effective to inhibit plaque.
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, besides being unsightly, it is implicated in the occurrence of gingivitis.
Accordingly, it is highly desirable to include antimicrobial agents which have been known to reduce plaque in oral compositions. Frequently, cationic antibacterial agents have been suggested. Moreover, in U.S. Patent 4,022,880 to Vinson et al, a compound providing zinc ions as an anticalculus agent is admixed with an antibacterial agent effective to retard the growth of plaque bacteria. A wide variety of antibacterial agents are described with the zinc compounds including cationic materials such as guanides and quaternary ammonium compounds as well as non-cationic compounds such as halogenated salicylanilides and halogenated hydroxydiphenyl ethers. The noncationic antibacterial antiplaque halogenated hydroxydiphenyl ether, triclosan, has also been described in combination with zinc citrate trihydrate in European Patent Publication 0161,899 to Saxton et al.
Triclosan is also disclosed in European Patent Publication 0271,332 to Davis as a toothpaste component in a carrier system containing a solubilizing agent such as propylene glycol.
The cationic antibacterial materials such as chlorhexidine, benzathonium chloride and cetyl pyridinium chloride have been the subject of greatest investigation as antibacterial antiplaque agents. However, they are generally not effective when used with anionic materials. ldoncationic antibacterial materials, on the other hand, can be compatible with anionic components in an oral composition.
However, oral compositions typically are mixtures of numerous components and even such typically neutral materials as humectants can affect performance of such compositions.
Moreover, even noncationic antibacterial antiplaque agents may have limited antiplaque effectiveness with commonly used materials such as polyphosphate anticalculus agents which are disclosed together in British Patent Publication 22 00551 of Gaffar et al and in EP 0251591 of Jackson et al. In Canadian Patent Application No. 2,006,718 it is shown that the antiplaque effectiveness is greatly enhanced by including an antibacterial-enhancing agent (AEA) which enhances the delivery of said antibacterial agent to, and retention thereof on, oral surfaces, and providing optimized amounts and ratios of polyphosphate and AEA.
Further, even when polyphosphate anticalculus agent is not present as in Canadian Patent Application No. 2,006,718 antiplaque effectiveness on soft oral tissue is optimized by including with the AEA a solubilizing material which dissolves the noncationic antibacterial agent in saliva when the polishing agent is a siliceous polishing agent present in amount of about 5-30%. Indeed, when the amount of noncationic antibacterial agent is optimized, even the special solubilizing material is not required, as in Canadian Patent Application No. 2,006,707 and Canadian Patent No. 2,006,703.
Moreover, even noncationic antibacterial antiplaque agents may have limited antiplaque effectiveness with commonly used materials such as polyphosphate anticalculus agents which are disclosed together in British Patent Publication 22 00551 of Gaffar et al and in EP 0251591 of Jackson et al. In Canadian Patent Application No. 2,006,718 it is shown that the antiplaque effectiveness is greatly enhanced by including an antibacterial-enhancing agent (AEA) which enhances the delivery of said antibacterial agent to, and retention thereof on, oral surfaces, and providing optimized amounts and ratios of polyphosphate and AEA.
Further, even when polyphosphate anticalculus agent is not present as in Canadian Patent Application No. 2,006,718 antiplaque effectiveness on soft oral tissue is optimized by including with the AEA a solubilizing material which dissolves the noncationic antibacterial agent in saliva when the polishing agent is a siliceous polishing agent present in amount of about 5-30%. Indeed, when the amount of noncationic antibacterial agent is optimized, even the special solubilizing material is not required, as in Canadian Patent Application No. 2,006,707 and Canadian Patent No. 2,006,703.
It is an advantage of this invention that an oral composition dentifrice containing an effective antiplaque amount of a substantially water-insoluble noncationic antibacterial antiplaque agent and said AEA to inhibit plaque formation and a dentally acceptable water-insoluble polishing agent in amount of about 30-75% is provided, wherein polyphosphate anticalculus agent is not present.
3a It is an advantage of this invention that the said AEA
enhance the delivery and retention of the antibacterial agent on teeth and on soft oral tissues but Examples 1 and 3 contain 0.5-2o propylene glycol without requiring the presence of a material which dissolves the antibacterial agent in saliva.
It is a further advantage of this invention that an antiplaque oral composition is provided which is directly or indirectly effective to reduce the occurrence of gingivitis.
Additional advantages of this invention will be apparent from consideration of the following specification.
In accordance with an aspect, this invention relates to an oral composition dentifrice comprising in an orally acceptable vehicle, about 30-75% of a dentally acceptable water-insoluble polishing agent, an effective antiplaque active ingredient amount of a substantially water insoluble noncationic anti-bacterial agent, at least one of a surface-active agent or a flavoring oil and about 0.005-4o by weight of the AEA, wherein the oral composition dentifrice is substantially free of polyphosphate anticalculus agent.
In accordance with another aspect, the invention relates to an oral dentifrice composition comprising in an orally acceptable vehicle, about 30-75% of a dentally acceptable water insoluble polishing agent, about 0.01-50 of a substantially water insoluble noncationic antibacterial agent, and about 0.05-4% of a copolymer of malefic acid or anhydride with methyl vinyl ether, the composition containing one or both of a surface active agent and a flavoring oil.
In accordance with a further aspect, the invention relates to an oral dentifrice composition comprising in an orally acceptable vehicle, about 30-75% of a dentally acceptable water insoluble polishing agent, about 0.01-5% of a substantially water insoluble noncationic antibacterial agent, and about 0.05-4% of poly (beta-styrenephosphonic acid), copoly (beta-styrenephosphonic acid/vinyl phosphonic acid) or poly (alpha-styrenephosphonic acid), the composition containing one or both of a surface active agent and a flavoring oil.
In accordance with still another aspect, the invention relates to an oral dentifrice composition comprising in an orally acceptable vehicle, about 30-75% by weight of a dentally acceptable water-insoluble polishing agent, an effective antiplaque amount of a substantially water insoluble noncationic antibacterial agent and an antibacterial-enhancing agent which has an average molecular weight or about 1,000 to about 1,000,000, contains at least one delivery enhancing functional group and at least one organic retention enhancing group, the agent containing the groups being free from or substantially free from water soluble alkali metal or ammonium synthetic anionic linear polymer polycarboxylate salt having a molecular weight of about 1,000 to about 1,000,000.
In accordance with a still further aspect, the invention relates to an oral composition dentifrice comprising about 30-4a 75% by weight of a dentally acceptable water insoluble polishing agent, an effective antiplaque amount of a substantially water insoluble noncationic antibacterial agent, about 0.05-4% by weight of a polyvinyl phosphate having a recurring group of the formula:
HO-P=O
I
OH
and an average molecular weight of about 1,000 to about 1,000,000 and an orally acceptable vehicle effective to enable the antibacterial agent to dissolve in saliva in effective antiplaque amount, wherein the oral composition has a pH of about 4.5 to about 10.
Typical examples of water insoluble noncationic antibacterial agents which are particularly desirable from considerations of antiplaque effectiveness, safety and formulation are:
Halogenated biphenyl Ethers 2',4,4'-trichloro-2'-hydroxy-diphenyl ether (Triclosan) 2,2'-dihydroxy-5,5'-dibromo-diphenyl ether.
Halogenated Salicylanilides 4',5-dibromosalicylanilide 3,4',5-trichlorosalcylanilide 3,4',5-tribromosalicylanilide 2,3,3',5-tetrachlorosalicylanilide 3,3,3',5-tetrachlorosalicylanilide 4b ~~~.i'~~.'~a 3,5-dibromo~3'-trifluoromethyl salicylanilide 5-n-octanoyl-3'-trif:Luoromethyl salicylanilide 3,5-dibromo-4'-trifluoromethyl salicylanilide 3,5-dibromo-3°-trifluora methyl salicylanilide (Flurophene) Benzoic Esters Methyl - p-Hydroxybenzoic Ester Ethyl - p-IIydroxybenzoic Ester Propyl - p-Hydroxybenzoic Ester Butyl - p-Hydroxybenzoic Ester Halo~enated Carbanilides 3,4,4'-trichlorocarbanilide 3-trifluoramethyl-4,4'-dichlorocarbanilide 3,3,4'-trichlorocarbanilide Phenolic Compounds (including phenol and its homologs, mono- and poly-alkyl and aromatic halo (e. g. F, C1, Br, I)-phenols, resorcinol and catechol and their derivatives and bisphenolic compounds). Such compounds include inter alias Phenol and its Homolo~s Phenol 2 Methyl - Phenol 3 Methyl - Phenol 4 Methyl - Phenol 4 Ethyl - Phenol 2,4-Dimethyl - Phenol 2,5-Dimethyl - Phenol 3,4-Dimethyl - Phenol 2,6-Dimethyl - Phenol 4-n Propyl - Phenol 4-n-Butyl - Phenol 4-n-Amyl - Phenol 4-tort-Amyl - Phenol 4-n-Hexyl - Phenol 4-n-Heptyl - Phenol 2-Methoxy-4-(2-Propenyl)-Phenol (Eugenol) 2-Isopropyl-5-Methyl- Phenol (T'hymol) Mono- and Poly-Alkyl and Aralkyl Halo~phenols Methyl - p-Chlorophenol Ethyl - p-Chlorphenol n-Propyl - p-Chlorophenol n-Butyl - p-Chlorophenol n-Amyl - p-Chlorophenol sec-Amyl p-Chlorophenol n-Hexyl - p-Chlorophenol Cyclohexyl - p-Chlorophenol n-Heptyl - p-Chlorophenol n-Octyl - p-Chlorophenol ~~~i'~~..~
0-Chlorophenol Methyl - o-Chlorophenol Ethyl - o-Chlorophenol n-Propyl - o-Chlorophenol n-Butyl - o-Chlorophenol n-Amyl - o-Chlorophenol tert-Amyl - o-Chlorophenol n-Hexyl - o-chlorophenol n-Heptyl - o-Chloropenol p-Chlorophenol o-Benzyl - p-Chlorophenol o-Benzyl-m-methyl - p-Chlorophenol o-Benzyl-m, m-dimethyl - p-Chlorophenol o-Phenylethyl - p-Chlorophenol o-Phenylethyl-m-methyl - p-Chlorophenol 3-Methyl - p-Chloxophenol 3,5-Dimethyl - p-Chlorophenol 6-Ethyl-3-methyl - p-Chlorophenol b-n-Propyl-3-methyl - p-Chlorophenol 6-iso-propyl-3-methyl - p-Chlorophenol 2-Ethyl-3,5-dimethyl - p-Chlorophenol 6-se~ 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 Octyl-3-methyl - p-Chlorophenol p-Bromophenol Methyl - p-Bromophenol ~~.)~~i'~~.~~
Ethyl - p-Bromophenol n-Propyl - p-Bromophenol n-Butyl - p-Bromophenol n-Amyl - p-Bromophenol sec-Amyl - p-Bromophenol n-FIexyl - p-Bromophenol cyclohexyl - p-Bromophenol o-Bromophenol tert-Amyl - o-Bromophenol n-Hexyl - o-Bromophenol n-Propyl-m,m-Dimethyl o-Bromophenol -2-Phenyl Phenol 4-Chlora-2-methyl phenol 4-chloro-3-methyl phenol 4-chloro-3,5-dimethyl phenol 2,4-dichloro-3,5-dimethyl phenol 3,4,5,6-tetrabromo-2-methylphenol 5-methyl-2-pentylphenol 4-isopropyl-3-methylphenol 5-chloro-2-hydroxydiphenyl methane Resorcinol and Its Derivat3~es Resorcinol Methyl - Resorcinol Ethyl - Resorc inol n-Propyl - Resorcinol n-Butyl - Resorcinol n_~yl - Resorcinol n-Hexyl - Resorcinol n-Heptyl - Resorcinol n-Octyl - Resorcinol ~'~a~'.~.~
n-Nonyi - Resorcinol Phenyl - Resorcinol Benzyl - Resorcinol Phenylethy:L- Resorcinol Phenylpropyl- Resorcinol p-ChlorobenzylResorcinol 5-Chloro -2,4-DihydroxydiphenylMethane 4'-Chloro -2,4-DihydroxydiphenylMethane 5-Bromo -2,4-DihydroxydiphenylMethane 4-Bromo -2,4-DihydroxydiphenylMethane Bisphenolic Compounds Bisphenol A
2,2'-methylene bis (4-chlorophenol) 2,2'-methylene bis (3,4,6-trichiorophenol) (hexachlorophene) 2,2'-methylene bis (4-chloro-6-bromophenol) bis (2-hydroxy-3,5-dichlorophenyl) sulfide bis (2-hydroxy-5-chlorobenzyl) sulfide The noncationic antibacterial agent is present in the oral composition in an effective antiplaque amount, typically about 0.01-5% by weight, preferably about 0.03-1% and more preferably about 0.3-0.5%. 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%.
