CA2006703C - Antibacterial anti-plaque oral composition - Google Patents

Abstract

An oral composition dentifrice comprising an orally acceptable vehicle, about 5-30% by weight of a siliceous polishing agent, a substantially water-insoluble noncationic antibacterial antiplaque agent, such as 2,4,4' -trichloro-2'-hydroxydiphenyl ether (triclosan), and an antibacterial-enhancing agent which enhances the delivery of said antibacterial agent to, and retention thereof on, oral surfaces, wherein said antiplaque agent is substantially completely dissolved in saliva present during tooth and gum cleaning in a solubilizing agent therefor. The solubilizing agent may be a humectant polyol such as propylene glycol, dipropylene glycol and hexylene glycol; a cellosolve such as methyl cellosolve and ethyl cellosolve; a vegetable oil or wax containing at least about 12 carbon atoms in a straight chain such as olive oil, castor oil and petrolatum; or an ester such as ethyl acetate, amyl acetate, glyceryl tristearate and benzyl benzoate.

Description

006'703 ., ~. ...

- .
- rhis invention relates to an antibacterial antiplaque ; oral composition dentifrice. More particularly, it relates to - an oral 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 ----O . well as non-cationic compounds such as halogenated ~, ~ salicylanilides and halogenated hydroxydiphenyl ethers. ~he ~, 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.
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~j XOOfi~03 ~ The cationic antibacterial materials such as .~,,: .
. chlorhexidine, benzthonium 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.
Noncationic 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.
, It is an advantage of this invention that an oral composition dentifrice cont~n~ne a substantially water-insoluble noncationic antibacterial agent and an antibacterial-enhancing agent which enhances the delivery -:. "::
of said antibacterial agent to, and retention ~hereof on, oral surfaces is provided to inhibit plaque formation.
, :.~ :..................................................... .
It is an advantage of this invention that said antibacterial-enhancing agents enhance the delivery and retention of the antibacterial agent on teeth and on soft .- oral tissues.
It is a further advantage of this invention that such an oral composition is provided with a solubilizing agent ` ;- which dissolves the noncationic antibacterial agent for i::
,1' ,' effective delivery onto soft oral tissues.
It is a further advantage of this invention that an , . . . .
antiplaque oral composition is provided which is effective ~i to reduce the occurence of gingivitis.
Additional advantages of this invention will be ,s ~
apparent from consideration of the following specification.
~ In accordance with certain of its aspects, this ,'"ii~'. .'~ invention relates to an oral composition dentifrice ", i ~ 3-:i. ~:i:~ :::
5 ~
i. ~ h .,,' ,~, ';~ "'~., ~ i~' ": .
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~006 703 comprlslng ln an orally acceptable vehlcle, about 5-30% by welght of a slllceous pollshlng agent, an effectlve antlplaque amount of a substantlally water lnsoluble noncatlonlc antlbacterlal agent, and about 0.005-5%, preferably 0.005-4%, by welght of an antlbacterlal-enhanclng agent whlch enhances the dellvery of sald antlbacterlal agent to, and retentlon thereof on, oral surfaces, whereln sald oral composltlon comprlses a solublllzlng materlal for sald antlbacterlal agent ln amount sufflclent to dlssolve sald antlbacterlal agent ln sallva whereln sald oral composltlon dentlfrlce ls substantlally free of polyphosphate antlcalculus agent.
Typlcal examples of water lnsoluble noncatlonlc antlbacterlal agents whlch are partlcularly deslrable from conslderatlons of antlplaque effectlveness, safety and formulatlon are:
Haloqenated Dlphenyl Ethers 2',4,4'-trlchloro-2-hydroxy-dlphenyl ether ~Trlclosan) 2,2'-dlhydroxy-5,5'-dlbromo-dlphenyl ether Haloqenated SallcYlanllldes 4',5-dlbromosallcylanlllde 3,4',5-trlchlorosallcylanlllde 3,4',5-trlbromosallcylanlllde 2,3,3',5-tetrachlorosallcylanlllde 3,3,3',5-tetrachlorosallcylanlllde 3,5-dlbromo-3'-trlfluoromethyl salicylanilide 5-n-octanoyl-3'-trlfluoromethyl sallcylanlllde 3,5-dlbromo-4'-trlfluoromethyl sallcylanlllde 20Q~7 03 3,5-dlbromo-3'-trlfluoromethyl salicylanlllde (Fluorophene) Benzolc Esters Methyl -p-Hydroxybenzolc Ester Ethyl -p-Hydroxybenzolc Ester Propyl -p-Hydroxybenzolc Ester Butyl -p-Hydroxybenzolc Ester - 4a -i :
~0067()3 ,i :
;.. ~ Halo~enated Carbanilides 3,4,4'-trichlorocarbanilide 3-trifluoromethyl-4,4'-dichlorocarbanilide . ~-::-:~" 3,3,4'-trichlorocarbanilide ~i Phenolic Compounds (including phenol and its homologs, ::' i~,i;,' .
,'. mono- and poly-alkyl and aromatic halo (e.g. F, Cl, Br, I)-h~ phenols, resorcinol and catechol and their derivatives and - bisphenolic compounds). Such phenolic compounds include inter alia:
:: ~ f.~.

. Phenol and its Homolo~s Phenol {
~:: 2 Methyl - Phehol -::: . . ,;
~ 3 Methyl - Phenol : -:
'i 4 Methyl - Phenol 4 Ethyl - Phenol . .
,s 2,4-Dimethyl - Phenol : 2,5-Dimethyl - Phenol .", ' ,J;

5 ~ 3,4-Dimethyl - Phenol -~,s~ : 2,6-Dimethyl - Phenol 4-n Propyl - Phenol ;. 4-n-Butyl - Phenol . . 4-n-Amyl - Phenol ,- :.i - . ., 4-tert-Amyl - Phenol ~5~'i 4-n-Hexyl - Phenol ~ ............................... 4-n-Heptyl - Phenol -- ~ 2-Methoxy-4-(2-Propenyl)-Phenol (Eugenol) ~:-, :-,, . ~::
2-Isopropyl-5-Methyl - Phenol (Thymol) :. Mono- and Poly-Alkyl and Aralkyl Halophenols , . -, ,. :
Methyl - p-Chlorophenol ~ '~ Ethyl - p-Chlorphenol "',.~-7,;t;', n-Propyl - p-Chlorophenol -- ~ n-Butyl - p-Chlorophenol ~i-'" .5,~
i ~ -5-,, "~'.
,,~: :;,.~., - : ,A
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~ ", S~"''i .
~ ."' 0067~13:
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., :~ n-Amyl - p-Chlorophenol sec-Amyl - p-Chlorophenol : n-Hexyl - p-Chlorophenol , :,:.; ,~
Cyclohexyl - p-Chlorophenol ~: n-Heptyl - p-Chlorophenol : n-Octyl - p-Chlorophenol - ` O-Chl~rophenol :$:::
Methyl - o-Chlorophenol : ~, :.:::
: ::: Ethyl - o-Chlorophenol n-Propyl - o-Chlorophenol $-n-Butyl - o-Chlorophenol '-:: n-Amyl - o-Chlorophenol tert-Amyl - o-Chlorophenol n-Hexyl - o-chlorophenol ~ n-Heptyl - o-Chloropenol , -:
~. p-Chlorophenol -: ~:
:~ o-Benzyl - p-Chlorophenol o-Benzyl-m-methyl - p-Chlorophenol ~:~ o-Benzyl-m, m-dimethyl - p-Chlorophenol ~:~: . .
-~-;3 ~ o-Phenylethyl - p-Chlorophenol ~: ~ ,::: o-Phenylethyl-m-methyi - p-Chlorophenol 3-Methyl - p-Chlorophenol ~:: , . 3,5-Dimethyl - p-Chlorophenol :: ~' .~:~:
:- 6-Ethyl-3-methyl - p-Chlorophenol :: :~: ",:~
: 6-n-Propyl-3-methyl - p-Chlorophenol -, ~ 6-iso-propyl-3-methyl - p-Chlorophenol .r,.~l '~ 2-Ethyl-3,5-dimethyl - p-Chlorophenol ~ ~ ~ 6-sec Butyl-3-methyl - p-Chlorophenol --"~ . 2-iso-Propyl-3,5-dimethyl - p-Chlorophenoi ~-~ ............................. 6-Diethylmethyl-3-methyl - p-Chlorophenol ~i 6-iso-Propyl-2-ethyl-3-methyl - p-Chlorophenol .::s : :: 2-sec Amyl-3,5-dimethyl - p-Chlorophenol 2-Diethylmethyl-3,5-dimethyl - p-Chlorophenoi ~:~ ~$ -6-~' -s~
~"-, ,-~ ~:
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"',,~",~' ' .,, ' ,-~:--': ~ .,' ' ' ~ X0~)670~

~ ..' - , i- 6-sec Octyl-3-methyl - p-Chlorophenol p-Bromophenol ~-~::
~,;:
; Methyl- p-Bromophenol Ethyl- p-Bromophenol : h, "; ' ~'';
~ - n-Propyl - p-Bromophenol ~: !
n-Butyl - p-Bromophenol ,. n-Amyl - p-Bromophenol sec-Amyl - p-Bromophenol 't ~. n-Hexyl - p-Bromophenol :~::: - cyclohexyl - p-Bromophenol . o-Bromophenol t ~ tert-Amyl - o-Bromophenol :~ -n-Hexyl - o-Bromophenol ~-:: : n-Propyl-m,m-Dimethyl - o-Bromophenol ::
~ 2-Phenyl Phenol ~ . ,, -:~: 4-Chloro-2-methyl phenol ~ 4-chloro-3-methyl phenol ,::::: ,-:
- ~ . 4-chloro-3,5-dimethyl phenol ~,., . : 2,4-dichloro-3,5-dimethyl phenol : 3,4,5,6-tetrabromo-2-methylphenol " 5-methyl-~-pentylphenol 4-isopropyl-3-methylphenol : :: :-, :: ~ 5-chloro-2-hydroxydiphenyl methane Resorcinol and Its Derivatives X-:~ Resorcinol .: Methyl - Resorcinol ~ a ~ Ethyl - Resorcinol ,~?~o3 ~ n-Propyl - Resorcinol s ,. n-Butyl - Resorcinol .,.,,. '.- ~ ::
,~, n-Amyl - Resorcinol :-:, ,~,. .
~: -:: n-Hexyl - Resorcinol --~ n-Heptyl - Resorcinol :,---, :::
n-Octyl - Resorcinol - : -7-::, : "
, :: .~"
: ~ -, .

