Note: Descriptions are shown in the official language in which they were submitted.
' ~000'~18
This invention relates to an antibacterial antiplaque
anticalculus oral composition. More particularly, it
relates to an oral composition containing a polyphosphate
anticalculus (that is, antitartar) agent and a compatible
antibacterial agent effective to inhibit plaque, wherein
antiplaque effectiveness is optimized by the presence of an
,y antibacterial-enhancing agent which enhances the delivery
of said antibacterial agent to, and retention thereof on,
oral surfaces.
In U.S. Patents 4,627,977 to Gaffar et al; 4,515,772 to
Parran et al; and 4,323,551 to Parran, oral compositions are
described Which include various polyphosphate compounds. In
the patent to Gaffar et al, a linear molecularly dehydrated
polyphosphate salt is employed in conjunction with a
fluoride ion-providing source and a synthetic linear
polymeric polycarboxylate to inhibit calculus formation. In
copending European Patent Application 89 200 710.5,
anticalculus effectiveness is optimized with a reduced
amount of the linear molecularly dehydrated polyphosphate
salt in conjunction with the fluoride ion-providing source
and increased amount of the synthetic linear polymeric
polycarboxylate.
In t:le patents to Parran et al and to Parran, water
soluble dialkali metal pyrophosphate alone or mixed with
tetraalkali metal pyrophosphate is employed. '
Oral compositions which inhibit calculus formation on
dental surfaces are highly desirable since calculus is one
of the causative factors in periodontal conditions. Thus,
its reduction promotes oral hygiene.
Dental plaque is a prP~~rsor of calculus. Unlike
calculus, however, plaque map form on any part of the tooth
surface, particularly Includi~o at the gingival margin.
_2_
~~v~'l~..f~
Hence, besides being unsightly, it is implicated in the
occurrence of gingivitis.
Accordingly, it would be highly desirable to include
antimicrobial agents which have been known to reduce plaque
in oral compositions containing anticalculus agents.
Indeed, this has been described in U.S. Patent 4,022,550 to
Vinson et al, wherein 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.
Hitherto, the cationic antibacterial materials such as
chlorhexidine, benzethonium chloride and cetyl pyridinium
chloride have been the subject of greatest investigation as
antibacterial antiplaque agents. However, in spite of their
being used in conjunction with zinc anticalculus agent, they
are not effective when used with anionic materials such as
polyphosphate anticalculus agent. This ineffectiveness is
__ _ ..~ ........~..b
considered to be quite surprising as polyphosphates are
chelati..g agents and the chelating effect has previously
been known to increase the efficacy of cationic
antibacterial agents. (see e.g. Disinfection, sterilization
and Preservation " 2nd Ed., Black, 1977, Page 915 and
Inhibition and Destruction of the Microbial Cell, Hugo,
1971, Page 215). Indeed, quaternary ammonium compound is
present in the plaque control mouthwash containing
pyrophosphate of U.S. Pat~n~ 4,323,551 to Parran and bis-
biguanide antipledue agent is suggested in the anticalculus
~ pyrophosphate or~i composl!1on of U.S. Patent 4,515,772- _
Parran et al.
-3-
CA 02006718 2000-06-02
62301-1607
In view of the surprising incompatibility of cationic
antibacterial agents with polyphosphates present as
anticalculus agents, it was quite unexpected that other
antibacterial agents would be effective.
It is an advantage of this invention that certain
antibacterial agents are effective in anticalculus oral
compositions containing a linear molecularly dehydrated
polyphosphate salt, a fluoride-ion-providing source and the
aforementioned antibacterial-enhancing agent to inhibit plaque
formation.
It is a further advantage of this invention that a
composition is provided which is effective to reduce calculus
formation and optimize plaque reduction.
It is a further advantage of this invention that an
antiplaque, anticalculus oral composition is provided which is
effective to reduce the occurrence of gingivitis.
Additional advantages of this invention will be
apparent from consideration of the following specification.
In accordance with certain of its aspects this
invention relates to an oral composition comprising in an
orally acceptable vehicle, an effective anticalculus amount of
material comprising about 0.1-3o by weight of at least one
linear molecularly dehydrated polyphosphate salt as
anticalculus agent, an effective antiplaque amount of a
substantially water insoluble noncationic antibacterial agent
and desirably up to about 4o by weight of an antibacterial-
enhancing agent which enhances the delivery of the
antibacterial agent to, and retention thereof on, oral
surfaces, wherein typically the weight ratio of antibacterial-
enhancing agent to polyphosphate ion ranges from in excess of
4
CA 02006718 2000-06-02
62301-1607
0.72:1 to less than 4:1, e.g. from about 1:1 to about 3.5:1,
especially from about 1.6:1 to about 2.7:1, preferably about
1.7:1 to about 2.3:1 and most preferably about 1.9:1 to about
2:1. For instance, when 20
4a
zoo~~s~
tetrasodium pyrophosphate (TSPP) is employed (providing
about 1.3~ of
pyrophosphate ion) with 2.5~ of the antibacterial-enhancing
agent, a highly desirable weight ratio of about 1.9:1 is
provided.
