U.S. patent application number 09/350965 was filed with the patent office on 2002-04-18 for mouthwash compositions.
Invention is credited to JOHANSEN, ERLING, OLSEN, THOR, PAPAS, ATHENA.
Application Number | 20020044910 09/350965 |
Document ID | / |
Family ID | 26310059 |
Filed Date | 2002-04-18 |
United States Patent
Application |
20020044910 |
Kind Code |
A1 |
JOHANSEN, ERLING ; et
al. |
April 18, 2002 |
MOUTHWASH COMPOSITIONS
Abstract
Aqueous solutions are disclosed which are supersaturated with
respect to calcium phosphate(s) and which further comprise a
stabilising agent in an amount sufficient to enable the calcium
ions and phosphate ions to remain in supersaturated solution so
that it may be used as a dental rinse or mouthwash. Such solutions
are suitable for treating patients having dental caries or other
conditions of the oral cavity.
Inventors: |
JOHANSEN, ERLING; (NEEDHAM,
MA) ; OLSEN, THOR; (ROCHESTER, NY) ; PAPAS,
ATHENA; (WESTON, MA) |
Correspondence
Address: |
ALEXIS BARRON ESQUIRE
SYNNESTVEDT & LECHNER
2600 ARAMARK TOWER
1101 MARKET STREET
PHILADELPHIA
PA
191072950
|
Family ID: |
26310059 |
Appl. No.: |
09/350965 |
Filed: |
July 9, 1999 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09350965 |
Jul 9, 1999 |
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08933481 |
Sep 18, 1997 |
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5993785 |
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60026578 |
Sep 18, 1996 |
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Current U.S.
Class: |
424/49 |
Current CPC
Class: |
A61P 1/02 20180101; A61P
29/00 20180101; A61P 31/18 20180101; A61Q 11/00 20130101; A61P 1/08
20180101; A61P 1/06 20180101; A61P 31/00 20180101; A61P 31/22
20180101; A61P 1/12 20180101; A61P 25/02 20180101; A61P 31/12
20180101; A61P 35/00 20180101; A61P 31/10 20180101; A61P 3/02
20180101; A61K 8/24 20130101; A61K 8/19 20130101; A61P 41/00
20180101; A61K 2800/52 20130101 |
Class at
Publication: |
424/49 |
International
Class: |
A61K 007/16 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 18, 1996 |
GB |
9619464.2 |
Claims
1. A formulation suitable for use as a dental rinse or mouthwash,
which formulation comprises: (a) a calcium component (calcium stock
solution) which itself comprises an aqueous solution of calcium
ions and stabilizing agent; and, associated therewith but separate
therefrom, (b) a phosphate component (phosphate stock solution)
which itself comprises an aqueous solution of phosphate ions and
stabilising agent; wherein the calcium and phosphate ions are
present in amounts sufficient to form, on mixing, a supersaturated
solution thereof, and the amount of stabilizing agent in each
component is sufficient to enable the calcium and phosphate ions to
remain for at least 1 minute at body temperature in supersaturated
solution once components (a) and (b) are mixed.
2. A formulation suitable for use as a dental rinse or mouthwash,
which formulation comprises: (a) a calcium component (calcium stock
solution) which itself comprises an aqueous solution of calcium
ions having a concentration in the range of from about 4 to about
80mM and from about 40 to about 40mM stabiliser; and, associated
therewith but separate therefrom, (b) a phospate component
(phosphate stock solution) which itself comprises an aqueous
solution of (ortho)phosphate ions having a concentration in the
range of from about 1 to about 64 mM and from about 40 to about 400
mM stabiliser whereby, on mixing, the components form a solution
supersaturated with respect to calcium phosphate(s).
3. A formulation according to claim 1, wherein the calcium
component (a) is substantially free from phosphate ions and the
phosphate component (b) is substantially free from calcium
ions.
4. A formulation according to claim 1, wherein the supersaturated
solution has a pH in the range of from about 5 to about 8.
5. A formulation according the claim 4, wherein the supersaturated
solution has a pH of about neutral.
6. A formulation according to claim 2, wherein the concentration of
calcium ions in the calcium stock solution is in the range of from
about 5 to 20 mM.
7. A formulation according to claim 6, wherein the concentration of
phosphate ions (total (ortho)phosphate) in the phosphate stock
solution is in the range of from about 4 to about 8 mM.
8. A formulation according to claim 6, wherein component (b)
comprises a mixture of monobasic phosphate with dibasic phosphate
in a ratio in the 20 order of about 1:2-1:8.
