Note: Descriptions are shown in the official language in which they were submitted.
IR 4795
PACKAGED ANTI-PLAOLTE ORAL COMPOSITIONS
This invention relates to packaged anti-plaque oral compositions
which comprise an anti-plaque antibacterial agent such as 2', 4, 4'-
trichloro-~-hydroxy-diphenyl ether (THDE), as an effective anti-plaque
component, which compositions are packaged in a container which includes a .
polymeric plastic material in contact with the oral composition, which
plastic is compatible with the antibacterial agent in the composition.
Although various plastics may diminish the anti-plaque action of the
mentioned antibacterial agents, certain plastics, such as
palyfluoroethylene and polyvinyl chloride, have been found to be compatible
with TIDE and it has been discovered that they do not cause excessive losses
of antibacterial and anti-plaque activities of contained pral compositions
on storage, at room or elevated temperatures. Even when the contacting
plastic parts) of the container is/are of a plastic which is not in itself
entirely compatible with the antibacterial compound, compatibility can be
improved by incorporating in the oral composition a stabilizing proportion
of a stabilizer for the antibacterial compound, such as a terpene, e.g.,
limonene, or an essential oil (natural or synthetic), which may be present
in a flavoring material for the oral compositions. Such stabilizing
material is present in sufficient proportion so that the oral composition,
as packaged and dispensed, is an effective anti-plaque composition, the
production of which is an object of this invention. Included within the
invention is a method of contacting oral surfaces with oral compositions
containing effective proportions of anti-plaque agent. Also within the
invention is a toothbrush having on its bristles an effective proportion of
an anti-plaque dentifrice.
a~~~~'~~.e.~
Plaque on teeth is considered to be causative factors of negative
periodontal conditions, and dental plaque i.s a precursor of calculi.
Plaque may form on any part of the tooth surface, including the gingival
margin. It makes the teeth appear dull and in addition to promoting
development of calculi, it has been implicated in occurrences of
gingivitis. Therefore, oral compositions that contain anti-plaque
components which prevent or inhibit the development of plaque on the
teeth are valuable dental care aids.
Although it has been known that antimicrobial agents in oral
compositions may reduce plaque, sometimes being especially effective in
combinations with othex materials, various such antibacterial compounds
possess disadvantageous properties which mitigate against their
employment in such oral compositions. For example, cationic
antibacterial compounds, such as quaternary ammonium halides, tend to
discolor the teeth and may be inactivated by the presence of anionic
materials in the oral preparations (and often it will be desirable to
employ anionic surfactants or detergents in oral..compositions).
Essentially water insoluble halogenated (and often hydroxylated)
diphenyl ethers, such as THDE (triclosan) and 2,2'-dihydroxy-5,5'-
dibromo-diphenyl ether (DDDE), are effective anti-plaque antibacterial
agents but can be inactivated by nonionic surfactants and by many
plastics, as has been discovered by applicants. Thus, an object of this
invention has been to incorporate antibacterial anti-plaque agents, such
as halogenated Biphenyl ethers, particularly THDE and DDDE; and similar
~ anti-plaque agents in oral compositions, and to store such compositions
in and dispense them from packages or containers in which they will not
lose an excessive proportion of the activity of such antibacterial agent
on storage, before intended use. In prior art triclosan denti.frices, as
delivered from the dispenser, the triclosan delivery has not been in an
effective amount to significantly reduce plaque when employed once or
2
i
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twice daily at 1.5 g./use with one minute brushings, which is considered
t.o approximate normal brushing practice. To be effective, such uses
should result in at least 257 reduction in plaque after three weeks' use,
compared to three weeks' use of a control toothpaste in the same manner.
~ The most preferred antibacterial anti-plaque component of the
present packaged oral compositions is THDE, which is also known as
triclosan. Such is disclosed in U.S. patent No. 6,022,880 as an
anti acterial agent, in combination with an anticalculus agent (which
provides zinc ions), and in German patent specification (OLS) No. 35 32
860 in combination with a copper compound. Tt is also disclosed in
European patent applications Nos. 0 161 898 and 0 161 899, and in
European patent application 0 220 890 it is disclosed in dentifrices with
polyethylene glycol and oil based flavor.
Various oral compositions or dental preparations are known,
including paste, gel, powder, liquid, tablet, lozenge, sachet and
packeted dentifrices, liquid and tableted mouthwashes; and professionally
applied tooth treating agents (such as tooth hardening compositions,
r
e.g., fluoride solutions). Such products have been packed in deformable
tubes, pump dispensers, pressurized dispensers, packets, bottles, jars
and other coatainexs. Although defoxmable ox collapsible tubes were
initially made of metals, such as lead and aluminum, and bottles were
made of glass, in recent years such containers have often been made of
synthetic organic polymeric plastics or made of laminates which included
such plastics. Tnteractions between oral compositions and the materials
of containers in which they were packed have been known, such as
reactions between toothpastes and aluminum containers, and to prevent
such reactions containers have been specially treated or different
container materials have been employed. However, applicants do not
believe that bafore their invention it had been known to the prior art
that some plastic packaging materials could adversely affect the anti-
3
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62301-1606
plaque activities of halogenated diphenyl ether antibacterial
compounds that had. been incorporated in oral compositions and
packed in containers in which they came into contact with such
plastics, nor do they believe that it had been discovered that
certain plastics could be employed for such container parts
without causing losses of the anti-plaque activities of
halogenated diphenyl ethers or that losses of such activities
of oral compositions packed in contact with "reactive" plastics
(which react with, absorb or otherwise reduce the anti-plaque
activity of the oral composition) could be inhibited or
prevented by incorporating in the compositions terpenes, such
as limonene, and other components of flavors for oral
preparations.