~ ~" 2006703 ~,:

- , ; n-Nonyl - Resorcinol " ~ Phenyl - Resorcinol ' ~ ~ Benzyl - Resorcinol v ~
Phenylethyl - Resorcinol '~f~ ~ Phenylpropyl - Resorcinol ~ p-Chlorobenzyl - Resorcinol r. ' ~:
~ 5-Chloro -2,4-Dihydroxydiphenyl Nethsne .,; .
4'-Chloro -2,4-Dihydroxydiphenyl Methane 5-Bromo -2,4-Dihydroxydiphenyl Methane "; 4'-Bromo -2,4-Dihydroxydiphenyl Methane Bisphenolic Compounds Bisphenol A
: ., 2,2'-methylene bis (4-chlorophenol) ~, 2,2'-methylene bis (3,4,6-trichlorophenol) (hexachlorophene) - ~-)~,, ~ ' 2,2'-methylene bis (4-chloro-6-bromophenol) 7, ::;~' ~ bis (2-hydroxy-3,5-dichlorophenyl) sulfide :: -:, :. :
5'}.'; : 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 most preferably aboutO.25-0.5%. The anti;bacterial agent is substantially water-insoluble, ~An;ng that its -,- :.'':-~
~ - solubility is less than about 1% by weight in water at 25C
: :-:::: s -:
and may be even less than about 0.1%.
The preferred halogenated diphenyl ether is triclosan.
--~ The preferred phenolic compound~ are phenol, thymol, ' ' ~ - eugenol,'hexyl resorcinol and 2,2'methylene bis (4-chloro-6-bromophenol). The most preferred antibacterial antiplaque ='~;'~ compound is triclosan. Triclosan is disclosed ins ,~ aforementioned U.S. Patent 4,022,880 as an antibacterial agent in combination with an anticalculus agent which provides zinc ions and in German Patent Disclosure 3,532,860 - ~ 8 ~-:::: : ;:

-~. -~
:,: ,, :- ~, $
-::-,~ ::

~--~n~ )U67r;!13 .Y~,' in combination with a copper c~ ~.d. In Europeon Pstent Disclosure 0278744 it is disclosed in combination with a tooth desensitizing agent containing a source`of potassium ions. It 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 : .: .
S- dentifrice containing zinc citrate trihydrate in published European Patent Application 0161899 to Saxton et al. In ~ Europeon Patent Application 271332 a typical drug release - ~ ~ system which could include triclosan in a toothpaste is '~ ''' ! described which contains a solubilizing agent s~ch as -::- :.':
; propylene glycol.

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, . ... ...
. ., The antlbacterlal-enhanclng agent (AEA) whlch enhances dellvery of sald antlbacterlal agent to, and retentlon thereof on, oral surfaces, ls employed ln amounts effectlve to achleve such enhancement wlthln the range ln the oral composltlon of about 0.05% to about 5%, preferably about 0.05% to about 4%, more preferably about 0.1% to about 3%, more preferably about 0.19 to about 2%, partlcularly about 0.5% to about 2.5% by welght.
Thls AEA may be a slmple compound, preferably a polymerlzable monomer, more preferably a polymer, whlch latter term ls entlrely generlc, lncludlng for example ollgomers, homopolymers, copolymers of two or more monomers, lonomers, block copolymers, graft copolymers, cross-llnked polymers and copolymers, and the llke. The AEA may be natural or synthetlc, and water lnsoluble or preferably water (sallva) soluble or swellable (hydratable, hydrogel formlng). It has an (welght) average molecular welght 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 ordlnarlly contalns at least one dellvery-enhanclng group, whlch ls preferably acldlc such as sulfonlc, phosphlnlc, or more preferably phosphonlc or carboxyllc, or salt thereof, e.g. alkall metal or ammonlum, and at least one organic retentlon-enhanclng group, preferably a plurallty of both the dellvery-enhanclng and retentlon-enhanclng groups, whlch latter groups preferably have the formula -(X)n-R
whereln X ls 0, N, S, S0, S02, P, P0 or Sl or the llke, R ls hydrophoblc alkyl, alkenyl, acyl, aryl, alkaryl, aralkyl, heterocyclic or their inert-substituted derlvatives, and n is zero or 1 or more. The aforesaid "lnert-substltuted derivatives", are lntended to lnclude substituents on R which are generally non-hydrophilic and do not significantly interfere with the desired functlons of the AEA as enhancing the dellvery of the antibacterial agent to, and retention thereof on, oral surfaces such as halo, e.g. Cl, Br, I, and carbo and the like. Illustrations of such retention-enhancing groups are tabulated below.

- lOa -;~006703 ,.~,~', .
. ,. ,.~
.. .
.-h~ n X . - (X~
:-::: .:
:~,: j ,,-,: .
O ---. methyl, ethyl, propyl, butyl, isobutyl, t-butyl ~ cyclohexyl, allyl, benzyl, phenyl, chlorophenyl, .~ xylyl, pyridyl, furanyl, acetyl, benzoyl, butyryl, terephthaloyl, etc.
,,:, .
' 1 0 ethoxy, benzyloxy, thioacetoxy, phenoxy, ~- carboethoxy, carbobenzyloxy, etc.
:: ..
N ethylamino, diethylamino, propylamido, benzylamino, benzoylamido, phenylacetamido, etc.
-~ S thiobutyl, thioisobutyl, thioallyl, thiobenzyl, .thiophenyl, thiopropionyl, phenylthioacetyl, ~hiobenzoyl, etc.

~- - SO butylsulfoxy, allylsulfoxy, benzylsulfoxy, .~ - phenylsulfoxy, etc.
::: ~. _ . '' S07 butylsulfonyl, allylsulfonyl, benzylsulfonyl, phenylsulfonyl, etc.

P diethylphosphinyl, ethylvinylphosphinyl, ethylallylphosphinyl, ethylbenzylphosphinyl, Y~;, ethylphenylphosphinyl, etc.
.- ~ , , .
: J~ PO diethylphosphinoxy, ethylvinylphosphinoxy, methylallylphosphinoxy, methylbenzylphosphinoxy, ~ methylphenylphosphinoxy, etc.

-~ Si trimethylsilyl, dimethylbutylsilyl, dimethyl-~-- benzylsilyl, dimethylvinylsilyl, dimethylallyl-, silyl, etc.
As emplDyed herein, the delivery-enhancing group refers to one which attaches or substantively, adhesively, cohesively or otherwise bonds the AEA (carrying the -: ''7i -'7- ~ ' antibacterial agent) to oral (e.g. tooth and gum) surfaces, 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 AEA and indirectly.on the oral ~ surfaces. In some instances, attachment of the anti---- ,, bacterial agent occurs through physical entrapment thereof ri:- by the AEA, especially when the AEA is a cross-linked . polymer, the structure of which inherently provides increased sites for such entrapment. The prese~ce of a -~".~ higher molecular weight, more hydrophobic cross-linking ~ ~ moiety in the cross-linked polymer , .
~ ~ 7 :~r - 11 -''-': ~ ~ j.:
",,,"~.,, ' .