The preferred halogenated diphenyl ether is triclosan. The preferred phenolic compounds are phenol, thymol, eugenol, hexyl resorcinol and 2,2'methylene bis (4-chioro-6-bromophenol). The most preferred antibacterial antiplaque compound is triclosan. Txiclosan is disclosed in aforementioned U.S. Patent 4,022,880 as an antibacterial agent in combination with an anticalculus agent which provides zinc ions and in ~~~'~~~..f~
German Patent Disclosure 3532860 in combination with a copper compound. In European Patent Disclosure 0278744 it is disclosed in combination with a tooth desensitizing agent containing a source of potassium ions. Tt is also disclosed as an antiplaque agent in a dentifrice formulated to contain a lamellar liquid crystal surfactant phase having a lamellar spacing of less than 6.0 nm and which may optionally contain a zinc salt in published European Patent Application 0161898 of Lane et al and in a dentifrice containing zinc citrate trihydrate in published European Patent Application 0161899 to Saxton et al.
The antibacterial-enhancing agent (AEA) which enhances delivery o.f said antibacterial agent to, and retention thereof on, oral surfaces, is employed in amounts effective to achieve such enhancement within the range in the oral composition of about 0.05 to about 4%, preferably about 0.1% to about 3%, more preferably about 0.5% to about 2.5% by weight.
This AEA may be a simple compound, preferably a polymerizable monomore, more preferably a polymer, which latter 'term is entirely generic, including for example oligomers, homopolymers, copolymers of two or more monomers, block copolymers, graft copolymers, crass-linked polymers and copolymers, and the like. The AEA may be natural or synthetic, and water insoluble or preferably water (saliva) soluble or swellable (hydratable, hydrogel forming). Tt has an (weight) average molecular weight of about 100 to about 1,000,000, preferably about 1,000 to about 1,000,000, more preferably about 2,000 or 2,500 to about 250,000 or 500,000.
The AEA ordinarily contains at least one delivery-enhancing group, which is preferably acidic such as sulfonic, phosphinic, or more preferably phosphonic or carboxylic, or salt thereof, e.g. alkali metal or ammonium, and at least one organic retention-enhancing group, preferably a plurality of both the delivery-enhancing and retention-enhancing groups, which latter groups preferably have the formula -(X)"-R wherein X is 0, N, S, S0, SOz, P, PO or Si or the likes, R is hydrophobic alkyl, alkenyl, acyl, aryl, alkaryl, aralkyl, heterocycl.ic or their inert-substituted derivatives, and n is zero or 1 or more. The aforesaid "inert-substituted derivatives", are intended to include substituents on R which are generally non-hydrophilic and do no significantly interfere with the desired functions of the AEA as enhancing the delivery of the antibacterial agent to, and retention thereof on, oral surfaces such as halo, e.g. Cl, Pr, I, and carbo and the like.
Illustrations of such retention-enhancing groups are tabulated below.
n X -(X)"R
p --- methyl, ethyl, propyl, butyl, isobutyl, t-buryl, cyclohexyl, allyl, benzyl, phenyl, chlorophenyl, xylyl, pyridyl, furanyl, acetyl, benzoyl, butyryl, terephthaloyl, etC.
1 D ethoxy, benzyloxy, thioacetoxy, phenoxy, carboethoxy, carbobenzyloxy, etc.
N ethylamino, diethylamino, propylamido, benzylamino, benzoylamido, phenylacetamido, etc.
S thiobutyl, thioisobutyl, thioallyl, thiobenzyl, thiophenyl, thiopropionyl; phenylth:ioacetyl, thiobenzoyl, etc.
SO butylsulfoxy, allylsulfoxy, benzylsulfoxy, phenylsulfoxy, etc.
SOZ butylsulfonyl, allylsulfonyl, benzylsulfonyl, phenylsulfonyl, etc.
p diethylphosphinyl, ethylvinylphosphinyl, ethylallylphosphinyl, ethylbenzylphosphinyl, ethylphenylphosphinyl, etc.
PO diethylphosphinoxy, ethylvinylphosphinoxy, methylallylphosphinoxy; methylbenzylphosphinoxy, methylphenylphosphinoxy, etc.
Si trimethylsilyl, dimethylbutylsilyl, dimethylbenzylsilyl, dimethylvinylsilyl, dimethylallylsilyl, etc.
As employed herein, the delivery-enhancing group refers to one which attaches or substantively, adhesively, cohesively or otherwise bonds the AEA
(carrying the antibacterial agent) to oral (e. g. tooth and gum) surfaces, ~~(~E~~"~~_~
thereby "delivering" the antibacterial agent to such surfaces. The organic retention-enhancing group, generally hydrophobic, attaches or otherwise bonds the antibacterial agent to the AEA, thereby promoting retention of the antibacterial agent to the AF.A and indirectly on the oral surfaces. In some instances, attachment of the antibacterial agent occurs through physical entrapment thereof by the AEA, especially when the AEA is a cross-linked polymer, the structure of which inherently provides increased sites for such entrapment. The presence of a higher molecular weight, ore hydrophobic cross-linking moiety in the cross-linked polymer still further promotes the physical entrapment of the antibacterial agent to or by the cross-linked AFA
polymer.
Preferably, the AEf1 is an anionic polymer comprising a chain or backbone containing repeating units each preferably containing at least one carbon atom and preferably at least one directly or indirectly pendant, monovalent delivery-enhancing group and at least one directly or indirectly pendant monovalent retention-enhancing group geminally, vicinally or less preferably otherwise bonded to atoms, preferably carbon, in the chain. Less preferably, the polymer may contain delivery-enhancing groups and/or retention-enhancing groups and/or other divalent atoms or groups as links in the polymer chain instead of or in addition to carbon atoms, or as cross-linking moieties.
It will be understood that any exacoples or illustrations of AF~I~s disclosed herein which do not contain 'both delivery-enhancing groups and retention enhancing groups may and preferably should be chemically modified in known manner to obtain the preferred AEA's containing both such groups and preferably a plurality of each such groups. In the case of the preferred polymeric AEA's, it is desirable, for maximizing substantivity and delivery of the antibacterial agent to oral surfaces, that the repeating units in the polymer chain or backbone containing the acidic delivery enhancing groups constitute at least about 10%, preferably at least about 507, more preferably at least about 807 up to 957 or 1007 by weight of the polymer.
According to a preferred embodiment of this invention, the AEA
comprises a polymer containing repeating units in which one or more phosphoric acid delivery-enhancing groups are bonded to one or more carbon atoms in the polymer chain. An example of such an AEA is poly (vinyl phosphoric acid) containing units of the formula:
I -[CHZ - ~H]-P03H~
which however does not contain a retention-enhancing group. A group of the latter type would however be present in poly (1-phosphonopropene) with units of the formula:
II -(CH - CH]-GH3 ~03Ha A preferred phosphoric acid-containing AEA for use herein is poly (beta styrene phosphoric acid) containing units of the formula:
III -(CH - CH]-Ph ,~03Ha wherein Ph is phenyl, the phosphoric delivery-enhancing group and the phenyl retention-enhancing group being bonded on vicinal carbon atoms in the chain, or a copolymer of beta styrene phosphoric acid with vinyl phosphonyl chloride having the units of the foregoing formula III alternating or in random association with units of formula I above, or poly (alpha styrene phosphoric acid) containing units of the formula:
IV -[CHZ - ~ -]_ Ph~03H2 in which the delivery - and retention - enhancing groups are geminally bonded to the chain.
These styrene phosphoric acid polymers and their copolymers with other inert ethylenically unsaturated monomers generally have molecular weights in ~
the range of about 2,000 to about 30,000, preferably about 2,500 to about 10,000, and are, with their methods of preparation disclosed and claimed in Canadian Patent No. 2,006,703. Such "inert" monomers do not significantly interfere with the intended function of any copolymer employed as an AEA herein.
Other phosphonic-containing polymers include, for example, phosphonated ethylene having units of the formula.
V -[CH2]14CHP03H2]n-where n may for example be an integer or have a value giving the polymer a molecular weight of about 3,000; and sodium poly (butene-4,4-diphosphonate) having units of the formula:
VI -[CH2 = CH ----]-CH2/ - CH < (P03Na2)2 and poly (allyl bis (phosphonoethyl) amine) having units of the formula:
VII - [CH2~CH ---] -CH2 - N < ( P03H2 ) 2 Other phosphonated polymers, for example poly (allyl phosphono acetate), phosphonated polymethacrylate, etc. and the geminal disphosphonate polymers disclosed in EP Publication 0321233 may be employed herein as AEA's, provided of course that they contain or are modified to contain the above-defined organic retention-enhancing groups.
In an aspect of the invention, the oral dentifrice composition comprises an orally acceptable vehicle, about 3-75%
by weight of a dentally acceptable water-insoluble polishing agent, an effective antiplaque amount of a substantially water insoluble noncationic antibacterial agent and an antibacterial-enhancing agent which has an average molecular weight of about 1,000 to about 1,000,000, contains at least one delivery enhancing functional group and at least one organic retention enhancing group, said 14a agent containing said groups being free from or substantially free from water soluble alkali metal or ammonium synthetic anionic linear polymer polycarboxylate salt having a molecular weight of about 1,000 to about 1,000,000 Although not used in the present invention to coact with polyphosphate anticalculus agent, synthetic anionic polymeric polycarboxylate having a molecular weight of about 1,000 to about 1,000,000, preferably about 30,000 to about 500,000, has been used as an inhibitor of alkaline phosphatase enzyme in optimizing anticalculus effectiveness of linear molecularly dehydrated polyphosphate salts, as disclosed in U.S. Patent 4,627,977 to Gaffer et al. Indeed, in published British Patent Publication 22 00551, the polymeric polycarboxylate is disclosed as an optional ingredient in oral compositions containing linear molecularly dehydrated polyphosphate salts and substantially water-insoluble noncationic antibacterial agent. It is further observed, in the context of the present invention that such polycarboxylate is markedly effective to enhance delivery and retention of the noncationic antibacterial, antiplaque agent to dental surfaces when another ingredient with which the polymeric polycarboxylate would coact (that is, molecularly dehydrated polyphosphate) is absent; for instance, when the ingredient with which the polymeric polycarboxylate coacts is especially the noncationic antibacterial agent.
Synthetic anionic polymeric polycarboxylates and their complexes with various cationic germicides, zinc and magnesium have been previously disclosed as anticalculus agents per se in, for example U.S. Patent No.
3,429,963 to Shedlovsky; U.S. Patent No. 4,152,420 to Gaffer; U.S. Patent No. 3,956,480 to Dichter et al; U.S. Patent No. 4,138,477 to Gaffer; and U.S. Patent No. 4,183,914 to Gaffer et al. It is to be understood that the synthetic anionic polymeric polycarboxylates so disclosed in these several patents when containing or modified to contain the above-defined retention-enhancing groups are operative as AEA's in the compositions and methods of ~~~.DFS~~~D
this invention and such disclosures are to, that extent incorporated herein by reference thereto.
These synthetic anionic polymeric polycarboxylates are often employed in the form of their free acids or preferably partially or more preferably fully neutralized water soluble or water-swe11ab1e (hydratable, gel-forming) alkali metal (e. g. potassium and preferably sodium) or ammonium salts.
Preferred are 1:4 to 4:1 copolymers of malefic anhydride or acid with another polymerizable ethylenically unsaturated monomer, preferably methyl vinyl ether (malefic 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, e.g. AN 139 (M. W. 500,000), AN 119 (M. W. 250,000); and preferably S-97 Pharmaceutical Grade (M. W.
70,000), of GAF Corporation.
Other AEA-operative polymeric polycarboxylates containing or modified to contain retention-enhancing gxoups include those disclosed in U.S. Patent No. 3,956,480 referred to above, such as the 1:1 copolymers of malefic anhydride with ethyl acxylate, 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, isobutyl vinyl ether or N-vinyl-2-pyrrolidone.
Additional operative polymeric polycarboxylates disclosed in above referred to U.S. Patent No. 4,138,477 and 4,183,914 containing or modified to contain retention-enhancing groups, include copolymers of malefic anhydride with styrene, isobutylene or ethyl vinyl ether, polyacrylic, polyitaconic and polymaleic acids, and sulfoacrylic oligomers of M.W. as low as 1,000, available as Uniroyal ND-2.