9. A formulation according to claim 1, wherein the stabilising
agent comprises sodium chloride.
10. A formulation according to claim 1, wherein each component (a)
and (b) comprises both sodium ions and chloride ions, each
independently in the range of from about 0 to about 0.5 M.
11. A formulation according to claim 1, wherein component (b)
further comprises fluoride ions.
12. A formulation according to claim 1, wherein component (a)
further comprises zinc ions.
13. A concentrate formulation comprising: (a) a calcium concentrate
which itself comprises an aqueous solution of calcium ions and
stabilising agent; and, associated therewith but separate
therefrom, (b) a phosphate concentrate which itself comprises an
aqueous solution of phosphate ions and a stabilising agent wherein
the calcium and phosphate ions and stabilising agent are present in
such amounts whereby, on diluting each concentrate (a) and (b) with
water and thereafter mixing the two stock solutions (a) and (b)
thereby formed, there is prepared a supersaturated solution which
remains so for at least 1 minute at body temperature.
14. A concentrate formulation comprising: (a) a calcium concentrate
which itself comprises an aqueous solution of calcium ions in the
range of from about 8 to about 2120 mM and 0 M to 6.5 M stabilising
agent and, associated therewith but separate therefrom, (b) a
phosphate concentrate which itself comprises an aqueous solution of
phosphate ions in the range of from about 2 to about 1440 mM and
from 0 M to 6.5 M of a stabilising agent.
15. A pacl( comprising a concentrate formulation according to claim
13 in association with instructions for diluting each concentrate
(a) and (b) with water and for thereafter mixing the resulting
stock solutions (a) and (b).
16. A pack comprising a stock( solution formulation according to
claim 1 in association with instructions for mixing stock( solution
components (a) and (b) and for thereafter using the resulting
supersaturated solution as a mouthwash or rinse for the oral
cavity.
17. A supersaturated solution prepared by mixing the calcium and
phosphate stock solutions (a) and (b) according to claim 1.
18. Method of treating or preventing a condition of the oral cavity
selected from: impaired salivary function or secretion; xerostomia;
infections including septicia originating from lesions of the oral
cavity; mucositis; Sj.phi.grens syndrome; rn noliasis; inflammatory
lesions and ulcerative lesions of the oral cavity; and dental
careand remineralisation and maturation of oral hard tissue; which
method comprise( administration to a patient in need thereof of a
nontoxic effective amount of a supersaturated solution according to
claim 17.
19. A method of treatment or prevention of any disease, patient or
condition which requires remineralisation or maturation of oral
hard tissue, which method comprises the administration to a patient
in need thereof of a non-toxic effective amount of a supersaturated
solution according to claim 17.
20. method of treatment of soft tissue of the oral cavity, which
method comprises the administration to a patient in need thereof of
a non-toxic effective amount of a supersaturated solution according
to claim 17.
21. A method according to claim 18 applied to bone marrow 5
transplant or AIDS tients.
22. A method of preparing a solution supersaturated with respect to
calcium a nd phosphate(s) for use as an oral rinse, which solution
comprises: calcium ions in a concentration in the range of from
about 2 to about 40 mM; (ortho)phosphate ions in a concentration in
the range of from about 0.5 to about 32 mM; and sodium ions in a
concentration in the range of from 0 to about 0.5 M which method
comprises (a) obtaining a calcium stock solution comprising from
about 4 to about 80 mM calcium ions and from about 0 to about 400
mM sodium chloride; (b) obtaining a phosphate stock solution
comprising from about 1 to about 64 mM(ortho)phosphates and from
about 0 to about 400 mM sodium chloride; and (c) mixing said stock
solutions (a) and (b).
Description
FIELD OF THE INVENTION
[0001] The present invention relates to calcium- and
phosphate-containing compositions for use as mouthwashes or dental
rinses. In particular, it relates to solutions supersaturated with
calcium and phosphate, their preparation and use.
BACKGROUND OF THE INVENTION
[0002] By "supersaturated" with calcium and phosphate is herein
meant that higher concentration of calcium ions and orthophosphate
ions is present in the solution than would be present in a
saturated solution of those ions.
[0003] British patent specification no. GB 1 090 340, published in
1967, discloses compositions for rehardening dental enamel
comprising fluoride, calcium, phosphate and sodium chloride which
yield, on contact with saliva, supersaturated solutions to form
hydroxyapatite. Because saliva is required to form the
supersaturated solution, the preferred compositions are in the form
of confectionery such as chewing gum. However, it is known that,
under most circumstances, saliva is already supersaturated with
calcium and phosphate. No disclosure is given of how to make a
supersaturated solution ab initio which can then be used
effectively in the form of a mouthwash or dental rinse.