2006703.
,.. .:
- .
. "~, ~ '; s~ill further promotes the phy~ical entrapment of the .
- antibacterial agent to or by the cross-linked AEA polymer.
: .::
. Preferably, the AEA 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 b~nded 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 : :~.. li, ~
~ groups as links in the polymer chain instead of or in addition to i:,. i ::
~ carbon atoms, or as cross-linking moieties.
~:
~ It will be understood that any examples or illustrations of -~hrj AEA's disclosed herein which do not contain both delivery-~ enhancing groups and retention enhancing groups may and : .ii :,::
~ '4 preferably should be chemically modified in known manner to :~::: ::::
, obtain the preferred AEA's contAin;ne 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 i:: :. ;:.::, ~ constitute at least about 10Z, preferably at least about 50%, '~ jyj ~
-~ ~ more preferably at least about 80Z up to 95% or 100% by weight of the polymer.
According to a preferred embodiment of this invention, the :~ ~ : :, - ~ ~ AEA comprises a polymer contA~in~ne repeating units in which one ~ ~ or more phosphonic acid delivery-enhancing groups are bonded to .~ , . .
~ one or more carbon atoms in the polymer chain. An example of .~.: ,.::
.j such an AEA is poly (vinyl phosphonic acid) contA;nine units of :::-::: .
~ the formula: .
~ ,. . .
' I -[CH2 - CH]-,,,.~::, \
~? pO3H2 - : which however does not contain a retention-enhancing group. A
`'- ' 4' - - 12-7 ~'', , . " ':.
,,- ~--. .
, ~. i ,.:' . ~; Z006703 ~ grouy of the latter type would however be present in poly -:.. .;
~ phosphonopropene) with units of the formula:
s:'~
II -5CH -fH]-, y CH3 PO3H2 ::::-:. ~::
A preferred phosphonic acid-containing AEA for.use herein ~:~ $~ is poly (beta styrene phosphonic acid) containing units of .: -- .~.:, ~ he formula:
- - . ~ ., ~ III -[CH - CH]-,: -~.............................. 1 1 ,i Ph PO3H2 wherein Ph is phenyl, the phosphonic delivery-enhancing :- ~ ::,. ,:
~ group and the phenyl retention-enhancing group being bonded ~?
~ . on vicinal carbon atoms in the chain, or a copolymer of beta ~" ' ' ?' ~
~ : styrene phosphonic acid with vinyl phosphonyl chloride -,: ~: ::~:
. having the units of formula III alternating or in random association with units of formula I above, or poly (alpha . styrene phosphonic acid) containing units of the formula:
::, :.. .
~ -: IV -[CH~ - C -----]--:: :-;~ //
Ph PO3H2 : ~ ''' ' - in which the delivery - and retention - enhancing groups are .J ~
~ . geminally bonded to the chain.
,::: :
~ ~- These styrene phosphonic 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. 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) l4CHPO3H2]rl~
::: :~.,;~:
?,. ~. .
'~ ::~' -Si,?~
~;:: -?'f?. :
:~:: ''1, .:' ~ .
~'",',Jl ~
,.-"~-:~'.:, ':~-:
,-. . ; ~
',"':-,.: ' '' ~':
-, ,J,~ ~ '? ' ','': ::
'i-' ~ :~: ' '''?' '~' ' .

- ~' 20067n3 .
.. .
;; .
. where n may Eor 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 -[CHz - CH----]- . -: : . /
CHz - CH < (PO3Na2)z and poly tallyl bis (phosphonoethyl amine) havin& units of the formula:
-',,Dt~,t,~-~ VII -[CH~ j CH---]-.. ~ . CHz - N < (PO3H2) 2 Other phosphonated polymers, for example poly ~allyl phosphono acetate), phosphonated polymethacrylate, etc. and the geminal diphosphonate polymers disclosed in EP Publica-.; tion 0321233 may be employed herein as AEA's, provided of :-,. course that they contain or are modified to contain the :: ~i,;
. - above-defined organic retention-enhancing groups.

In an aspect of this invention, the oral : ~ "
composition dentifrice comprises an orally acceptable - vehicle, about 5-30% by weight of a siliceous polishing -, :::~ . .:,' agent, an effective antiplaque amount of a substantially ~,3 water insoluble noncationic antibacterial agent and an .:::: - "'' -~ . . antibacterial-enhancing agent which has an average molecular : : ::,~ .: :
--i.............................. weight or about l,000 to about 1,000,000, contains at least , j t .
:.:~ one delivery enhancing functional group and at least one ~ organic retention enhancing group,said agent containing said ::i':
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.
, .
i,,- ~:,........................ ...
, . ,s "
~ .-. ':',. ' ,-~ .: -, -::::-:-: , :: -~:
",, ~; .
.. ~,..
, :. . - 14 -,:.:., ~.:, ,'" ~ r ';.: ', ', ~, .:J ~'r ~ - 2006703 -, ., The novel alpha- and beta- styrene phosph~nic acid polymers and copolymers with other ethylenically unsaturated : ,;:
monomers may in general be prepared by heating the monomers or mixtures of monomers, preferably under nitrogen, in the presence of an effective amount, e.g.. about 3-5%, of a radical initiator, e.g. AIBN, benzoyl peroxide, t-butyl : :~;:
hydroperoxide, persulfate or the like, neat or as solutions in an inert solution such as acetonitrile, methylene chloride or 1,2-dichloromethane; at elevated temperatures, ~ e.g. about 125C or at solvent reflux, for periods of about , 8 to 200 hours. The crude polymeric products after removal ~ of any lnert solvent, lS mixed with water and the aqueous - . r, mixture adjusted to a pH of about 8-10, e.g. with aqueous sodium hydroxide. After filtration of any solid - s; impurities, the filtrate solution is dialyzed against water ~ (e.g. at 3500 Dalton cutoff), and the purified polymer -~ isolated from the retentate solution as by lyophilization.
According to another preferred embodiment, the AEA may comprise a synthetic anionic polymeric polycarboxylate.
Although not used in the present invention to coact with h ~' polyphosphate anticalculus agent, synthetic anionic - polymeric polycarboxylate having a molecular weight of about ~,! ~' - ' ' ' ' .
r~: ~ 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 Gaffar et al. Indeed, ~- ~ in published British Patent Publication 22 00551, the , : . ::
- :j polymeric polycarboxylate is disclosed as an op~ional -: -:~ :. .. .
~ ingredient in oral compositions containing linear r~ molecularly dehydrated polyphosphate salts and noncationic ~a r,~ ~ antibacterial agent. It is further observed, in the context - ~: ~5 -... ~ 5': _ of the present invention that such polycarboxylate when --, ~ -~ containing or modified to contain retention-enhancing groups ~ ~ is markedly effective to enhance delivery and retention of ".~ ", .~
~ iFI l ~:~ ::.
~:-- .,;, ~" .
~ - l5 -the noncatlonic antlbacterlal, antlplaque agent to dental surfaces when another lngredlent wlth whlch the polymerlc polycarboxylate would coact (that ls, molecularly dehydrated polyphosphate) ls absent; for lnstance, when the lngredlent wlth whlch the polymerlc polycarboxylate coacts ls especlally the noncatlonlc antlbacterlal agent.
Synthetlc anlonlc polymerlc polycarboxylates and thelr complexes wlth varlous catlonlc germlcldes, zlnc and magneslum have been prevlously dlsclosed as antlcalculus agents per se ln, for example U.S. Patent No. 3,429,963 to Shedlovsky; U.S Patent No. 4,152,420 to Gaffar; U.S. Patent No. 3,956,480 to Dlchter et al; U.S. Patent No. 4,138,477 to Gaffar; and U.S. Patent No. 4,183,914 to Gaffar et al. It ls to be understood that the synthetlc anlonlc polymerlc polycarboxylates so dlsclosed ln these several patents when contalnlng or modlfled to contaln the retentlon-enhanclng groups deflned above are operatlve as AEA's ln the composltlons and methods of thls lnventlon.
These synthetlc anlonlc polymerlc polycarboxylates are often employed ln the form of thelr free aclds or preferably partlally or more preferably fully neutrallzed water soluble or water-swellable (hydratable, gel formlng) alkall metal (e.g. potasslum and preferably sodlum) or ammonlum salts. Preferred are 1:4 to 4:1 copolymers of malelc anhydrlde or acld wlth another polymerlzable ethylenlcally unsaturated monomer, preferably methyl vlnyl ether/malelc anhydrlde havlng a molecular welght (M.W.) of about 30,000 to about 1,000,000, more preferably about 30,000 to about r~

200670~

500,000. These copolymers are avallable for example as Gantrez e.g. AN 139 ~M.W. 500,000), AN ll9 (M.W. 250,000); and preferably S-97 Pharmaceutical Grade (M.W. 70,000), of GAF
Corporatlon.
Other AEA-operative polymerlc polycarboxylates contalnlng or modlfled to contaln retentlon-enhanclng groups lnclude those dlsclosed ln U.S. Patent No. 3,956,480 referred to above, such as the 1:1 copolymers of malelc anhydrlde wlth ethyl acrylate, hydroxyethyl methacrylate, N-vlnyl-2-pyrollldone, or ethylene, the latter belng avallable forexample as Monsanto EMA No. 1103 M.W. 10,000 and EMA Grade 61, and 1:1 copolymers of acryllc acld wlth methyl or hydroxyethyl methacrylate, methyl or ethyl acrylate, lsobutyl, lsobutyl vlnyl ether or N-vlnyl-2-pyrollldone.
Addltlonal operatlve polymerlc polycarboxylates dlsclosed ln above referred to U.S. Patent No. 4,138,477 and 4,183,914 contalnlng or modlfled to contaln retentlon enhanclng groups lnclude copolymers of malelc anhydrlde wlth styrene, lsobutylene or ethyl vlnyl ether, polyacryllc, polyltaconlc and polymalelc aclds, and sulfoacryllc ollgomers of M.W. as low as 1,000 avallable as Unlroyal ND-2.
Sultable generally are retentlon-enhanclng group-contalnlng polymerlzed oleflnlcally or ethylenlcally unsaturated carboxyllc aclds contalnlng an actlvated carbon-to-carbon oleflnlc double bond and at least one carboxyl group, that ls, an acld contalnlng an oleflnlc double bond whlch readlly functlons ln polymerlzation because of lts presence in the monomer molecule elther ln the alpha-beta 20~6703 position wlth respect to a carboxyl group or a part of a terminal methylene grouplng. Illustratlve of such aclds are acryllc, methacryllc, ethacrylic, alpha-chloroacryllc, crotonic, beta-acryloxyproplonic, sorblc, alpha-chlorosorblc, clnnamlc, beta-styrylacryllc, muconlc, ltaconlc, cltraconlc, mesaconlc, glutaconlc, aconltlc, alpha-phenylacryllc, 2-benzyl acryllc, 2-cyclohexylacryllc, angellc, umbellic, fumarlc, malelc aclds and anhydrldes. Other dlfferent oleflnlc monomer copolymerlzable with such carboxylic monomers include vlnylacetate, vlnyl chorllde, dlmethyl maleate and the llke.
Copolymers ordlnarily contaln sufflclent carboxyllc salty groups for water-solublllty.