In accordance with certain of its aspects, the
present invention relates to an oral composition containing an
effective anti-plaque proportion of a substantially water
insoluble non-cationic antibacterial agent when dispensed,
which is packaged in a dispensing container which includes a
solid polymeric material, such as a synthetic organic polymeric
plastic material, in contact with the oral composition, which
solid polymeric material is compatible with the antibacterial
agent in the presence of the oral composition and does not
cause excessive loss of antibacterial and anti-plaque
activities of the oral composition on storage in the container
(such as at temperatures in the range of 20 to 40°C for several
weeks, preferably up to a year or more). The packaged oral
composition is usualy a toothpaste, gel dentifrice or mouthwash
contained in a deformable dispensing tube, pump dispenser or
bottle, respectively, having no plastic parts which adversely
affect the anti-plaque action of the antibacterial agent,
(which is preferably a halogenated diphenyl ether, such as
4
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62301-1606
triclosan), or containing in the oral composition a component
which inhibits or prevents any such detrimental "reaction"
between the antibacterial agent and any plastic part of the
4a
i~~~~z'~~.~
container which could otherwise adversely affect the composition's anti-
plaque action.
The invention will be readily understood from the description
thereof in this specification, taken in conjunction with the drawing, in
which:
FIG. 1 is a perspective view of a toothpaste tube and its removed
cap, with toothpaste having been squeezed from the tube onto a brush;
FIG. 2 is an enlarged partial sectional view of a laminated wall
of a squeezable tube like that of FIG. 1;
FIG. 3 is a vertical sectional elevation of a pump dispenser for
containing and dispensing toothpaste or dentifrice gel, as desired;
FIG. 4 is a side elevational view of a heat sealed sachet or pouch
containing a single use au~ount of a toothpaste; and
FIG. 5 is an elevational view of a capped bottle of mouthwash.
In FIG. 1 packaged anti-plaque toothpaste article l1 includes
deformable toothpaste tube 13, which contains anti-plaque toothpaste 15,
shown dispensed in a unitary amount such as about 0.8 to 2 grams by
squeezing onto brush 17. Tube 13 is opaque and is made of a synthetic
organic polymeric plastic material, such as polyfluoroethylene or is
lined with such a material, as in a la~iinate, which does not adversely
affect tha anti-plaque activity of the toothpaste on storage.
Alternatively, tube 13 may be made of ar lined with a plastic which has
been found to adversely affect anti-plaque action of the toothpaste (by
decreasing the anti-plaque action of antibacterial and anti-plaque
. halogenated Biphenyl ether component of the toothpaste) but in such case
the adverse effect on anti-plaque action is prevented or inhibited by the
presence in the dentifrice of a stabilizing agent, which may be a
terpene, e.g., limonene, or ather effective flavor components. Preferably
neither the toothpaste tube nor the cap 19 thereof nor any other part of
the tube which may come into contact with the toothpaste (such as a liner
5
~.
J'
for the cap) should be made of co-polyester/polyether elastomer or of
other plastic which substantially diminishes the anti-plaque action of
the oral preparation, even in the presence of a stabilizer for the anti-
plaque component. It is also considered to be desirable to avoid the
presence of other elastomers, such as isobutadienes, polychloroprenes,
butadiene rubbers and nitrile rubbers, which might react with or absorb
~E. Desirably, such parts will be made of plastics which do not
adversely affect anti-plaque activity, even in the absence of terpenes or
other stabilizing agents in the dentifrice, but such other destabilizing
plastics may be eanployed when such stabilizer is present in the
toothpaste to counteract the inactivating effect of the plastic (except
that elastomeric co-polyester/polyether and other adverse elastomers will
preferably be avoided).
In FIG. 2 there is shown a laminate of polyfluoroethylene film 21,
aluminum sheet 23 and polyethylene fiLn 25, with the polyfluoroethylene
being on the inside of the tube wall, where it will be in contact with
the toothpaste. The linex, not shown, for the cap 19 of FIG. 1, may also
be of polyfluoroethylene, so that all surfaces in contact with the
toothpaste during the storage are compatible with the halogenated
Biphenyl ether antibacterial component of the toothpaste and do not
promote excessive losses of its anti-plaque activity on storage. Instead
of having the inner wall 21 of the laminate of polyfluoroethylene, it may
be of polyethylene and wall 21 may be of polyethylene or other suitable
polymer.
In FIG. 3 the pump dispenser far toothpaste is of a type marketed
by Guala S.p.A., of Italy, which is the subject of U.S. Patent 4,776,496.
Pump dispenser 27, when ready for use, contains toothpaste in compartment
29, which is defined by bottom wall 31 and membrane 33. Depression of
actuating lever 35 causes a downward movement of membrane 33, forcing
toothpaste through conduit 37 arid out spout 39. When pressure on the
6
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~,
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actuating lever 35 is released membrane 33, which is elastic, returns to
its original configuration and moves conduit 37 and lever 35 back to
their initial positions. At the same time, bottom 31 is pushed upwardly
by atmospheric pxessure. The various internal parts of the pump
dispenser that contact the toothpaste are preferably of plastics) that
do not inactivate the halogenated diphenyl ether antibacterial and anti-
plaque agent. However, in the event that it is not feasible to utilize
plastics that have the necessary physical properties far the various
contacting parts and still are compatible with the anti-plaque agent
other plastics may be employed, providing that the toothpaste composition
(or gel dentifrice) includes a stabilizing substance, such as limonene or
other operative terpene or flavor component. However, it is considered
best to avoid employing any co-polyester/polyether elastomers, especially
for the pumping membrane (33), which plastic appears to be especially
active against THDE in oral compositions of the types described.
In FIG. 4 sachet, pouch or packet 41 is shown as a heat sealed
unit, with heat sealing about three sides thereof, represented by
numerals 43 and 45. The fourth side 47 is merely folded back on itself
and need not be heat sealed. Inside the sealed packet is an oral
composition, such as toothpaste, not shown, and the interior surface of
such sachet is of a plastic material which does not promote excessive
loss of anti-plaque action of the antibacterial compound of the contained
oral composition. As with the other containers for the anti-plaque oral
compositions, laminates may be utilized, with a plastic layer on the
interior thereof which does not adversely affect the antibacterial agent,
or when the plastic does have such a negative affect, it may be
counteracted by the presence in the oral composition of a suitable
stabilizer, which is preferably also useful as a flavoring agent thereof.