Furthermore, no mention is made of the possibility of excluding
fluoride; or of the formation of octacalcium phosphate by the
supersaturated solution in the saliva. In any case, in the absence
of or where there is a significantly reduced amount of saliva,
these compositions would not work as described.
[0004] A supersaturated solution is disclosed in U.S. Pat. No. 5
427 768 which is supersaturated with calcium phosphate and carbon
dioxide and used to deposit apatite on the teeth. However, in this
case, the supersaturation is caused by release of carbon dioxide,
and carbonate is absorbed by the teeth which results in a deposited
mineral phase with decreased resistance to dental caries.
[0005] British patent specification No. GB 1 408 922, published
in-1975, discloses an oral treatment pack which comprises two
phases for sequential application to teeth, the isolated phases
comprising calcium (50 to 35000 ppm) and phosphate (50 to 40000
ppm) compounds, respectively. However, there is no disclosure or
teaching . regarding how to make a single phase, supersaturated
solution within these concentration ranges which cover four orders
of magnitude. Indeed, Example 3 thereof teaches two phases which,
if mixed, would result in immediate precipitation of calcium
phosphates.
[0006] A further solution containing calcium and phosphate is
disclosed in British patent specification no. GB 1 509 977,
published in 1978. This solution comprises one component containing
calcium ions (at least 30 ppm) and another component containing at
least 100 ppm fluoride, one or both components also containing
phosphate ions (at least 0.1 M) such that on mixing the components
hydroxyapatite can be deposited therefrom on teeth. However, such
solutions are not stably supersaturated (indeed, this patent
teaches that the phosphate ions can be incorporated only in the
solution containing calcium ions (at low concentration) which would
not allow for the preparation of a stable, non-precipitating,
supersaturated solution), and contains greater fluoride than
considered to be clinically safe if accidentally swallowed. Again,
no reference is made to producing octacalcium phosphate
deposits.
BRIEF DESCRIPTION OF THE INVENTION
[0007] On the other hand, the present invention relates to an
aqueous solution suitable for use as a dental rinse or mouthwash,
which solution is supersaturated with respect to calcium
phosphate(s) and which solution further comprises a stabilising
agent such as sodium chloride (NaCI).
[0008] Although, as previously mentioned, it is known that,
normally, saliva is supersaturated with respect to calcium and
phosphates, the supersaturated solutions of the present invention
contain significantly higher concentrations of those ions. Since
the degree of supersaturation of saliva is variable from individual
to individual, it is not possible to state definitively how much
more supersaturated are the solutions of the present invention, but
they may in many cases contain of the order of from 5 to 10 times
the concentrations of calcium and phosphate ions than normal
saliva.
[0009] The present inventors have disclosed (Gerodontics 3, 4750
(1987)) the remineralisation of carious lesions in elderly patients
using an experimental regimen which included mouthwashing with a
solution comprising 5 mM Ca, 3mM PO.sub.4 and 0.25 mM (5 ppm)
fluoride, stabilised by NaCI, at pH 7.0. No other uses of the
solution were mentioned and no details concerning the preparation
of the solution were given other than that "two stock solutions
were stored separately and mixed in proper volumes immediately
before use".
[0010] The supersaturated solutions of the present invention are
required to be prepared just prior to use due to the degree of
supersaturation thereof and the risk of precipitation of calcium
phosphate (mineral) therefrom.
DETAILED DESCRIPTION OF THE INVENTION
[0011] Accordingly, the present invention provides a formulation
suitable for use as a dental rinse or mouthwash, which formulation
comprises:
[0012] (a) a calcium component (calcium stock solution) which
itself comprises an aqueous solution of calcium ions and
stabiliser; and, associated therewith but separate therefrom,
[0013] (b) a phosphate component (phosphate stock solution) which
itself comprises an aqueous solution of phosphate ions and
stabiliser
[0014] wherein the calcium and phosphate are present in amounts
sufficient to form, on mixing, a supersaturated solution thereof,
as described hereinbelow.