- 17a -E

. ~ ~
0~)6703:
... . .
~-~` Also useful herein are so-called carboxyvinyl polymers ;t;," 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 .~ ~o~ , "~'r''rt~t''.' al; U.S. 3,911,904 to Harrison, and U.S. 3,711,604 to Colodney : ::, , , :
~t;'.~ et al. They are commercially available for example under the .~, '~'t~.'', trademarks Carbopol 934, 940 and 941 of B.F. Goodrich, these ~ :' products consisting essentially of a colloidaIly water-soluble ; ~ polymer of polyacrylic acid crosslinked with from about 0.75% to about 2.0% of polyallyl sucrose or polyallyl pentaerythritol as ,: :. ,-.-ross linking agent, the cross-linked structure and cross-linkages providing the desired retention-enhancement by hydrophobicity and/or physical entrapment of the antibacterial :
i- agent or the like. Polycarbophil is somewhat similar, being '~ polyacrylic acid cross-linked with less than 0.2% of divinyl : ~;- :.:
glyco~, the lower proportion, molecular weight and/or .; hydrophobicity of this cross-linking agent tending to provide little or no retention enhancement. 2,5-dimethyl-1,5-hexadiene exemplifies a more effective retention-enhanc-ing cross-linking agent.
. ~}t~ The synthetic anionic polymeric polycarboxylate component :: : t."' is most often a hydrocarbon with optional halogen and O-containing substituents and linkages as present in for example , ester, ether and OH groups.
The AEA may also comprise natural anionic poly~eric i~;. 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 ~ .: .-~ 'i - from the polymerization of vinyl or allyl phosphinic and/or ,. ., 't ~ .t~ . sulfonic acids substituted as needed on the 1 or 2 (or 3) carbon ~- :: ,~: .
atom by an organic retention-enhancing group, or example having s,- the formula -(X)~-R defined above. Mixtures of these monomers , ~ ;~ . .
- ,: ,,~:
- ~-i,:
~ ~ - l8 -: :: ,~ .

: ;r :l ~
~ . .
2006'~03 , - -i may be employed, and copolymers thereof with one or more inert . polymerizable ethylenically unsaturated monomers such as those . r~
~X 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 acidic i~,2 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 ~olume, John Wiley ~ Sons, Inc. copyright ,. ~,...
1984, which description is incorporated herein by reference.
Also effective as AEA's herein, provided they contain or are :, :, i::
~ modified to contain retention-enhancing groups, are polyesters, -- - polyurethanes and synthetic and natural polyamides including ,",~ ~ :
~ proteins and proteinaceous materials such as collagen, poly :
~ -` (arginine) and other polymerized amino acids.
~: ,~: .

: :::
: ,. ., .~ ~ .
: ::::: -~::: ., .
: ~:: ::

:;,j.:

, ::
:: ~, :
~: ~. ::
:: :~.j ~ .
. ~f ~:, -:-.
;':~
,'''. ", i,-'' ::~' .

~ : ' -'~ :'`, ~:: ' ' ' '''J,~ ;;~::.
,: ' ' ,i .:,::
~ - 19 -:,-.-- :::i: :
,',~ :~. ' .
:', '' .

,: , - ; . ~ , ~
,, ., ~ - - .;. .
Without being bound to a theory, it is beileved that the AEA, especially polymeric AEA, is generally and deslrably 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 8 complex or the like of the two over tooth surfaces. The film forming property of the AEA and the enhanced delivery and film forming property of the AEA and the enhanced delivery snd retention of the antibacterial agent on tooth surfacès due to the AEA appears to make tooth surfaces unfavourable 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) enhs~nced delivery, 2) long retention time on tooth surfaces, ant 3) prevention of bacterial attachment to tooth surfaces the oral composition is made efficacious for reducing plaque. Similar antiplaque effectiveness is sttained on soft oral tissue at or near the gum line.
In the oral preparation dentifrice, an orally acceptable , ,~,, .
vehicle including a water-phase with humectant is present. The humecant - ~',5. is preferably glycerine and/or sorbitol. Water is present tjpically in ; .
~; amoun~ of at least about 3% by weight, generally about 3-35% and glycerine and/or sorbitol typically total about 6. 5-75X by weight of the ::, .
~ oral preparation dentifrice, more typically about 10-75%. Moreover, -~ ~ there is also present with the water-humectant vehicle a material which '~ ~ is particularly effective to tissolve the antibacterial agent in saliva, -~ typically in amount of about 0. 5-50~ by weight. Together with this ~s solubilizing material, the water-l ~ctant phase typically amounts to about 10-80% by weight of the oral preparation tentifrice. Reference -: ::,:,: ~
hereto to sorbitol refers to the material typically as avaliable p commercially In 70% aqueous solutions. Significant amounts of :,,:::
polyethylene glycol, particularly of molecular weight of 600 or more, should be avoided since polyethylene glycol effectively inhibits the :, :: ::
~ ~ antibacterial activity of the noncationic antibacterial agent. For :, ::: ::: -~ ~5,, -20--:: -! ~, ~ ''" .
: ~ , ,.:
5,, - ~oo67c~3 , -., ~-~ lnstance, polyethylene glycol ~PEG) 600 when preseht with trlclosan ln a - welght ratio of 25 triclosan:l PEG 600 reduces the antlbacterlal ,,~ ~
~ ,~ actlvlty of trlclosan by 8 factor of about 16 from that prevalllng ln - .;
~ -~ - the absence of the polyethylene glycol.
m Materials which substantlally dlssolve the antlbacterlal agent, : ,_ - to permit its delivery to the soft oral tissues at or near the gumline, are employed in the present invention. Typical solubilizing materials f' . .
~ include the humectant polyols such as propylene glycol; dipropylene :.~; , .- glycol and hexylene glycol, cellosolves such as methyl cellosolve and ~- ethyl cellosolve, vegetable 0118 and waxes containing a~ least about 12 :: ., carbon atoms in a straight chain such as olive oil, castor oil, and - petrolatum and esters such as amyl acetate, ethyl acetate, glyceryl ~~ tristearate and benzyl benzoate. Propylene glycol 18 preferred. As . :,, .:
used hereln, "propylene glycol" lncludes 1,2-propylene glycol and ~ - 1,3-propylene glycol.
- - When the amount of su~tAn~iAl]y water-lnsoluble noncatlonic - ~ ~ antibacterial agent is low, say up to about 0.3% by welght, as little as 7'~, ~ about 0.5% by weight of the sol~ 171ng agent can be sufficient to r,r":~ solubllize the antibacterial agent. When higher amounts such as at least about 0.5Z by weight, of antlbacterlal agent are present, lt is ,ot.
---~ desirable that at least about 5% by weight, typically up to about 20% or : ~ .
'- ~ more by weight, of the solub~li7~n~ agent be present.
The pH of oral preparatlon dentlfrlce of the invention 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 applled orally at a pH below 5 wlthout substantlally decalcifying or otherwise d~ ~ln~ dental enamel. The pH can be - controlled with acid (e.g. cltrlc acld or benzolc acld) or base (e.g.
:: ,, ~ ~ ~ sodlum hydroxide) or buffered (as with sodium citrate, benzoate, -~ ; carbonate, or bicarbonate, disodium hydrogen phosphate, sodium .:: :~ :,:
~ dihydrogen phosphate, etc.).
., :: . .
' In this invention, the oral compositlon dentifrice may be substantlally gel in character, such as a gel dentifrice; Such gel oral : :~:~ :
-:. .,~"~ ~ -~ 21-., , ~-., ,::
:, ~5 .` .: '~' .
, - ~', ;<,-,:
,, ,, t.

- 20U67()3 .
~ ~ preparatlons generally contain siliceous tentally acceptable polishlng ,::- : :-materlal. Preferred pollshing materisls include crystalline silica havlng partlcle slzed of up to about 5 microns, a mean particle size of up to about 1.1 mlcrons, and a surface area of up to about 50, 000 --~ cm.2/gm.~ silica gel or colloldal gilica and complex amorphous alkall metal alumlnosilicate.
, -: ,.
When visually clear or opscified gels are employed, a polishing - $~ ~ agent of colloldal silica, such as those sold under the trademark SYLOID

"; as Syloid 72 and Syloid 74 or under the trademark SANTOCEL as Santocel 100 or alkali metal almuinosllicate complexes (that is, silica .: :, containing alumlna col;:blned in its matrix) are partlcularly useful, :~ . ,:...
-- ~ slnce they are conslstant with gel-llke texture and have refractlve indices close to the refractive indices of gelling agent-liquld -~: :: , .:
- ' (includlng water and/or humectant)systems commonly uset in dentifices.
,:., .:
The polishlng material is generally present in the oral composition dentifrlces such as toothpaste cream paste or gel .
~ ~ ;; composltion6 in welght concentrations of about 5% to about 30%.
~. :::
-~ In a gel toothpaste, the liquid vehicle may typically comprlse :'' , .
about 3-35% by welght of water, such as about 10-35X, a~id humectant ln ; an amount ranging from about 6.5Z to about 80X, such as about lOZ to ::,, ,:- ~:, about 80Z by weight of the preparation. In clear gels where the - refractive index ls an lmportant consideration, about i-30~ of water, O
::: :.
to about 70% of glycerlne and about 20-25% of sorbltol are preferably -' employed. The solublllzlng material, typically present in amount of about 0.5-20i or more by weight, may be consldered to be a part of the :- ;, :.:
~ ", llquld vehlcle ln the oral preparation dentifrice as prepared. As ',, -- ',s-c ~-, indicated, the solubilizing materlals lnclute polyol humectants such as , ' :~:'~. .
propylene glycol and tipropylene glycol.