Typical examples of antibacterial agents which are
particularly desirable from considerations of antiplaque
'_ effectiveness, safety and formulation are:
Halogenated Diphenvl Ethers
2',4,4'-trichloro-2-hydroxy-diphenyl ether (Triclosan)
2,2'-dihydroxy-5,5'-dibromo-diphenyl ether. .
Halogenated Salicvlanilides
4',5-dibromosalicylanilide
3,4',5-trichlorosalcylanilide
3,4',5-tribromosalicylanilide
2,3,3',5-tetrachlorosalicylanilide
3,3,3',5-tetrachlorosalicylanilide
3,5-dibromo-3'-trifluoromethyl salicylanilide
' S-n-octanoyl-3'-trifluoromethyl salicylanilide
3,5-dibromo-4'-trifluoromethyl salicylanilide
3,5-dibromo-3'-trifluoro methyl salicylanilide (Flurophene)
Benzoic Esters
Methyl - p-Hydroxybenzoic Ester
Ethyl - p-Hydroxybenzoic Ester
Propyl - p-Hydroxybenzoic Ester
Butyl - p-Hydroxybenzoic Ester
Halogenated Carbanilides
3,4,4'-trichlorocarbanilide
3-trifluoromethyl-4,4'-dichlorocarbanilide
3,3,4'-trichlorocarbanilide
Phenolic Compounds ( ir:w 1 :ding phenol and its homologs,
mono- and poly-alkyl and arcrometic halo (e. g. F, C1, Br, I.)-
~,U~)f~'71~
phenols, resorcinol and catechol and their derivatives
and
bisphenolic compounds). Such phenolic compounds include,
- :Y ~y..~
inter alias
Phenol and its Homologs
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-tert-Amyl - Phenol
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
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
O-Chlorophenol
Methyl - o-c 't ; r~rophenol
6
2(~tlt ~'71
Ethyl - o-Chlorophenol
n-Propyl - o-Chlorophenol
n-Butyl - o-Chlorophenol
f,~~''~~
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-Chlorophenol
3,5-Dimethyl - p-Chlorophenol
6-Ethyl-3-methyl - p-Chlorophenol
6-n-Propyl-3-methyl - p-Chlorophenol
6-iso-propyl-3-methyl - p-Chlorophenol
2-Ethyl-3,5-dimethyl - p-Chlorophenol
6-sec Butyl-3-methyl - p-Chlorophenol
2-iso-Propyl-3,5-dimethyl - p-Chlorophenol
6-Diethylmethyl-3-methyl - p-Chlorophenol
6-iso-Propyl-2-ethyl-3-methyl - p-Chlorophenol
2-sec Amyl-3,5-dimethyl - p-Chlorophenol
2-Diethylmethyl-3,5-dimethyl - p-Chlorophenol
6-sec Octyl-3-methyl - p-Chlorophenol
p-Bromophenol
Methyl - p-Bromophenol
Ethyl - p-Bromophenol
n-Propyl - p-Bromophenol
n-Butyl - p-Bromophenol
n-Amyl - p-Bromophenol
sec-Amyl - p-Bromophenol
7
2~OE~'~1~
n=Hexyl - 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-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-2-pentylphenol
4-isopropyl-3-methylphenol
5-chloro-2-hydroxydiphenyl methane
Resorcinol and Its Derivatives
- Resorcinol
Methyl - Resorcinol
Ethyl - Resorcinol
n-Propyl - Resorcinol
n-Butyl - Resorcinol
n-Amyl - Resorcinol
n-Hexyl - Resorcinol
n-Heptyl - Resorcinol
n-Octyl - Resorcinol
n-Nonyl - Resorcinol
Phenyl - Resorcinol
Benzyl - Resorcinol
Phenylethyl - Resorcinol
Phenylpropyl - Resorcinol
p-Chlorobenzyl - Resorcinol
5-Chloro -2,4-Dihydroxydiphenyl Methane -
4'-Chloro -2,4-Dihydroxydiphenyl Methane
r.- -
CA 02006718 1999-12-22
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)
bis (2-hydroxy-3,5-dichlorophenyl) sulfide
bis (2-hydroxy-5-chlorobenzyl) sulfide
The 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 very preferably about 0.25-
0.5% and most preferably about 0.25-0.35%. The antibacterial
agent is substantially water insoluble, meaning that its
solubility is less than about 1% by weight in water at 25° C and
may be even less than about 0.1. If an ionizable group is
present solubility is determined at a pH at which ionization
does not occur.
The preferred halogenated diphenyl ether is Triclosan*.