[0015] The present invention therefore specifically provides a
multi-component formulation suitable for use as a dental rinse or
mouthwash, which formulation comprises:
[0016] (a) a calcium component (calcium stock solution) which
itself comprises an aqueous solution of calcium ions having a
concentration in the range of from about 4 to about 80 mM and from
about 40 to about 400 mM stabiliser, and, associated therewith but
separate therefrom,
[0017] (b) a phospate component (phosphate stock solution) which
itself comprises an aqueous solution of (ortho)phosphate ions
having a concentration in the range of from about 1 to about 64 mM
and from about 40 to about 400 mM stabiliser
[0018] whereby, on mixing, the components form a solution
supersaturated with respect to calcium phosphate(s).
[0019] The supersaturated solutions of the present invention remain
stable at least for the length of time and under normal conditions
of their use. By this is meant that the supersaturated solution
remains substantially supersaturated with respect to calcium and
orthophosphate ions for the normal time the solution is rinsed or
washed around the oral cavity. After this time, the solution may
begin to contain some precipitate of calcium phosphates which would
reduce its therapeutic effectiveness. Therefore, conveniently, the
solution may remain supersaturated in the oral cavity for up to
about five minutes, especially up to 2-3 minutes and necessarily up
to about 1 minuie, all measurements therefore taken at body
temperature. It will be understood that, at lower temperatures such
as room or ambient temperature, the supersaturated solution will
remain so for significantly longer periods such as of the order of
up to 2 hours, especially up to 1 hour and necessarily for the
length of time taken to use the supersaturated solution just mixed
as a dental rinse or mouthwash which may be in the range of from
about 3 minutes to about 15 minutes.
[0020] Preferably components (a) and (b) do not, respectively,
contain any phosphate or calcium, although minor amounts (up to
10-20% either way--less at higher pH and vice versa) could be
tolerated.
[0021] Preferably, the supersaturated solution has a pH of from
about 5 to about 8.0, more preferably of from about 6 to about 7.5,
such as about 6.5 to about 7.5; especially preferred is when the pH
is about neutral such as 7.0.+-.0.2. The pH of each stock solution
component may vary widely: for component (a), it is in the range 1
to 12.5, preferably 3.5 to 8, more preferably 4 to 7.5; for
component (b), it is in the range 2 to 13, preferably 4 to 8.5,
more preferably 5 to 7.5. The pHs of components (a) and (b) in the
case where the pH of the supersaturated solution is to be around
neutral are preferably around 4 to 7.5, more preferably 4 to 6,
especially around 4; and 5 to 7.5, preferably 7 to 7.3, more
preferably around 7.2, respectively.
[0022] Preferably, the concentration of calcium ions (total
Ca.sup.2+ i.e. free and complexed) in the supersaturated solution
is in the range of from 2 to about 40 mM, such as 2 to about 21 mM,
more preferably in the range of from 2.5 to 16 mM. At around
neutral pH, the concentration of calcium ions in the supersaturated
solution is suitably in the range of from 2.5 to about 10mM,
preferably 3 to 5 mM, for example, about 3.87, 4.5 or 5 mM calcium
ions. Especially suitable is when the concentration of calcium ions
is around 4.5 to 5 mM, for example, 4.74 mM particularly to promote
formation of octacalcium phosphate.
[0023] Component (a) most preferably contains calcium as calcium
chloride. Other sources of calcium which have been used in
mouthwashes include calcium nitrate, calcium hydroxide or calcium
carbonate, optionally including a minor amount of calcium
phosphate, dissolved in an acid such as HCI. Preferred sources of
calcium are calcium nitrate and calcium hydroxide, but calcium
chloride is most preferred. The concentration of calcium ions in
component (a) is conveniently double that in the supersaturated
solution and therefore suitably in the range of from about 4 to
about 80 mM. Preferably, the range is from about 4 to about 40 mM,
more preferably 5 to 32 mM, especially 5 to 20 mM, and more
especially around 10 mM, for example 9.47 mM.
[0024] Preferably, the concentration of phosphate ions (total
(ortho)phosphate) in the supersaturated solution is in the range of
from about 0.5 to about 32 mM, preferably about I to 20 mM such as
1.5 to about 10 mM. At around neutral pH, the concentration of
phosphate is suitably in the range of from about 2 to about 6 mM,
preferably 2 to 4 mM, for example, about 2, 3, 3.4 or 3.87 mM.
Especially suitable is when the concentration of phosphate ions is
around 2.7 to 3.4 mM, for example, 2.96mM to promote formation of
octacalcium phosphate.