~ The oral composition dentlfrlces typically contain a natural or --~ - $-synthetic thickener or gelling agent in proportlons of about 0.1 to : . -::
~ ~, about 10%, preferably about 0.5 to about 5Z. A suitable thickener is ~ :::: :..: ~:
--~ ' - synthetic 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 :,, " : .: ..
',';- ' :, ,:;, ::
~ ,c' ~-- -22-"',-:-' :.~
,~" . ':~
~ ,, ~ , ' , ','': ,, ~0(~6~n3 shows, approximately by welght, 58.00X SiO2, 25.40% MgO, 3.05% Na20, ~ 0.98% Li20, and some water and trace metals. Its true specific gravity - is 2.53 and it has an apparent bulk density (g./ml. at 8% moisture) of 1Ø
Other suitable gelllng agent6 or thickeners include Irish moss, carrageenan, gum tragacanth, starch, polyvinylpyrrolidone, hydroxyethypropyl cellulose, hydroxybutyl methyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose (e.g. avallable ' ~ as Natrosol), sodium carboxymethyl cellulose, and colloidal sllica such those available as flnely ground Syloid 244 and Sylodent 15.
Since there maybe a tendency for the dentlfrice to separate .: ~. :
into liquid and solid portions when about 5% by weight or more of the ., solubilizing material such as propylene glycol is present and since excellent antiplaque effects can be obtained with small amounts of antibacterial agent which do not require so much solubilizing humectant :: ,:
~; to effect solubilization, a preferred dentifrice contains about 0.25-0.35%, say about 0.3%, by weight of the antibacterial agent, about 1.5-2% by weight of the polycarboxylate and about 0.5%-1% by weight of , ~
the solubillzing material.
: ..-.., 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 ln surfactant micelles in the mobile phase (that is, not including gelling agent and polishing agent) of a dentifrice formula. The phase solutlon of dentifrice during use becomes ::
~ ~; diluted with saliva which causes trlclosan to precipitate. However, the ::
solubilizing material of the present lnventlon permits the antibacterial agent to remain in solution ln the moblle phase in the presence of ~, saliva and to effectively reach the soft oral tissues. Propylene glycol being a strong solubilizing humectant for triclosan, appears to prevent ~-- its precipitating and permit its continued presence within the mobile ~; phase. In this regard it is noted that propylene glycol is widely used ~'.:
in drug delivery systems (for instance ln European Patent Publication . 271,332) for its strong lnteractlon wlth blological membranes. It may ~ ;~ be that in the oral cavity, trlclosan 18 partltioned from the aqueous :- ,.
~:~ :.:
- ; -23-.. .
~ .
::

- ~0()~7()~3 -, environment oral preparatlon into propylene glycol-surfactant emulslon and further that propylene glycol in the bulk moblle phase allows greater probability of triciosan emergence out of surfactant micelles, - thereby rendering triclosan 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 a source of fluoride ions, or fluorine-providlng component, as antl-carles agent, ln an amount sufficlent to supply about 25 ppm to 5,000 ppm of fluorlde lons. Thls compound may be alightly soluble in water or may be fully water-soluble. They are characterlzed by thelr ablllty to release fluorlde ions in water and by substantlal freedom from undeslred reactlon with oeher compounds of the oral preparation. Among these maeerials are lnorganlc fluorlde salts, such as soluble alkall metal, alkaline eareh meeal sales, or example, sodlum fluorlde, potasslum fluoride, ammonium fluorlde, calclum fluorlde, a copper fluorlde such as cuprous fluoride, zinc fluorlde, barlum fluorlde, sodlum flouroslllcate, ammonium flourosillcate, sodium fluorozirconate, sodium fluorozirconate, sodlum monofluorphosphate, alumlnum mono-and dl-fluorophosphate, and fluorinated sodium calclum pyrophosphate. Alkall metal and tln fluorldes, such as sodlum and stannous fluorides, sodlum -.: ,:
~ monofluorophosphate (MFP) and mixturea thereof, are preferred.
-:::: ~..:
~ . The amount of fluorine-providing compound is dependent to some -: ; : .:J:, -~ extent upon the type of c o 1, its solubility, and the type of oral ;, preparatlon, but lt must be a non-toxlc amount, generally about 0.0005 :: :, :~:
to about 3.0% in the preparatlon. In a dentlfrlce preparatlon, e.g.

dental gel, an amount of such compound whlch releases up to about 5,000 ppm of F lon by weight of the preparatlon 18 consldered satlsfactory.
Any sultable mlnlmum amount of such compound may be used, but lt ls preferably to employ sufficient c- .- ' to release about 300 to 2,000 ppm, more preferably about 800 to about 1,500 ppm of fluoride ion.
Typlcally, ln the cases of alkall metal fluorldes, thls :::
~ component ls present ln an amount up to about 2% by welght, based on the ..... .
~; weight of the preparation, and preferably in the range of about 0.05% to :.~:
.-::::-:
~ -24-.rJ:

,. ~
"-- . . .

2no67~;~

1X. In the case of sodium monofluorophosphste, the compound may be present in an amount of about 0.1-3%, more typically about 0.76X.
It will be understood that, as is conventional, oral -~ preparations are to be sold or otherwise distributed in suitable ~ labelled packages. Thus a dentifrice gel will usually be in a : .
collapsible tube, typlcally 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 dentifrice gel or the like.
: :: .- ~; -:
- Organic surface-active agent6 are u6ed in the compositions of : ~',.:
~ - the present inventlon to achieve increased prophylactiç action, assist ,:
~- ~ in achieving thorough and complete di6per6ion of the antiplaque antibacterial agent throughout the oral cavity, and render the instant compositions more cosmetically acceptable. The organlc surface-active : :
material is preferably anionic, nonlonlc 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 monoglycerlde monosulfates, such as the sodium salt of the monosulfated monoglyceride of hydrogenated coconut oil fatty acld6, ~,:
- higher alkyl sulfates such as sodium lauryl sulfate, alkyl aryl sulfonates such as sodium dodecyl benzene sulfonate, higher alkyl - ::, ~ sulfoacetates, higher fatty acid e6ter6 of 1,2-dihydroxy propane ?,, ~'''.'' sulfonate, and the substantially 6aturated higher aliphatic acyl amides .:-:-~ of lower aliphatic amino carboxylic acid compounds, such a6 those having - : .::
12 to 16 carbons in the fatty acid, alkyl or acyl radicals, and the like. Examples of the la6t mentioned amide6 are N-lauroyl 6arcosine, :: .: :::
-- ~?~_ and the sodium, potassium, and ethanolamine salts of N-lauroyl, N-myristoyl, or N-palmitoyl sarco6ine which 6hould be 6ub6tantially free ~ from soap or similar higher fatty acid material. The u6e of these .~
sarcosinate compounds in the oral compositions of the present invention :'"
is particularly advantageous since these materials exhibit a prolonged and marked effect in the inhibition of acid formation in the oral cavity : . :::
:.
:~ : "
~ . -25--,:, :: ,~
:~:

' X00~i7(~3 :
~; due to carbohydrate breakdown in attition to exerting some reduction in ,. ':
the solubility of tooth enamel in acid 601utions. 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 corlden~ation products ("ethoxamers") ; contain hydrophilic polyoxyethylene moieties, such as condensation '~ products of poly(ethylene oxlte) with fatty acids, fatty alcohols, fatty - amides, polyhydric alcohols (e.g. sorbitan monosterate) and polypropyleneoxide (e.g. Pluronic materials).
Surface active agent is typically present in amount of about ~ 0.5-5% by weight, preferably about 1-2.5%. It is noteworthy, that :~' surface active agent may assist in the dissolving of the noncationic :~-;i antibacterial agent and thereby diminish the amount of solubilizing ~$i i humectant needed.

Various other materials may be incorporated in the oral : : , ::
preparations of this invention such as whitening agents, preservatives, ::, silicones, chlorophyll compounds ant/or ammoniated material such as . .. .
~ ~ i urea, diammonium phosphate, ant mixtures thereof. These ad~uvants, :: ::
where present, are incorporatet 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 which are generally soluble and which would complex with :::
:, ~
active components of the instant invention are to be avoided.
Any suitable flavoring or sweetening material may also be employed. Examples of suitable flavoring constituents are flavoring .

oils, e.g. oil of spearmint, pepperment, wintergreen, sassafras, clove, :: :
sage, eucalyptus, mar~oram, r~nr~~ -n, lemon, and orange, and methyl ~ , ~ sallcylate. Suitable sweetening agents include sucrose, lactose, - ~-'; maltose, xylitol, sodium cyclamate, perillartine, A~P (aspartyl phenyl ~, alanine, methyl ester), saccharine ant the like. Suitably, flavor and : -:: -~
r; ~ ~ ' sweetening agents may each or together comprise from about 0.1% to 5%
. ~' , more of the preparation. Ilureo~er, flavor oil is believed to aid the dissolving of the anti-bacterial agent.
: .. . .. .

