U.S. patent application number 15/857973 was filed with the patent office on 2018-11-15 for multicomponent oral care composition.
The applicant listed for this patent is PERIPRODUCTS LTD. Invention is credited to Ian Baynes, Alan J. Collings, David G. Gillam, Robert Hill.
Application Number | 20180325942 15/857973 |
Document ID | / |
Family ID | 45929942 |
Filed Date | 2018-11-15 |
United States Patent
Application |
20180325942 |
Kind Code |
A1 |
Hill; Robert ; et
al. |
November 15, 2018 |
MULTICOMPONENT ORAL CARE COMPOSITION
Abstract
The present invention relates to a multicomponent oral health
care composition, comprising a source of a fluoride ion, a source
of a calcium ion, a source of a phosphate ion, and stabilised
chlorine dioxide, that can be used as a toothpaste, oral spray or a
mouth wash/oral rinse formulation. The different components in the
composition act synergistically together to clean the teeth and
mucous membranes of an oral cavity of a subject, perfuming them or
protecting them in order to keep them in good condition, change
their appearance or correct unpleasant odours. They achieve this by
inhibiting caries, promoting teeth remineralisation, and helping to
alleviate dentine hypersensitivity, gingivitis and periodontal
disease.
Inventors: |
Hill; Robert; (Berkshire,
GB) ; Collings; Alan J.; (East Sussex, GB) ;
Baynes; Ian; (Hertfordshire, GB) ; Gillam; David
G.; (London, GB) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
PERIPRODUCTS LTD |
Middlesex |
|
GB |
|
|
Family ID: |
45929942 |
Appl. No.: |
15/857973 |
Filed: |
December 29, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15229757 |
Aug 5, 2016 |
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15857973 |
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14959700 |
Dec 4, 2015 |
9408788 |
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15229757 |
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14378045 |
Aug 11, 2014 |
9211240 |
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PCT/GB2013/050250 |
Feb 4, 2013 |
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14959700 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 8/21 20130101; A61K
8/20 20130101; A61K 33/20 20130101; A61K 8/24 20130101; A61Q 11/00
20130101; A61K 33/42 20130101; A61K 33/06 20130101; A61K 8/73
20130101; A61K 2800/5922 20130101; A61K 8/19 20130101; A61K 33/16
20130101; A61K 2800/92 20130101; A61P 43/00 20180101; A61K 8/22
20130101; A61K 33/42 20130101; A61K 2300/00 20130101; A61K 33/16
20130101; A61K 2300/00 20130101; A61K 33/06 20130101; A61K 2300/00
20130101; A61K 33/20 20130101; A61K 2300/00 20130101 |
International
Class: |
A61K 33/16 20060101
A61K033/16; A61K 8/22 20060101 A61K008/22; A61K 8/19 20060101
A61K008/19; A61K 8/73 20060101 A61K008/73; A61K 8/24 20060101
A61K008/24; A61Q 11/00 20060101 A61Q011/00; A61K 8/20 20060101
A61K008/20; A61K 33/42 20060101 A61K033/42; A61K 33/20 20060101
A61K033/20; A61K 33/06 20060101 A61K033/06; A61K 8/21 20060101
A61K008/21 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 10, 2012 |
GB |
1202341.2 |
Claims
1. An oral care composition for forming fluorapatite in or on teeth
comprising: i) a source of a fluoride ion; ii) a source of a
calcium ion; ii) a source of a phosphate ion; and iv) stabilized
chlorine dioxide.
2. The oral care composition according to claim 1, wherein the
source of a calcium ion and the source of a phosphate ion is an
apatite species.
3. The oral care composition according to claim 1, wherein the
source of a calcium ion and the source of a phosphate ion is an
apatite species based on the formula M.sub.5(PO.sub.4).sub.3X,
wherein M is Ca, Sr, Zn or Mg, and X is F, Cl or OH.
4. The oral care composition according to claim 2, wherein the
apatite species is a substituted or unsubstituted hydroxyapatite or
a substituted or unsubstituted fluorapatite.
5. The oral care composition according to claim 2, wherein the
apatite species is selected from calcium hydroxyapatite, strontium
hydroxyapatite, calcium hydroxycarbonated apatite, strontium
hydroxycarbonated apatite, calcium fluorapatite, strontium
fluorapatite, mixed strontium calcium apatites or a mixed
hydroxyfluorapatite, zinc substituted hydroxyapatite, zinc
carbonated hydroxyapatite, zinc fluorapatite, octacalcium
phosphate, or a mixture of any two or more thereof.
6. The oral care composition according to claim 2, wherein the
apatite species is present in an amount of from about 0.5 to about
30 weight percent of the composition, and/or the apatite species
has a article size distribution, where at least about 3% of the
mass of the particles have a size less than about 5 microns and
where the apatite species has a crystallite size of less than about
200 nm, as determined using Scherrer Line Broadening.
7. The oral care composition according to claim 1, wherein the
source of a fluoride ion is selected from sodium fluoride,
potassium fluoride, disodium monofluorophosphate, tin (II)
fluoride, dipotassium fluorophosphates, calcium fluorophosphates,
calcium fluoride, ammonium fluoride, aluminium fluoride, hexadecyl
ammonium fluoride, 3-(N-hexadecyl-N-2-hydroxyethylammonio) ammonium
difluoride,
N,N',N'-tris(polyoxyethylene)-N-hexadecylpropylenediaminedihydrofuloride
disodium hexafluorosilicate, disodium hexafluorosilicate,
dipotassiumhexafluorosilicate, ammonium hexafluorosilicate,
magnesium hexafluorosilicate or ammonium fluorophosphates, or any
combinations of two or more thereof.
8. The oral care composition according to claim 1, wherein the
source of a fluoride ion has a concentration between 20 and 1500
ppm as fluorine.