The preferred phenolic compounds are phenol, 2,2'methylene bis
(4-chloro-6-bromophenol), thymol and eugenol. The most
preferred antibacterial antiplaque compound is Triclosan.
Triclosan is disclosed in aforementioned U.S. patent 4,022,880
as an antibacterial agent in combination with an anticalculus
*Trade-mark
9
CA 02006718 1999-12-22
agent which provides zinc ions and in German Patent Disclosure
35 32 860 in combination with a copper compound. 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 dentifrice containing zinc
citrate trihydrate in published European Patent Application
0161899 to Saxton.
*Trade-mark
9a
CA 02006718 2000-06-02
62301-1607
The linear molecularly dehydrated polyphosphate salts
operative herein as anticalculus agents are well known, being
generally employed in the form of their wholly or partially
neutralized water soluble alkali metal (e.g. potassium and
preferable sodium) or ammonium salts, and any mixtures thereof.
Representative examples include sodium hexametaphosphate,
sodium tripolyphosphate, disodium diacid, trisodium monoacid
and tetrasodium pyrophosphates, the corresponding potassium
salts and the like. Linear polyphosphates correspond to
(NaP03)n where n is about 2 to 125. In the present invention,
they are employed in the oral compositions in approximate
weight amounts of 0.1 to 3o typically 1 to 2.5o more typically
1.5 to 20. When n is at least 3 in (NaP03)n, the polyphosphates
are glassy in character.
Particularly desirable anticalculus agents are
tetraalkali metal pyrophosphates, including mixtures thereof,
such as tetrasodium pyrophosphate, tetrapotassium pyrophosphate
and mixtures thereof. Thus, the oral composition may contain
polyphosphate anticalculus agent which is substantially free
from tetra sodium pyrophosphate or substantially free from
combination of tetra potassium pyrophosphate and tetra sodium
pyrophosphate in which the ratio of potassium to sodium
pyrophosphate is 3:1 or in excess of 3:1. An anticalculus
agent comprising about 2o by weight of the oral compositions of
tetrasodium pyrophosphate is especially effective.
The antibacterial-enhancing agent (AEA) which
enhances delivery of the 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 0.050 to about 40, preferably about O.lo
to about 30, more preferably about 0.5% to about 2.5o by
weight.
CA 02006718 2000-06-02
62301-1607
The AEA may be a simple compound, preferably a
polymerizable monomer, more preferably a polymer, which latter
term is entirely generic, including for example oligomers,
homopolymers, copolymers of two or more monomers, ionomers,
block copolymers, graft copolymers, cross-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). It 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 2,5000 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)n-R wherein
X is 0, N, S, SO, SO2, P, PO or Si or the like, R is hydrophobic
alkyl, alkenyl, acyl, aryl, alkaryl, aralkyl, heterocyclic 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 not significantly interfere with the
11
2c~nf~~l~
desired functions of the AEA as enhanr_ing the delivery of
the antibacterial agent to, and retention thereof on, oral
surfaces such as halo, e.g. C1, Br, I, and carbo and the
like. Illustrations of such retention-enhancing groups are
tabulated below.
n X -(X)nR
0 --- 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,
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, dimethyl-
benzylsilyl, dimethylvinylsilyl, dimethylallyl-
silyl, 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 ( a . 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
12
Y
x
s
20~(~"71_t~
x
antibacterial agent to the AEA 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, more 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 AEA polymer.
Preferably, the AEA is a anionic polymer
.,y,,;,:
comprising a chain or backbone containing repeating units
each preferably containing at least one carbon atom and
preferably at least one directly or indirectly pendent,
monovalent delivery-enhancing group and at least one
directly or indirectly pendent 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 examples or
illustratio;.s of AEA'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 pref erred 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 tn oral sorfn~~ ~. that the repeating
units in the polymer <:Inn t n «r backt":,nn containing the
13
CA 02006718 2000-06-02
62301-1607
acidic delivery enhancing groups constitute at least about 100,
preferably at least about 500, more preferably at least about
80o up to 95% or 1000 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 phosphonic 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 phosphonic
acid) containing units of the formula:
I - [CHZ - CH] -
P03H2
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] -
CH3 P03H2
A preferred phosphonic acid-containing AEA for use herein is
poly (beta styrene phosphonic acid) containing units of the
formula:
III - [CH - CH] -
Ph P03H2
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
14
CA 02006718 2000-06-02
62301-1607
with units of formula I above, or poly (alpha styrene
phosphonic acid) containing units of the formula:
IV - [CHZ - C -----] -
Ph P03H2
in which the delivery - and retention - enhancing groups are
geminally bonded to the chain.
These styrene phosphonic acid polymers and their
14a
20~f,'718
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
., ~..",~",~.~... -.
f:
example, phosphonated ethylene having units of the formula.