Tn FTG. 5 is sho~m an opaque bottle 49 having sealing cap 51
thereon. $oth the bottle and the sealing insert (not shown) in the cap
7
. :'
are of plastic materials which are campatible with the TfmE that is the
anti-plaque component in the mouthwash 53 contained in the bottle. As in
the other examples given, when a "reactive" plastic is employed as the
material of the inner portion of the bottle or of the cap seal a suitable
stabilizer will be present in the mouthwash to prevent excessive loss of
anti-plaque action of the 'i'IiDE or other halogenated diphenyl ether.
In addition to the compositions described as being present in the
illustrated packages, which include gel dentifrices and thick liquids
instead of toothpastes, there may also be incorporated in such packages
tooth treating compositions suitable for professional use, such as tooth
hardeners, which may include fluorides and phosphates, compounded
antibacterial agents, plaque-indicating dye solutions and other suitable
oral compositions. Also, pressurized or "aerosol" compositions
containing 'the mentioned anti-plaque compounds may be packed in
pressurized containers (usually pressurized with gaseous nitrogen)
providing that contacting plastic parts of such containers are of
materials which do not cause excessive losses of anti-plaque properties
of the anti°plaque agent in the contained toothpastes or other oral
compositions.
In addition to the various containers illustrated in the drawing
and mentioned above there may also be employed squeezes bottles, capsules,
jars, sponge-like media and various types of mechanical dispensing
containers. Because some of the halogenated diphenyl ether antibacterial
compounds are photosensitive it will sometimes be desirable for such
containers to be composed of, coated or laminated with a chemical or
physical light screening material, many of which are known, to prevent
transmission to the oral composition and to the anti-plaque compound of
any inactivating radiation, e.g., ultraviolet light. Also, such
containers will often desirably be opaque to prevent such actinic
8
radiation from inactivating the anti-plaque component of the contained
oral preparation, such as a toothpaste.
The causes) of inactivation by plastics of THDE and other
substantially non-cationic antibacterial agents that have anti-plaque
properties in oral compositions has/have not yet been established.
Research to date has not pinpointed the mechanism responsible for losses
of such desirable activity but so far the results do not conclusively
point to either chemical xeactions or physical absorptions. Tests of
basic mouthwash or mouth rinse formulations containing THDE show that
when such a mouthwash or mouth rinse is aged in dispensing containers at
room temperature, 38°C and ~~9°C, for up to twelve weeks, there
are
"excessive°' losses (over 257 of the initial concentration of THDE)
when
the mouth rinse has been in contact with such container walls and parts
of low density polyethylenes, high density polyethylenes, polyethylene
terephthalates, polypropylenes, nylons, polyallomers and
polymethylpentenes. Similarly, high losses result when such storage is
in containers with inner walls or parts of co-polyester/polyether
elastomers, such as those which have previously been employed in Guala
pump membranes. It was found that polyfluoroethylenes, such as
polytetrafluoroethylenes, polyvinyl chlorides, polycarbonates and
polysulfones did not absorb or react with excessive proportions of the
TkIDE. However, polycarbonates and polysulfones are brittle and hence
often are unsuitable for employment as dispensing container parts.
Polyvinyl chlorides sometimes impart a foreign taste to oral
compositions, such as toothpastes, and therefore will often be avoided as
a container material, except in certain cases whexe such taste is
compatible with the taste of the toothpaste flavoring employed. Thus, of
all the polymeric plastic materials available, polyfluoroethylene is
especially identified as a feasible material for use in the present
containers or packages which does riot seriously diminish the anti-plaque
9
y
activity of the anti-plaque agents. However, as was indicated
previously, by incorporating in the oral compositions stabilizing
compounds for the anti-plaque agents, such as terpenes, of which limonene
is representative, essential oils (which often contain terpenes), and
S other flavor components with similar "stabilizing" properties, one is
able to reduce the activity losses of the antiplaque agents when they are
in contact with containers or container parts made of the various
mentioned polymeric plastics with which excessive losses in antiplaque
activity occur. Therefore, one need not be dependent on
polyfluoroethylene as a container dispenser material, providing that the '
oral composition also contains a stabilizing proportion of terpene or
other suitable "stabilizer". When such stabilizer is present in the oral
compositions or when polyfluoroethylene (or polyvinyl chloride,
polycarbonate or polysulfone) is the only polymeric plastic in contact
,15 with the oral composition, storage losses of anti-plaque activity are
less than 257, and preferably will be less than 107, even after ambient
to relatively high temperature storage, for example 20° to 40°C,
for
periods of time of several weeks to up to a year or more. It is
considered that the most stable oral compositions are those which include
a stabilizing proportion of terpene or other suitable stabilizer and also
include contacting container parts only of polyfluoroethylene (or any of
the other unreactive plastics). Although the terpenes and essential oils
are the primary stabilizers according to the present invention, other
flavor components may also contribute to the stabilization of the anti-
plaque material, either by interfering with any destabilizing reaction or
by inhibiting absorption of the halogenated Biphenyl ether by the plastic
(or by other unknown mechanism). Thus, it has been theorized that some
components of the oral compositions that tend to solubilize the TTiDE can
act to maintain it in the oral composition and inhibit or prevent its
migration into the plastic. On the other hand, it has also been
:3
y
M
theorized that such a solubilizing action could promote migration of the
solubilized THDE into the plastic. Because the issue has not been
resolved applicants are not bound by either theory. Also, while it is
desirable for the terpenes and other stabilizers to be flavor components,
that is not necessary, and the stabilizers may be useful for only a
stabilization purpose.