9. The oral care composition according to claim 1, wherein when the
composition is to be used as toothpaste, the fluoride concentration
is between 300 and 1500 ppm.
10. The oral care composition according to claim 1, wherein when
the composition is to be used as mouth wash, the compositions has
an active fluoride concentration between 5 and 500 ppm.
11. The oral care composition according to claim 1, further
comprising a buffer system. cm 12. The oral care composition
according to claim 1, wherein the buffer system comprises one or
more selected from acetate, carbonate, citrate or
phosphate-containing species.
13. The oral care composition according to claim 1, wherein the pH
of the composition is between about 6.0 and about 8.0.
14. The oral care composition according to claim 1, wherein the
composition is a mouth wash or oral rinse, and further comprises a
linear polysaccharide polymer.
15. The oral care composition according to claim 14, wherein the
linear polysaccharide polymer is a linear polysaccharide gum,
wherein one or more hydroxyl groups on a monosaccharide of the
linear polysaccharide gum is substituted with a function group
comprising a group selected from a carboxyl group (R--COOH), an
acyl group (RCO--) or a sulphate group (R--OSO.sub.3.sup.-).
16. (canceled)
17. A toothpaste, oral spray, mouthwash or oral rinse formulation
comprising an oral care composition according claim 1.
18. A method for generating gaseous chlorine dioxide within an oral
cavity of a subject for a medical purpose comprising, combining
stabilized chorine dioxide solution, an apatite species, and a
source of a fluoride ion.
19. The method according to claim 18, wherein the stabilized
chlorine dioxide solution has a concentration of between about
0.05% to about 2.0% (w/v).
20. The method according to claim 18, wherein the medical purpose
is cleaning teeth and mucous membranes, perfuming teeth and mucous
membranes, protecting teeth and mucous membranes, change the
appearance of teeth and mucous membranes, correct unpleasant
odours, remineralization of teeth, dentine hypersensitivity, or a
combination of medical purposes.
21. A method of cleaning teeth and mucous membranes of an oral
cavity of a subject, or perfuming them or protecting them,
comprising applying an oral care composition according to claim 1.
Description
[0001] The present invention relates to a multicomponent oral
health care composition that can be used as a toothpaste, oral
spray or a mouth wash/oral rinse formulation. The different
components in the composition act synergistically together to clean
the teeth and mucous membranes of an oral cavity of a subject,
perfuming them or protecting them in order to keep them in good
condition, change their appearance or correct unpleasant odours.
They achieve this by inhibiting caries, promoting teeth
remineralisation, and helping to alleviate dentine
hypersensitivity, gingivitis and periodontal disease.
[0002] Tooth mineral in humans and animals is based on calcium
apatite, Ca.sub.5(PO.sub.4).sub.3OH. Natural tooth apatites are
heavily solid substituted, and the Ca.sup.2+ cations in the crystal
lattice may be replaced by, for example, Sr.sup.2+, Mg.sup.2+ or
Zn.sup.2+, or by two Na.sup.+ cations. The phosphate
(PO.sub.4).sup.3- anions may be replaced by carbonate ions
(CO.sub.3.sup.2-), with an associated Na.sup.+ cation replacing a
Ca.sup.2+ cation or the associated loss of a hydroxyl ion
(PH.sup.-). The hydroxyl ion may also be replaced by a fluoride ion
(F.sup.-). This latter substitution occurs readily in tooth enamel
and has several beneficial effects. In the crystal structure of
calcium apatite, the hydroxyl ion is displaced slightly above the
plane of a triangle of Ca (II) ions (as depicted in FIG. 3), whilst
the smaller fluoride ion sits in the centre of the Ca) (II)
triangle. This results in hydroxyapatite (HA) having a slightly
distorted monoclinic crystal structure, whilst fluorapatite has a
more symmetric hexagonal crystal structure. This difference leads
to fluorapatite being: [0003] i) More stable to acid dissolution
and more resistant to the acids produced by carries forming
bacteria; and [0004] ii) Formed more readily, since fluorapatite
has a lower solubility product than hydroxyapatite.
[0005] As a consequence of these two factors, soluble fluoride
salts have been added to toothpastes, mouth rinses and drinking
water for over fifty years, and fluoride has a well-documented and
recognized role in anti-caries treatment. The use of fluoride as a
preventive measure is well established.
[0006] It is generally recognized that plaque that forms on teeth
as a result of the activity of bacteria is not completely removed
by the act of brushing teeth. The plaque may act as a reservoir for
fluoride in the mouth, where it is thought to form fluorite-like
species, such as calcium fluoride (CaF.sub.2). The accumulation of
dental plaque biofilms whilst it may possibly be desirable as a
fluoride reservoir, is also the source of the acid-producing
bacteria that cause caries and gingivitis, which can progress to
become periodontal disease. Their presence is therefor undesirable.
However, fluoride becomes integrated within the hydroxyapatite
crystals, creating enlarged and less soluble crystals. Because
these crystals are less soluble and less reactive, as they are more
stable to acid dissolution and more resistant to the acids produced
by caries-forming bacteria, dissolution of tooth structure by acid
by-products of microorganism metabolism cannot occur as readily.
The action of fluoride on hydroxyapatite crystals therefore makes
it an aid in the prevention or minimmisation of dental caries and
periodontal disease.
[0007] In contrast, free fluoride in saliva is rapidly diluted by
salivary flow and exchange. Salivary flow rates vary enormously
from individual to individual and vary during the course of the
day, reducing almost to zero during sleep. Salivary flow rates are
typically about 0.25 to 1.2 ml/min during the day, while the
salivary volumes are typically about 1-10 ml. Additionally,
salivary flow rates are observed to reduce with age and with
smoking.