Suitable generally axe retention-enhancing group-containing polymerized olefinically or ethylenically unsaturated carboxylic acids containing an activated carbon-to-carbon olefinic double bond which readily functions in ~~a'~'_'~...
polymerization because of its presence in the monomer molecule either in the alpha-beta position with respect to a carboxyl group or a part of a terminal methylene grouping. Illustrative of such acids are acrylic, methacrylic, ethacrylic, alpha-chloroacrylic, crotonic, beta-acryloxy propionic, sorbic, alpha-chlorsorbic, cinnamic, beta-styrylacrylic, muconic, itaconic, citraconic, mesaconic, glutaconic, aconitic, alpha-phenylacrylic, 2-benzyl acrylic, 2-cyclohexylacrylic, angelic, umbellic, fumaric, malefic acids and anhydrides. Other different olefinic monomer copolymerizable with such carboxylic monomers includ vinylacetate, vinyl chloride, dimethyl maleate and the like. Copolymers ordinarily contain sufficient carboxylic salt groups for water-solubility.
Also useful herein are so-called carboxyvinyl polymers disclosed as toothpaste components in U.S. 3,980,767 to Chown et al;U.S. 3,935,306 to Roberts et al; U.S. 3,919,409 to Perla et al; U.S. 3,911,904 to Harrison, and U.S. 3,711,604 to Colodney et al. 'they axe commercially available for example under the trademarks Carbopol 934, 940 and 941 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 2.07 of polyallyl sucrose or polyallyl pentaerythritol as cross linking agent, the cross-linked structures and linkages in these and other cross-linked polymeric AEA~s,providing the desired retention enhancement by hydrophobicity when adequate, and/or physical entrapment of the antibacterial agent. Polycarbophil, being polyacrylic cross-linked with less than 0.1% divinyl glycol, the lowex proportion, molecular weight, and/or hydrophobicity of this cross-linking agent tending to provide decreased or no retention enhancement 2,5-dimethyl--1,5-hexadiane, exemplifies a more effective retention-enhancing cross-linking agent.
The synthetic anionic polymeric polycarboxylate component is most often a hydrocarbon with option halogen and 0-containing substituents and linkages as present in for example ester, ether and OH groups, and is employed in the instant compositions in approximate weight amounts of 0.05 to 47, preferably 0.05 to 3%, more preferably 0.1 to 2%.
The AEA may also comprise natural anionic polymeric polycarboxylates containing retention-enhancing groups. Carboxymethyl cellulose and other binding agents gums and film-formers devoid of the above-defined delivery-enhancing and/or retention-enhancing groups are ineffective as AEA's.
As illustrative of AEA's containing phosphinic acid and/or sulfonic acid delivery enhancing groups, there may be mentioned polymers and copolymers containing units or moieties derived from the polymerization of vinyl or allyl phosphinic and/or sulfonic acids substituted as needed on the 1 or 2 (or 3) carbon atom by an organic retention-enhancing group, for example having the formula -(X)"-li defined above. Mixtures of these monomers may be employed, and copolymers thereof with one or more inert polymerizable thylenically unsaturated monomers such as those described above with respect to the operative synthetic anionic polymeric polycarboxylates. As will be noted, in these and other polymeric AEA's operative herein, usually only one acid-.ic delivery-enhancing group is bonded to any given carbon or other atom in the polymer backbone or branch thereon.
Polysiloxanes containing or modified to contain pendant delivery-enhancing groups and retention enhancing groups may also be employed as AEA's herein.
Also effective as AEA's herein are ionomers containing or modified to contain delivery-and retention-enhancing groups. Ionomers are described on pages 546°573 of the Kirk-Othmer Encyclopedia of Chemical Technology, third edition, Supplement Volume, John Wiley & Sons, Inc., copywright 1984, which description is incorporated herein by reference. Also effective as AEA's herein, provided they contain or are modified to contain retention-enhancing groups, are polyesters, polyurethanes and synthetic and natural polyamides including proteins and proteinaceous materials such as collagen, poly (argenine) and other polymerized amino acids.
~~~~'~.~a Without being bound to a theory, it is believed that the AFA, especially polymeric AEA is most often and desirably an anionic film forming material and is thought to attach to tooth surfaces and form a continuous film over the surfaces, thereby preventing bacterial attachment to tooth surfaces. It is possible that the noncationic antibacterial agent forms a complex or other form of association with the AEA, thus forming a film of a complex or the like over tooth surfaces. The enhanced delivery and film forming property of the AEA and the enhanced delivery and retention of the antibacterial agent on tooth surfaces due to the AEA appears to make tooth surfaces unfavorable for bacterial accumulation particularly since the direct bacteriostatic action of the antibacterial agent controls bacterial growth. Therefore, through the combination of three modes of actions: 1) enhanced delivery, 2) long retention time on tooth surfaces, and 3) prevention of bacterial attachment to tooth surfaces, the oral composition is made efficacious for reducing plaque. Similar effectiveness is attained on soft oral tissue at or near the gum line.
In aforementioned application U.S.S.N. 398,606 filed August 25, 1989 titled "Antibacterial Antiplaque Oral Composition" wherein the dentifrices thereof contain about 5-3U% by weight of a siliceous polishing agent, a material which solubilizes the noncationic antibacterial. agent to render it effective in delivery to soft oral tissues at the gum line is employed. In the present invention, wherein about 30-75% by weight of a dentally acceptable water-insoluble polishing agent is present, it is found that the solubilizing material is not required; but is rather optional.
In the oral preparation dentifrice, an orally acceptable vehicle including a water-phase witty humectant is present. The humectant is preferably glycerine and/or sorbitol. Water is present typically in amount of about 15-35% or ~SO% by weight and glycerine and/or sorbital typically total about ZO-75% by weight of the oral preparation dentifrice, more typically about 25-60%. Reference hereto to sorbitol refers to the material typically as available commercially in 70% aqueous solutions. The optional ingredients which assist solubilization of the antibacterial agent in saliva are typically incorporated in the water-humectant phase in amount of about 0.5-20% by weight. These optional solubilizing agents include humectant polyols such propylene glycol, dipropylene glycol and hexylene glycol, cellosolves such as methyl cellosolve and ethyl cellosolve, vegetable oils and waxes containing at least about 12 carbons in a straight chain such as olive oil, castor oil and petrolatum and esters such as amyl acetate, ethyl acetate and benzyl benzoate. As used herein, "propylene glycol" includes 1,2-propylene glycol and 1,3-propylene glycol. Significant amounts of polyethylene glycol particularly of molecular weight of 600 ar more should be avoided since polythylene glycol effectively inhibits the antibacterial activity of the noncationic antibacterial agent. For instance, polyethylene glycol (PEG) 600 when present with tricolosan in a weight ratio of 25 triclosan:l PEG 600 can reduce the antibacterial activity of triclosan by a factor of about 16 from that prevailing in the absence of the polyethylene glycol.
The pH of such oral preparation dentifrice of the nvention is generally in the range of about 4.5 to about 9 or 10 and preferably about 6.5 to about 7.5. It is noteworthy that the compositions of the invention may be applied orally at a pH below 5 without substantially decalcifying or otherwise damaging dental enamel. The pH can be controlled with acid (e. g.
citric acid or benzoic acid) or base (e.g. sodium hydroxide) or buffered (as with sodium citrate, benzoate, carbonate, or bicarbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate, etc.).
In this invention, the oral composition dentifrice may be substantially pasty in character, such as a tooth paste (dental cream), although when siliceous polishing agent is employed (which is not generally the case, since such material is typically not employed in amount above about 30% by weight) it can be gel in character. The vehicle of the oral composition dentifrice contains dentally acceptable polishing material, examples of which polishing materials are water-insoluble sodium metaphosphate, potassium metaphosphate, tricalcium phosphate, dihydrated dicalcium phosphate, anhydrous dicalcium phosphate,, calcium pyrophosphate, magnesium orthophosphate, trimagnesitum phosphate, calcium carbonate, aluminum silicate, hydrated alumina, silica, bentonite, and mixtures thereof with each other or with hard polishing materials such as calcined alumina and zirconium silicate, maternal including the particulate thermosetting resins described in U.S. Pat. Ido. 3,070,510 issued Dec. 15, 1962, such as melamine-, phenolic, and urea-formaldehydes, and cross-linked polyepoxides and polyesters. Preferred polishing materials include insoluble sodium metaphosphates, dicalcium phosphate and hydrated alumina.
Many of the so-called "water-insoluble" polishing materials are anionic in character and also include small amounts of soluble material. Thus, insoluble sodium metaphosphate may be formed in any suitable manner as illustated by Thorpe's Dictionary of Applied Chemistry, Volume 9, 4th Kdition, pp. 510-511. The forms of insoluble sodium metaphosphate known as Madrell's salt and Kurrol;s salt are further examples of suitable materials.
These metaphosphate salts exhibit only a minute solubility in water, and therefore are commonly referred to as insoluble metaphnsphates (IMP). There is present therein a minor amount of soluble phosphate material as impurities, usually a few percent such as up to 4~ by weight. The amount of soluble phosphate material, which is believed to include a soluble sodium trimetaphosphate in the case of insoluble metaphosphate, may be reduced or eliminated by washing with water if desired. The insoluble alkali metal metaphosphate is typically employed in powder form of a particle size such that no more than 1% of the material is larger than 37 microns.
Hydrated alumina is an example of a polishing material which is essentially nonionic in nature. Typically, it is small. in particle size, i.e., at least about 857 of the particles are smaller than 20 microns and C~~~>'~'~..~
is such as that classified as gibbsite (alpha alumina trihydrate) and normally represented chemically as A120~.3H20 or A1(0H)3. The average particle size of. gibbsite is generally about 6 to 9 microns. A typical grade has the following size distributions Micron Percent <30 94--99 <20 85-93 <10 56-67 ~ 5 28-40 The polishing material is generally present in the cream, paste or gel compositions in weight amounts of about 30% to about 75%.
Toothpastes or dental cream typically contain a natural or synthetic thickener or gelling agent in proportions of about 0.1 to about 10%, preferably about 0.5 to about 5%. A suitable thickener is syxzthetic hectorite, a synthetic colloidal magnesium alkali metal silicate complex clay available for example as Laponite (e.g. CP, SP 2002, D) marketed by Laporte Industries Limited. Laponite D analysis shows, approximately by weight, 58.00% Si02, 25.40% MgO, 3.05% Na20, 0.98% Li20); and some water and trace metals. lts true specific gravity is 2.53 and it has an apparent bulk density (g./ml. at 8% moisture) of 1,0.
Other suitable thickeners or gelling agents include Irish moss, iota-carrageenan, gum tragacanth, starch, polyvinylpyrrolidone, hydroxyethpropyl-cellulose, hydroxybutyl methyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose (e.g. available as Natrosol) and sodium carboxymethyl cellulose.
Without being bound to a theory whereby the advantages of this invention are achieved, it is believed that an aqueous, humectant vehicle is normally solubilized in the surfactant micelles in the mobile, e.g. liquid, phase (that is, not including gelling agent and polishing agent) of a dentrifi.ce formula. The mobile phase solution of dentifrice during use can ~~~i'7_'~.~a become diluted with saliva and a portion of the antibacterial agent, e.g.
triclosan, could precipitate out. However, when the amount of polishing agent is 30% by weight or more of the oral composition dentifrice, the amotuit of triclosan soluble in the mobile phase is sufficient to provide substantial antiplaque effect on soft oral tissues as well as on dental surfaces. This effect can be increased, if desired, if a solubilizing material compatible with the antibacteral agent which increases its solubility in saliva is present. In this regard it is noted that the solubi.lizing agent propylene glycol is widely used in drug delivery systems, for instance, in European Patent Publication 0271,332 for its strong interaction with biological membranes. It is expected that triclosan is partitioned from aqueous environment into propylene glycol and surfactant emulsions during use and further that propylene glycol in bulk phase allows greater probability of triclosan emergence out of surfactant micelles, thereby rendering triclosan mare completely available for delivery into bacterial and soft surfaces as well as onto tooth surfaces. Similar remarks apply to other water insoluble noncationic antibacterial agents herein described.
The oral composition dentifrice may also contain an anticaries amount of a fluoride ion source sufficient to supply about 25 ppm to 5000 ppm of fluoride ions.
The sources of fluoride ions, or fluoride~providing component are well known in the art as anti-caries agents. 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 substantial 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, potassium fluoride, ammonium fluoride, calcium fluoride, a copper fluoride such as cuprous fluoride, zinc fluoride, barium fluoride, sodium fluorosilicate, ammonium ~~.~~i'~:~~~
fluorosilicate, sodium fluorozirconate, ammonium fluorozirconate, sodium monofluorphasphate, aluminum mono-and di-fluorophosphate, and fluorinated sodium calcium pyrophosphate. Alkali metal and tin fluorides, such as sodium and stannous fluorides, sodium monafluarophosphate (MFP) and mixtures thereof, are preferred.
The amount of .fluorine-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 non-toxic amount, generally about 0.0005 to about 3.0% in the preparation. In a dentifrice preparation, 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 sufficent compound to release about X00 to 2,000 ppm, more preferably about 800 to about 1,500 ppm of fluoride ion.