Although it is preferred that the packages of this invention
include internal walls (in contact with the compasitions) of or lined
with solid synthetic oxganic polymeric plastic material, it is within the
invention to utilize other solid (and/or film-forming) polymeric
materials, whether or net they are synthetic, organic or even plastic.
Thus, polyethylene glycols and methoxypolyethylene glycols, such as those
of the CarbowaxR type, e.g., Carbowax 4,000 and Carbowax 6,000, may be
employed, often as lining materials in dispensing containers of the
Z5 described compositions. Inorganic silicon polymers, such as siloxanes,
and non-synthetic organic film-forming materials, such as gums, e.g.,
carrageenan, tragacanth, karaya, are also useful as liners for
dispensers. Additionally solid polymeric materials, such as cellulose
and starch and derivatives thereof, are also useful as container
materials in contact with the contained antibacterial and antiplaque
components of the present packaged ora:L compositions.
The various oral packaged compositions of this invention that are
most frequently made are toothpastes, dentifrice gels and mouthwashes
(sometimes called mouth rinses). The foryner two will be referred to
herein as dentifrices and the last will usually be called mauthwashes.
Dentifrices comprise three major groups of components, the vehicle,
polishing material and surfactant (or detergent). The antibacterial
agent, e.g., halogenated Biphenyl ether, is normally present in the
vehicle, which vehicle usually comprises about 10 to 807 (all figures are
on a final composition basis) of the dentifrice. Of the vehicle, about 3
11
~~~i'~'~.~
to 40% will be water, about 7 to 77% will be humectant, such as glycerol,
sorbitol, propylene glycol or mixtures thereof and 0.5 to 10% will be
gelling agent, such as sodium carboxymethyl cellulose, Irish moss, iota
carrageenan or hydroxyethyl cellulose or the like including mixtures
thereof. The polishing material of the~dentifrice will normally be from
about 10 to 75% thereof in a gel or toothpaste ox about 50 to 99% in a
powder and such polishing material may be colloidal silica, precipitated
silica, sodium aluminosilicate, insoluble sodium metaphosphate, hydrated
alumina, calcined alumina; dicalcium phosphate dihydrate, anhydrous
dicalcium phosphate or calcium carbonate, other known materials, or
mixtures thereof. The surfactants include anionic, nonionic, cationic
and zwitterionic surfactants but often the employment of nonionic
surfactant is avoided because of its adverse affect on the antibacterial
compounds, e.g., THD~, and the employment of cationic and zwitterionic
surfactants are also often avoided because they tend to stain or darken
the teeth. Thus, synthetic organic anionic surfactants, which are also
detergents, ars the preferred cleaning agents in the dentifrices, and of
these, sodium lauryl sulfate and other sodium higher alkyl sulfates of 10
to 18 carbon atoms in the alkyl groups thereof are preferred, although
various other well known sulfated and sulfonated detergents may be
substituted for them, at least in part. Other active ingredients, such
as fluoride-providing compounds, e.g., sodium fluoride ox sodium
monofluorophosphate, may be present to harden the teeth, usually in
proportions providing about O.OOl to 1% of fluoride to the composition,
~ and adJuvants, such as flavoring and sweetener, in progortions of 0.1 to
10%, may be utilized. Additionally, it may be desirable to employ a
polycarboxylate, such as polyvinyl methyl ether malefic anhydride (PVM/MA)
copolymer (OantrezR) in an amount corresponding to about 0.5 to 4% of the
dentifrice. Such polycarboxylate material has been found substantially
~0 to improve the anti-plaque action of the antibacterial compound. Use of
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CA 02006713 2000-04-10
62301-1606
such polycarboxylat=es in oral compositions is described in U.S.
Patent No. 4,627,9'77.
In mouthwashes the oral vehicle is preferably aqueous
and alcoholic, with the alcohol being ethanol or isopropanol.
The vehicle will normally be 90 to 99.9% of the composition, of
which the alcohol is 5 to 30% and propylene glycol is often 2
to 10%, on a final product basis. The remainder of the
composition, 0.1 to 10%, may include flavor, surfactant,
sweetener, colorant,, anti-plaque agent and other adjuvants for
specific purposes. In dentifrice and mouthwash compositions
the effective amount of antibacterial anti-plaque compounds)
will normally be in the range of 0.02 to 0.2%, more preferably
0.03 to 0.1% in mouthwashes, and normally about 0.25 to 1%,
more preferably 0.25 to 0.5 or 0.6% in dentifrices, with the
proportion ranges not exceeding 0.8% for THDE in toothpastes
and not exceeding 0.2% THDE in mouthwashes (because of possible
mouth numbing effects at higher concentrations), and not being
less than indicated in order to avoid ineffectiveness against
plaque at low concE:ntrat:ions. Preferably the dispensed
compositions will contain proportions of the anti-plaque agent
and THDE within thE: given ranges but when the initial
concentration thereof is within the given range a loss of up to
25% may be acceptable and such dispensed compositions are
within the scope of. the :invention.
To stabi7_ize oral compositions that are to be
packaged in containers containing plastic walls or other parts,
wherein the plastics are those which are "reactive" with the
antibacterial compounds, 0.01 to 2% of terpene(s) or
stabilizers) will desirably be present in the oral
compositions, preferably 0.05 to 1% and more preferably 0.1 to
0.5%. Such stabilizers may be present in a suitable flavoring
13
CA 02006713 2000-04-10
62301-1606
agent for the dentifrice, if desired (and it often is), and
will be at least 5% of the flavor, preferably at least 10%,
more preferably at least 25% and most preferably at least 50%.