[0008] Fluoride uptake into enamel, and into incipient caries
lesions and the resulting formation of fluorapatite, is retarded by
the presence of plaque. The plaque acts as a barrier to fluoride
uptake. In the absence of plaque, fluoride uptake into enamel is
extremely rapid. It is important to note that remineralisation
requires a source of both Ca.sup.2+ and PO.sub.4.sup.3- ions in
addition to fluoride in order to form fluorapatite. Fluoride is
proposed to enhance the precipitation of fluorapatite crystals in
solutions containing calcium and phosphate and therefore tends to
prevent the demineralisation of teeth. Evidence has linked fluorite
to enhancing iron absorption. The calcium and phosphate may come
from the saliva itself. However, particularly in individuals with
low salivary flow rates, such as the elderly and smokers, or during
night times when salivary flow rates are reduced, it is preferable
to have an additional source of F.sup.-, Ca.sup.2+, and
PO.sub.4.sup.3- within the toothpaste itself. This may b provided
by soluble forms of F.sup.-, Ca.sup.2+, and PO.sub.4.sup.3-, or
more preferably particulate, sparingly soluble forms that give rise
to controlled release of calcium and phosphate as a result of the
particles adhering to the teeth and gingivae and slowly dissolving.
Examples include bioactive glasses, and particularly
hydroxyapatite.
[0009] Studies have demonstrated that oral gram-negative anaerobic
bacteria and several species of other oral bacteria can produce
volatile sulphur compounds (VSC), such as hydrogen sulphide methyl
mercaptan and dimethyl sulphide. Malodorous VSC are generated
primarily through the putrefactive action of oral microorganisms on
sulphur-containing amino acids, peptones or proteins found in the
oral cavity of a human or animal subject. These substrates are
readily available in saliva and dental plaque, or may be derived
from proteinaceous food particles, as well as exfoliated oral
epithelium food debris.
[0010] Stablished chlorine dioxide (ClO.sub.2) is an aqueous
solution containing chlorite ions and stabilisers. The stabilisers
may comprise, for example, a carbonate or bicarbonate buffering
system. When the pH of stabilised chorine dioxide falls below a
neutral pH, the molecular chlorine dioxide radical is released. The
chlorine dioxide has bacteriocidal and bacteriostatic effects on
the bacteria in the oral cavity of a human or animal subject.
Stabilised chlorine dioxide reacts with the cell walls of
microorganisms (changing the proteins and fats in the cell wall
membrane), acts as a strong oxidising agent (oxidising the
polysaccharide matrix that keeps the biofilm together) and
effectively kills pathogenic microorganisms such as fungi, bacteria
and viruses.
[0011] Chloride dioxide has a well proven role in destroying the
bacteria involved in plaque formation, caries, gingivitis and
periodontal disease, as well as eliminating halitosis. As chlorine
dioxide destroys the plaque-forming bacteria, it is particularly
effective in plaque removal, in conjunction with physical tooth
brushing. Removal of this plaque will remove the physical barrier
to fluoride, calcium and phosphate ions being able to reach the
demineralised tooth surface, and thus promotes and enhances
remineralisation of the tooth surface.
[0012] However, there is always a need and a desire in the
technical field to provide oral care compositions which are more
effective still in effecting the minimisation of the amount of
plaque within the oral cavity and facilitating the remineralisation
of teeth.
[0013] Therefore, in accordance with the present invention there is
provided an oral care composition comprising: [0014] i) A source of
a fluoride ion; [0015] ii) A source of a calcium ion; [0016] iii) A
source of a phosphate ion; and [0017] iv) stabilised chlorine
dioxide.
[0018] These components have, to date, never been employed together
in a single oral care composition. The combination of the
components is surprisingly able to exhibit a synergistic effect
over and above the effects observed when using each component on an
individual basis, or when using a composition which does not
contain all of the components.
[0019] According to one embodiment of the invention, the source of
a fluoride ion is typically a soluble fluoride salt. Exemplary
sources of fluoride ions which are envisaged by the present
invention include, but are not limited to, sodium fluoride,
potassium fluoride, disodium monofluorophospate, tin (II) fluoride
(stannous fluoride), dipotassium fluorophosphates, calcium
fluorophosphates, calcium fluoride, ammonium fluoride, aluminium
fluoride, hexadecyl ammonium fluoride, 3-(N-hexadecyl-N-2-hydroxy
-ethylammonio) ammonium difluoride,
N,N',N'-Tris)polyoxyethylene)-N-hexadecyl
-propylenediaminedihydrofluoride disodium hexafluorosilicate,
dipotassiumhexafluorosilicate, ammonium hexafluorosilicate,
magnesium hexafluorosilicate, or ammonium fluorophosphates, or any
combinations of two or more thereof.
[0020] According to one embodiment, the source of fluoride ions has
a concentration of fluoride between about 20 and 1500 ppm as
fluorine.
[0021] The source of fluoride ions may have a concentration in the
range of between about 0.1% to about 3.0% (w/v) in the oral care
composition, typically between about 0.25% to about 2.0% (w/v),
more typically between about 0.50% to about 1.5% (w/v), still more
typically between about 1.00% to about 1.2% (w/v).
[0022] According to another embodiment of the invention, both the
calcium ions and the phosphate ions are typically provided by an
apatite species, such as a nano-crystalline apatite.
Nano-crystalline is defined herein as where the crystallites have a
size of less than about 100 nm.
[0023] In the present invention, the cyrstallite sizes of the
apatites are determined from X-ray diffraction line width data
using the Scherrer Line broadening method. In this method, the
width at half height of the 002 reflection .beta..sub.002 is
inversely proportional to cyrstallite length in the c-axis
direction (Cullity 1956) and is given by the equation:
D=0.9.lamda.(.beta..sub.002 cos .theta.)
[0024] Where D is the crystallite size in nm; .lamda. is the
wavelength of the incident X-rays, 0.154 nm; .beta..sub.002 is the
width at half height of the 002 reflection and cos.theta. is the
cosine of the X-ray incident angle (25.85.degree.). The 002
reflection is a term well known to a person skilled in the art, and
is explained in, for example, the textbook `Elements of X-Ray
Diffraction`, (3rd Edition); B. D. Cullity (2001); Addison-Wesley
Chapter 2; ISBN-10: 0201610914.