20()67~)3 :
In the preferred prsctice of this invention an oral composition dentifrlce containing the composition of the present invention is preferably applied regularly to dental enamel and soft oral tis6ues, particularly at or near the gum line, 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 P-;;i to about 9, generally about 5.5 to about 8, preferably about 6.5 to 7.5, -~ for at least 2 weeks up to 8 weeks or more up to lifetime.

The composition of this invention can be incorporated in ~- ~ lozenges, or in chewing gum or other 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 conventionsl plastizers or softeners, sugar or other sweeteners or carbohydrates such as glucose, sorbitol and the like.

J',';

. . ' ' .

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;~
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ZoO6703 EXAMPLE A
: -::
,~
Poly (beta-styrenephosphonic acid) , .

A mixture of 18.1 g. (0.1 M) of beta-styrenephosphonic acid and 0.82 g. (0.005 M) of azobisisobutyronitrile (AIBN) in 300 ml. of anhydrous acetonitrile is stirred under reflux under dry nitrogen for 96 hrs. The mixture is cooled and the crude product :::
precipitate is isolated by filtration, washed with acetonitrile, and air dried. The crude product is dissolved in aqueous sodium ::
hydroxide (to pH 11) and dialyzed against water at 3000 Dalton cutoff. The retentate solution is reduced to 100 ml., in vacuo, ::::
J,~ and freeze-dried to yield the purified product polymer as a white powdery solid in 0.91 g. yield. Infrared spectrum: 1610, 1550, 745 cm~' (aryl,5 adjacent H); 1240, 1020, 950 cm~l (phosphonate).
Proton nmr (DzO): tr,6.4 ppm. (H on carbon bearing phosphonate);
::::
~ m,7.3 ppm. (aryl and benzylic protons); area ratio 1 to 6.
~ ;.
~ . Phosphorus nmr (DzO): m,6.2 ppm. (alkyl phosphonate).
::
: ., EXAMPLE B

:: :::~:
; Copoly (beta-styrenephosphonic acid/vinylphosphonic acid) - A mixture of 10.68 g. (0.058 M) of beta-styrenephosphonic acid, 6.0 ml. (8.4 g., 0.058 M) of vinylphosphonyl dichloride, and 0.5 ~ ~: :"
~ g. of AIBN is heated, with stirring, under an anhydrous nitrogen ;:
;~ atmosphere intermittently for a few hours, then overnight at 80-90 C. The material is transferred to a beaker with 60-70 ml.
:, ,, of water. A crystalline precipitate forms as the warm solution cools. The mixture is filtered, the aqueous filtrate is diluted .~.....
to 125 ml. with water, and the resulting solution is dialyzed vs.
water at 3500 Dalton cutoff. The retentate solution is evaporated in vacuo to give 0.600 g. purified acid form of the copolymer.
Proton nmr (DzO) shows two broad regions at 1.0-2.8 (alkyl, llH) ; -28-- -:

-~:

- - -~ 20U6703 ~ , and 6.9-7.5 ppm. (aryl, 5H). These data indicate a ratio of :'.' beta-styrenephosphonic acid to vinylphosphonic acid of 1:3 in the -~ copolymer. Phosphorus nmr (D2O) shows two maln phosphorus - signals centered at about 23.4 and 29.2 ppm. respectively.
:

: :

::
~ EXAMPLE C
, Poly (alpha-styrenephosphonic acid) A mixture of 2.21 g. (0.01 M) of alpha-styrenephosphonyl dichloride and 0.01 g. of AIBN is stirred under a nitrogen atmosphere at 115 C. At 12 hour intervals, successive 0.01 g.
AIBN portions are added to the mixture. After 96 hours, the mixture is allowed to cool and dissolved in water. The pH is adjusted to 8-10 with aq. sodium hydroxide in a total volume of 125 ml. The solution is filtered and the filtrate is dialyzed :: .
: ~ 5~: against water in a 3500 Dalton cutoff cellulose bag. The ; :~:- .
~; retentate is reduced to about 50 ml. in vacuo, then freeze dried.
-~ The polymer is obtained as a tan powdery solid in 0.08 g. yield.
,, ::;;
- Proton nmr (D2O): 7.2-7.4 ppm. (m, phenyl). Phosphorus nmr (D~O): 23-25 ppm. (m).

;::

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200~n~
. .

The followlng examples are further lllustrative of the nature of the present lnventlon, but lt is understood that the lnventlon is not limited thereto. All amounts and proportions referred to herein and ln the appended clalms are by welght, unless otherwlse lndicated.
EXAMPLE l The effect of synthetic anionic linear polycarboxylste on the uptake, retentlon to and release from tooth surfaces of water-lnsoluble noncatlonic antibacterial agent is assessed ln vltro on a saliva coated hydroxyapatite disk and on exfoliated buccal epithellal cells. The in : ::
vitro assessments are correlatable to ln vlvo delivery, and retention on ~;~ oral surfaces.

For the test of delivery of antibacterlal agent to a saliva .1, coated hydroxyapatite disk, hydroxyapatlte (HA) obtalned from the Monsanto Co. ls washed extensively with dlstilled water, collected by vacuum filtration, and permitted to dry overnight at 37C. The dried HA

is ground into a powder with a mortar and pestle. 150.00 mgs of HA are placed into the chamber of a KBr pellet die (Barnes Analytical, Stanford, CT.) and compressed for 6 minutes at lO,000 pound in a Carver Laboratory press. The resultlng 13 mm disks are sintered for 4 hours at : .
~ - 800C ln a Thermolyne furnace. Parafilm stlmulated whole saliva ls ., :,: .
collected into an ice-chllled glass beaker. The saliva ls clarlfled by centrifugation at 15,000 Xg (times gravity) for 15 minutes at 4C.

Sterilization of the clarified-saliva is done at 4C with stirring by ' lrradlatlon of the sample wlth UV light for l.0 hour.
., :: ,,:~
Each sl~tered dlsk 18 hydrated with sterlle water ln a . ~,..
polyethylene test tube. The water is then removed and replaced with 2.00 ml of saliva. A salivary pellicle is formed by incubating the disk overnight at 37C with continuous shaking ln a water bath. After thls -::::
treatment, the sallva ls removed and the disks are treated with l.00 ml -~ of a solutlon containing antibacterial agent (Triclosan) dentifrice ~- llquld phase solutlon and incubated at 37C with continuous shaking ln the water bath. After 30 minutes, the disk is transferred into a new .~
tube and 5.00 ml of water are added followed by shaking the disk gently - ' wlth a Vortex. The disk is then transferred lnto a new tube and the ~., : :

::: .

~ 2~06703 washing procedure repeated twice. Finally, the dlsk ls transferred carefully into a new tube to avoid co-transfer of any liquid along with the disk. Then 1.00 ml of methanol is added to the disk and shaken vigorously with a Vortex. The sample is left at room temperature for 30 ':' minutes to extract adsorbed Triclosan into the methanol. The methanol , is then aspirated and clarified by centrifugation in a Beckman Microfuge ll at lO,000 rpm to 5 minutes. After this treatment, the methanol is transferred into HPLC (high performance liquid chromatography) vials for determination of antibacterial agent. Triplicate samples are used in :: -: :::::
all experiments.
For the test of retention of antibacterial agent to a saliva coated HA disk, a saliva coated HA disk is treated with dentifrice slurries as described above. After incubation for 30 minutes at 37C, -..~,:
-- the HA disk is removed from the dentifrice slurry, washed twice with water, and then reincubated with parafilm stimulated human whole saliva which had been clarified by centrifugation. After incubation at 37C
with constant shaking for various periods, the HA disk is removed from :::
- the saliva, and the amount of antibacterial agent (Triclosan) retained , .
onto the disk and released into saliva is determined by analytical .,1.
method using HPLC.
~- For the assay of delivery of antibacterial agent to buccal epithelial cells, the delivery is measured in order to determine the ~.::-: :
effect of PVM/MA on the delivery of antibacterial agent (Triclosan) to soft oral tissue from a dentifrice product. Buccal epithelial cells are ,. ~
~ ~ collected with a wooden applicator stick by gently rubbing the oral . ~
mucosa. The cells are suspended in Restlng Saliva Salts (RSS) Buffer (50 mM NaCl, l.l mM CaC12, and 0.6 mM KH2P04 pH 7.0) to 5-6x105 cells/ml ~ using a hemocytometer to enumerate the cells and kept in ice until use.
;
, 0.5 ml of cell suspen810n, preincubated to 37C in a waterbath, is added with 0.5 ml of the test antibacterlal agent solution and incubated at 37C. The antibacterial agent solution in the incubation mixture is dlluted at least 10 times ln order to lower the surfactant concentration :
and prevent destructlon of cell membranes by the surfactant. After 30 ~, minutes of incubation, the cells are harvested by centrifugation in '~"
'' ' ~ -31-: ' ;:~:
::
: , .