13a
~1
Although the above description is primarily relevant to
dentifrices and mouthwashes, other oral compositions (e. g., including
chewing gums) of the invention will contain similar proportions of
components, depending on the form of the composition (liquids containing
less, as in the mouth rinses, and thicker compositions containing more as
in the toothpastes), often with the additions of specific agents for
accomplishing the purposes of such compositions. Thus, tooth hardening
compositions may include fluorides and phosphates, such as sodium or
potassium fluoride and sodium fluorophosphate, in either dentifrice or
mouthwash bases, often in percentages in the range of 1 to 5%. Plaque-
indicating dye solutions may include a suitable dye (red is apparently
the most favored color for such products), often at a concentration in
the range of 0.001 to 0.1%, in a mouthwash base. The compositions of the
other products will be adjusted accordingly, as will be known to those of
skill in the art.
The antibacterial agent is a non-cationic material which is water
insoluble or essentially water insoluble (having a solubility in water at
25°C of less than 10 g./l., and sometimes less than 1 or O.lg./l.) Such
materials are soluble or dispersible in dentifrice vehicles that contain
glycerol, sorbitol and/or propylene glycol, and in final products based
on such media. They are also soluble or dispersible in the aqueous
alcoholic media of mouthwashes.
Of the antibacterial agents, the halogenated diphenyl ethers will
normally contain bromine and/or chlorine, with chlorine being the
preferred halogen. They will preferably be substituted with 1 to 3
hydroxyls.and 1 to 4 halogens. More preferably they will b$ substituted
with 1 or 2 hydroxyls and 2 or 3 halogens, preferably with four
substituents, two an each ring. Among the more preferred of such
compounds are 2, 2'-dihydroxy-5,5'-dibromo-diphenyl ether and 2', 4, 4'-
trichloro-2-hydroxy-diphenyl ether, with the latter compound (TFmE) being
14
CA 02006713 2000-04-10
62301-1606
most preferred. Various replacement halogenated phenolic, non-
cationic, substantially water insoluble antibacterial anti-
plaque compounds may be substituted in whole or in part for the
halogenated diphenol ethers, when that is considered to be
appropriate.
The terpenes, which term, for the purpose of this
specification, inc:Ludes the terpene hydrocarbons and oxygenated
derivatives thereo:E, include such compounds as dl-limonene,
menthol, diterpenes, polyterpenes and derivatives thereof, many
of which are found in various essential oils and other flavors.
In addition to being useful as stabilizers for halogenated
diphenyl ethers they often contribute desirable flavors to the
present oral compo:~itions. Of the terpenes and their
derivatives it is considered that limonene best balances these
properties, although other terpenes, including those which are
not flavors, are a:Lso useful, as are other emulsifiable
lipophilic essential oils and flavoring agents which contain
stabilizing components.
The various plastics that were previously described
as the components of container and/or dispenser parts have been
described only briefly because it is considered that their
chemical natures and degrees of polymerization are well known,
so detailing thereof is 'unnecessary in this specification. If
further details are' wanted reference should be made to Modern
Plastics Encyclopedia, which is published on an annual basis by
McGraw-Hill Inc., New York, New York.
The compositions of the invention may contain a
source of fluoride ions, capable of supplying 25 to 5,000 ppm
of fluoride ion in the oral cavity, preferably 300 to 2,000 ppm
and more preferabl~r 800 to 1,500 ppm. See U.S. Patent
4,627,977 for further details about suitable fluorides,
proportions and manufacturing details. The fluoride acts
CA 02006713 2000-04-10
62301-1606
primarily as a tooth hardener but also serves to stabilize
polyphosphate anti-calculus compound when present. Such
polyphosphate is preferably a mixture of sodium and potassium
pyrophosphates and it is also stabilized by Gantrez~ S-97.
Proportion ranges .are given in U.S. Patent 4,627,977 and U.S.
Patent 4,806,340.
For other details of formulations, components,
adjuvants, manufacturings and uses, see the patent,
specifications and applications previously mentioned in this
specification.
Manufacture of the described oral compositions is by
any of various standard techniques for producing such classes
of compositions. Deferring to specific examples for
simplicity, the THDE is dispersed and/or dissolved in the
vehicle portion of the dentifrice and the terpene is present in
the flavoring agent. To make a dentifrice, the vehicle is
prepared containing glycerol, sorbitol, and propylene glycol,
gelling agents and suitable adjuvants (including Gantrez~ S-97
and triclosan), and the vehicle and aqueous anionic detergent
(preferably sodium lauryl sulfate or a mixture of sodium lauryl
sulfate and sodium methyl cocoyl taurate) solution are mixed,
followed by blending in of the polishing agent component with
the pre-mix. Fina:Lly, flavoring agent, including terpene,
dissolved in ethanol, is admixed and the pH is adjusted. To
make the mouthwash the various components thereof are merely
admixed into the a:Lcohol or aqueous alcoholic medium and are
stirred until dissolved. A mix of sodium lauryl sulfate (SLS)
and sodium methyl cocoyl taurate (of a ratio in the range of
1:4 to 4:1) is pre:Eerably employed as the anionic surfactant
component of the mouthwash, with the presence of the taurate
permitting a corre;~pondingly desirable decrease in the SLS
content, which
16
~~~~m'~~.~
is desirable. Other oral compositions are prepared according to similar
relevant procedures.
In packaging of the oral composition into the dispensing
containers, it will be desirable to avoid contacting of the compositions
with plastic parts of co-polyester/polyether elastomer and it will also
be desirable to avoid contacting of any compositions not containing
stabilizing agent (such as terpene or flavor containing it) with plastic
parts made of those plastics previously listed in this specification as
reactive with THDE and other such antibacterial and anti-plaque
compounds. It will be especially important to avoid the mentioned
plastic parts for holding tanks or any other containers, piping, pumps or
equipment in which the oral composition may be held for any appreciable
length of time or held for shorter lengths of time at elevated
temperatures.