[0025] It is to be noted that this method neglects instrumental
line broadening which is negligible for small nm sized crystals,
and also neglects strain effects in the lattice and solid
substitution effects.
[0026] It is the unique combination of fluoride, calcium,
phosphate, and stabilised chlorine dioxide, in one single oral care
composition, that is able to act synergistically together to
inhibit caries, promote remineralisation of the teeth, and help
with dentine hypersensitivity, gingivitis and periodontal
disease.
[0027] According to one embodiment, the composition contains an
appropriate buffering system. Exemplary buffer systems which are
envisaged by the present invention include, but are not limited to,
those comprising one or more of acetate, carbonate, citrate of
phosphate salts.
[0028] The oral care composition may be contained within, for
example, a toothpaste, oral spray or a mouth wash/oral rinse
formulation, or in any other formulation which may be used for the
improvement of oral hygiene. Such formulations will of course be
readily apparent to a person skilled in the art.
[0029] The oral care composition of the invention is able to
achieve remineralisation of incipient caries lesions much more
effectively than when the components therein are utilised
individually or separately. The fluoride source provides fluoride
ions for forming fluorapatite, whilst the hydroxyapatite can
provide both the calcium and phosphate ions, and the chlorine
dioxide kills the bacteria forming the plaque. Use of this
composition substantially eliminates the plaque and facilitates the
uptake of Ca.sup.2+, PO.sub.4.sup.3- and F.sup.- ions into the
tooth structure and enables remineralisation to occur. The effect
of the composition is further enhanced when employed in combination
with physical brushing of the teeth.
[0030] According to another embodiment, the apatite is based on the
formula M.sub.5(PO.sub.4).sub.3X, wherein M may be Ca, Sr, Zn or
Mg, and X may be F, Cl or OH. Specific apatite compounds used in
accordance with the invention may therefore include, but are not
limited to, substituted or unsubstituted hydroxyapatites,
substituted or unsubstituted fluorapatites, or substituted or
unsubstituted hydroxycarbonated apatites, such as calcium
hydroxyapatite, strontium hydroxyapatite, calcium hydroxycarbonated
apatite, strontium hydroxycarbonated apatite, calcium fluorapatite,
strontium fluorapatite, mixed strontium/calcium apatites or a mixed
hydroxyfluorapatite, zinc substituted hydroxyapatite, zinc
carbonated hydroxyapatite, zinc fluorapatite, or octacalcium
phosphate.
[0031] The stabilised chlorine dioxide solution may have a
concentration in the range of between about 0.05% to about 2.0%
(w/v) in the oral care composition, typically between about 0.075%
to about 1.0% (w/v), more typically between about 0.10% to about
0.5% (w/v), still more typically between about 0.12% to about 0.2%
(w/v), and/or may have a pH or be buffered to a pH of between about
6.0 and about 8.0, typically between about 7.0 and about 8.0.
[0032] When the composition is to be used as toothpaste
formulation, the source of fluoride ions may have a fluoride ion
concentration of between about 300 ppm and about 1500 ppm.
[0033] When the composition is to be used as mouth wash or oral
rinse formulation, the source of fluoride ions may have an active
fluoride ion concentration of between about 5 and about 500 ppm. By
`active` fluoride ion concentration is meant the amount of fluoride
ion that is free and available for reaction and involvement in the
remineralisation process. Depending upon the fluoride ion source
used, this may be less than the total fluoride ion concentration in
the overall oral composition.
[0034] Also provided in accordance with the present invention is
the use of a stabilised chlorine dioxide solution in combination
with a source of calcium ions, a source of phosphate ions and a
source of fluoride ions, to generate gaseous chlorine dioxide
within the oral cavity without the use of extra oral sources of
acidification. The calcium ions and phosphate ions may be provided
together by an apatite species as detailed hereinabove.
[0035] According to another embodiment, the apatite may be present
in an amount of from about 0.5 to about 30 weight percent of the
oral care composition. Alternatively, or in addition, the apatite
may have a article size distribution such that at least about 3% of
the mass of the particles have a size less than about 5 microns and
where the apatite has a crystallite size of less than about 200
nm.
[0036] According to another embodiment of the invention, the
apatite may be present in an amount of rom about 0.5 to about 25
weight percent of the composition. Alternatively, or in addition,
the apatite particle size distribution may have at least about 15%
of the mass of the particles below about 5 microns and where the
apatite crystallite size is from about 30 to about 50 nm.
[0037] According to another embodiment, the apatite may be present
from about 0.5 to about 15 weight percent of the composition.
Alternatively, or in addition, at least about 50% of the mass of
the particles may have a particle size less than about 5
microns.
[0038] The composition of the invention may also contain other
components selected form one or more of a solvent, a thickening
agent or viscosity modifier, an abrasive, a flavour, an aromatic
component, a humectant, a sweetener, a carrier, a remineralising
agent, a film forming agent, a buffering agent, a cooling agent, a
pH adjusting agent, an oxidizing agent, and a colorant.
[0039] Exemplary such compounds which may be added to the
composition of the invention may include, but are not limited to,
glycerol, water, hydrated silica, cellulose gum, trisodium
phosphate, sodium saccharin, mentha extracts, citric acid,
limonene, linalool, and titanium dioxide.
[0040] According to one embodiment of the mouth wash or oral rinse
formulation of the invention, this formulation may also comprise a
linear polysaccharide polymer with a high yield value that exhibits
pseudoplastic flow to stabilise the HA in suspension. Typically, a
linear polysaccharide gum where one or more hydroxyl groups on the
monosaccharide is substituted with a functional group that
comprises a carboxyl group (R--COOH), an acyl group (RCO--) or a
sulphate group (R--OSO.sub.3.sup.-) is used. Examples of such types
of substituted polysaccharide include, but are not limited to,
algin, xanthan gum, gellan gum and carrageenan.