Typically, in the cases of alkali metal fluorides, 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 monofluarophosphate, the compownd may be the present in an amount of about 0.1-3%, more typically about 0.76%.
It will be understood that, as is conventional, the oral preparations are to be sold or otherwise distributed in suitable labelled packages. Thus a toothpaste or cream will usually be in a collapsible tube typically aluminum, lined lead or plastic, or other squeeze, pump or pressurized dispenser for metering out the contents, having a label describing it, in substance, as a toothpaste, dental cream or the like.
Organic surface-active agents are used in the compositions of the present invention to achieve increased prophylactic action. Moreover, they assist in achieving thorough and complete dispersion of the anticalculus agent arid antiplaque agent throughout the oral cavity, and render the instant compositions more cosmetically acceptable. Indeed, at least one of ~~~~f surface-active agent or flavoring oil is present to effect desired solubilization of the antibacterial agent. The organic surface-active material is preferably anionic, nonionic or ampholytic in nature, and it is preferred to employ as the surface-active agent a detersive material which imparts to the composition detersive and foaming properties. Suitable examples of anionic surfactants are water-soluble salts of higher fatty acid monoglyceride monosulfates, such as the sodium salt of the monosulfated monoglyceride of hydrogenated coconut oil fatty acids, higher alkyl sulfates such as sodium lauryl. sulfate, alkyl aryl sulfonates such as sodium dodecyl benzene sulfonate, higher alkyl sulfoacetates, higher .fatty acid esters of 1,2-dihydroxy propane sulfonate, and the substantially saturated higher aliphatic acyl amides of lower aliphatic amino carboxylic acid compounds, such as those having 12 to 16 carbons in the fatty acid, alkyl or acyl radicals, and the like. Examples of the last mentioned amides are N-lauroyl sarcosine, and the sodium, potassium, and ethanolamine salts of N-lauroyl, N-myristoyl, or N-palmitoyl sarcosine which should be substantially free from soap or similar higher fatty acid material. The use of these sarcosinate compounds in the oral compositions of the present invention is particularly advantageous since these materials exhibit a prolonged a marked effect in the inhibition of acid formation in the oral cavity due to carbohydrates breakdown in addition to exerting some reduction in the solubility of tooth enamel in acid solutions. Examples of water-soluble nonionic surfactants are condensation products of ethylene oxide with various reactive hydrogen-containing compounds reactive therewith having long hydrophobic chains (e. g. aliphatic chains of about 12 to 20 carbon atoms), which condensation products ("ethoxamers") contain hydrophilic polyoxyethylene moieties, such as condensation products of polyethylene oxide) with fatty acids, fatty alcohols, fatty amides, polyhydric alcohols (e. g. sorbitan monostearate) and polypropyleneoxide (e. g. Pluronic materials).
~~~~o'~~.~a Surface active agent is typically present in amo~mt of about 0.5-5% by weight, preferably about 1-Z.5%. As indicated, surface active agent is believed to assist in the dissolving of the noncationic antibacterial agents.
Various other materials may be incorporated in the oral preparations of this invention such as whitening agents, preservatives, silicones, chlorophyll compounds and/or ammoniated material such as urea, diammonium phosphate, and mixtures thereof. These adjuvants, where present, are incorporated in the preparations in amounts which do not substantially adversely affect the properties and characteristics desired. Significant amounts of zinc, magnesium and other metal salts and materials, generally soluble, which would complex with active components of the instant invention are to be avoided.
Any suitable flavoring or sweetening material may also be employed.
Hxamples of suitable flavoring constituents are flavoring oils, e.g. oil of spearmint, peppermint, wintergreen, sassafras, clove, sage, eucalyptus, marjoram, cinnamon, lemon, and orange, and methyl salicylate. Suitable sweetening agents include sucrose, lactcrse, maltose, sorbitol, xylitol, sodium cyclamate, perillartine, AMP (aspartyl phenyl alanine, methyl ester), saccharine and the like. Suitably, flavor and sweetening agents each or together comprise from about 0.1% to 5% more of the preparation. Moreover, flavor oil is believed to aid the dissolving of the antibacterial agent together with or even in the absence of surface-active agent.
In the preferred practice of this invention an oral composition containing the composition of the present invention is preferably applied regularly to dental enamel, such as every day or every second or third day or preferably from 1 to 3 times daily, at a pH of about 4.5 to about 9, generally about 5.5 to about 8, preferably about 6 to 8, for at least 2 weeks up to 8 weeks or more up to lifetime.
~~~~1 6~~~
The compositions of this invention can be incorporated in lozenges, or in chewing gum or othex products, e.g. by stirring into a warm gum base or coating the outer surface of a gum base, illustrative of which may be mentioned jelutong, rubber latex, vinylite resins, etc., desirably with conventional plasticizers of softeners, sugar or other sweeteners or carbohydrates such as glucose, sorbitol and the like.
The following 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 in the appended claims are by weight, unless otherwise indicated.
Example 1 The following dentifrice is prepareds Parts A B C
Alpha Alumina Trihydrate48.00 48:00 48.00 Propylene Glycol - 0.50 0.50 Sorbitol (70%) 21.70 21.70 21.70 Gantrez S-97 (13% solution)15.00 15.00 -Gantrez S-97 (powder) - - 2.00 Sodium Lauryl Sulfate 2.00 2.13 2.13 Sodium Saccharine 0,30 0.30 0.30 Sodium Hyroxide (50%) 1.20 1.20 1.20 Flavor Oil 0.95 0.95 0.95 Irish Moss 1.00 -Sodium carboxymethyl - 1.00 1.00 celluose Sodium monofluorophosphate0.76 0.76 0.76 Titanium Dioxide - 0.50 0.50 Triclosan 0.30 0.30 0.30 4later Q.S. to Q.S. to Q.S.
to 100.00100.00 100.00 ~~~~'~~.~
The foregoing dentifrices deliver triclosan to the teeth and soft tissue areas of the gums substantially more effectively than corresponding dentifrices in which the Gantrez polycarboxylate is absent.
The following dentifrices are prepared:
Parts Glycerine 22.00 10.00 Sorbitol (707) - 17:00 Sodium Carboxymethyl cellulose 1.00 1.00 Gantrez S-97 2.00 2.00 Sodium Saccharin 0.20 0.20 Sodium Benzoate 0.50 0.50 Sodium Monofluorophsophate 0.76 0.76 Dicalcium Phosphate Dihydrate 48.76 48.76 Triclosan 0.30 0.30 Sodium Lauryl Sulfate 1.20 1.20 Flavor Oil 0.89 0.89 Water Q:S. to 100.00 100.00 Q.S. to The foregoing dentifrices deliver triclosanto saliva coated hydroxyphate disk more effectively ding dentifrices;in than correspon which the Gantrez polycarboxylate is absent.
The following antiplaque dentifrice is prepared:
Parts Glycerine 15.00 Propylene Glycol 2.00 Sodium Carboxymethyl cellulose J..50 Water 24.93 Vinyl Methyl Ether/Maleic Anhydride copolymer 4.76 (42~ solution) Sodium Monofluorophosphate 0~76 Sodium Saccharin 0.30 Insoluble Sodium Metaphosphate 47.00 Titanium Dioxide 0.50 Sodium Lauryl Sulfate 2.00 Triclosan 0.30 Flavor Oil 0.95 In the foregoing Examples improved results are also achievable when triclosan is replaced with each of phenol, 2,2'-methylene bis (4-chloro-6-Bromophenol), eugenoi and thymol, and/or when Gantrez is replaced by other AEA's such as Carbopols (e. g. 934), or styrene phosphoric acid polkymers having molecular weights within the range of about 3,000 to 10,000 such as poly (beta-styrenephosphonic acid), copolymers of vinyl phosphoric acid with beta-styrenephosphonic acid, and poly (alpha-styrenephosphonic acid), or sulfoacrylic oligoraers, or a 1:1 copolymer of malefic anhydridge with ethyl acrylate.
Dentifrice Mobile Phases Containing Triclosan Components ----- --------Composition,%w/w--------------A B
Sorbitol (70%) 53.33 40.00 Water 40.48 39.15 Gantrez S (15%) ---- 13.33 NaOH (50%) 1.33 Saccharin 0.40 0.40 Sodium Fluoride 0.32 0.32 Flavor Oil 1.47 1.47 Sodium Lauryl Sulfate 3.33 3.33 Triclosan 0.67 0.67 The Concentration of the above components are 1.33%
dentifrice level to reflect 25% level of abrasive which may be needed to make a complete dentifrice.
The above mobile phases of the indicated dentifrice formulations are tested for triclosan uptake on saliva coated HA
disks following the standard procedure described in assignee's Canadian Patent No. 2,006,703. Results are shown in Table I
below.
TABLE I
Uptake of triclosan by Saliva Coated Hydroxyapatite (HA) Disks from Diluted and Undiluted Dentifrice Mobile Phases.
A B
Trinlnc~n 0.67 0.67 Ionic Strength (M/L) 0.375 ----(calculated) PH 8.7 7.6 Triclosan Uptake (ug/disk) Undiluted 55 122 30a Gantr ~E~~Ei'°~'E.E~
The above results show a greater then two fold increase in triclosan uptake achieved with the B formulation containing Gantrez relative to the A
formulation without the Gantrez.
Concentration and Uptatke of Triclosan by HA from Supernatant of 1:1 Dentifrice/Water Slurries.
Dentifrice Containing Trilosan (ug/ml) in Trilosan Uptake 0.5% Triclosan, 2.5% Supernatant of 1:1 pg/di.sk Sodium Laurvl Sulfate Slurry 25% Hydrated Silica 1,650 52 +1.5% Gantrez S-97 50% Alumina, 1.905 74 +1.5% Gantrez S-97 Supernatents of 1:1 Dentifrice/Water slurries of the above dentifrices are tested for concentraton of the triclosan in the supernatant and for triclosan uptake on saliva coated 13A disks. The results indicate that using , 50% alumina abrasive increases the triclosan substantially under low 1:1 dilution conditions (from 1,650 to 1,905), resulting in a substantial increase in the triclosan uptake (fxom 52 to 74).
This invention has been described with respect to certain preferred embodiments and it will be understood that modifications and variations thereof obvious to those skilled in the art are to be included within the purview of this application and the scope of the appended claims.
3a It is an advantage of this invention that the said AEA
enhance the delivery and retention of the antibacterial agent on teeth and on soft oral tissues but Examples 1 and 3 contain 0.5-2o propylene glycol without requiring the presence of a material which dissolves the antibacterial agent in saliva.
It is a further advantage of this invention that an antiplaque oral composition is provided which is directly or indirectly effective to reduce the occurrence of gingivitis.
Additional advantages of this invention will be apparent from consideration of the following specification.
In accordance with an aspect, this invention relates to an oral composition dentifrice comprising in an orally acceptable vehicle, about 30-75% of a dentally acceptable water-insoluble polishing agent, an effective antiplaque active ingredient amount of a substantially water insoluble noncationic anti-bacterial agent, at least one of a surface-active agent or a flavoring oil and about 0.005-4o by weight of the AEA, wherein the oral composition dentifrice is substantially free of polyphosphate anticalculus agent.
In accordance with another aspect, the invention relates to an oral dentifrice composition comprising in an orally acceptable vehicle, about 30-75% of a dentally acceptable water insoluble polishing agent, about 0.01-50 of a substantially water insoluble noncationic antibacterial agent, and about 0.05-4% of a copolymer of malefic acid or anhydride with methyl vinyl ether, the composition containing one or both of a surface active agent and a flavoring oil.
In accordance with a further aspect, the invention relates to an oral dentifrice composition comprising in an orally acceptable vehicle, about 30-75% of a dentally acceptable water insoluble polishing agent, about 0.01-5% of a substantially water insoluble noncationic antibacterial agent, and about 0.05-4% of poly (beta-styrenephosphonic acid), copoly (beta-styrenephosphonic acid/vinyl phosphonic acid) or poly (alpha-styrenephosphonic acid), the composition containing one or both of a surface active agent and a flavoring oil.
In accordance with still another aspect, the invention relates to an oral dentifrice composition comprising in an orally acceptable vehicle, about 30-75% by weight of a dentally acceptable water-insoluble polishing agent, an effective antiplaque amount of a substantially water insoluble noncationic antibacterial agent and an antibacterial-enhancing agent which has an average molecular weight or about 1,000 to about 1,000,000, contains at least one delivery enhancing functional group and at least one organic retention enhancing group, the agent containing the groups being free from or substantially free from water soluble alkali metal or ammonium synthetic anionic linear polymer polycarboxylate salt having a molecular weight of about 1,000 to about 1,000,000.