Even when the packaged compositions of this invention are prepared
and contacts of the oral compositions containing TTHDE or other
halogenated diphenyl ether antibacterial compositian with the reactant
plastics are avoided it will still be desirable to minimize exposures of
such packaged compositions to heat and to light, both of which have been
found to accelerate loss of anti-plaque activity. Thus, the invented
compositions are preferably stored and packaged in opaque containers and
dispensers at a temperature in the range of 10° to 38°C and are
stored at
such a temperature, too. Otherwise, the packaged campositions may be
stored and used in normal manner and the desirable anti-plaque effects
thereof will be obtained. Such effects have been verified by laboratory
testing and by evaluations of the teeth of volunteers serving on human
panels, who employed the various packaged compositions and controls as
directed. Significant improvements in anti-plaque activities of the
packaged compositions of this invention are observed, compared to
control packaged compositions wherein the packaging included plastic
17
"- ,. ~.31
parts that were "reactive" with the halogenated diphenyl ether
antibacterial compound and which do not contain stabilizing agent in the
oral composition. Such improvements are also found when packages made
of "reactive" plastics (but not co-polyester/polyether e:Lastomers) are
employed with oral compositions containing terpenes and are compared to
controls in which the oral compositions contains no terpenes and no
flavoring agents.
The following examples illustrate but do not limit the invention.
Unless otherwise indicated, all percentages and proportions in these
examples, the specification and the appended claims are by weight, and
all temperatures are in °C.
EXAMPLE 1
Component Percentage
Water, deionized 47.84
Sorbitol (70% aqueous solution) 20.00
Ethanol (95% aqueous solution) 12.50
Glycerol 10.00
Propylene glycol 7.00
* Gantrez S-97 (13% solution) 1.92
Sodium hydroxide (50% aqueous solution) 0.12
Sodium lauryl sulfate 0.25
*Tauranol WSHP 0.20
***Flavor Mixture 0.12
**%~*Triclosan (IrgasanR DP 300, manufactured by CIBA-
GEIGY) 0.05
100.0
* Polyvinyl methyl ether/maleic anhydride copolymer (GAF Corp.)
Sodium methyl cocoyl taurate
*** Contains at least 25% terpenes, including at least 25% of limonene
****THDE (2',4,4'-trichloro-2-hydroxy-diphenyl ether)
The mouth rinse (or mouthwash) of this example is made by mixing
together the various listed components in any suitable order, according
18
to standard procedures, but preferably the triclosan is first dissolved
in the propylene glycol and ethanol mixture, after which it is mixed with
an aqueous solution of sorbitol, glycerol and the anionic surfactants,
with the flavor mixture being added last. The sodium hydroxide solution
is employed for neutralization of the resulting acidic mixture, which
neutralization is to a pH of fi.84 (it being desirable to have the product
at or near to a neutral pH) .
The mouth rinse resulting is of excellent cosmetic stability and
is of acceptable flavor, and the flavor and triclosan are satisfactorily
dissolved, with such dissolving being at least partially attributable to
the presence of the Tauranol WSHP. When only 0.257 of SLS is employed as
the anionic surfactant solubilizations of the flavoring agent and
triclosan are not as satisfactory. Although such solubilizations can be
increased by using more SLS the maximum acceptable limit of such compound
in the mouth rinses is often about 0.25, and the TauranolR WSHP and SLS
are safe and acceptable in the proportions employed. The described mouth
rinse is tested in vitro for bioavailability of triclosan against
comparable mouth rinses of formulas omitting the Tauranol WSHP, in one
case, and replacing it with half as much of a nonionic surfactant
(Pluronic F-127) in another case. By triclosan uptake tests, measuring
triclosan absorption by hydroxyapatite discs that had been coated with
saliva, and by protein absorption "zone of inhibition" tests it is found
that the presence of the mixed anionic surfactant results in comparable
bioavai.lability of triclosan, compared to such availability from the 5LS-
' only formula, and such availability is significantly higher far the
formulas containing no nonionic detergent than for that wherein the
nonionic detergent (PluronicR F-127) is present.
'fhe mouth rinse of the formula of this example is aged at elevated
temperature (41°C) for three and five weeks, which is considered
equivalent to at least about six months and one year's actual aging at
19
.,
room temperature. Such aging tests are conducted in dispensing
containers (bottles) made of glass, polyvinyl chloride and polyethylene
terephthalate {or lined with the plastic materials). Although chemical
analyses of the mouth rinses after such aging periods find no losses of
txiclosan when the container is glass, losses of triclosan from the
mouth rinses are noted when the containers are of polyethylene
terephthalate or of this sample of polyvinyl chloride but they are
significantly less than a tolerable 25% (of the original concentration),
and can be under 5 or 10%.
When, in place of the flavor mixture, dl limonene is employed in
0,1, 0.2 and 0.4% quantities, even better stabilizations of the triclosan
in the described package dentifrices of the invention are obtainable, and
such stabilizations also result when othex terpenes from any of various
essential oils, and flavoring agents, are present in similar
proportions. Such good results are also obtainable when the container
material or the liner thereof is of po:lymethyl pentene, polyallomer,
polypropylene, high and low density polyethylenes, and nylon, although
such materials; in the absence of the :Flavor mixture (and contained
terpenes) cause significant and excessive losses of available triclosan
from the mouth rinse on storage, especially at elevated temperatures.
EXAMPLE 2
Component Percent
Water, deionized 84.42
Ethanol (95%) 10.0
Propylene glycol 5.0
Sodium lauryl sulfate 0.50
Triclosan 0.06
Sodium saccharin 0.02
100.00
'1
~I,1
~ Jo
. z,
i~~~.~ a ~.~
A mouth rinse of the above formula is tested for triclosan
availability after storage fox three weeks in dispensing containers made
from or lined with various plastics. Testings are at room temperature,
38°C and 49°C, with the elevated temperature storages simulating
lengthier storage times, up to a year or more at room temperature.
Losses of over 257 of the triclosan from the stored mouth rinse are noted
when the containers are polymethyl pentene, polyallomer, polypropylene,
high and low density polyethylenes and nylon, with unacceptable results
(excessive losses) being noted when the containers are polypropylene,
polyethylene and nylon (with nylon being the worst).