V -[CH2)~4CHP03H2]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 -[CHz ~ H____]- ,
CHZ - CH < (P03Na2)2 and .
poly (allyl bis (phosphonoethyl amine) having units of the
formula:
. , VII -[CHz - CH-__]-
C~ - N < ( P03H2 ) z
~~
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 modif ied to contain the
above-defined organic retention-enhancing groups.
. 15
1 r
_)
2(~aE~'~1R
In an aspect of this invention the oral
composition comprises an orally acceptable vehicle, an agent
which is effective to enhance the anti-bacterial effect of
an antibacterial agent which has an average molecular weight
of about 1,000 to about 1,000,000, contains at least one
functional group which enhances delivery of antibacterial
effect and at least one organic group which enhances
retention of antibacterial effects, 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 1,000,000, and polyphosphate anticalculus
agent, such as a mixture of potassium and sodium salts, the
ratio of potassium to sodium in the said composition being
in the range of up to less than about 3:1, e.g. from about
' w
0.37 to about 1.04:1.
According to another preferred embodiment, the AEA
comprises a synthetic anionic polymeric polycarboxylate
which is also an inhibitor of alkaline phosphatase enzyme.
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 Gaffar; U.S. Patent
No. 3,956,480 to Dichter et al; U.S. Patent No. 4,138,477 to
Gaffar; and U.S. Patent No. 4,183,914 to Gaffar et al.
However, c.nly in disclosure essentially corresponding to
U.S. Patent 4;627,977 to Gaffar et al is there described use
of such polycarboxylates for inhibiting salivary hydrolysis
of pyrophosphate anticalculus agents in combination with a
compound providing a source of fluoride ion. It is to be
understood that the synthetic anionic polymeric
polycarboxylates so disclosed in these several patents when
containing or modified to con~~~n the retention-enhancing
groups defined arrive are opecn~~ve as AEA's in the
compositions and ~~thr~ds of ~his invention and such
___ ~ 16
CA 02006718 1999-12-22
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 swellable (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/maleic anhydride having a
molecular weight (M. W.) of about 30,000 to about 1,000,000.
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 groups 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 acrylate,
hydroxyethyl methacrylate, N-vinyl-2-pyrollidone, or ethylene,
the latter being available for example as Monsanto EMA No. 1103,
M.W. 10,000 and EMA Grade 61, and 1:1 copolymers of acrylic acid
with methyl or hydroxyethyl methacrylate, methyl or ethyl
acrylate, isobutyl vinyl ether or N-vinyl-2-pyrollidone.
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
*Trade-mark
17
CA 02006718 1999-12-22
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 are polymerized retention-enhancing
group-containing olefinically or ethylenically unsaturated
carboxylic acids containing an activated carbon-to-carbon
*Trade-mark
17a
200('; 718
olefinic double bond and at least one carboxyl group, that
is, an acid containing an olefinic double bond which readily
functions in polymerization because of its presence in the
' monomer molecule either in the alpha-beta position with
respect to a carboxyl group or as part of a terminal
methylene grouping. Illustrative of such acids are acrylic,
methacrylic, ethacrylic, alpha-chloroacrylic, crotonic,
beta-acryloxy propionic, sorbic, alpha-chlorosorbic,
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 monomers copolymerizable with such carboxylic
monomers include 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 are commercially
available for example under the trademarks Carbopol 934, 940
and 941 of B. V. Goodrich, these products consisting
essentially of a colloidally water-soluble polymer of
polyacrylic acid crosslinked with from about 0.75 to about
2.Oo of polyallyl sucrose or polyallyl pentaerythritol as
' cross linking agent, the cross-linked structures and
linkages providing the desired retention enhancement by
hydrophcaicity and/or physical entrapment of the
antibacterial agent or the like. Polycarbophil is somewhat
similar, being polyacrylic acid cross-linked with less than
V
0.2~ of divinyl glycol, the lower proportion, molecular
weight, and/or hydrophobicity of this cross-linking agent -
tending to provide decreased, or no, retention enhancement.
2,5-dimethyl-1,5- hexadiene exemplifies a more effective
retention-enhancing cross-lir,x.ing agent.
s
CA 02006718 1999-12-22
The synthetic anionic polymeric polycarboxylate component
is most often a hydrocarbon with optional halogen and O-
containing substituents and linkages as present in for example
ester, ether and OH groups, and when present is generally
employed in the instant compositions in approximate weight
amounts of up to about 4% (generally at least about 0.05%).
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)n-R defined above. Mixtures of these monomers
may be employed, and copolymers thereof with one or more inert
polymerizable ehtylenically 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 acidic
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 may also be employed as
19
CA 02006718 1999-12-22
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 and Sons, Inc. copyright
1984. Also
19a
20~)fi'718
effective as AEA's herein, provided they contain or are
modified to contain retention-enhancing groups, are
polyesters, polyurethanes and synthetic and natural
polyamoides including proteins and proteinaceous materials
such as collagen, poly (argenine) and other polymerized
amino acids.