In accordance with a still further aspect, the invention relates to an oral composition dentifrice comprising about 30-4a 75% by weight of a dentally acceptable water insoluble polishing agent, an effective antiplaque amount of a substantially water insoluble noncationic antibacterial agent, about 0.05-4% by weight of a polyvinyl phosphate having a recurring group of the formula:
HO-P=O
I
OH
and an average molecular weight of about 1,000 to about 1,000,000 and an orally acceptable vehicle effective to enable the antibacterial agent to dissolve in saliva in effective antiplaque amount, wherein the oral composition has a pH of about 4.5 to about 10.
Typical examples of water insoluble noncationic antibacterial agents which are particularly desirable from considerations of antiplaque effectiveness, safety and formulation are:
Halogenated biphenyl Ethers 2',4,4'-trichloro-2'-hydroxy-diphenyl ether (Triclosan) 2,2'-dihydroxy-5,5'-dibromo-diphenyl ether.
Halogenated Salicylanilides 4',5-dibromosalicylanilide 3,4',5-trichlorosalcylanilide 3,4',5-tribromosalicylanilide 2,3,3',5-tetrachlorosalicylanilide 3,3,3',5-tetrachlorosalicylanilide 4b ~~~.i'~~.'~a 3,5-dibromo~3'-trifluoromethyl salicylanilide 5-n-octanoyl-3'-trif:Luoromethyl salicylanilide 3,5-dibromo-4'-trifluoromethyl salicylanilide 3,5-dibromo-3°-trifluora methyl salicylanilide (Flurophene) Benzoic Esters Methyl - p-Hydroxybenzoic Ester Ethyl - p-IIydroxybenzoic Ester Propyl - p-Hydroxybenzoic Ester Butyl - p-Hydroxybenzoic Ester Halo~enated Carbanilides 3,4,4'-trichlorocarbanilide 3-trifluoramethyl-4,4'-dichlorocarbanilide 3,3,4'-trichlorocarbanilide Phenolic Compounds (including phenol and its homologs, mono- and poly-alkyl and aromatic halo (e. g. F, C1, Br, I)-phenols, resorcinol and catechol and their derivatives and bisphenolic compounds). Such compounds include inter alias Phenol and its Homolo~s Phenol 2 Methyl - Phenol 3 Methyl - Phenol 4 Methyl - Phenol 4 Ethyl - Phenol 2,4-Dimethyl - Phenol 2,5-Dimethyl - Phenol 3,4-Dimethyl - Phenol 2,6-Dimethyl - Phenol 4-n Propyl - Phenol 4-n-Butyl - Phenol 4-n-Amyl - Phenol 4-tort-Amyl - Phenol 4-n-Hexyl - Phenol 4-n-Heptyl - Phenol 2-Methoxy-4-(2-Propenyl)-Phenol (Eugenol) 2-Isopropyl-5-Methyl- Phenol (T'hymol) Mono- and Poly-Alkyl and Aralkyl Halo~phenols Methyl - p-Chlorophenol Ethyl - p-Chlorphenol n-Propyl - p-Chlorophenol n-Butyl - p-Chlorophenol n-Amyl - p-Chlorophenol sec-Amyl p-Chlorophenol n-Hexyl - p-Chlorophenol Cyclohexyl - p-Chlorophenol n-Heptyl - p-Chlorophenol n-Octyl - p-Chlorophenol ~~~i'~~..~
0-Chlorophenol Methyl - o-Chlorophenol Ethyl - o-Chlorophenol n-Propyl - o-Chlorophenol n-Butyl - o-Chlorophenol n-Amyl - o-Chlorophenol tert-Amyl - o-Chlorophenol n-Hexyl - o-chlorophenol n-Heptyl - o-Chloropenol p-Chlorophenol o-Benzyl - p-Chlorophenol o-Benzyl-m-methyl - p-Chlorophenol o-Benzyl-m, m-dimethyl - p-Chlorophenol o-Phenylethyl - p-Chlorophenol o-Phenylethyl-m-methyl - p-Chlorophenol 3-Methyl - p-Chloxophenol 3,5-Dimethyl - p-Chlorophenol 6-Ethyl-3-methyl - p-Chlorophenol b-n-Propyl-3-methyl - p-Chlorophenol 6-iso-propyl-3-methyl - p-Chlorophenol 2-Ethyl-3,5-dimethyl - p-Chlorophenol 6-se~ 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 Octyl-3-methyl - p-Chlorophenol p-Bromophenol Methyl - p-Bromophenol ~~.)~~i'~~.~~
Ethyl - p-Bromophenol n-Propyl - p-Bromophenol n-Butyl - p-Bromophenol n-Amyl - p-Bromophenol sec-Amyl - p-Bromophenol n-FIexyl - p-Bromophenol cyclohexyl - p-Bromophenol o-Bromophenol tert-Amyl - o-Bromophenol n-Hexyl - o-Bromophenol n-Propyl-m,m-Dimethyl o-Bromophenol -2-Phenyl Phenol 4-Chlora-2-methyl phenol 4-chloro-3-methyl phenol 4-chloro-3,5-dimethyl phenol 2,4-dichloro-3,5-dimethyl phenol 3,4,5,6-tetrabromo-2-methylphenol 5-methyl-2-pentylphenol 4-isopropyl-3-methylphenol 5-chloro-2-hydroxydiphenyl methane Resorcinol and Its Derivat3~es Resorcinol Methyl - Resorcinol Ethyl - Resorc inol n-Propyl - Resorcinol n-Butyl - Resorcinol n_~yl - Resorcinol n-Hexyl - Resorcinol n-Heptyl - Resorcinol n-Octyl - Resorcinol ~'~a~'.~.~
n-Nonyi - Resorcinol Phenyl - Resorcinol Benzyl - Resorcinol Phenylethy:L- Resorcinol Phenylpropyl- Resorcinol p-ChlorobenzylResorcinol 5-Chloro -2,4-DihydroxydiphenylMethane 4'-Chloro -2,4-DihydroxydiphenylMethane 5-Bromo -2,4-DihydroxydiphenylMethane 4-Bromo -2,4-DihydroxydiphenylMethane Bisphenolic Compounds Bisphenol A
2,2'-methylene bis (4-chlorophenol) 2,2'-methylene bis (3,4,6-trichiorophenol) (hexachlorophene) 2,2'-methylene bis (4-chloro-6-bromophenol) bis (2-hydroxy-3,5-dichlorophenyl) sulfide bis (2-hydroxy-5-chlorobenzyl) sulfide The noncationic antibacterial agent is present in the oral composition in an effective antiplaque amount, typically about 0.01-5% by weight, preferably about 0.03-1% and more preferably about 0.3-0.5%. 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%.
The preferred halogenated diphenyl ether is triclosan. The preferred phenolic compounds are phenol, thymol, eugenol, hexyl resorcinol and 2,2'methylene bis (4-chioro-6-bromophenol). The most preferred antibacterial antiplaque compound is triclosan. Txiclosan is disclosed in aforementioned U.S. Patent 4,022,880 as an antibacterial agent in combination with an anticalculus agent which provides zinc ions and in ~~~'~~~..f~
German Patent Disclosure 3532860 in combination with a copper compound. In European Patent Disclosure 0278744 it is disclosed in combination with a tooth desensitizing agent containing a source of potassium ions. Tt is also disclosed as an antiplaque agent in a dentifrice formulated to contain a lamellar liquid crystal surfactant phase having a lamellar spacing of less than 6.0 nm and which may optionally contain a zinc salt in published European Patent Application 0161898 of Lane et al and in a dentifrice containing zinc citrate trihydrate in published European Patent Application 0161899 to Saxton et al.
The antibacterial-enhancing agent (AEA) which enhances delivery o.f said antibacterial agent to, and retention thereof on, oral surfaces, is employed in amounts effective to achieve such enhancement within the range in the oral composition of about 0.05 to about 4%, preferably about 0.1% to about 3%, more preferably about 0.5% to about 2.5% by weight.
This AEA may be a simple compound, preferably a polymerizable monomore, more preferably a polymer, which latter 'term is entirely generic, including for example oligomers, homopolymers, copolymers of two or more monomers, block copolymers, graft copolymers, crass-linked polymers and copolymers, and the like. The AEA may be natural or synthetic, and water insoluble or preferably water (saliva) soluble or swellable (hydratable, hydrogel forming). Tt has an (weight) average molecular weight of about 100 to about 1,000,000, preferably about 1,000 to about 1,000,000, more preferably about 2,000 or 2,500 to about 250,000 or 500,000.
The AEA ordinarily contains at least one delivery-enhancing group, which is preferably acidic such as sulfonic, phosphinic, or more preferably phosphonic or carboxylic, or salt thereof, e.g. alkali metal or ammonium, and at least one organic retention-enhancing group, preferably a plurality of both the delivery-enhancing and retention-enhancing groups, which latter groups preferably have the formula -(X)"-R wherein X is 0, N, S, S0, SOz, P, PO or Si or the likes, R is hydrophobic alkyl, alkenyl, acyl, aryl, alkaryl, aralkyl, heterocycl.ic or their inert-substituted derivatives, and n is zero or 1 or more. The aforesaid "inert-substituted derivatives", are intended to include substituents on R which are generally non-hydrophilic and do no significantly interfere with the desired functions of the AEA as enhancing the delivery of the antibacterial agent to, and retention thereof on, oral surfaces such as halo, e.g. Cl, Pr, I, and carbo and the like.
Illustrations of such retention-enhancing groups are tabulated below.
n X -(X)"R
p --- methyl, ethyl, propyl, butyl, isobutyl, t-buryl, cyclohexyl, allyl, benzyl, phenyl, chlorophenyl, xylyl, pyridyl, furanyl, acetyl, benzoyl, butyryl, terephthaloyl, etC.
1 D ethoxy, benzyloxy, thioacetoxy, phenoxy, carboethoxy, carbobenzyloxy, etc.
N ethylamino, diethylamino, propylamido, benzylamino, benzoylamido, phenylacetamido, etc.
S thiobutyl, thioisobutyl, thioallyl, thiobenzyl, thiophenyl, thiopropionyl; phenylth:ioacetyl, thiobenzoyl, etc.
SO butylsulfoxy, allylsulfoxy, benzylsulfoxy, phenylsulfoxy, etc.
SOZ butylsulfonyl, allylsulfonyl, benzylsulfonyl, phenylsulfonyl, etc.
p diethylphosphinyl, ethylvinylphosphinyl, ethylallylphosphinyl, ethylbenzylphosphinyl, ethylphenylphosphinyl, etc.
PO diethylphosphinoxy, ethylvinylphosphinoxy, methylallylphosphinoxy; methylbenzylphosphinoxy, methylphenylphosphinoxy, etc.
Si trimethylsilyl, dimethylbutylsilyl, dimethylbenzylsilyl, dimethylvinylsilyl, dimethylallylsilyl, etc.
As employed herein, the delivery-enhancing group refers to one which attaches or substantively, adhesively, cohesively or otherwise bonds the AEA
(carrying the antibacterial agent) to oral (e. g. tooth and gum) surfaces, ~~(~E~~"~~_~
thereby "delivering" the antibacterial agent to such surfaces. The organic retention-enhancing group, generally hydrophobic, attaches or otherwise bonds the antibacterial agent to the AEA, thereby promoting retention of the antibacterial agent to the AF.A and indirectly on the oral surfaces. In some instances, attachment of the antibacterial agent occurs through physical entrapment thereof by the AEA, especially when the AEA is a cross-linked polymer, the structure of which inherently provides increased sites for such entrapment. The presence of a higher molecular weight, ore hydrophobic cross-linking moiety in the cross-linked polymer still further promotes the physical entrapment of the antibacterial agent to or by the cross-linked AFA
polymer.
Preferably, the AEf1 is an anionic polymer comprising a chain or backbone containing repeating units each preferably containing at least one carbon atom and preferably at least one directly or indirectly pendant, monovalent delivery-enhancing group and at least one directly or indirectly pendant monovalent retention-enhancing group geminally, vicinally or less preferably otherwise bonded to atoms, preferably carbon, in the chain. Less preferably, the polymer may contain delivery-enhancing groups and/or retention-enhancing groups and/or other divalent atoms or groups as links in the polymer chain instead of or in addition to carbon atoms, or as cross-linking moieties.
It will be understood that any exacoples or illustrations of AF~I~s disclosed herein which do not contain 'both delivery-enhancing groups and retention enhancing groups may and preferably should be chemically modified in known manner to obtain the preferred AEA's containing both such groups and preferably a plurality of each such groups. In the case of the preferred polymeric AEA's, it is desirable, for maximizing substantivity and delivery of the antibacterial agent to oral surfaces, that the repeating units in the polymer chain or backbone containing the acidic delivery enhancing groups constitute at least about 10%, preferably at least about 507, more preferably at least about 807 up to 957 or 1007 by weight of the polymer.