[0041] Also provided in accordance with the present invention is
the use of an oral care composition in the cleaning of teeth and
mucous membranes of the oral cavity of a subject, perfuming them or
protecting them in order to keep them in good condition, change
their appearance or correct unpleasant odours.
[0042] A second aspect of the invention deals with dentine
hypersensitivity. Dentine hypersensitivity is felt when nerves
inside the dentin of the teeth are exposed, and results in pain
associated with mechanical stimuli, such as that caused by the
intake of hot or cold foodstuffs into the mouth. This typical
affects more than 40% of the population. It is a result of fluid
flow in exposed open dentinal tubules that results in pressure
changes that trigger nerve transmission within the pulp chamber of
a tooth. Dentinal tubules become exposed as a result of three
causes: [0043] i) Gingival recession where the gums recede exposing
the dentine; [0044] ii) Loss of the enamel as a result of caries or
acid erosion; or [0045] iii) Loss of the enamel as a result of
abrasive wear accompanying tooth brushing.
[0046] Treatment generally involves sealing or blocking the
dentinal tubules. This is often achieved using specialised
toothpastes that are designed to occlude the dentinal tubules. The
dentinal tubule openings are typically about 2-5 microns in
diameter.
[0047] One way these tubules can be blocked is to precipitate a
material onto the surface over the top of the tubules. Another
approach, i.e. that used by the present invention, is to have
particles comparable in size to the openings of the dentinal
tubules, so the particles are able to enter into the tubules and
occlude them. It is important that there are sufficient particle so
the required size present to give effective numbers penetrating the
dental tubules.
[0048] Also provide in accordance with the present invention is an
oral car composition as defined herein above in the
remineralisation of teeth or in the treatment of dentine
hypersensitivity.
[0049] According to a further embodiment of the invention, there is
provided a method of cleaning teeth and mucous membranes of the
oral cavity of a subject, or perfuming them or protecting them in
order to keep them in good condition, comprising applying an oral
care composition as defined hereinabove.
[0050] According to another embodiment, the apatite may be present
in an amount of rom about 0.5 to about 30 weight percent of the
oral care composition. Alternatively, or in addition, the apatite
may have a particle size distribution such that at least about 3%
of the mass of the particles have a size less than about 5 microns
and where the apatite has a crystallite size of less than about 200
nm.
[0051] According to another embodiment of the invention, the
apatite may be present in an amount of from about 0.5 to about 25
weight percent of the composition. Alternatively, or in addition,
the apatite particle size distribution may have at least about 15%
of the mass of the particles below about 5 microns and where the
apatite crystallite size is from about 30 to about 50 nm.
[0052] According to another embodiment, the apatite may be present
from about 0.5 to about 15 weight percent of the composition.
Alternatively, or in addition, at least about 50% of the mass of
the particles may have a particle size less than about 5
microns.
[0053] Also provided by the present invention is a toothpaste
comprising an oral care composition of the invention as defined
hereinabove. The apatite species in the toothpaste, such as a
nano-crystalline hydroxyapatite, comprises small crystallite
shaving a size of less than about 100 nm and a large surface area
to facilitate dissolution. However, the larger particles which can
occlude the dentinal tubules comprise may hundreds of crystallites
aggregated together to form an approximately spherical particle
with dimensions in the range 0.1 to 5 microns, and thus are similar
in size to the openings to the dentinal tubules.
[0054] Table 1 summarises the particle size data from a range of
nano-crystalline hydroxyapatites in terms of the D10, D50 and D90
values which represent the volume fractions below the specified
values. It can be seen from the particle sizes in the Table that
they are of a similar size to the openings to the dentinal tubules,
and are therefore ale to occlude dentinal tubules.
TABLE-US-00001 TABLE 1 Particle Size Hydroxyapatite D10/D50/D90
Samples X-ray results FTIR (microns) A Nanocrystalline Minimal
CO.sub.3.sup.2- 1.20/4.16/11.40 Hydroxyapatite content B
Nanocrystalline Minimal CO.sub.3.sup.2- 1.19 3.78/11.15
Hydroxyapatite content C Nanocrystalline Minimal CO.sub.3.sup.2-
0.32/2.50/22.58 Hydroxycarbonate content content Broad Particle
Size D Pure Hydroxyapatite No CO.sub.3.sup.2- 0.25/1.29/8.71 No
Nanocrystallinity E Pure Hydroxyapatite Minimal CO.sub.3.sup.2-
1.20/3.35/6.32 No Nanocrystallinity content F Nano Minimal
CO.sub.3.sup.2- 1.57/4.47/10.14 Hydroxyapatite content
[0055] All carbonate contents were <1%, and are so low they are
not quantifiable. The carbonate detected is purely derived from
atmospheric contamination during synthesis.
[0056] The invention will now be described further by way o example
with reference to the following Figures which are intended to be
illustrative only and in no way limiting upon the scope of the
invention.
[0057] FIG. 1 shows a scanning electron micrograph of open dentinal
tubules.
[0058] FIG. 2 shows a scanning electron micrograph of dentinal
tubules being blocked by precipitate of a material over the top of
the tubules.
[0059] FIG. 3 shows a scanning electron micrograph of acid-etched
dentine.
[0060] FIG. 4 shows a scanning electron micrograph of dentinal
tubules following blocking with a composition according to the
invention.
[0061] FIG. 5 shows the crystal structure of hydroxyapatite.
[0062] FIG. 6 shows X-ray powder diffraction patterns of a
nano-crystalline hydroxyapatite (nHA) and of a micro-crystalline
hydroxyapatite.