When the oral preparation is made by initially
dissolving the polyphosphate and the antibacterial agent in
humectant and surface active agent and adding thereto the
AEA, especially the polycarboxylate, incrementally, the
solution becomes clear and may be characterized as a
"microemulsion". As the amount of the polycarboxylate
increases such that the complete oral preparation contains
ri at least about 2.2% by weight thereof, the solution becomes
cloudy and may be characterized as a "macroemulsion". In
~r
such "macroemulsion" type compositions, the antiplaque
effect of the antibacterial agent appears to be optimized.
~. A desirable weight ratio of the substantially water-
_:.r~~~'rr insoluble noncationic antibacterial agent to the agent to
the polyphosphate anticalculus agent is in excess of about
0.72:1 to less than about 4:1, e.g. from about 1:1 to about
3.5:1, especially from about 1.6:1 to about 2.7:1.
In order to optimize the anticalculus effectiveness of
the oral composition, inhibitors against enzymatic
hydrolysis of the polyphosphate are desirably present. Such
agents are an amount of a fluoride ion source sufficient to
supply 25 ppm. to 5 , 000 ppm. of f luoride ions , and up to 3%
or more of the 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.
The so..rces of fluoride ions, or fluorine-providing
._ __ -..._.....".,...
component, as acid phosphatase and pyrophosphatase enzyme
inhibitor 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
~~
;~0~)1 ~ 71.8
.freedom from undesired reaction with other compounds of the
.<,;r:::
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 such as cuprous fluoride, zinc fluoride, barium
fluoride, sodium fluorosilicate, ammonium fluorosilicate,
sodium fluorozirconate, ammonium fluorozirconate, sodium
monofluorophosphate, aluminum mono- and di-
fluorophosphate, and fluorinated sodium calcium
pyrophosphate. Alkali metal and tin fluorides, such as
sodium and stannous fluorides, sodium monofluorophosphate
(MFP) and mixtures thereof, are preferred.
The amount of fluorine-providing compound is dependent
h
to some extent upon the type of compound, its solubility,
and the type or oral preparation, but it must be a non-toxic
amount, gene-rally about 0.005 to about 3.0% in the
preparation. In a dentifrice preparation, e.g. dental gel,
toothpaste (including cream), toothpowder, or dental tablet,
an amount of such compound which releases up to about 5,000
ppm of F ion by weight of the preparation is considered
satisfactory. Any suitable minimum amount of such compound
may be used, but it is preferable to employ sufficient
compound to release about 300 to 2,000 ppm, more preferably
about 800 to about 1,500 ppm of fluoride ion.
Typically, in the cases of alkali metal fluorides, this
component is present in an amount up to about 2% by weight,
based on the weight of the preparation, and preferably in
the range of about 0.05% to 1%. In the case of sodium
monofluorophosphate, the compound may be present in an
amount of about 0.1-3%, more typically about 0.76%.
In oral preparations such as mouthwashes, lozenges and
chewing gum, the fluorine-providing compound is typically
present in an amount sufficient to release up to about 500
ppm, preferably about 25 to 300 ppm by weight of fluoride
71
20~~'73.8
ion. Generally about 0.005 to about 1.0 wt. x of such
:,
compound is present.
In certain highly preferred forms of the invention the 1
oral composition may be substantially liquid in character,
such as a mouthwash or rinse. In such a preparation the
vehicle is typically a water-alcohol mixture desirably
including a humectant as described below. Generally, the
weight ratio of water to alcohol is in the range of from
about 1: 1 to about 20 :1, pref erably about 3 :1 to 10 :1 and
more preferably about 4:1 to about 6:1. The total amount of
water-alcohol mixture in this type of preparation is
typically in the range of from about 70 to about 99.9X by
weight of t:~e preparation. The alcohol is typically ethanol
or isopropanol. Ethanol is preferred.
The pH of such liquid and other preparations of the
invention is generally in the range of from about 4.5 to
about 9 and typically from about 5.5 to 8. The pH is
preferably in the range of from about 6 to about 8Ø It is
noteworthy that the compositions of the invention may be
applied orally at a rf1 h~ 1 ow 5 w i ~ s ~ut: substantially
decalcifying or oth~r~,~is~ <fama~iry~ dental enamel. The pH
can be controlled w s ~ ~~ ;ic i d ( ~ . n o itric acid or benzoic
acid ) or base ( a . g . w ~~1 i um hydra ~: i <1e ) or buffered (as with
sodium citrate, ben- .r e, carbonar e, or bicarbonate,
disodium hydrogen p! ~~~hnte, sodium dihydrogen phsophate,
etc.).