According to a preferred embodiment of this invention, the AEA
comprises a polymer containing repeating units in which one or more phosphoric acid delivery-enhancing groups are bonded to one or more carbon atoms in the polymer chain. An example of such an AEA is poly (vinyl phosphoric acid) containing units of the formula:
I -[CHZ - ~H]-P03H~
which however does not contain a retention-enhancing group. A group of the latter type would however be present in poly (1-phosphonopropene) with units of the formula:
II -(CH - CH]-GH3 ~03Ha A preferred phosphoric acid-containing AEA for use herein is poly (beta styrene phosphoric acid) containing units of the formula:
III -(CH - CH]-Ph ,~03Ha wherein Ph is phenyl, the phosphoric delivery-enhancing group and the phenyl retention-enhancing group being bonded on vicinal carbon atoms in the chain, or a copolymer of beta styrene phosphoric acid with vinyl phosphonyl chloride having the units of the foregoing formula III alternating or in random association with units of formula I above, or poly (alpha styrene phosphoric acid) containing units of the formula:
IV -[CHZ - ~ -]_ Ph~03H2 in which the delivery - and retention - enhancing groups are geminally bonded to the chain.
These styrene phosphoric acid polymers and their copolymers with other inert ethylenically unsaturated monomers generally have molecular weights in ~
the range of about 2,000 to about 30,000, preferably about 2,500 to about 10,000, and are, with their methods of preparation disclosed and claimed in Canadian Patent No. 2,006,703. Such "inert" monomers do not significantly interfere with the intended function of any copolymer employed as an AEA herein.
Other phosphonic-containing polymers include, for example, phosphonated ethylene having units of the formula.
V -[CH2]14CHP03H2]n-where n may for example be an integer or have a value giving the polymer a molecular weight of about 3,000; and sodium poly (butene-4,4-diphosphonate) having units of the formula:
VI -[CH2 = CH ----]-CH2/ - CH < (P03Na2)2 and poly (allyl bis (phosphonoethyl) amine) having units of the formula:
VII - [CH2~CH ---] -CH2 - N < ( P03H2 ) 2 Other phosphonated polymers, for example poly (allyl phosphono acetate), phosphonated polymethacrylate, etc. and the geminal disphosphonate polymers disclosed in EP Publication 0321233 may be employed herein as AEA's, provided of course that they contain or are modified to contain the above-defined organic retention-enhancing groups.
In an aspect of the invention, the oral dentifrice composition comprises an orally acceptable vehicle, about 3-75%
by weight of a dentally acceptable water-insoluble polishing agent, an effective antiplaque amount of a substantially water insoluble noncationic antibacterial agent and an antibacterial-enhancing agent which has an average molecular weight of about 1,000 to about 1,000,000, contains at least one delivery enhancing functional group and at least one organic retention enhancing group, said 14a agent containing said groups being free from or substantially free from water soluble alkali metal or ammonium synthetic anionic linear polymer polycarboxylate salt having a molecular weight of about 1,000 to about 1,000,000 Although not used in the present invention to coact with polyphosphate anticalculus agent, synthetic anionic polymeric polycarboxylate having a molecular weight of about 1,000 to about 1,000,000, preferably about 30,000 to about 500,000, has been used as an inhibitor of alkaline phosphatase enzyme in optimizing anticalculus effectiveness of linear molecularly dehydrated polyphosphate salts, as disclosed in U.S. Patent 4,627,977 to Gaffer et al. Indeed, in published British Patent Publication 22 00551, the polymeric polycarboxylate is disclosed as an optional ingredient in oral compositions containing linear molecularly dehydrated polyphosphate salts and substantially water-insoluble noncationic antibacterial agent. It is further observed, in the context of the present invention that such polycarboxylate is markedly effective to enhance delivery and retention of the noncationic antibacterial, antiplaque agent to dental surfaces when another ingredient with which the polymeric polycarboxylate would coact (that is, molecularly dehydrated polyphosphate) is absent; for instance, when the ingredient with which the polymeric polycarboxylate coacts is especially the noncationic antibacterial agent.
Synthetic anionic polymeric polycarboxylates and their complexes with various cationic germicides, zinc and magnesium have been previously disclosed as anticalculus agents per se in, for example U.S. Patent No.
3,429,963 to Shedlovsky; U.S. Patent No. 4,152,420 to Gaffer; U.S. Patent No. 3,956,480 to Dichter et al; U.S. Patent No. 4,138,477 to Gaffer; and U.S. Patent No. 4,183,914 to Gaffer et al. It is to be understood that the synthetic anionic polymeric polycarboxylates so disclosed in these several patents when containing or modified to contain the above-defined retention-enhancing groups are operative as AEA's in the compositions and methods of ~~~.DFS~~~D
this invention and such disclosures are to, that extent incorporated herein by reference thereto.
These synthetic anionic polymeric polycarboxylates are often employed in the form of their free acids or preferably partially or more preferably fully neutralized water soluble or water-swe11ab1e (hydratable, gel-forming) alkali metal (e. g. potassium and preferably sodium) or ammonium salts.
Preferred are 1:4 to 4:1 copolymers of malefic anhydride or acid with another polymerizable ethylenically unsaturated monomer, preferably methyl vinyl ether (malefic 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, e.g. AN 139 (M. W. 500,000), AN 119 (M. W. 250,000); and preferably S-97 Pharmaceutical Grade (M. W.
70,000), of GAF Corporation.
Other AEA-operative polymeric polycarboxylates containing or modified to contain retention-enhancing gxoups include those disclosed in U.S. Patent No. 3,956,480 referred to above, such as the 1:1 copolymers of malefic anhydride with ethyl acxylate, 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, isobutyl vinyl ether or N-vinyl-2-pyrrolidone.
Additional operative polymeric polycarboxylates disclosed in above referred to U.S. Patent No. 4,138,477 and 4,183,914 containing or modified to contain retention-enhancing groups, include copolymers of malefic anhydride with styrene, isobutylene or ethyl vinyl ether, polyacrylic, polyitaconic and polymaleic acids, and sulfoacrylic oligomers of M.W. as low as 1,000, available as Uniroyal ND-2.
Suitable generally axe retention-enhancing group-containing polymerized olefinically or ethylenically unsaturated carboxylic acids containing an activated carbon-to-carbon olefinic double bond which readily functions in ~~a'~'_'~...
polymerization because of its presence in the monomer molecule either in the alpha-beta position with respect to a carboxyl group or a part of a terminal methylene grouping. Illustrative of such acids are acrylic, methacrylic, ethacrylic, alpha-chloroacrylic, crotonic, beta-acryloxy propionic, sorbic, alpha-chlorsorbic, cinnamic, beta-styrylacrylic, muconic, itaconic, citraconic, mesaconic, glutaconic, aconitic, alpha-phenylacrylic, 2-benzyl acrylic, 2-cyclohexylacrylic, angelic, umbellic, fumaric, malefic acids and anhydrides. Other different olefinic monomer copolymerizable with such carboxylic monomers includ vinylacetate, vinyl chloride, dimethyl maleate and the like. Copolymers ordinarily contain sufficient carboxylic salt groups for water-solubility.
Also useful herein are so-called carboxyvinyl polymers disclosed as toothpaste components in U.S. 3,980,767 to Chown et al;U.S. 3,935,306 to Roberts et al; U.S. 3,919,409 to Perla et al; U.S. 3,911,904 to Harrison, and U.S. 3,711,604 to Colodney et al. 'they axe commercially available for example under the trademarks Carbopol 934, 940 and 941 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 2.07 of polyallyl sucrose or polyallyl pentaerythritol as cross linking agent, the cross-linked structures and linkages in these and other cross-linked polymeric AEA~s,providing the desired retention enhancement by hydrophobicity when adequate, and/or physical entrapment of the antibacterial agent. Polycarbophil, being polyacrylic cross-linked with less than 0.1% divinyl glycol, the lowex proportion, molecular weight, and/or hydrophobicity of this cross-linking agent tending to provide decreased or no retention enhancement 2,5-dimethyl--1,5-hexadiane, exemplifies a more effective retention-enhancing cross-linking agent.
The synthetic anionic polymeric polycarboxylate component is most often a hydrocarbon with option halogen and 0-containing substituents and linkages as present in for example ester, ether and OH groups, and is employed in the instant compositions in approximate weight amounts of 0.05 to 47, preferably 0.05 to 3%, more preferably 0.1 to 2%.
The AEA may also comprise natural anionic polymeric polycarboxylates containing retention-enhancing groups. Carboxymethyl cellulose and other binding agents gums and film-formers devoid of the above-defined delivery-enhancing and/or retention-enhancing groups are ineffective as AEA's.
As illustrative of AEA's containing phosphinic acid and/or sulfonic acid delivery enhancing groups, there may be mentioned polymers and copolymers containing units or moieties derived from the polymerization of vinyl or allyl phosphinic and/or sulfonic acids substituted as needed on the 1 or 2 (or 3) carbon atom by an organic retention-enhancing group, for example having the formula -(X)"-li defined above. Mixtures of these monomers may be employed, and copolymers thereof with one or more inert polymerizable thylenically unsaturated monomers such as those described above with respect to the operative synthetic anionic polymeric polycarboxylates. As will be noted, in these and other polymeric AEA's operative herein, usually only one acid-.ic delivery-enhancing group is bonded to any given carbon or other atom in the polymer backbone or branch thereon.
Polysiloxanes containing or modified to contain pendant delivery-enhancing groups and retention enhancing groups may also be employed as AEA's herein.
Also effective as AEA's herein are ionomers containing or modified to contain delivery-and retention-enhancing groups. Ionomers are described on pages 546°573 of the Kirk-Othmer Encyclopedia of Chemical Technology, third edition, Supplement Volume, John Wiley & Sons, Inc., copywright 1984, which description is incorporated herein by reference. Also effective as AEA's herein, provided they contain or are modified to contain retention-enhancing groups, are polyesters, polyurethanes and synthetic and natural polyamides including proteins and proteinaceous materials such as collagen, poly (argenine) and other polymerized amino acids.
~~~~'~.~a Without being bound to a theory, it is believed that the AFA, especially polymeric AEA is most often and desirably an anionic film forming material and is thought to attach to tooth surfaces and form a continuous film over the surfaces, thereby preventing bacterial attachment to tooth surfaces. It is possible that the noncationic antibacterial agent forms a complex or other form of association with the AEA, thus forming a film of a complex or the like over tooth surfaces. The enhanced delivery and film forming property of the AEA and the enhanced delivery and retention of the antibacterial agent on tooth surfaces due to the AEA appears to make tooth surfaces unfavorable for bacterial accumulation particularly since the direct bacteriostatic action of the antibacterial agent controls bacterial growth. Therefore, through the combination of three modes of actions: 1) enhanced delivery, 2) long retention time on tooth surfaces, and 3) prevention of bacterial attachment to tooth surfaces, the oral composition is made efficacious for reducing plaque. Similar effectiveness is attained on soft oral tissue at or near the gum line.
In aforementioned application U.S.S.N. 398,606 filed August 25, 1989 titled "Antibacterial Antiplaque Oral Composition" wherein the dentifrices thereof contain about 5-3U% by weight of a siliceous polishing agent, a material which solubilizes the noncationic antibacterial. agent to render it effective in delivery to soft oral tissues at the gum line is employed. In the present invention, wherein about 30-75% by weight of a dentally acceptable water-insoluble polishing agent is present, it is found that the solubilizing material is not required; but is rather optional.
In the oral preparation dentifrice, an orally acceptable vehicle including a water-phase witty humectant is present. The humectant is preferably glycerine and/or sorbitol. Water is present typically in amount of about 15-35% or ~SO% by weight and glycerine and/or sorbital typically total about ZO-75% by weight of the oral preparation dentifrice, more typically about 25-60%. Reference hereto to sorbitol refers to the material typically as available commercially in 70% aqueous solutions. The optional ingredients which assist solubilization of the antibacterial agent in saliva are typically incorporated in the water-humectant phase in amount of about 0.5-20% by weight. These optional solubilizing agents include humectant polyols such propylene glycol, dipropylene glycol and hexylene glycol, cellosolves such as methyl cellosolve and ethyl cellosolve, vegetable oils and waxes containing at least about 12 carbons in a straight chain such as olive oil, castor oil and petrolatum and esters such as amyl acetate, ethyl acetate and benzyl benzoate. As used herein, "propylene glycol" includes 1,2-propylene glycol and 1,3-propylene glycol. Significant amounts of polyethylene glycol particularly of molecular weight of 600 ar more should be avoided since polythylene glycol effectively inhibits the antibacterial activity of the noncationic antibacterial agent. For instance, polyethylene glycol (PEG) 600 when present with tricolosan in a weight ratio of 25 triclosan:l PEG 600 can reduce the antibacterial activity of triclosan by a factor of about 16 from that prevailing in the absence of the polyethylene glycol.