[0025] Component (b) preferably contains phosphate as a mixture of
monobasic phosphate with dibasic phosphate. To comply with the much
preferred pH of the supersaturated solution (pH=7.0.+-.0.2), the
ratio of mono:dibasic phosphate is in the order of about 1:2-1:8,
preferably 1:2.5-1:3.5, such as about 1:3. At the higher
concentrations of calcium and phosphate in the stock solutions, the
amount of dibasic phosphate would increase relative to monobasic
phosphate.
[0026] Alternatively, a pH adjuster such as alkalimetal hydroxide
or ammonium hydroxide or tribasic phosphate such as a
tri(alkalimetal) phosphate could be used to deliver the preferred
pH of the supersaturated solution. Since the quantity of hydroxide
is more difficult to measure than that of dibasic phosphate, it is
preferred to use monobasic phosphates and dibasic phosphates.
Another alternative is to use a combination of phosphoric acid with
a dibasic or tribasic such as tri(alkalimetal) phosphate. Preferred
alkali metals in this context are sodium and potassium, especially
sodium.
[0027] The concentration of phosphates in component (b) is
conveniently double that for the supersaturated solution and
therefore is preferably in the range of from about 1 to about 64
mM, preferably from about 2 to about 40 mM, such as about 3 to
about 20 mM, preferably at the preferred pH ranges about 4 to about
12 mM, more preferably about 4 to about 8 mM, for example, 5.92 mM.
The phosphates are preferably incorporated in the form of their
sodium, potassium or ammonium salts; more preferably, sodium salts
are employed. However, in cases where hypertensive effects of
sodium ions are of concern, mono-and di-potassium phosphates may be
used.
[0028] To permit use of high concentrations of calcium and
phosphate, the solutions incorporate a stabilizing agent which
comprises one or more salts of innocuous ions such as the cations
Na.sup.+, K.sup.+, NH.sub.4.sup.+, Mg.sup.++ and Sr.sup.++, and
anions CI.sup.-, CO.sub.3.sup.=, HCO.sub.3.sup.-, SO.sub.4.sup.=
and NO.sub.3.sup.-, but preferably comprises primarily sodium
chloride or potassium chloride, and most preferably sodium
chloride, except when the solution is for use by hypertensive
patients.
[0029] When present as the stabiliser, the concentration of sodium
chloride in the supersaturated solution preferably ranges from
about 4OmM to about 400 mM, more preferably 80 mM to 200 mM, such
as around 100 mM. The concentration of NaCI is not very dependent
upon pH but it is important not to reduce its concentration
substantially below this range or precipitation, rather than a
supersaturated solution, will result. Alternative stabilising
agents may be used provided they are physiologically acceptable,
such as other alkali metal halides such as KCI or other compounds
having equivalent effect such as ammonium chloride; but NaCI Is
much preferred. The lower end of the range of stabiliser
concentration is employed when lower ends of the ranges of calcium
and phosphate concentrations are employed, and vice versa.
[0030] The amount of stabiliser in each component is sufficient to
enable the calcium and phosphate ions to remain in supersaturated
solution once components (a) and (b) are mixed. The concentration
of sodium chloride (when used in both components) in each component
is equivalent to that in the supersaturated solution and therefore
preferably ranges from about 40 mM to about 400 mM, more preferably
80 mM to 200 mM, such as around 100 mM. Incorporation of a
stabiliser in.both components (a) and (b) allows the use of
higher-than-otherwise concentrations of calcium and phosphate ions
due to the effect of the stabiiiser on total ionic strength and
thus on the activities of the calcium and phosphate ions (`salt
effect`). Increasing the quantity of stabiliser present increases
the possible amounts of calcium and phosphate ions which can be
present without rapid or spontaneous precipitation However, due to
the intended use of the supersaturated solution as a mouthwash, the
amount of NaCI present in each component (a) and (b) should be
limited so that the supersaturated solution is approximately
isotonic, to avoid irritation or pain in the oral cavity.
Preferably, the ratio of NaCI present in component (a):component
(b) is in the order of about 1:1.
[0031] Since some of the sodium and chloride ions in the stock or
supersaturated solutions may arise front: ingredients other than
sodium chloride, as guidance, the following amounts of each ion may
be present: in the supersaturated solution, chloride may be present
in the range of from 0 to about 0.5 M, preferably 0.05 to 0.3 M,
more preferably 0.05 to 0.25 M, for example 0.103 M; and sodium
(ion) may be present in a similar concentration independently
selected from similar ranges, for example 0,107 M. In the calcium
or phosphate stock solutions (a) or (b), both ions may again be
present in similar concentrations in the range of from 0 to about 1
M, preferably from 0 to about 0.6 M, more preferably 0 to 0.5 M,
for example, 0.098 M (Na.sup.+) and 0.11 7 M (CI.sup.-) in the
calcium stock solution (a); and, for example, 0.1 08 M (Na.sup.+)
and 0.098 M (CI.sup.-) in the phosphate stock solution (b).