In certain other ~tesirnble form of this invention, the
oral composition may he substantially solid or pasty in
character, such as toothpowder, a dental tablet or a
dentifrice, that is a toothpaste (dental cream) or gel
dentifrice. The vehicle of such solid or pasty oral
preparations generally contains dentally acceptable
polishing material. Examples of polishing materials are
Water-insoluble sodium metaphosphate, potassium
metaphosphate, tricalcium phosphate, dihydrated calcium
phosphate, anhydrous dicalcium phosphate, calcium
22
2006'718
pyrophosphate, magnesium orthophosphate, trimagnesium
phosphate, calcium carbonate, hydrated alumina, calcined
alumina, aluminum silicate, zirconium silicate, silica,
bentonite, and mixtures thereof. Other suitable polishing
material include the particulate thermosetting resins
described in U.S. Pat. No. 3,070,510, issued Dec. 15, 1962,
such as melamine-, phenolic, and urea-formaldehydes, and
cross-linked polyepoxides and polyesters. Preferred
polishing materials include crystalline silica having
particle sized of up to about 5 microns, a mean particle
size of up to about 1.1 microns, and a surface area of up
to about 50,000 cm.2/gm., silica gel or colloidal silica,
and complex amorphous alkali metal aluminosilicate.
When visually clear gels are employed, a polishing
agent of colloidal silica, such as those sold under the
trademark SYLOID as Syloid 72 and Syloid 74 or under the
trademark SANTOCEL as Santocel 100, alkali metal alumino-
silicate complexes are particularly useful, since they have
refractive indices close to the refractive indices of
gelling agent-liquid (including w.nPr and/or humectant)
systems commonly moo! in ~fontif r i..s.
Many of the sue- ~ ~~ 1 1 ~~1 "wat:~ ~ i nsoluble" polishing
materials are anicm, ~ i n ofrarau= f and also include small
- amounts of soluble ~ ~ r ~r i al . Tl~~,~ , insoluble sodium
metaphosphate may t~ t ~~rmed in any suitable manner as
E illustrated by Thorti~ ' s S~ictionary of Applied Chemistry
,
,~
Volume 9, 4th Editinr~; pj~. 510-511. The forms of insoluble
sodium metaphosphatE~ known as Madrell's salt and Kurrol's
' salt are further examples of suitat,lc' materials. These
metaphosphate salts exhibit only a minute solubility in
- ' water, and therefore are commonly referred to as insoluble
~
:;
~;
,: ,-: -
~
, metaphosphates (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
20~1~'71.~
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 site such
that no more than 1% of the material is larger than 37
microns.
The polishing material is generally present in the
solid or pasty compositions in weight concentrations of
about 10% to about 99%. Preferably, it is present in
''~ amounts ranging from about 10% to about 75% in toothpaste,
j -'
and from about 70% to about 99% in toothpowder. In
toothpastes, when the polishing material is silicious in
nature, it is generally present in amount of about 10-30% by
:.._
weight. Other polishing materials are typically present in
amount of about 30-75% by weight.
In a toothpaste, the liquid vehicle may comprise water
and humectant typically in an amount ranging from about 10%
to about 80% by weight of the preparation. Glycerine,
propylene glycol, sorbitol and polypropylene glycol ,
exemplify suitable humectants/carriers. Also advantageous
are liquid mixtures of water, glycerine and sorbitol. In
clear gels where the refractive frwlex is an important
consideration, about ? . '~- 10 wt 2 wf water, 0 to about 70
wt.% of glycerine nr,~1 ~ts«ut 20-~~ wt. % of sorbitol are
preferably employrr!
Toothpastes, c r ~ gyms and gel ~, t ypically contain a
natural or synthet9 =hickener or gelling agent in
proportions of about ~t.i to about 10, preferably about 0.5
to about 5 wt. %. A ~>uit lhle thickener is synthetic
hectorite, a synther~.~ 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% SiOz, 25.40% MgO, 3.05% Na,O, 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
CA 02006718 1999-12-22
Other suitable thickeners include Irish moss, iota
carrageenan, gum tragacanth, starch, polyvinylpyrrolidone,
hydroxyethylpropylcellulose, hydroxybutyl methyl cellulose,
hydroxy propyl methyl cellulose, hydroxyethyl cellulose (e. g.
available as Natrosol*), sodium carboxymethyl cellulose, and
colloidal silica such as finely ground Syloid (e.g. 244). In
some dentifrices prepared in accordance with the present
invention particularly when more than about 0.35% by weight
of the water insoluble antibacterial agent is employed and a
sliceous polishing agent is present in amount of less than
about 30% by weight, it may be desirable to include an agent
which dissolves the antibacterial agent. Such solubilizing
agents include humectant polyols such as 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.