The pH of such oral preparation dentifrice of the nvention is generally in the range of about 4.5 to about 9 or 10 and preferably about 6.5 to about 7.5. It is noteworthy that the compositions of the invention may be applied orally at a pH below 5 without substantially decalcifying or otherwise damaging dental enamel. The pH can be controlled with acid (e. g.
citric acid or benzoic acid) or base (e.g. sodium hydroxide) or buffered (as with sodium citrate, benzoate, carbonate, or bicarbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate, etc.).
In this invention, the oral composition dentifrice may be substantially pasty in character, such as a tooth paste (dental cream), although when siliceous polishing agent is employed (which is not generally the case, since such material is typically not employed in amount above about 30% by weight) it can be gel in character. The vehicle of the oral composition dentifrice contains dentally acceptable polishing material, examples of which polishing materials are water-insoluble sodium metaphosphate, potassium metaphosphate, tricalcium phosphate, dihydrated dicalcium phosphate, anhydrous dicalcium phosphate,, calcium pyrophosphate, magnesium orthophosphate, trimagnesitum phosphate, calcium carbonate, aluminum silicate, hydrated alumina, silica, bentonite, and mixtures thereof with each other or with hard polishing materials such as calcined alumina and zirconium silicate, maternal including the particulate thermosetting resins described in U.S. Pat. Ido. 3,070,510 issued Dec. 15, 1962, such as melamine-, phenolic, and urea-formaldehydes, and cross-linked polyepoxides and polyesters. Preferred polishing materials include insoluble sodium metaphosphates, dicalcium phosphate and hydrated alumina.
Many of the so-called "water-insoluble" polishing materials are anionic in character and also include small amounts of soluble material. Thus, insoluble sodium metaphosphate may be formed in any suitable manner as illustated by Thorpe's Dictionary of Applied Chemistry, Volume 9, 4th Kdition, pp. 510-511. The forms of insoluble sodium metaphosphate known as Madrell's salt and Kurrol;s salt are further examples of suitable materials.
These metaphosphate salts exhibit only a minute solubility in water, and therefore are commonly referred to as insoluble metaphnsphates (IMP). There is present therein a minor amount of soluble phosphate material as impurities, usually a few percent such as up to 4~ by weight. The amount of soluble phosphate material, which is believed to include a soluble sodium trimetaphosphate in the case of insoluble metaphosphate, may be reduced or eliminated by washing with water if desired. The insoluble alkali metal metaphosphate is typically employed in powder form of a particle size such that no more than 1% of the material is larger than 37 microns.
Hydrated alumina is an example of a polishing material which is essentially nonionic in nature. Typically, it is small. in particle size, i.e., at least about 857 of the particles are smaller than 20 microns and C~~~>'~'~..~
is such as that classified as gibbsite (alpha alumina trihydrate) and normally represented chemically as A120~.3H20 or A1(0H)3. The average particle size of. gibbsite is generally about 6 to 9 microns. A typical grade has the following size distributions Micron Percent <30 94--99 <20 85-93 <10 56-67 ~ 5 28-40 The polishing material is generally present in the cream, paste or gel compositions in weight amounts of about 30% to about 75%.
Toothpastes or dental cream typically contain a natural or synthetic thickener or gelling agent in proportions of about 0.1 to about 10%, preferably about 0.5 to about 5%. A suitable thickener is syxzthetic hectorite, a synthetic colloidal magnesium alkali metal silicate complex clay available for example as Laponite (e.g. CP, SP 2002, D) marketed by Laporte Industries Limited. Laponite D analysis shows, approximately by weight, 58.00% Si02, 25.40% MgO, 3.05% Na20, 0.98% Li20); and some water and trace metals. lts true specific gravity is 2.53 and it has an apparent bulk density (g./ml. at 8% moisture) of 1,0.
Other suitable thickeners or gelling agents include Irish moss, iota-carrageenan, gum tragacanth, starch, polyvinylpyrrolidone, hydroxyethpropyl-cellulose, hydroxybutyl methyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose (e.g. available as Natrosol) and sodium carboxymethyl cellulose.
Without being bound to a theory whereby the advantages of this invention are achieved, it is believed that an aqueous, humectant vehicle is normally solubilized in the surfactant micelles in the mobile, e.g. liquid, phase (that is, not including gelling agent and polishing agent) of a dentrifi.ce formula. The mobile phase solution of dentifrice during use can ~~~i'7_'~.~a become diluted with saliva and a portion of the antibacterial agent, e.g.
triclosan, could precipitate out. However, when the amount of polishing agent is 30% by weight or more of the oral composition dentifrice, the amotuit of triclosan soluble in the mobile phase is sufficient to provide substantial antiplaque effect on soft oral tissues as well as on dental surfaces. This effect can be increased, if desired, if a solubilizing material compatible with the antibacteral agent which increases its solubility in saliva is present. In this regard it is noted that the solubi.lizing agent propylene glycol is widely used in drug delivery systems, for instance, in European Patent Publication 0271,332 for its strong interaction with biological membranes. It is expected that triclosan is partitioned from aqueous environment into propylene glycol and surfactant emulsions during use and further that propylene glycol in bulk phase allows greater probability of triclosan emergence out of surfactant micelles, thereby rendering triclosan mare completely available for delivery into bacterial and soft surfaces as well as onto tooth surfaces. Similar remarks apply to other water insoluble noncationic antibacterial agents herein described.
The oral composition dentifrice may also contain an anticaries amount of a fluoride ion source sufficient to supply about 25 ppm to 5000 ppm of fluoride ions.
The sources of fluoride ions, or fluoride~providing component are well known in the art as anti-caries agents. 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 substantial 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, potassium fluoride, ammonium fluoride, calcium fluoride, a copper fluoride such as cuprous fluoride, zinc fluoride, barium fluoride, sodium fluorosilicate, ammonium ~~.~~i'~:~~~
fluorosilicate, sodium fluorozirconate, ammonium fluorozirconate, sodium monofluorphasphate, aluminum mono-and di-fluorophosphate, and fluorinated sodium calcium pyrophosphate. Alkali metal and tin fluorides, such as sodium and stannous fluorides, sodium monafluarophosphate (MFP) and mixtures thereof, are preferred.
The amount of .fluorine-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 non-toxic amount, generally about 0.0005 to about 3.0% in the preparation. In a dentifrice preparation, 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 sufficent compound to release about X00 to 2,000 ppm, more preferably about 800 to about 1,500 ppm of fluoride ion.
Typically, in the cases of alkali metal fluorides, 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 monofluarophosphate, the compownd may be the present in an amount of about 0.1-3%, more typically about 0.76%.
It will be understood that, as is conventional, the oral preparations are to be sold or otherwise distributed in suitable labelled packages. Thus a toothpaste or cream will usually be in a collapsible tube typically aluminum, lined lead or plastic, or other squeeze, pump or pressurized dispenser for metering out the contents, having a label describing it, in substance, as a toothpaste, dental cream or the like.
Organic surface-active agents are used in the compositions of the present invention to achieve increased prophylactic action. Moreover, they assist in achieving thorough and complete dispersion of the anticalculus agent arid antiplaque agent throughout the oral cavity, and render the instant compositions more cosmetically acceptable. Indeed, at least one of ~~~~f surface-active agent or flavoring oil is present to effect desired solubilization of the antibacterial agent. The organic surface-active material is preferably anionic, nonionic or ampholytic in nature, and it is preferred to employ as the surface-active agent a detersive material which imparts to the composition detersive and foaming properties. Suitable examples of anionic surfactants are water-soluble salts of higher fatty acid monoglyceride monosulfates, such as the sodium salt of the monosulfated monoglyceride of hydrogenated coconut oil fatty acids, higher alkyl sulfates such as sodium lauryl. sulfate, alkyl aryl sulfonates such as sodium dodecyl benzene sulfonate, higher alkyl sulfoacetates, higher .fatty acid esters of 1,2-dihydroxy propane sulfonate, and the substantially saturated higher aliphatic acyl amides of lower aliphatic amino carboxylic acid compounds, such as those having 12 to 16 carbons in the fatty acid, alkyl or acyl radicals, and the like. Examples of the last mentioned amides are N-lauroyl sarcosine, and the sodium, potassium, and ethanolamine salts of N-lauroyl, N-myristoyl, or N-palmitoyl sarcosine which should be substantially free from soap or similar higher fatty acid material. The use of these sarcosinate compounds in the oral compositions of the present invention is particularly advantageous since these materials exhibit a prolonged a marked effect in the inhibition of acid formation in the oral cavity due to carbohydrates breakdown in addition to exerting some reduction in the solubility of tooth enamel in acid solutions. Examples of water-soluble nonionic surfactants are condensation products of ethylene oxide with various reactive hydrogen-containing compounds reactive therewith having long hydrophobic chains (e. g. aliphatic chains of about 12 to 20 carbon atoms), which condensation products ("ethoxamers") contain hydrophilic polyoxyethylene moieties, such as condensation products of polyethylene oxide) with fatty acids, fatty alcohols, fatty amides, polyhydric alcohols (e. g. sorbitan monostearate) and polypropyleneoxide (e. g. Pluronic materials).
~~~~o'~~.~a Surface active agent is typically present in amo~mt of about 0.5-5% by weight, preferably about 1-Z.5%. As indicated, surface active agent is believed to assist in the dissolving of the noncationic antibacterial agents.
Various other materials may be incorporated in the oral preparations of this invention such as whitening agents, preservatives, silicones, chlorophyll compounds and/or ammoniated material such as urea, diammonium phosphate, and mixtures thereof. These adjuvants, where present, are incorporated in the preparations in amounts which do not substantially adversely affect the properties and characteristics desired. Significant amounts of zinc, magnesium and other metal salts and materials, generally soluble, which would complex with active components of the instant invention are to be avoided.
Any suitable flavoring or sweetening material may also be employed.
Hxamples of suitable flavoring constituents are flavoring oils, e.g. oil of spearmint, peppermint, wintergreen, sassafras, clove, sage, eucalyptus, marjoram, cinnamon, lemon, and orange, and methyl salicylate. Suitable sweetening agents include sucrose, lactcrse, maltose, sorbitol, xylitol, sodium cyclamate, perillartine, AMP (aspartyl phenyl alanine, methyl ester), saccharine and the like. Suitably, flavor and sweetening agents each or together comprise from about 0.1% to 5% more of the preparation. Moreover, flavor oil is believed to aid the dissolving of the antibacterial agent together with or even in the absence of surface-active agent.
In the preferred practice of this invention an oral composition containing the composition of the present invention is preferably applied regularly to dental enamel, such as every day or every second or third day or preferably from 1 to 3 times daily, at a pH of about 4.5 to about 9, generally about 5.5 to about 8, preferably about 6 to 8, for at least 2 weeks up to 8 weeks or more up to lifetime.
~~~~1 6~~~
The compositions of this invention can be incorporated in lozenges, or in chewing gum or othex products, e.g. by stirring into a warm gum base or coating the outer surface of a gum base, illustrative of which may be mentioned jelutong, rubber latex, vinylite resins, etc., desirably with conventional plasticizers of softeners, sugar or other sweeteners or carbohydrates such as glucose, sorbitol and the like.
The following 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 in the appended claims are by weight, unless otherwise indicated.
Example 1 The following dentifrice is prepareds Parts A B C
Alpha Alumina Trihydrate48.00 48:00 48.00 Propylene Glycol - 0.50 0.50 Sorbitol (70%) 21.70 21.70 21.70 Gantrez S-97 (13% solution)15.00 15.00 -Gantrez S-97 (powder) - - 2.00 Sodium Lauryl Sulfate 2.00 2.13 2.13 Sodium Saccharine 0,30 0.30 0.30 Sodium Hyroxide (50%) 1.20 1.20 1.20 Flavor Oil 0.95 0.95 0.95 Irish Moss 1.00 -Sodium carboxymethyl - 1.00 1.00 celluose Sodium monofluorophosphate0.76 0.76 0.76 Titanium Dioxide - 0.50 0.50 Triclosan 0.30 0.30 0.30 4later Q.S. to Q.S. to Q.S.
to 100.00100.00 100.00 ~~~~'~~.~
The foregoing dentifrices deliver triclosan to the teeth and soft tissue areas of the gums substantially more effectively than corresponding dentifrices in which the Gantrez polycarboxylate is absent.
The following dentifrices are prepared:
Parts Glycerine 22.00 10.00 Sorbitol (707) - 17:00 Sodium Carboxymethyl cellulose 1.00 1.00 Gantrez S-97 2.00 2.00 Sodium Saccharin 0.20 0.20 Sodium Benzoate 0.50 0.50 Sodium Monofluorophsophate 0.76 0.76 Dicalcium Phosphate Dihydrate 48.76 48.76 Triclosan 0.30 0.30 Sodium Lauryl Sulfate 1.20 1.20 Flavor Oil 0.89 0.89 Water Q:S. to 100.00 100.00 Q.S. to The foregoing dentifrices deliver triclosanto saliva coated hydroxyphate disk more effectively ding dentifrices;in than correspon which the Gantrez polycarboxylate is absent.