2006~703 "
Beckman Microfuge 11 at 5,000 rpm for 5 mlnutes. The cells, collected as the pellet, are washed,3 times wlth RSS buffer and treated wieh 1.5 ml of met~anol. The sample is mixed vigorously by Vortex and then centifuged as described above. The supernatsnt is analyzed for antibacterial agent by the HPLC method.
Dentifrices are prepared havlng the following formulas:
~ Parts : .
A B
: , :::
Propylene Glycol (1,2)10.00 10.00 ~,~ Iota Carrageenan 0.75 0.75 - ~, Gantrez S-97 - 2.00 Tltanium Dioxide 0.50 0.50 - Sorbitol (70~) 30.00 30.00 Sodium Fluoride 0.332 0.332 Sodium Saccharin 0.40 0.40 Silica Thickener (Sylodent 15) 3.00 3.00 ~'~ Silica Polishing Agent (Zeodent 113) 20.00 20.00 Triclosan 0.20 0.20 , , Sodium Lauryl Sulfate 2.00 2.00 ~i":: .
~ Flavor Oil 0.95 0.95 Ethyl Alcohol 1.00 1.00 -::J';
Sodium Hydroxide (50%) 0.80 0.80 ' Water Q.S. to lO0.0 Q.S. to lO0.0~:~ ,"'" .
J~
~'' ..... ..
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-~ i -32-,,,-~, .
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:i.:
.
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: The uptake of triclosan on the saliva coated hydroxyapatite disk and on buccal epithelial cells with and without the polymeric polycarboxylate, Gantrez S-97, is set forth in Table 1 below:

Uptake of TriclosanIn Micrograms in micrograms x 105 Buccal -Dentifrice On Saliva Coated Disk Epithelial Cells ~ A 25.0 38.0 .~ B 54.0 96.0 ., .

:,-.
.......................................... These results reveal that the Gantrez material (present in :- Dentifrice B) greatly enhances the delivery and uptake of triclosan to ~ saliva coated hydroxyapatite disk and to the exfoliated buccal :: :-:: epithelial cells.

Slmilar results are obtained when the dentlfrices contain 0.30 ~: parts of tricolosan.
:", , .
::
~ EXAMPLE 2 :::
:: .,: .
In tests with saliva coated hydroxapatite disks and exfoliated buccal epithelical cells different from those set forth in Example 1 - above, said dentifrice B containing 2.00% Gantrez S-97 and 0.20% of ,, .
:~ .. : triclosan, 10.00% of propylene glycol and 2.00% of sodium lauryl sulfate ::
-~ and an equivalently formulated Dentifrice (B'), except for the presence ~ of 0.30% of triclosan were compared with a commercially available :~, : Dentifrice (C) containing hydrated alumina polishing agent and (a) 0.2%
.:~:
. of triclosan, (b) no Gantrez material, (c) no propylene glycol, (d) 0.5%

~-~ zinc citrate, (e) 2.5% of surface active agents (f) sodium ~ monofluorophosphate and hydrated alumina polishing agent; and the :~ . dentifrice formulation below (C') which is similar to commercial - .. :: Dentifrice C except for the presence of 0.30X of triclosan:
:
: :,:
s; . -33-~ ~)"'~
- :: :- . ~

: -~

-67n3 ~: DENTIFRICE C' :~ %
Sorbitol (70%) 27.00 :~ Sodium Carboxymethyl Cellulose 0.80 Sodium Monofluorophosphste 0.85 Zinc Citrate 0.50 a~ Sodium Saccharin 0.18 ~-~ Water 16.47 ~: Hydrated Alumina Polishing Agent50.00 . Ethanol 0.20 Sodium Lauryl Sulfate 1.875 .,~ .
::: Sodium Dodecyl Benzene Sulfonate0.625 ~: Triclosan 0.30 Flavor 1.20 Since Dentifrices C snd C' contain a total of 2.50% of surface : ::
active agent, more surface actlve agent is available to dissolve ,., triclosan than in Dentifrices B and B' which contain 2.00%. However, ~; propylene glycol present in siliceous polishing agent Dentlfrices B and B' (but not in hydrated alumina polishing agent Dentifrices C and :, :;: C') insures optimum dissolutlon of triclosan.
:' : ~,: The advantage of Dentifrices B and B' (contalning propylene glycol) and Gantrez) over Dentifrices C and C' in triclosan uptake on : .~
.:. saliva coated hydroxyapatite disks and on exfoliated buccal epithelial ~: ;.; cells is shown in the Table 2 below:
~.:
'~
,. - . TABLE 2 :~ Dellvery of Trlclosan To Sallva Coated To Buccal Epithelial Hydroxyapatlte Dlsk Cells ~ (in micrograms) ~n mlcrograms .. : x 10 Epithelisl Cells) Dentifrice B 41.1 101.6 B' 77.4 142.0 :
C 20.4 61.0 C' 42.6 100.0 : :::: --34--:
:::
~:,;

:'~ .

---- Z00671)3 ~ 4:'~ Additional experlments with Dentifrlce B' (0.3X Triclosan;
. .
.- ~Gantrez; Propylene Glycol) in a 50% slurry of the dentifrice to determine the retention of triclossn on the saliva coated hydroxyapatite -:disk over a period of time reveals retention of excellent levels of .. triclosan as shown in Table 3 below:
~ TABLE 3 .-~ Retention of Triclosan Adsorption . fro~ Dentifrice Slurry .. . .
.. - Time Retention of Triclosan .- (in Minutes) (Micrograms/Disk) ;' ' :: 0 70 ::~ 30 60 .. 60 70 .- - 180 57 :: : 240 59 "

, ~ These results indicate that dentifrices containing triclosan, ;~ Gantrez material and propylene glycol can provide enhanced delivery of triclosan to, and retention on, tooth surfaces and soft surfaces in the . .
:: oral cavity, thereby providing improved antlplaque and antibacterial :: effects.

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:.-, Example 3 .
For purpose of comparison formulas a and b below are prepared ~':
Dentifrice a b :: . IV
.. ~.
::, Glycerln10.00 Propylene Glycol - 10.00 Iota Carrageenan 0.60 0.60 :::
Sorbitol (70%) 25.00 25.00 Sodium Saccharin 0.40 0.40 :': .
Sodium Fluoride 0.243 0.243 Titanium Dioxide 0.50 0.50 Gantrez S-97 2.00 2.00 :::
Water 29.157 29.157 :,, NaOH(50%)2.00 2.00 Zeodent 113(Silica Polishing ~-" Agent) 20.00 20.00 - ~ Sylodent 15 (Silica Thickener)5.50 5.50 ::
Flavor1.10 1.10 Triclosan 0.50 0.50 Sodium Lauryl Sulfate 2.00 2.00 ::~
; Ethanol1.00 1.00 .....

::~ . .
., .

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~ 36-:~:
,.,~ ,.
., .: .
~"':

.j .

2006~0~'3 Formula a is a dentlfrlce conealnlng a Gantrez polycarboxylste, wlth trlclosan as an antlbacterlal antlplaque agent and no solublizing agent. In Formula b, propylene glycol solubilizing agent is present.

~ Formula a ls poor in delivery of triclosan on buccal eplthellal -~ cells whlle Formula b ls markedly effective.

~ he foregolng results reveal excellent dellvery of Trlclosan dentlfrice.

An "in-house" study was conducted on a group of volunteers to assess the effects of partlcular dentifrices in lnfluenclng plaque regrowth ln accordance with the method descrlbed by Addy, Willls and Moran, J. Clln. Perlo., 1983, Vol. 10, Pages 89-99. The dentifrlces tested lncluded a placebo control containing no triclosan ~i) and a dentlfrlce ln accordance wlth this inventlon contalnlng 0.3% of trlclosan, 10% propylene glycol (lnstead of 3% polyethylene glycol 600) and 2% of Gantrez S-97 and humectant of propylene glycol and sorbltol (11). The formulas of the dentlfrices are as follows:

. ' .
::

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200~ 3 ., .
:,.
;, ~ Part , (i) (ii :~. .
~ .
~: Placebo Invention .lj:
Polyethylene Glycol 600 3.00 Glycerine 25.00 Propylene Glycol - 10.00 Sorbitol (70%) 41.617 . 25.00 Sodium Carboxymethyl Cellulose 0.35 Iota Carrageenan - 0.60 Sodium Benzoate 0.50 Sodium Saccharin 0.20 0.40 -::: ,~
: Sodium Fluoride 0.243 0.243 Silica Polishing Agent (Zeodent 113) 18.00 20.00 Silica thickener (Sylox 15) 5.50 5.50 : .
: Water 3.00 28.757 '~, Gantrez S-97 - 2.00 :::::
::~ , Triclosan - 0.30 ~:' Titanium Dioxide 0.50 0-50 -~. Sodium Lauryl Sulfate 1.20 2.50 Flavor 0.89 1.10 : Ethyl Alcohol 1.00 :::
,:--:~ Sodium Hydroxlde (50~) 2.00 :~

~ -38-:::
:.
"

:::
:'~
.

0()67C)3 .~
With regard to plsque reduction, on the teeth of the ; volunteers, compared to placebo (i), invention (ii) provided a ~.......................... . I
significant decrease of 20%.

~; Since lesser amounts of propylene glycol can dissolve the 0.3 --:
of triclosan present in Toothpaste (ii), similar results are expected when the amount of propylene glycol is reduced to 0.5 parts and the amount of sorbitol is increased to 39.5 parts. Likewise, the other solubilizing materials dipropylene glycol, hexylene glycol, methyl cellosolve, ethyl cellosolve, olive oil, castor oil, petrolatum amyl acetate, ethyl acetate, glyceryl tristearate and benzyl benzoate., in place of propylene glycol, can effectively deliver triclosan to soft oral tissues.