It will be understood that, as is conventional, the oral
preparations are to be sold or otherwise distributed in
suitable labelled packages. Thus, a jar of mouthrinse will
have a label describing it, in substance, as a mouthrinse or
mouthwash and having directions for its use; and a
toothpaste, cream or gel will usually be in a collapsible
*trade-mark
CA 02006718 1999-12-22
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, gel or dental creme.
Organic surface-active agents are used in the
compositions of the present invention to achieve increased
prophylactic action, assist in achieving thorough and
complete dispersion of the anticalculus agent and antiplaque
agent throughout the oral cavity, and render the instant
compositions more cosmetically acceptable. The organic
surface-active material is preferably anionic, nonionic or
*Trade-mark
25a
20~6'~18
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
x sodium salt of the monosulfated monoglyceride of
3
hydrogenated coconut oil fatty acids, higher alkyl sulfates
such as sodium lauryl sulfate, alkyl aryl sulfonates such as
sodium dodecyl benzene sulfonate, higher alkylsulfo-
acetates, higher fatty acid esters of 1,2-dihydroxy propane
sulfonate, arid 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 p~~id formation in the
oral cavity due to carhnhyclr:rt~~q ~~r w~.~kdown in addition to
exerting some reduc t i ~~n i n t he sc~ i nt~ i 1 ity of tooth enamel in
acid solutions. Exnr<w; ;~,~; ~,C wat.~~- soluble nonionic
surfactants are concl~~~ _at.ion prociw~ is of ethylene oxide with
various reactive hydr ,~n-containirsg compounds reactive
therewith having long ~irnphobic chains (e. g. aliphatic
chains of about 12 to .' 0 c:~ rbon atoms ) , which condensation
products ("ethoxamers"~ cent:ain 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).
Surface active agent is typically present in amount of
about 0.1-5% by weight, preferably about 1-2.5%. It is
2006'7113
noteworthy, that surface active agent may assist in the
dissolving of the noncationic antibacterial agent and
thereby diminish the amount of solubilizing humectant
needed.
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 employee. Examples 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, lactose,
maltose, sorbitol, xylitol, sodium cyclamate, perillartine,
''V
AMP (aspartyl phenyl alanine, met.hvl ester), saccharine and
the like. Suitably, flavs,r anti ~-~~~~~tening agents may each
or together comprisr t~rc,m at,out ~ . 1'~ to 5% more of the
preparation. More<~~. i ~ , f 1 avor t 1 appears to aid the
dissolving of the an~ t,~ct.erial -ynnt.
In the preferre~' ~ F~ct.ice of t his invention an oral
composition accorditm ~~5 .his invention such as a mouthwash
or dentifrice contai~,lc,p the composition of the present
invention is preferat~ ~;: aE,plied 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.
The compositions of this invention can be incorporated
~'l
200f '7~.8
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 conventional plasticizers or softeners, sugar or other
sweeteners or 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.
In the following Examples, the agent Triclosan, 2,4,4'-
trichloro-2'-hydroxydiphenyl ether is indicated as "TCHE";
sodium lauryl sulfate is indicated as "SLS"; the copolymer
of malefic anhydride and methyl vinyl ether available from
GAF Corporation as "Gantrez S-97" is identified as
"Gantrez"; tetrasodium pyrophosphate is identified as
"pyrophosphate"; and sodium fluoride is identified as "NaF".
Example 1
The adsorption to and release from tooth minerals for
antiplaque/antitartar efficacy of agents is assessed by
adsorption of antibacterial agent to saliva coated tooth
mineral hydroxyapatite disk in the presence of pyrophosphate
and differing amounts of polycarh~fylate.
28
CA 02006718 2000-06-02
62301-1607
The formulations of the toothpastes evaluated are:
Parts b y Weight
A B
Glycerine 10.000 10.000
Iota-carrageenan 0.750 0.750
Sorbitol (700 solution) 30.000 30.000
Propylene Glycol 0.500 0.500
Gantrez (13.020 solution) 19.000 15.500
Titanium dioxide 0.500 0.500
Water (deionized) 9.957 13.457
NaF 0.243 0.243
Sodium Saccharine 0.300 0.300
Pyrophosphate 2.000 2.000
Sodium Hydroxide (50%) 1.000 1.000
Silica polishing agent
(Zeodent 113) 20.000 20.000
Silica Thickener (Sylodent 15) 2.500 2.500
Flavor oil 0.950 0.950
TCHE 0.300 0.300
SLS 2.000 2.000
Gantrez is present as A.I. in of 2.5 parts
amount in
toothpaste A and 2.0 parts in toothpaste B.
29
CA 02006718 2000-06-02
62301-1607
For the test of delivery of antibacterial agent to a
saliva coated hydroxyapatite disk, hydroxyapatite (HA) obtained
from the Monsanto Co. is washed extensively with distilled
water, collected by vacuum filtration, and permitted to dry
overnight at 37°C. 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 pellete die (Barnes Analytical, Stanford, CT.)
and compressed for 6 minutes at 10,000 pounds in a Carver
Laboratory press. The resulting 13 mm disks are sintered for 4
hours at 800°C in a Thermolyne furnace. Parafilm stimulated
whole saliva is collected into an ice-chilled glass beaker.