The following antiplaque dentifrice is prepared:
Parts Glycerine 15.00 Propylene Glycol 2.00 Sodium Carboxymethyl cellulose J..50 Water 24.93 Vinyl Methyl Ether/Maleic Anhydride copolymer 4.76 (42~ solution) Sodium Monofluorophosphate 0~76 Sodium Saccharin 0.30 Insoluble Sodium Metaphosphate 47.00 Titanium Dioxide 0.50 Sodium Lauryl Sulfate 2.00 Triclosan 0.30 Flavor Oil 0.95 In the foregoing Examples improved results are also achievable when triclosan is replaced with each of phenol, 2,2'-methylene bis (4-chloro-6-Bromophenol), eugenoi and thymol, and/or when Gantrez is replaced by other AEA's such as Carbopols (e. g. 934), or styrene phosphoric acid polkymers having molecular weights within the range of about 3,000 to 10,000 such as poly (beta-styrenephosphonic acid), copolymers of vinyl phosphoric acid with beta-styrenephosphonic acid, and poly (alpha-styrenephosphonic acid), or sulfoacrylic oligoraers, or a 1:1 copolymer of malefic anhydridge with ethyl acrylate.
Dentifrice Mobile Phases Containing Triclosan Components ----- --------Composition,%w/w--------------A B
Sorbitol (70%) 53.33 40.00 Water 40.48 39.15 Gantrez S (15%) ---- 13.33 NaOH (50%) 1.33 Saccharin 0.40 0.40 Sodium Fluoride 0.32 0.32 Flavor Oil 1.47 1.47 Sodium Lauryl Sulfate 3.33 3.33 Triclosan 0.67 0.67 The Concentration of the above components are 1.33%
dentifrice level to reflect 25% level of abrasive which may be needed to make a complete dentifrice.
The above mobile phases of the indicated dentifrice formulations are tested for triclosan uptake on saliva coated HA
disks following the standard procedure described in assignee's Canadian Patent No. 2,006,703. Results are shown in Table I
below.
TABLE I
Uptake of triclosan by Saliva Coated Hydroxyapatite (HA) Disks from Diluted and Undiluted Dentifrice Mobile Phases.
A B
Trinlnc~n 0.67 0.67 Ionic Strength (M/L) 0.375 ----(calculated) PH 8.7 7.6 Triclosan Uptake (ug/disk) Undiluted 55 122 30a Gantr ~E~~Ei'°~'E.E~
The above results show a greater then two fold increase in triclosan uptake achieved with the B formulation containing Gantrez relative to the A
formulation without the Gantrez.
Concentration and Uptatke of Triclosan by HA from Supernatant of 1:1 Dentifrice/Water Slurries.
Dentifrice Containing Trilosan (ug/ml) in Trilosan Uptake 0.5% Triclosan, 2.5% Supernatant of 1:1 pg/di.sk Sodium Laurvl Sulfate Slurry 25% Hydrated Silica 1,650 52 +1.5% Gantrez S-97 50% Alumina, 1.905 74 +1.5% Gantrez S-97 Supernatents of 1:1 Dentifrice/Water slurries of the above dentifrices are tested for concentraton of the triclosan in the supernatant and for triclosan uptake on saliva coated 13A disks. The results indicate that using , 50% alumina abrasive increases the triclosan substantially under low 1:1 dilution conditions (from 1,650 to 1,905), resulting in a substantial increase in the triclosan uptake (fxom 52 to 74).
This invention has been described with respect to certain preferred embodiments and it will be understood that modifications and variations thereof obvious to those skilled in the art are to be included within the purview of this application and the scope of the appended claims.
Claims (40)
1. An oral composition dentifrice comprising in an orally acceptable vehicle, about 30-75% by weight of a dentally acceptable water-insoluble polishing agent, an effective antiplaque active ingredient amount of a substantially water insoluble noncationic antibacterial agent, said oral composition dentifrice comprising at least one of a surface-active agent or a flavoring oil and about 0.005-4% by weight of an antibacterial-enhancing agent which enhances delivery of said antibacterial agent to, and the retention thereof on, oral surfaces, wherein said oral composition dentifrice is substantially free of polyphosphate anticalculus agent.
2. The oral composition claimed in Claim 1 wherein said antibacterial agent is selected from the group consisting of halogenated diphenyl ethers, halogenated salicylanilides, benzoic esters, halogenated carbanilides and phenolic compounds.
3. The oral composition claimed in Claim 2 wherein said antibacterial agent is a halogenated diphenyl ether.
4. The oral composition claimed in Claim 3 wherein said halogenated diphenyl ether is 2,4,4'-trichloro-2'-hydroxyphenyl ether.
5. The oral composition claimed in Claim 2 wherein said antibacterial agent is a phenolic compound.
6. The oral composition claimed in Claim 5 wherein said phenolic compound is selected from the group consisting of phenol, thymol, eugenol and 2,2'-methylene bis(4-chloro-6-bromophenol).
7. The oral composition according to any of the preceding claims wherein said antibacterial agent is present in amount of about 0.01-5% by weight.
8. The oral composition claimed in Claim 5 wherein said amount of antibacterial agent is about 0.3-0.5%.
9. The oral composition dentifrice claimed in any of the preceding claims wherein said polishing agent is selected from the group consisting of sodium metaphosphate, tricalcium phosphate, dehydrated dicalcium phosphate, anhydrous dicalcium phosphate, calcium pyrophosphate, magnesium orthophosphate, trimagnesium phosphate, calcium carbonate, aluminum silicate, hydrated alumina, silica, bentonite and mixtures thereof.
10. The oral composition dentifrice claimed in Claim 9 wherein said polishing agent is dicalcium phosphate dehydrate.
11. The oral composition dentifrice claimed in Claim 9 wherein said polishing agent is hydrated alumina.
12. The oral composition claimed in any of the preceding claims wherein said surface active agent is present in amount of about 0.5-5% by weight.
13. The oral composition dentifrice claimed in any of the preceding claims wherein said surface active agent is present in amount of about a 1-2.5% by weight.
14. The oral composition according to any of the preceeding claims wherein said antibacterial-enhancing agent has an average molecular weight of about 100 to about 1,000,000.
15. The oral composition according to any of the preceding claims wherein said antibacterial-enhancing agent contains at least one delivery-enhancing functional group and at least one organic retention-enhancing group.
16. The oral composition according to the preceding claim wherein said deliver-enhancing group is acidic.
17. The oral composition according to the preceding claim wherein said delivery-enhancing group is selected from the group consisting of carboxylic, phosphonic, phosphinic, and sulfonic acids, and their salts, and mixtures thereof.
18. The oral composition according to any of claims 15-17 wherein said organic retention-enhancing group comprises the formula -(X)n-R wherein X is O, N, S, SO, SO2, P, PO or Si, R is hydrophobic alkyl, alkenyl, acyl, aryl, alkaryl, aralkyl, heterocyclic, or their inert-substituted derivatives, and n is 1 or zero.
19. The oral composition according to any of the preceding claims wherein said antibacterial-enhancing agent is on anionic polymer containing a plurality of said delivery-enhancing and retention-enhancing groups.
20. The oral composition according to the preceding claim wherein said anionic polymer comprises a chain containing repeating units each containing at least one carbon atom.
21. The oral composition according to the preceding claim wherein each unit contains at least one delivery-enhancing group and at least one retention-enhancing group bonded to the same, vincinal, or other atoms in the chain.
22. The oral composition according to any of claims 15-21 wherein the delivery-enhancing group is a carboxylic group or salt thereof.
23. The oral composition according to any of the preceding claims wherein the antibacterial-enhancing agent is a copolymer of maleic acid or anhydride with another ethylenically unsaturated polymerizable monomer.
24. The oral composition according to Claim 23 wherein said other monomer of said copolymer is methyl vinyl ether in a 4:1 to 1:4 molar ratio with the maleic acid or anhydride.
25. The oral composition according to Claims 23 or 24 wherein said copolymer has a molecular weight of about 30,000 - 1,000,000 and is present in amount of about 0.1-2% by weight.
26. A composition according to Claims 23 or 24 wherein the copolmer has an average molecular weight of about 70,000.
27. A composition according to any of claims 1-22 wherein the delivery-enhancing group is a phosphonic group or salt thereof.
28. A composition according to any of the preceding claims wherein the antibacterial-enhancing agent is poly (beta-styrene- phosphonic acid) poly (alpha-styrenephosphonic acid) polymer, or a copolymer of either styrenephosphonic acid monomer with the other or with another ethylenically unsaturated polymerizable monomer.
29. A composition according to any of the preceding claims containing a fluoride ion-providing source.
30. A method of controlling oral plaque comprising applying to oral surfaces an effective plaque-controlling amount of a composition as defined in any of the preceding claims.
31. An oral dentifrice composition comprising in an orally acceptable vehicle, about 30-75% of a dentally acceptable water insoluble polishing agent, about 0.01-5% of a substantially water insoluble noncationic antibacterial agent, and about 0.05-4% of a copolymer of malefic acid or anhydride with methyl vinyl ether, the composition containing one or both of a surface active agent and a flavoring oil.
32. An oral dentifrice composition comprising in an orally acceptable vehicle, about 30-75% of a dentally acceptable water insoluble polishing agent, about 0.01-5% of a substantially water insoluble noncationic antibacterial agent, and about 0.05-4% of poly (beta-styrenephosphonic acid), copoly (beta-styrenephosphonic acid/vinyl phosphonic acid) or poly (alpha-styrenephosphonic acid), the composition containing one or both of a surface active agent and a flavoring oil.
33. An oral dentifrice composition comprising in an orally acceptable vehicle, about 30-75% by weight of a dentally acceptable water-insoluble polishing agent, an effective antiplaque amount of a substantially water insoluble noncationic antibacterial agent and an antibacterial-enhancing agent which has an average molecular weight or about 1,000 to about 1,000,000, contains at least one delivery enhancing functional group and at least one organic retention enhancing group, the agent containing the groups being free from or substantially free from water soluble alkali metal or ammonium synthetic anionic linear polymer polycarboxylate salt having a molecular weight of about 1,000 to about 1,000,000.
34. The oral preparation claimed in Claim 33, wherein the antibacterial agent is present in amount of from about 0.3% to 0.5% by weight.
35. An oral composition dentifrice comprising about 30-75%
by weight of a dentally acceptable water insoluble polishing agent, an effective antiplaque amount of a substantially water insoluble noncationic antibacterial agent, about 0.05-4% by weight of a polyvinyl phosphate having a recurring group of the formula:
and an average molecular weight of about 1,000 to about 1,000,000 and an orally acceptable vehicle effective to enable the antibacterial agent to dissolve in saliva in effective antiplaque amount, wherein the oral composition has a pH of about 4.5 to about 10.
by weight of a dentally acceptable water insoluble polishing agent, an effective antiplaque amount of a substantially water insoluble noncationic antibacterial agent, about 0.05-4% by weight of a polyvinyl phosphate having a recurring group of the formula:
and an average molecular weight of about 1,000 to about 1,000,000 and an orally acceptable vehicle effective to enable the antibacterial agent to dissolve in saliva in effective antiplaque amount, wherein the oral composition has a pH of about 4.5 to about 10.
36 36. The oral composition claimed in Claim 35, in which the antibacterial agent is selected from the group consisting of halogenated diphenyl ethers, halogenated salicylanides, benzoic esters, halogenated carbanilides, and phenolic compounds.
37. The oral composition claimed in Claim 36 in which the antibacterial agent is a halogenated diphenyl ether.
38. The oral composition claimed in Claim 37 in which the halogenated diphenyl ether is 2,4,4'-trichloro-2'-hydroxy-phenyl ether.
36a
36a
39. The oral composition claimed in any one of Claims 35 to 38, wherein said polyvinyl phosphonate is present in amount of about 0.5-2.5% by weight.
40. A method of inhibiting dental plaque comprising applying to tooth and soft gum surfaces the oral composition claimed in any one of Claims 35 to 39.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US07/291,712 US4894220A (en) | 1987-01-30 | 1988-12-29 | Antibacterial antiplaque oral composition |
| US291,712 | 1988-12-29 | ||
| US39966989A | 1989-08-25 | 1989-08-25 | |
| US399,669 | 1989-08-25 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2006716A1 CA2006716A1 (en) | 1990-06-29 |
| CA2006716C true CA2006716C (en) | 2000-07-18 |
Family
ID=26966933
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2006716 Expired - Lifetime CA2006716C (en) | 1988-12-29 | 1989-12-27 | Antibacterial antiplaque oral composition |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2006716C (en) |
-
1989
- 1989-12-27 CA CA 2006716 patent/CA2006716C/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| CA2006716A1 (en) | 1990-06-29 |
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