[0063] FIG. 7a shows an etched dentine surface of a mid-coronal
section of a human molar.
[0064] FIG. 7b shows a mucin-coated dentine surface to mimic
biofilm.
[0065] FIG. 7c shows a tooth surface after treatment with a
chlorine dioxide toothpaste according to the invention, but
containing silica powder instead of hydroxyapatite.
[0066] FIG. 8 shows the hardness values of the tooth surface of the
molars after applying a toothpaste according to the invention.
[0067] FIG. 9 shows NMR spectra for enamel samples, non-treated,
demineralised and treated with a toothpaste according to the
invention.
[0068] FIG. 10 shows NMR spectra for enamel samples non-treated,
demineralised and treated with a mouth wash according to the
invention.
[0069] FIG. 11 shows a graph illustrating the amount of total
fluoride in a mouth wash according to the invention in relation to
the amount of active, or free, fluoride available for
remineralisation.
[0070] FIG. 12 shows a graph illustrating the enamel weight loss
during the demineralisation and treatment with a toothpaste
according to the invention.
[0071] FIG. 13 shows a scanning electron micrograph of a dentine
surface of a specimen treated for 1 day with a mouth wash according
to the invention (4.times.2 minutes of treatment, followed by
remineralisation).
[0072] FIG. 14 shows a graph illustrating reduction fluid flow
through dentinal tubules following tooth brushing with a toothpaste
according to the invention.
[0073] FIG. 1 shows a scanning electron micrograph of open dentinal
tubules. One way these tubules can be blocked is to precipitate
material onto the surface over the opt of the tubules. This is
shown in FIG. 2, which depicts a material in this instance, Colgate
ProRelief) over the top of the tubules. As can be seen, mot many of
the openings of the tubules are blocked.
[0074] FIG. 3 shows a scanning electron micrograph of acid etched
dentine, i.e., a molar tooth cut through the mid coronal section,
which has been acid etched using 6% citric acid for 2 minute. The
tubules are clearly visible. The scanning electron micrograph in
FIG. 4 shows these same tubules after a composition according to
the invention comprising 7.5 wt % hydroxyapatite has been applied
to the tooth. It can be seen that the dentinal tubules are
substantially blocked by the particles in the composition, thus
preventing the fluid flow through the dentinal tubules and
minimising pain for the subject.
[0075] In FIG. 5, the crystal structure of hydroxyapatite, it can
be seen that the smaller fluoride ion sits in the centre of the Ca
(II) triangle, while the hydroxyl ion is displaced slightly above
the plane of the triangle of Ca (II) ions.
[0076] In FIG. 6, there is a comparison between the X-ray powder
diffraction patterns of a nano-crystalline hydroxyapatite (nHA) and
of a larger microcrystalline hydroxyapatite. It can be seen that
the diffraction pattern of the nHA shows pronounced line broadening
compared with that of microcrystalline hydroxyapatite. Using
Sherrer line broadening analysis, the nHCA has a crystallite size
of 30 to 50 nm.
Example 1
[0077] The method of manufacture of a typical toothpaste
formulation according to the invention may be carried out in
accordance with the following procedure:
[0078] To a vessel, purified water BP is added and stirring
commences. Sodium saccharin, trisodium phosphate and sodium
monofluorophosphate are added and allowed to dissolve. Glycerin and
cellulose gum are premixed thoroughly and added to the main vessel
using high shear mixing. Hydrated silica, hydroxyapatite and
titanium dioxide are added and mixed under high shear until a
smooth homogenous paste is created. The vessel has a jacket which
is cooled with chilled water to ensure the contents remain below
40.degree. C.
[0079] Menthol, peppermint oil BP and spearmint oil BP are premixed
in a separate vessel to create the flavour blend. This is
subsequently added to the paste in the main vessel with mixing.
[0080] Chloride dioxide 5% solution (proprietary blend) is added to
the paste with mixing, and the pH of the paste is adjusted to
comply with the specification using a citric acid/purified water BP
premix and adequate stirring.
[0081] The final toothpaste formulation contains 1250 ppm of
chlorine dioxide, 10900 ppm of sodium monofluorophosphate (which
equates to 1428 ppm of fluoride in the monofluorophosphate,
calculated by using the respective atomic and molecular weights of
fluorine and sodium monofluorophosphate, which are 19 and 145,
respectively), and 75000 ppm of hydroxyapatite.
Example 2
[0082] The method of manufacture of a typical oral rinse or mouth
wash formulation according to the invention may be carried out in
accordance with the following procedure:
[0083] To a vessel, purified water BP/EP is added and is heated to
80.degree. C. (.+-.5.degree. C.). The water is then stirred and
recirculated through an in-line high shear homogeniser.
[0084] Kelcogel HA (high acyl content gellan gum--a polysaccharide
consisting of glucose, rhamnose, and glucuronic acid repeat units
and with a substituent glycerate moiety on every glucose unit and
an acetate moiety on every second glucose moiety) and Cekol 4000 (a
carboxymethyl cellulose polymer, used to minimise flocculation and
aid bioadhesion) are pre-mixed in glycerol to wet-out. The glycerol
containing the pre-mix is then added to the hot water. The
resultant mixture is stirred and homogenised for 15 minutes before
cooling.
[0085] When the temperature of the water reached .ltoreq.65.degree.
C., sodium monofluorophosphate is then added to the vessel,
followed by sodium citrate, tridsodium citrate and sodium
saccharin. The introduction of Na.sup.+ ions to the mixture causes
the high acyl content gellan gum to thicken and form a fluid,
highly mobile gel. The mixing and homogenising is continued.
[0086] When the temperature of the mixture in the vessel reaches
.ltoreq.55.degree. C., hydroxyapatite is added. The stirring and
homogenising is continued until the mixture is fully dispersed and
free from lumps. the homogeniser is then turned off and the mixture
is stirred as it cools further.
