Note: Descriptions are shown in the official language in which they were submitted.
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Composition
The present invention relates to oral hygiene compositions comprising the
cationic
antibacterial agent, chlorhexidine, for combating halitosis. .
Cationic antibacterial agents such as chlorhexidine have long been recognised
as
useful therapeutic agents for treating various oral health conditions such as
plaque,
caries, periodontal diseases and halitosis due not only to their intrinsic in
vitro
antibacterial activity but also because of their substantivity to oral tissue.
They are
thus adsorbed onto oral surfaces and gradually released over a period of time,
to
produce a prolonged antibacterial effect.
EP-A-920857 describes an oral composition for the treatment of halitosis
comprising
a combination of 0.025 to 0.20% by weight of a chlorhexidine salt, 0.025 to
0.10% by
weight of a quaternary ammonium salt such as cetylpyridinium chloride and a Zn
or
Cu salt providing 100 to 1000ppm of Zn or Cu ions.
WO-00/51559 (which was published on 8 September 2000 after the priority date
of
the present application) describes a mouthwash composition for the treatment
of
halitosis containing 0.005 to 0.05% wlv of an antibacterial agent selected
from bis-
guanides and quaternary ammonium compounds and 0.05 to 0.5% w/v of zinc
acetate.
It has now been discovered that particularly low concentrations of
chlorhexidine are
surprisingly effective in combating halitosis.
Accordingly in a first aspect the present invention provides an oral hygiene
composition comprising chlorhexidine or an orally acceptable addition salt
thereof in
a concentration not greater than 0.025% by weight of the total composition and
an
orally acceptable carrier or excipient with the proviso that when the oral
hygiene
composition is a mouthwash composition it does not contain from 0.05 to 0.5%
w/v of
zinc acetate.
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In a second aspect the present invention provides the use of chlorhexidine or
an orally
acceptable addition salt thereof in the manufacture of an oral hygiene
composition as
hereinbefore described for combating halitosis.
In a third aspect the present invention provides a method of combating
halitosis by
administering to a patient in need thereof of an oral hygiene composition as
hereinbefore described.
Suitably chlorhexidine or an orally acceptable addition salt thereof is
present in an
amount from 0.001 to 0.024%, preferably 0.002 to 0.020%, and more preferably
0.005
to 0.015 % by weight of the oral hygiene composition.
Suitably the oral hygiene composition does not contain a Zn or Cu salt.
Preferably
chlorhexidine or an orally acceptable addition salt thereof is present as the
sole
antibacterial agent.
Suitable such salts of chlorhexidine include those which have a solubility at
20°C of
at least 0.005% w/v and include the digluconate, diformate, diacetate,
dipropionate,
dihydroiodide, dihydrochloride, dilactate, dinitrate, sulphate, and tartrate.
Of these, the
digluconate, diacetate~ and dihydrochloride are favoured.
Oral hygiene compositions of the present invention may also usefully contain
an ionic
fluorine-containing compound. Suitable ionic fluorine-containing compounds
include, for instance, fluoride salts such as amine fluorides and alkali metal
fluoride
salts, for example sodium fluoride, and monofluorophosphate salts such as
alkali
metal monofluorophosphate salts, for example sodium monofluorophosphate.
Suitably
the ionic fluorine-containing compound is incorporated into the composition to
provide between 100 and 3000ppm, preferably between 500 and 2000ppm of
fluoride
ions.
Oral hygiene compositions of the present invention maybe provided in any of
the
presentations normally used for such products, for instance, dentifrices
including
toothpastes and toothpowders, abrasive and non-abrasive gels, mouthwashes,
gargles,
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irrigating solutions, mouthsprays and presentations for sucking or chewing by
the user
such as gums, pastilles, lozenges and wafers which can rapidly dissolve in the
mouth.
Components for the orally acceptable carrier or excipient will be selected
according to
the particular type of presentation involved.
It will be appreciated by those skilled in the art that in order to ensure
that the
antibacterial efficacy of the cationic antibacterial agent is not
substantially diminished,
compatible components will be selected for inclusion in the orally acceptable
carrier
or excipient. Accordingly, the skilled man will readily appreciate that where
necessary
anionic species should be preferably avoided as such species may cause
inactivation
of the cationic antibacterial agent by the formation of an insoluble
precipitate
therewith. Thus, anionic surfactants and anionic thickening agents should
preferably
be rejected in favour of non-anionic counterparts such as nonionic, cationic
or
amphoteric surfactants and nonionic thickening agents. Similarly, abrasives
capable of
acting as a source of anions, either because they are sparingly soluble or
whilst being
essentially insoluble per se are contaminated with soluble impurities arising
from, for
instance, the manufacture thereof, are preferably avoided in favour of
compatible
abrasives.