When the container material or liner is polyvinyl chloride,
polycarbonate, polysulfone or polyfluoroethylene, e.g.,
polytetrafluoroethylene or TeflonR, essentially no losses of triclosan
occur. Losses of triclosan from mouth rinses stored in containers of or
lined with the polymers mentioned (polymethyl pentene, etc.) may be
decreased in the same manner as described in Example 1 by incorporating
in the mouth rinse formula limonene, other terpenes, or essential oils in
which such may be present, with the proportion of terpene preferably
being at least 0.17, and more preferably being greater, e.g., 0.2Z or
0.4%, on a final composition basis. In some instances even the
employment of flavoring material which does not contain any significant
proportion of terpenes will have a positive effect, although such effect
will not be expected to be as good as with terpenes in the formulation.
EXAMPLE 3
Component Percent
Propylene glycol 10.00
Iota carrageenan 0.75
Sodium fluoride 0.33
Sorbitol (707) 30.00
Sodium saccharin 0.30
21
_.
Titanium dioxide 0.50
Sodium hydroxide (50~ aqueous solution) 0.80
Water, deionized 27.71
+ Luviform'z''~ (357 solution) 4.76
++Zeodent'r''' 113 20.00
+++Sident'I'M 22S 2.00
Sodium lauryl sulfate (947 active) 1.60
Flavor 0.95
Triclosan 0.30
100.00
+ Polyvinyl methyl ether/maleic anhydride copolymer (BASF Corp.)
++Silica polishing agent (J. M. Huber Corp.)
-i-h+Silica thickening agent (Hegussa Co.)
A dentifrice of the above formulation is made in normal manner and
is employed as a medium for testing the stability of triclosan when the
dentifrice containing it is exposed to different plastics which are
employed as materials of containers or of parts of the dispensers in
which dentifrices are stored and from which they are dispensed. The
plastics for the tests are PibiflexT'"' 46, made by Inmont, and
ArnitelT'°'
460 EM, mf'd. by AKZO, which are plastics that are employed as the
membranes or bellows of a pump dispenser, as illustrated in FIG. 3. Six
samples of plastics are tested, thxee of each of the mentioned plastics,
with each of the three being treated with a different mold release agent
(to determine whether the nature of the release agent is relevant to the
problem of triclosan stability in contact with plastics during storage).
The release agents are Silicone MasterT"' (57 silicone oil and 95~
polypropylene), Silicone Master plus Silicone Oil (with extra silicone
oil) and Armid 0 MasterT"' (S7 oleo amide and 95~ polypropylene),
respectively. After two weeks storage of the test samples in contact
with the dentifrice at different temperatures (room temperature, 38°C.
22
i
7
f~
and 49°C.), the dentifrice is removed from the plastic container
materials and the plastics are washed with water and immersed in
methanol to dissolve any triclosan which might have been taken up by them
during storage. T'he methanol washings are collected and are analyzed,
using high pexformance liquid chromatrography. It is found that
essentially the same types of absorptions of triclosan take place with
the different membrane materials and although there are variations
between them and such are somewhat dependent on the release agents
employed, the results axe essentially the same in all cases. The co-
polyester/polyether elastomers are found to absorb significant
percentages of triclosan from the dentifrice, which results are
confirmable when the co-polyester/polyether elastomers are used as
bellows materials in pump dispensers containing the described dentifrice
and other dentifrices within the invention. Accordingly, it is
considered undesirable to employ co-polyester/polyether elastomers in
contact with the present dentifrices or mouthwashes, even when the
dentifrices and mouthwashes contain flavoring materials which include
terpenes (which are present in the flavoring of the dentifrice
formulation), to the extent of at least 0.1~ of the dentifrice.
When the tests are repeated, using actual Guala pump dispensers as
containers for the dentifrices, with co-polyester/polyether elastomer
membranes of ArnitelT''t, the losses of triclosan are also unacceptable but
when the co-polyester/polyether elastomer is replaced by others of the
acceptable plastics, e.g., polyfluoroethylene, the triclosan activity is
improved to within acceptable limits. Also, other plastic parts of such
pump dispensers, such as polypropylene inner walls thereof, are not found
to absorb excessive amounts of triclosan and do not seriously decrease
the anti-plaque activity of the dentifrice, apparently due to the ,
presence of terpenes in the flavoring agent of the contained dentifrice.
23
.a
.s
~ ~i
A panel test is run, involving at least ten human subjects, who
employ the dentifrice of this example, dispensed from polyethylene
terephthalate and polyethylene lined tubes, in twice-a-day brushings for
one month, during which time plaque evaluations of the subjects' teeth
are made by trained observers. The test results establish that the
dentifrice composition has a definite anti-plaque activity, similar to
that which is also observable in tests with the mouth rinses of Examples
1 and 2, and also prove that the triclosan has riot been unacceptably
inactivated, and still is present in an effective antibacterial and anti-
plaque proportion in the dentifrice.
EXAMPT~E 4
Component Percent
Glycerol 7.00
Propylene glycol 3.00
Iota carrageenan 0.75
Sorbitol (70%) 30.00
Sodium sacchaxin 0.30
Sodium fluoride 0.33
Titanium dioxide 0.50
GantrezR S-97 (13% solution) 15.00
Deionized water ~ 16.07
Sodium hydroxide (50Z aqueous solution) 0.80
Zeodent~ 113 (J. M. Huber Corp.) 20.00
SylodentR lS (a silica thickenerg W.R. Grace 3.00
Corp.)