[0087] In a separate vessel, a flavour pre-mix is prepared by
adding polysorbate 20, PEG-60 hydrogenated castor oil, Frescolat
MGA and Coolmint FL72627. These components are mixed thoroughly
until a clear solution is obtained.
[0088] When the temperature of the mixture in the vessel reaches
.ltoreq.40.degree. C., sodium benzoate is added, and is allowed to
fully dissolve with mixing. The flavour pre-mix is then also added
to the main vessel, and the mixing continues.
[0089] When the temperature of the mixture in the vessel reaches
.ltoreq.35.degree. C., chlorine dioxide solution is added. The
homogeniser is turned back on and the mixture is allowed to mix and
homogenise for at least 15 minute.
[0090] Citric acid is then added, and the mixture is allowed to mix
for a further 15 minutes, to ensure that the pH of the product is
8.0-8.5. The homogenising and stirring then ceases, and the
resultant product is protected from exposure to sunlight.
[0091] The final mouth wash or oral rinse formulation contains 1250
ppm of chlorine dioxide 5000 ppm of sodium monofluoroposphate
(which equates to 655 ppm of fluoride in the monofluorophosphate,
again calculated by using the respective atomic and molecular
weights of fluorine and sodium monofluorophosphate), and 50000 ppm
of hydroxyapatite.
[0092] One of the key aspects of the present invention is the use
of chlorine dioxide combined with the use of an apatite and
fluoride. The chlorine dioxide role in the formulation is to remove
plaque and biofilm from the tooth surface and particularly from
exposed dentine surfaces; this serves to open the dentinal tubules
and facilitates the subsequent occlusion of the dentinal tubules by
the apatite particles. Conventionally, in laboratory studies of
dentinal tubule, occlusion of mid coronal sections of human molars
this is achieved using 6% citric acid or 35% orthophosphoric acid.
Chlorine dioxide fulfils the same purpose within the toothpaste or
oral rinse.
[0093] FIG. 7a shows an SEM of a mid-coronal section of a human
molar treated with 6% citric acid for 2 minutes to open he dentinal
tubules then painted with a 2.5% solution of mucin, a common
salivary protein, air dried and then followed by a stabilisation
treatment with 10% formalin solution. The process was repeated to
produce a water stable protein biofilm. It can be seen (FIG. 7b)
that following treatment the tubules are occluded with the biofilm.
A toothpaste based on Table 2, but where the occluding agent in the
formulation, hydroxyapatite, is replaced by silica powder was then
applied to the tooth surface for 2 minutes, followed by rinsing
with distilled water. It can be seen (FIG. 7c) that the chlorine
dioxide in the toothpaste breaks down the protein layer and opens
the dentinal tubules. However, it must also be noted that the
silica added to replace the hydroxyapatite in the toothpaste acts
in a negative manner to partially occlude some of the dentinal
tubules. Application of formulations without the chlorine dioxide
failed to result in opening of the dentinal tubules.
[0094] One of the key aspects of the invention is the ability of
the apatite to work in conjunction with a source of fluoride to
promote remineralisation. This is particularly important with
regard to replacing lost tooth mineral due to acid erosion,
incipient caries, or to promote the conversion of the apatite
occluding the dentinal tubules to more durable fluoridate apatite.
This is illustrated by two techniques: [0095] i) Surface
micro-hardness measurements, since an increase in mineral content
results in an increase in hardness; or [0096] ii) direct evidence
of the formation of the formation of fluoridate apatite using
.sup.19F solid state nuclear magnetic resonance spectroscopy using
enamel slices and associated weight changes and fluoride
measurements.
Quantification of the Enamel Remineralisation by Micro-hardness
Test
[0097] Studies were carried out according to the following
experiment protocol. Fifteen human molars were collected,
disinfected, embedded in resin, polished down to reveal
longitudinal section and finished with 1 micron diamond paste.
Enamel hardness was evaluated using a microhardness tester
(Duramin-1-2; Struers, Copenhagen, Denmark) with a Vicker's
indenter (a square pyramid diamond shape indenter) under a load of
50 g for 15 seconds. 10 indentations per sample were taken. The two
diagonal indentation lengths were measured and then used for
microhardness calculation using the following equation:
HV = F A .apprxeq. 1.8544 F d 2 ##EQU00001##
where F is in kilogram-force (kgf), A is the area of the point of
the indenter, and d is the average length of the diagonal left by
the indenter in millimeters.
[0098] The teeth specimens were demineralised in a demineralisation
solution (pH32 4.5, 50 mM acetic acid to mimic an acidic challenge
during a caries attach) and the harness was then again
measured.
[0099] The toothpaste of the invention was then applied to the
tooth surface and the harness again measured. FIG. 8 shows the
hardness values. Following the acid challenge the hardness
decreases significantly, but increases significantly after exposure
to the toothpaste providing clear evidence of remineralisation.
.sup.19 F MAS-NMR Study of the Fluoroapatite Formation
[0100] Caries-free first molar and premolars were collected and
stored in 3% sodium hypochlorite solution for 20 hours. Teeth were
mounted in acrylic resin, and sliced using an annular diamond blade
(Microslice 2, Malvern Instrument, UK) to get enamel sections
(approximately 6.times.5.times.1 mm.sup.3). Excess dentine area was
removed by polishing against P600 silicon carbide paper.