Suitable nonionic surfactants include, for example, polyethoxylated sorbitol
esters, in
particular polyethoxylated sorbitol monoesters, for instance, PEG(40) sorbitan
di-
isostearate, and the products marketed under the trade name 'Tween' by ICI;
polycondensates of ethylene oxide and propylene oxide (poloxamers), for
instance the
products marketed under the trade name 1'luronic' by BASF-Wyandotte;
condensates
of propylene glycol; polyethoxylated hydrogenated castor oil, for instance,
cremophors; and sorbitan fatty esters.
Suitable amphoteric surfactants include, for example, long chain imidazoline
derivatives such as the product marketed under the trade name ~VIiranol C2M'
by
Miranol; long chain alkyl betaines, such as the product marketed under the
tradename
~mpigen BB' by Albright + Wilson, and long chain alkyl amidoalkyl betaines,
such as
cocamidopropylbetaine, and mixtures thereof.
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Suitable cationic surfactants include the D,L-2-pyrrolidone-5-carboxylic acid
salt of
ethyl-N-cocoyl-L-arginate, marketed under the trade name CAE by Ajinomoto Co.
Inc.
Advantageously, the surfactant is present in the range 0.005 to 20%,
preferably 0.1 to
10%, more preferably 0.1 to 5% by weight of the dentifrice.
Suitable nonionic thickening agents include, for example, (C1-6)-
alkylcellulose
ethers, for instance methylcellulose, hydroxy(Cl-6)-alkylcellulose ethers, for
instance
hydroxypropylcellulose,. (C2-6)-alkylene oxide modified (C1-6)-alkylcellulose
ethers,
for instance hydroxypropyl methylcellulose, and mixtures thereof.
Advantageously
the nonionic thickening agent is present in the range 0.01 to 30%, preferably
0.1 to
15%, more preferably 1 to 5%, by weight of the composition.
Suitable abrasives include a sparingly soluble salt in combination with an
agent to
suppress anion formation or an essentially insoluble compound.
Suitable sparingly soluble salts that may be used as an abrasive include
calcium
carbonate, calcium phosphates, magnesium carbonate, insoluble sodium
metaphosphate, and suitable mixtures thereof. The agent to suppress anion
formation
typically comprises a water soluble salt containing a cation which may be same
as the
cation of the abrasive and which forms an essentially insoluble or sparingly
soluble
salt with the anion of the abrasive. Preferably the sparingly soluble salt
used as an
abrasive is calcium carbonate, advantageously used in combination with
dicalcium
phosphate, which also usefully buffers the pH of the formulation. Suitable
types of
calcium carbonate include both natural and synthetic chalks. The agent to
suppress
anion formation may be an alkaline earth metal salt, for instance calcium
chloride.
The agent is preferably present in from 0.0001 to 1 %, more preferably 0.005
to 0. I %
by weight of the dentifrice.
The term 'essentially insoluble compound' as used herein refers to a compound
which
is intrinsically insoluble in aqueous solution and includes those compounds
which are
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listed as being 'insoluble' in cold water in the TIandbook of Chemistry and
Physics',
48th Edition, Chemical Rubber Company, Section B, Physical Constants of
Inorganic
Compounds. Furthermore, such compounds when used as an abrasive shall contain
little if any contaminating anionic impurities. Preferably the insoluble
abrasive
compound should contains less than 1%, preferably less than 0.5%, and more
preferably less than 0.25% of anionic impurities, based on the weight of the
abrasive.
Suitable essentially insoluble compounds for use as abrasives include, for
example,
silica, zinc orthophosphate, plastics particles, alumina, hydrated alumina,
and calcium
pyrophosphate or mixtures thereof.
I0
Preferably, the abrasive is silica. Suitable silicas include natural amorphous
silica, for
instance diatomaceous earth; and synthetic amorphous silicas, for instance a
precipitated silica, or a silica gel, such as a silica xerogel; or mixtures
thereof. The
preferred synthetic amorphous silicas are those with a low-level of water
soluble
anionic impurities (hereinafter referred to as "low-anion silica"). These are
obtainable
from manufacturing process. which are carefully controlled so that the level
of anion
impurities, particularly sulphate and silicate from sodium sulphate and sodium
silicate, respectively, is kept to a minimum. Alternatively, or in addition,
the level of
anion impurities may be reduced to the required level by careful washing of
the
initially produced silica with, for instance, deionised or distilled water.