Flavoring agent 0.95
Sodium lauryl sulfate 2.00
Triclosan 0.30
100.00
A toothpaste of the above formula is made and stored in
is Guala''''
pump dispensers having bellows membranes of type. The
the Arnitel
24
:'s
a~~~~'o~.~
dentifrice is also filled into laminated tubes, having polyethylene
terephthalate on the interior of the laminate, in contact with the
dentifrice. The dentifrices are aged at 5°C., 25°C., and
39°C., for two,
four and six weeks. After such aging periods, the dentifrices are
dispensed at the rate of about 1.5 grams per day and at weekly intervals
the triclosan contents of the dispensed dentifrices are determined by
analyses. In the case of the Guala pump dispenser the dispensed
dentifrice loses about 277 of the triclosan, which is excessive and
objectionable. The loss is about constant, regardless of storage
temperature or time of storage, which can be explained by absorption of
the triclosan by the pump membrane, with which it is brought into contact
prior to dispensing. Such membrane is of a co-polyester/polyether
elastomer, which class of plastics is to be avoided as a container
material or as a part in a container or dispenser for dentifrices
containing triclosan. However, when the elastomeric co-
polyester/polyether membrane is replaced by one made of any of the
previously mentioned acceptable plastics, such as polyethylene
r
terephthalate, which can serve as membrane materials in modified pump
dispensers (modified to compensate for different properties of such
Mastics), triclosan stability is increased and the dispensed
composition is satisfactory and effective as an anti-plaque toothpaste.
Gel toothpaste formulations in such packages behave similarly with
respect to triclosan stability after storage and on dispensing.
Tn similar tests, using polyethylene terephthalate lined tubes
little loss (less than 5%) of triclosan is noted, indicating that the
presence of the terpenes (0.17 or more of. the composition), including
limonene, in the flavoring agent (or the flavoring agent itself) prevents
loss of the triclosan or inactivation thereof. When polyfluoroethylene-
lined tubes are employed there will be little loss of triclosan even when
the flavoring agent is omitted fxom the dentifrice composition and such
~~~~ i~~,~
will also be the case when polyvinyl chloride is employed as the linex
material in contact with the dentifrice or when polysulfone or
polycarbonate package parts are in contact with such dentifrice.
However, as was indicated previously, one will not usually employ such
three last named pJ.astics.
When in the reported test in which the dentifrice is dispensed
from the Guala dispenser the Gantrez S-97 is replaced by 4.76 parts of
Luviform (357), with the difference being made up in deionized water, no
appreciable difference in triclosan stability is noted between the
formulas.
In the above formulas the polishing system is a siliceous system
rather than one based on alumina. When the polishing agent is changed to
an alumina, tl~~e problems previously mentioned as having been noted with
some plastics are decreased but still exist. Also, the prasences of
terpenes in the dentifrices promote triclosan stability, as such
presences do in similar dentifrice compositions based on siliceous
polishing agents.
EXAMPLE 5
The mouth rinses and the dentifrices of the foregoing examples may
z0 be varied in composition +10% and +25% for the various components
thereof, providing that such percentages are not outside ranges givexr
elsewhere in this specification, and operative and effective
antibacterial and anti-plaque products are obtainable, which are
dispensable in effective anti-plaque state from the mentioned dispensing
containers that axe made of compatible plastics. The products may also
be modified by being converted to dentifrice gels, oral gels, pastes,
liquids, lozenges, capsules, tablets, and sachets of the types previously
mentioned in the specification. Such products also will behave in
similar manners, with the triclosan or othex halogenated diphenyl ether
or antibacterial anti°plaque agent being sufficiently stable in the
zs
t
~31~4~
presence of polyfluoroethylene, polyvinyl chloride, polycarbonate and
polysulfone packaging or package component materials, even when no
flavoring agent and no terpenes are present in the oral compositions, and
being stable in the presence of polyethylenes, polypropylenes,
polyethylene terephthalates, polyallomers, nylons and
polymethylpentenes, as package or component materials, providing that a
terpene, such as limonene, or a stabilizing flavor component is present
in the oral composition. As with the other dentifrices and mouthwashes
previously discussed, because of excessive absorption or other adverse
action with respect to triclosan by co-polyester/polyether and other
elastomers, uses of such materials will preferably be avoided.
EXAMPLE 6
Dentifrices of the formulas of Examples 3 and 4 are made and are
dispensed after one month's storage at 30°C in collapsible toothpaste
,15 tubes lined with polyethylene, in one case, and polyethylene
terephthalate, in another, onto bristled toothbrushes, as illustrated in
FIG. 1. The amounts of toothpaste on the toothbrush are in the range of
0.8 to 2.0 grams with 1 to 1.5 g. being preferred. When 1.5 g. is
dispensed the active triclosan in the dentifrice on the brush is about
four milligrams (with only 10~ of the triclosan being inactivated). When
storage is for a longer time or at a higher temperature or with a more
destabilizing plastic in contact with the dentifrice during storage the
packaged compositions can contain about 3 mg. of triclosan in the 1.5 g
on the brush. Thus, with l g. of dentifrice on the brush the amounts of
triclosan will be about 2.7 mg. and 2 mg. respectively. For dentifrices
containing from 0.25 to O.S~ of tricl.osan the toothbrush can contain from
2.2 to 8 mg. of triclosan if the triclosan inactivation is in the 10 to
25% range, or up to about 9 mg. when no triclosan is inactivated.
The described packaged dentifrices axe employed to brush the teeth
with typically about 0.8 to 2 g being dispensed onto toothbrushes for
27
a,
each brushing. Brushings are twice a day, morning and night, one minute
at a time, .for four weeks, after which definite improvement in anti-
plaque action is apparent, compared to a control dentifrice that contains
no triclosan. Improvement in anti-plaque action is also visible,
compared to an unflavored control (containing no terpene) that contains
triclosan in a dentifrice package in polyethylene and polyethylene
terephthalate lined tubes.
The present invention has been described with respect to
illustrative examples and embodiments thereof but is not to be limited to
those because it is evident that one of skill in the art, with the
present specification before him or her, will be able to utilize
substitutes and equivalents without departing from the invention.
28