The saliva is clarified by centrifugation at 15,000 Xg (times
gravity
29a
206''718
for 15 minutes at 4°C. Sterilization of the clarified-
saliva is done at 4°C with stirring by irradiation of the
sample with W light for 1.0 hour.
Each sintered disk is hydrated with sterile water in 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 37°C with
continuous shaking in a water bath. After this treatment,
the saliva is removed and the disks are treated with 1.00 ml
of a solution containing antibacterial agent (triclosan) in
a dentifrice liquid phase solution and incubated at 37°C
with continuous shaking in 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 with
a Vortex. The disk is then transferred into a new tube and
the washing procedure repeated twice. Finally, the disk is
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 t-~ the disk and shaken vigorously with a Vortex.
The sample is left at room temperature for 30 minutes to
extract adsorbed triclosan in the methanol. The methanol is
then aspirated and clarified by centrifugation in a Beckman
Microfuge 11 at 10,000 rpm for 5 minutes. After this
treatment, the methanol is transferred into HPLC(high
performance liquid chromatography) vials for determination
of antibacterial agent concent~n!ion. Triplicate samples
are used in all experiments.
The Table bel«v aummnri~~~~ ttie data:
Table
Delivery of TCHE to
Toothpaste Saliva Coated Hydroxyapatite
Disc in Micrograms
A 130
B 30
The data indicatPS that with the increasing amount of
Gantrpz (Toothpaste A) there is a very great increase in
delivery of TCHE to saliva coated tooth minerals.
- .. . 3 0
200f'~18
Example 2
The following toothpaste is effective as an antiplaque
and anticalculus composition:
Parts by
Weight
Sorbitol (70~) 22.00
Irish Moss 1.00
Sodium Hydroxide (50~) 1.00
Gantrez (13.02 solution) 19.00
'z
Water (deionized) 2.69
Sodium Monofluorophsophate 0.76
Sodium saccharine 0.30
k
x
Pyrophosphate 2.00
Hydrated alumina 48.00
Flavor oil 0.95
TCHE 0.30
SLS 2.00
Example 3
y
Mouthrinse Parts
Tetrasodium Pyrophosphate 2.00
' Gantrez S-97 2.50
Glycerine 10.00
Sodium Fluoride 0.05
Sodium Lauryl Sulfate 0.20
TCHE
0.06
Flavor oil 0.40
Water g.S. to 1 00.00
31
~(~~~i'~~..~
Example 4
Lozenge
75-80% Sugar
1-20% Corn Syrup
0.1-1.0 Flavor Oil
2% Tetrasodium Pyrophosphate
2.50% Gantrez S-97
0.01 to 0.05% NaF
0.01 to 0.1% TCHE
1 to 5% Magnesium Stearate Lubricant
0.01 to 0.2% Water
Example 5
Chewing Gum Parts
Gum Base 25.00
Sorbitol (70$) 17.00
w
TCHE 0.50 to 0.10
Tetrasodium Pyrophosphate 2.00
Gantrez 5.97 2.50
In a variant Example of the foregoing Example, Gantrez S-97
can .~e omitted.
Example 6
Chewing Gum Parts
Gum Base 30.00
TCHE 0.50
Gantrez 2.00
NaF 0.05
Glycerine 0.50
Crystalline Satbitol 53.00
Tetrasodium Fjl~phosphatc~ 2.00
Flavor Oil and water Q.S. to 100.00
In the foreE>, ~ ~ r,p, Examples improved results are also
achievable when T!:)tE is replaced with each of phenol, 2,2'-
met~ylene bis(4-c!rloxo-6-Bromophenol), eugenol and thymol,
and/or when Gantrez is replaced by other AEA's such as
2006'718
Carbopols (e. g. 934), or styrene phosphonic acid polymers
having molecular weights within the range of about 3, 000 to
10,000 such as poly (beta-styrenephosphonic acid),
copolymers of vinyl phosphonic acid with beta-
~r-c
styrenephosphonic acid, and poly (alpha-styrenephosphonic
acid), or sulfoacrylic oligomers, or a 1:1 copolymer of
malefic anhydride with ethyl acrylate.
.~:....~, .x__.~:
Likewise similar results are achieved when
pyrophosphate (tetrasodium pyrophosphate) is replaced by
tetrasodium pyrophosphate and tetrapotassium pyrophosphate,
with the weight ratio of potassium to sodium being a) 0.37:1
b) 1.04:1; c) 3:1; and 3.5:1.
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.
~,-....,~.,.e".~
i