[0101] The enamel blocks were then rinsed off with de-ionized
water, dried in air for 30 minutes and weighted using a digital
microbalance. Each enamel section was immersed in 50 ml acetic acid
solution (0.1 M, pH=4.0) and agitated at a rate of 60 rpm in a
37.degree. C. incubator (KS 4000 I control, IKA) for 24 hours. The
enamel specimens were then immersed in the toothpaste according to
the invention, Ultradex Toothpaste (dilute 1:10 with acetic acid
solution (pH=4.0) to give a 0.1M final solution, to mimic the real
mouth situation), or in the mouth wash according to the invention,
Ultradex Recalcifying and Whitening Oral Rinse treatment solution
(diluted 1:2 both with 9.2 M acetic acid solution (pH=4.0) to mimic
the real mouth situation), placed back in the incubator, and
agitated at a rate of 60 rpm for 96 hours. After treatment, the
enamel blocks were cleaned, dried and weighed. The enamel weight
loss was presented in percentages. Enamel samples (no treatment, 24
hours demineralised and demineralization followed by the
treatments) were ground to powder using a vibratory mill (MM200,
Glen Creston Ltd, UK) with a 25 ml zirconia grinding jar for 15
seconds under 20 Hz. The powder was then used for solid-state NMR
experiments using the 600 MHz (14.1T) Bruker spectrometer. the
.sup.F solid state NMR measurements were run a the resonance
frequency of 564.7 MHz with a 2.5 mm rotor spun at 18 and 21 kHz.
Spectra were obtained by overnight scans with 8 preliminary dummy
scans and 60 seconds recycling delay. The chemical shift was
referenced using the signal from the 1M NaF solution scaled to -120
ppm relative to the CF.sub.3Cl primary standard.
[0102] The NMR spectra showed flat lines for both the non-treated
enamel sample and the demineralised enamel sample (FIGS. 9 and 10).
Therefore, there was no fluoride detected for both samples. This
indicated that no significant fluoride was present in the original
tooth samples. The spectra were then run for the toothpaste and
oral rinse samples. The toothpaste with both HA and
monofluorophosphate (MFP) showed the presence of fluorapatite with
a chemical shift of -103 ppm, the position being almost identical
to the chemical shift of the fluorine in fluorapatite (-120 ppm),
as did the toothpaste with MFP alone treated samples. The HA
toothpaste alone gave a very small signal close to that of
fluorite, which was probably present in the original tooth. The
oral rinse treated enamel sample showed a broad peak centered at
around --103 ppm, This demonstrates that after demineralisation
treatment, the Ultradex Recalcifying and Whitening Toothpaste and
Oral Rinse treatment of the invention led to fluorapatite
formation. The reference spectrum for the fluorapatite was based on
synthetic pure fluorapatite, which demonstrates a distinct sharp
peak with a chemical shift at -102 ppm. The apatite that comprises
the tooth enamel is a solid solution formed rather than
stoichiometric. It could contain different ions such as Magnesium
(Mg.sup.2+) and Manganese (Mn.sup.2+) substituted for Ca.sup.2+,
fluoride (F) substituted for hydroxyl (OH.sup.-), and carbonate
(CO.sub.3.sup.2-) substituted for phosphate (PO.sub.4.sup.3-). The
crystal structure is therefore distorted. With demineralisation and
subsequent remineralisation, the fluorapatite crystals formed could
therefore be slightly disordered. This may explain why the spectrum
for the Ultradex Recalcifying and Whitening toothpaste and Oral
Rinse of the invention treated enamel showed broader peaks when
compared with the fluorapatite reference. Fluoride promotes
remineralisation and the fluorapatite formed is more acid resistant
compared with the hydroxyapatite and carbonated hydroxyapatite.
However, high concentrations of fluoride with insufficient
phosphate ions may result in the formation of the undesirable
calcium fluoride phase.
[0103] An Ultradex Recalcifying and Whitening Oral Rinse/mouth wash
of the invention contains 660 ppm F.sup.- in the form of
monofluorophosphate, with a 1:2 dilution, the total available
F.sup.- was 330 ppm. However, the actual available F.sup.- detected
by a fluoride selective electrode (ORION 9609BN PH/ISE meter model
710 A, USA) (FIG. 11) was only 24.5 ppm. The F.sup.- after the
remineralisation was 19.5 and this gave an F.sup.- loss of 5 ppm.
This further confirms fluoride is being incorporated into the
apatite.
[0104] The weight loss of the sample toothpaste specimens are given
in FIG. 12. Both MFP and HA acted to reduce weight loss and enamel
demineralisation. However the biggest reduction in weight loss was
found for the Ultradex Recalcifying and Whitening Oral Toothpaste
treatment (i.e. the composition of Table 2). This indicates that
the fluoride acts synergistically with the HA to inhibit
demineralisation and promote remineralisation.
[0105] Further, the scanning electron micrograph in FIG. 13 clearly
demonstrates that a tooth specimen that is treated over a period
using the mouth wash of the invention--in this case over 1 day,
with 4 lots of 2 minutes' worth of treatment with the mouth wash,
followed by the remineralisation--achieves the aim of successfully
occluding the dentinal tubules, and thus reduce dentine
hypersensitivity.
[0106] In FIG. 14, it can be seen from the graph that there is a
reduction in fluid flow through dentinal tubules following tooth
brushing with a toothpaste according to the invention, thus
indicating that the tubules have been successfully blocked by the
action of the fluoride in the remineralisation process. This is a
test that is routinely used as a measure of the efficacy of a
hypersensitivity toothpaste.
[0107] Therefore, in summary, it can be seen that the composition
of the invention provides technical advantages over existing
formulations lacking any one of the defined components. Application
to the surface of teeth of formulations containing no chlorine
dioxide results in a failure to break down the biofilm and open up
the dentinal tubules to be filled, as illustrated in relation to
FIG. 7c above. Application of formulations containing no
hydroxyapatite (i.e. a source of both calcium and phosphate ions)
and using another component instead results in the opened tubules
being undesirably partially occluded, thus hindering their
refilling during the remineralisation process, and thus hindering
the treatment of dentine hypersensitivity. Finally, it is clear
that formulations lacking any fluoride ion source would not be able
to provide any remineralisation of the tooth at all.
[0108] It is of course to be understood that the present invention
is not intended to be restricted to the foregoing examples which
are described by way of example only.
* * * * *