[0032] Preferably, the ratio of concentrations of calcium to
phosphate in the supersaturated solution corresponds to 1:1 to 5:3;
more preferably 4:3 to 5:3 to increase the amount of octacalcium
phosphate formed.
[0033] The supersaturated solution may also contain other
physiologically-acceptable ions. However, due to the formation of a
supersaturated solution (as hereinabove described) on mixing, we
have surprisingly found that it is not necessary to incorporate
fluoride for clinical effectiveness. But if it should be desired to
include fluoride, it is present in the supersaturated solution in
the range of from 0 to about 10 mM, preferably 0 to 2.5 mM such as
0 to 0.5 mM, for example 0.25 mM. This preferred range corresponds
to a maximum concentration of around 50 ppm, preferably around 5-10
ppm. Inclusion of fluoride in the supersaturated solutions of this
invention does not require adjustment of calcium and/or phosphate
ion concentrations; in these supersaturated solutions, fluoride and
calcium fluoride complexes are formed. In prior art solutions,
monofluorophosphate is usually formed.
[0034] Where fluoride is to be present, it is preferably added to
component (b). It should not all be added to component (a).
Therefore, about twice the concentration of fluoride must be
present in the phosphate concentrate (b) as specified above for the
supersaturated solution. The fact that the supersaturated solutions
of the present invention are clinically effective in remineralising
teeth in the absence of fluoride is surprising, especially given
the emphasis on including fluoride in remineralising solutions in
the prior art. For example, Koulorides in Experimental Changes of
Enamel Mineral Density [in Harris: Art and Science of Dental Caries
Research, pp 355-378 (Acad. Press, NY, 1968)] showed that, in
enamel re-hardening experiments using calciumiphosphate solutions,
the addition of fluoride to the solution resulted in a (about) four
times increase in hardness of dental enamel compared to similar
solutions excluding fluoride.
[0035] Another, optional, ion which may be present in the
supersaturated solution is zinc, in the range of from 0 to about 1
mM, such as 0 to 0.5 mM, preferably in the range of from 0 to 0.1
mM. Zinc is particularly advantageous in speeding up wound healing
and in decreasing the solubility of the mineral (eg. hydroxyapatite
and especially octacalcium phosphate) formed. When present, the
amount of zinc is preferably chosen so that up to 50 mg, more
preferably around 1 5 mg, is administered per treatment dose.
[0036] Where zinc is to be present in the supersaturated solution,
it is preferably added to component (a) although it may also be
added, at lower concentrations, to component (b). Therefore, twice
the concentration of zinc must be present in the calcium
concentrate (a) as specified above for the supersaturated
solution.
[0037] Other, known, additives may be present in the supersaturated
solution such as flavouring or colouring agents, or preservatives.
Mint flavouring is especially preferred where the supersaturated
solution is to be used in `normal` patients (but it can be an
irritant in bone marrow transplant (BMT) or irradiation patients).
Of the usual preservatives, sodium benzoate is preferred in
concentrations insufficient substantially to alter the pH of the
supersaturated solution, otherwise the ratio of mono:dibasic
phosphates would need to be adjusted to arrive at the desired
pH.
[0038] However, other ingredients which have been known in prior
art calcium/phosphate solutions are preferably excluded from the
formulations of the present invention. Therefore, the aqueous,
supersaturated solutions described herein are most preferably
substantially free from: carbon dioxide; alcohol; silicate; acetate
or other organic acid salts; chelating agent; antinucleating agent;
fluophosphate; and the like.
[0039] The solutions (including concentrates, stock solutions and
supersaturated solutions) described herein preferably consist
essentially of calcium ions, orthophosphate ions, sodium ions,
chloride ions and, optionally, fluoride ions and/or zinc ions in
the concentrations already specified, and, if desired,
colouring(s), flavouring(s) and/or preservative(s). More
preferably, the solutions are substantially free from any ion or
other ingredient which is not normally present in saliva.