Suitable low-
anion silicas contain less than 0.5%, preferably less than 0.25%, more
preferably less
than 0.1 % by weight of water soluble impurities such as sodium sulphate
and/or
sodium silicate.
The abrasive is advantageously present in the range 1 to 80%, preferably 5 to
70%,
more preferably 5 to 60% by weight of the dentifrice.
It will be appreciated that each of the thickening agent, the surfactant and
abrasive
should be, at the level employed in the dentifrice, compatible with the
cationic
antibacterial agent, that is, each will not substantially reduce the
availability of the
cationic antibacterial agent, for instance, by more than 30%, preferably more
than
20%. This may be confirmed by, for instance, determining the biological
activity of
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the formulation, by conventional microbiological assay using, for instance, M.
luteus
as the assay organism in a standard agar diffusion method, in the presence and
absence
of each of the aforementioned thickening agent, surfactant and abrasive.
Mouthwashes according to the present invention will preferably comprise as
components of the carrier a surfactant and a humectant in an aqueous or an
aqueous/ethanol solution. Gels according to the present invention will
preferably
comprise as components of the carrier a surfactant, humectant, thickening
agent and
optionally water. Dentifrices according to the present invention will
preferably
comprise as components of the carrier a surfactant, humectant, thickening
agent,
abrasive and if necessary, water.
Suitable humectants for use in compositions of the invention include for
instance
glycerine, sorbitol, propylene glycol or polyethylene glycol, or mixtures
thereof. The
humectant may be present in the range from 5 to 70%, preferably 5 to 30%, more
preferably 10 to 30% by weight of the dentifrice.
Other materials may be added to the compositions if required, for instance
sweetening
agents, flavouring agents, colouring and whitening agents, preservatives and
emulsifiers.
The pH of a composition according to the invention will be orally acceptable
and
typically in the range pH 4 to 9.
Oral hygiene compositions according to the present invention may be prepared
by
mixing the ingredients thereof in the required proportions and in any order
that is
convenient and thereafter and if necessary adjusting the pH to the required
value.
The invention will now be illustrated by reference to the following examples.
Example 1: Evaluation of halitosis efficacy
The ability of low doses of chlorhexidine to combat halitosis (oral malodor)
was
assessed using the cysteine challenge method. This measures the ability of
oral
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bacteria to produce volatile sulfur compounds (VSC), the major odor component
of
oral malodor, from cysteine and is correlated with organoleptic evaluation by
odor
judges.
Testing consists of rinsing the mouth with 5mI of 6mM cysteine for 30 seconds
and
measuring the resulting the VSC response (mainly hydrogen sulphide) with a
chemical
sensor instrument such as the Iialimeter. Cysteine challenge testing consisted
of the
obtaining of an initial baseline VSC determination, the subsequent
introduction of the
cysteine challenge substrate, measuring the VSC response over a 20 minute
period,
introducing the test rinse and at set times thereafter, repeating the cysteine
challenge
for up to 7 hours.
Inhibition was assessed quantitatively by the degree of inhibition of VSC
production
from cysteine by the test agent, chlorhexidine digluconate, as compared to VSC
production from cysteine at baseline. Duration of the inhibition was assessed
as the
time it takes for VSC production with successive cysteine challenges to return
to that
seen at baseline.
A mouthrinse comprising chlorhexidine digluconate at a concentration of 0.025%
(vlv) was found to significantly inhibit the production of VSCs. Most
inhibition was
seen two hours after the rinse, with inhibition being maintained at gradually
decreasing levels for over 7 hours from the initial rinse. Similarly
advantageous
results are obtained at lower concentrations of chlorhexidine digluconate such
as
0.020, 0.015, 0.0125 and 0.010 % by weight of the composition.
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Example 2: Low dose chlorhexidine
mouthwash
% wlw
Chlorhexidine digluconate 0.0125
Sorbitol 3.0
Ethanol 96% 6.0
Cremophor RH60 0.20
Flavour oil 0.12
Dye solution 0.10
Sodium saccharin 0.01
Water to 100
_g_