, ', ''~

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- ~ -39-: ~
:~,.

:.~:, ~.' ' ' ; ., ;~ )6703 :

The following dentifrlces of the lnvention are prepared:
Parts A B

Glycerine - - 20.00 Propylene Glycol 10.00 0.50 Sorbitol (70%) 25.00 19.50 Sodium Carboxymethyl Cellulose - 1.10 Iota Carrageenan 0.600 Sodium Saccharin 0.40 0.30 Sodium Fluoride 0.243 0.243 Silica Polishing Agent (Zeodent 113) 20.00 20.00 Silica thickener (Sylox 15)5.50 3.00 ~ Water 28.757 15.307 -~--~ Gantrez S-97 2.00 2.00 Triclosan 0.50 0.30 Titanium Dioxide 0.50 0.50 Sodium Lauryl Sulfate 2.50 2.00 Flavor 1.10 0.95 Ethanol 1.00 Sodium Hydroxide (50%) 2.00 1.60 In the foregoing examples, lmproved results may also be obtained by replacing triclosan wlth other antibacterial agents herein described such as phenol, thymol, eugenol and 2,2'-methylene bis ~ (4-chloro-6-bromophenol) and/or by replaclng Gantrez wlth other AEA's -~ such as a 1:1 copolymer of malelc anhyrlde and ethyl acrylate, sulfoacrylic oligomers, Carbopols (e.g. 934),polymer6 of monomeric alpha- or beta-styrene phosphonic acid and copolymers of these styrene phosphonic acid monomers with each other or with other ethylenically unsaturated polymerizable monomers such a6 vinyl phosphonic acid.
.

.,.~:
~~:

,, ZOOf~703 The following liquid phase dentifrice solutions are tested for uptake and retention of triclosan on saliva coated HA disks following the test procedures described in Example 1 with the indicated results:

In~redients Parts -. A 3 C D
: Sorbitol (70% solution) 30.0 30.0 30.0 30.0 Glycerol 9.5 9.5 9.5 9.5 Propylene Glycol 0.5 0.5 0.5 0.5 ~:
.. SLS 20.0 20.0 20.0 20.0 NaF 0.243 0.243 0.243 0.243 Flavor Oil 0.95 0.95 0.95 0.95 Triclosan 0.3 0.3 0.3 0.3 water 56.507 54.50754.507 54.507 :: Poly (beta-styrenephosphonic acid) 2.0 Poly (alpha-styrenephosphonic acid) 2.0 `~ Polyvinyl Alcohol 2.0 - Adjusted to pH6.5 with NaOH
Triclosan Uptake in Micrograms on Saliva Coated ::, Disks 31.0 174.0 86.0 36.0 Retention of Triclosan on ::: Saliva Coated HA Disks After-~ Initial 183.0 : 30 minutes 136.0 1 hour 105.0 3 hours 83.0 ~ .
The above results show that solution (D) containing ~: polyvinyl alcohol, not an AEA hereunder, produce~ a triclosan uptake of only 36.0, guite similar to the 31.0 uptake of the ::: ~
control solution (A) without additive. In contrast, solution (C) with poly (alpha-styrenephosphonic acid) produces an uptake of ::

X0~)6~ 3 ... .
. 86.0, more than double that of solutions (A) and (D), and :
solution (B) with poly (beta- styrenephosphonic acid) produces an uptake about 5 times that of solutions (A) and (D), tending to indicate further that vicinal substitution of the delivery-enhancing group yields superior results. The above results also show the surprisingly good retention of triclosan on the HA disks over time obtained with solution (B) containing poly (beta-styrenephosphonic acid (M.W's about 3,000 to 10,000).

" .

;:

20067a;~
~e .
; .
Thls inventlon has been described with respect to certain preferred embodiments and it will be understood that modifications and variations thereof obvlous to those skilled in the art are to be included withln the spirit and purview of this application and the scope of the appended claims.

.,

Claims (37)

1. An oral composition dentifrice comprising in an orally acceptable vehicle, about 5-30% by weight of a siliceous polishing agent, an effective antiplaque amount of a substantially water insoluble noncationic antibacterial agent, and about 0.005-5% 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 comprises a solubilizing material for said antibacterial agent in amount sufficient to dissolve said antibacterial agent in saliva, 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 claim 1, wherein said antibacterial agent is present in amount of about 0.01-5%
by weight.

8. The oral composition claimed in claim 7, wherein said amount of antibacterial agent is about 0.25-0.5%.

9. The oral composition dentifrice according to any one of claims 1 to 8, wherein said solubilizing material is present in amount of about 0.5 to 50% by weight and is selected from the group consisting of propylene glycol, dipropylene glycol, hexylene glycol, methyl cellosolve, ethyl cellosolve, vegetable oil and wax containing at least about 12 carbon atoms, amyl acetate, ethyl acetate, glyceryl tristearate and benzyl benzoate.

10. The oral composition dentifrice claimed in claim 9, wherein-said solubilizing is propylene glycol and is present in amount of about 0.5% by weight.

11. The oral composition according to any one of claims 1 to 8, wherein said antibacterial-enhancing agent has an average molecular weight of about 100 to about 1,000,000.

12. The oral composition according to any one of claims 1 to 8, wherein said antibacterial-enhancing agent contains at least one delivery-enhancing functional group and at least one organic retention-enhancing group.

13. The oral composition according to claim 12, wherein said delivery-enhancing group is acidic.

14. The oral composition according to claim 13, wherein said delivery-enhancing group is selected from the group consisting of carboxlic, phosphonic, phosphinic and sulfonic acids and their salts and mixtures thereof.

15. The oral composition according to claim 14, 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 or 1 or more.

16. The oral composition according to claim 15, wherein said antibacterial-enhancing agent is an anionic polymer containing a plurality of said delivery-enhancing and retention-enhancing groups.

17. The oral composition according to claim 16, wherein said anionic polymer comprises a chain containing repeating units each containing at least one carbon atom.

18. The oral composition according to claim 17, wherein each unit contains at least one delivery-enhancing group and at least one organic retention-enhancing group bonded to the same on vicinal, or other atoms in the chain.

19. The oral composition according to claim 18, wherein the delivery-enhancing group is a carboxlic group or salt thereof.

20. The oral composition according to claim 19, wherein the antibacterial-enhancing agent is a copolymer of maleic acid or anhydride with another ethylenically unsaturated polymerizable monomer.

21. The oral composition according to claim 20, wherein said other monomer of said copolymer in methyl vinyl ether in a 4:1 to 1:4 molar ratio with the maleic acid or anhydride.

22. The oral composition according to claim 21, 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.

23. A composition according to claim 22, wherein the copolymer has an average molecular weight of about 70,000.

24. A composition according to claim 14, wherein the delivery-enhancing group is a phosphonic group or salt thereof.

25. A composition according to claim 24, wherein the antibacterial-enhancing agent is poly (beta-styrenephosphonic acid) or poly (alpha-styrenephosphonic acid) polymer or a copolymer thereof with another ethylenically unsaturated monomer.

26. A composition according to any one of claims 1 to 8, containing a fluoride ion-providing source.

- 46a -

27. A method of controlling oral plaque comprising applying to oral surfaces an effective plaque-controlling amount of a composition as defined in any one of claims 1 to 8.

28. An oral composition dentifrice comprising in an orally acceptable vehicle, about 5-30% of a siliceous polishing agent, about 0.01-5% of triclosan, about 0.05-5% of a copolymer of maleic acid or anhydride with methyl vinyl ether, and propylene glycol in amount sufficient to dissolve the triclosan in saliva.

- 46b -

29. A oral composition dentifrice comprising in an orally acceptable vehicle, about 5-30% of a siliceous polishing agent, about 0.01-5% of triclosan, about 0.05% of poly (beta-styrenephosphonic acid), poly (alpha-styrenephosphonic acid) or a copolymer of either styrenephosphonic acid monomer with the other or with another inert polymerizable ethylenically unsaturated monomer.

30. An oral composition dentifrice comprising an orally acceptable vehicle about 5-30% by weight of a siliceous 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, said 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.

31. The oral preparation claimed in Claim 30 wherein said antibacterial agent is present in amount of from about 0.25%-0.5%
by weight.

32. An oral composition dentrifice comprising in an orally acceptable vehicle, about 5-30% by weight of a siliceous polishing agent, an effective antiplaque amount of a substantially water insoluble noncationic antibacterial agent, 0.05-5% by weight of polyvinyl phosphonate having recurring groups and average molecular weight of about 1,000 to about 1,000,000 and an orally acceptable vehicle comprising a solubilizing material for said antibacterial agent in amount effective to dissolve said antibacterial agent in saliva, wherein said oral composition has a pH of about 4.5 to about 10.

33. The oral composition claimed in Claim 32 in which the said antibacterial agent is selected from the group consisting of halogenated diphenyl ethers, halogenated salicylanides, benzoic esters, halogenated carbanilides, and phenolic compounds.

34. The oral composition claimed in Claim 33 in which the said antibacterial agent is a halogenated diphenyl ether.

35. The oral composition claimed in Claim 34 in which the said halogenated diphenyl ether is 2,4,4'-trichloro-2'-hydroxy-phenyl ether.

36. The oral composition claimed in any one of Claims 32 to 35, wherein said polyvinyl phosphonate is present in amount of about 0.5-2.5% by weight.

37. A use of the oral composition claimed in any one of claims 32 to 35 to inhibit dental plaque.