[0040] The present invention further provides a system for
preparing an oral rinse that comprises a supersaturated calcium
phosphate solution, said system comprising (a) a calcium stock
solution containing calcium ions in a concentration of from about 2
to about 40 mM and sodium chloride or another physiologically
acceptable stabilizer in a concentration of from about 40 to about
400 mM; (b) a phosphate stock solution separated from said calcium
stock solutions, said phosphate stock solution containing phosphate
ions in a concentration of from about 0.5 to about 32 mM; and
sodium chloride or another physiologically acceptable stabilizer in
a concentration of about 40 to about 400 mM; and (c) means for
combining said calcium stock solution and said phosphate stock
solution shortly before use thereof to form a supersaturated
solution of calcium phosphate.
[0041] A preferred system is one wherein the pH of said stock
solutions is maintained such that the pH of the supersaturated
solution is in the range from about 5.0 to about 8.0. Other
preferred features of the system will be appreciated from the
foregoing description.
[0042] The present invention therefore still further provides a
method of preparing a supersaturated calcium phosphate solution for
use an an oral rinse, the solution comprising:
[0043] calcium in a concentration of from about 2 to about 40
mM;
[0044] phosphate in a concentration of from about 0.5 to about 32
mM;
[0045] sodium in a concentration of from 0 to about 0.5 M;
[0046] chloride in a concentration of from 0 to about 0.5 M,
[0047] which method comprises (a) preparing a calcium stock
solution comprising from about 4 to about 80 mM calcium ions and
from about 40 to about 400 mM sodium chloride; (b) separately
preparing a phosphate stock solution comprising from about 1 to
about 64 mM phosphates and from about 40 to about 400 mM sodium
chloride; and (c) mixing said stock solutions (a) and (b).
[0048] A preferred method is one wherein said calcium stock
solution (a) is prepared by diluting a calcium concentrate with
sufficient water to form said calcium stock solution; and said
phosphate stock solution (b) is prepared by diluting a phosphate
concentrate to form said phosphate stock solution.
[0049] Therefore, the components (a) and (b) (stock solutions) to
be mixed to form the supersaturated solutions according to this
invention are preferably provided as two respective concentrates
(ie. each to be separately mixed with water to form the respective
stock solutions prior to being mixed together to form the final,
supersaturated solution or mouthwash).
[0050] For example, an optionally flavoured and coloured calcium
concentrate may be provided in a container (such as a 25 ml
container) which is packaged together with an optionally flavoured
and colored phosphate concentrate provided in another 25 ml
container, together with instructions for dilution with,
preferably, distilled water.
[0051] Therefore, the present invention further provides a
formulation comprising:
[0052] (a) a calcium concentrate which itself comprises an aqueous
solution of 5 calcium ions in the range of from about 8 to about
2120 mM, such as 10 to 2080 mM, preferably 25 to 1300 mM, for
.example 360 mM, and 0 M to 6.5 M sodium chloride or equivalent
stabiliser as described above, for example about 3.7 M; and,
associated therewith but separate therefrom
[0053] (b) a phosphate concentrate which itself comprises an
aqueous solution of phosphate ions in the range of from about 2 to
about 1440 mM, such as 4 to 1300 mM, preferably 20 to 780 mM, for
example 225 mM; and a stabilising amount of a
physiologically-acceptable stabiliser such as an alkalimetal or
ammonium halide such as from OM to 6.5 M sodium chloride, for
example, 3.71 M NaCl;
[0054] whereby, on diluting each concentrate with water in a range
of ratios of from 1:1 to 1:64, preferably about 1:4 to 1:64 such as
about 1:40 (concentrate:water), for example, 1:37 and thereafter
mixing the two stock solutions thereby formed in a range of ratios
of from 3:7 to 7:3, preferably 4:6 to 6:4, more preferably about
1:1 (calcium stock solution (a):phosphate stock solution (b)), a
supersaturated solution is formed which is suitable for use as a
mouthwash or dental rinse,
[0055] The calcium concentrate preferably contains sodium (ions) in
the range specified above for NaCI in concentrate (a), and chloride
in a range of from 0 to about 10.7 M.sub.1, for example 4.43 M. The
phosphate concentrate preferably contains chloride in the ranges
given above for NaCl in concentrate (b); and sodium (ions) in the
range of from 0 to about 9.38 M, preferably 0.05 to 11.4 M such as
0 to 9.5 M, for example 4.11 M. Zinc may be present in the calcium
concentrate in the range of from 0 to about 640 mM, preferably 0 to
260 mM, such as 0 to 65 mM, for example, 1.9 mM. Fluoride may be
present in the phosphate concentrate in the range of from 0 to
about 500 mM, preferably 0 to 325 mM, such as 0 to 65 mM, for
example 19 mM,
[0056] Optionally, coloring(s), flavouring(s) and/or
preservatives(s) may also be present, as hereinbefore
described.
[0057] The package preferably contains patient instructions (i)
separately to mix the contents of each of the above-mentioned 25.0
ml containers with 925 ml of water (for a final volume of 950 ml
[one U.S. quart]) or 13.2 ml volumes of concentrate to be diluted
to form 0.5 1 stock solution; (ii) then to mix at least 8 ml of
each preferably in a ratio 1 :1 but no less 30% calcium stock
solution and no more than 70% calcium stock solution; and (iii) how
to use these final, diluted, supersaturated solutions as a
mouthwash or rinse for the oral cavity.
[0058] However, more preferably, the stock solutions (components
(a) and (b)) are provided ready-made so that the patient or medic
who is to administer the supersaturated solution only has to mix
the two components to form the supersaturated solution, thereby
avoid the dilution step. Conveniently, therefore, the stock
solutions (a) and (b) are provided in separate, unit dose
containers such as sterilised, hermetically-sealed 15 ml containers
such as those available from Rommel A.G. (Stuttgart, Germany).
[0059] Very conveniently, packages may contain multiples of thirty
doses with instructions for an appropriate treatment programme as
herein described. For example, for OTC use, a pack may contain
thirty doses as a month's daily treatment, or for clinical use such
a pack may comprise a week's treatment. Alternatively, for the
clinic, a pack may provide 120 doses comprising a month's
treatment, depending upon the treatment programme to be
followed,
[0060] Dental caries is an ubiquitous problem, particularly in
elderly patients. The predominant forms of dental caries in elderly
patients are root surface and recurrent carious lesions. The
supersaturated solutions of the present invention have been found
to have a particularly beneficial effect when used as part of a
multi-component preventative treatment programme. This treatment
programme aims simultaneously to increase tooth resistance,
decrease the acid attack rate and enhance the intraoral
physiological maintenance processes. For example, the
supersaturated solutions are preferably used in conjunction with
treatment components selected from:
[0061] A. Oral hygiene. selected from flossing, standardised tooth
brushing with fluoride toothpaste and cleaning of tooth surfaces
with cotton swabs. Daily use of fluoride toothpaste is to maintain
the fluoride levels obtained from step B below;
[0062] B. Topical fluoride applications: for example,
self-administration of fluoride gel by means of custom-made trays
of soft plastic (such as Mouthguard(.RTM.) material) e.g. neutral
sodium fluoride gel containing 112-1% F. The fluoride application
is preferably followed by the mouth being thoroughly rinsed with
water to remove residual gel and prevent swallowing of fluoride;
and
[0063] C. Salivary gland stimulation: for example, by a
non-sweetened gum for patients with xerostomia to stimulate
salivary secretion.
[0064] It is especially preferred that such a preventative
treatment programmed should be followed before restorative
procedures are undertaken in highly caries-susceptible patients.
The remineralisation of some lesiorns will facilitate preparation
procedures by strengthening the tissues. Also, the sensitivity of
the teeth is decreased as the lesion rehardens and exposed dentinal
canals close. Furthermore, it is desirable to improve the chemistry
of sound tooth surfaces before major reconstructive or restorative
work is begun especially since many remineralised lesions may not
need to be restored, unless the patient requests restoration for
aesthetic reasons.
[0065] Treatment using the supersaturated solutions in conjunction
with component B has been found to be especially beneficial,
particularly in cancer patients. Cancer, in all its forms, is
highly prevalent in present-day society, and many of the treatments
associated with the various forms exhibit severe side-effects. For
example, of the one million people in the United States who develop
cancer annually, over 400,000 individuals suffer oral complications
from their cancer therapies. Additionally, there are 25,000
individuals per year who develop leukaemia. Unfortunately, most
cancer treatments affect normal tissues as well as diseased cells.
As treatments become more intensive and more successful, their
effects on `normal` tissues have increased, and the oral cavity is
frequently the site of severe sideeffects.
[0066] The oral complications of cancer therapy are, at minimum,
painful and, at their most severe, life threatening. These oral
sideeffects (particularly in patients undergoing chemotherapy and
radiation therapy for head and neck cancer including Hodgkins
disease and lymphomas) include mucositis, xerostomia,
osteoradionecrosis, candidiasis and secondary infections such as
herpes. Chemotherapeutic drugs also cause a variety of symptoms
which may discourage eating, such as stomatitis, sore throat,
change in taste sensation, stomach cramping, feeling of fullness,
nausea, vomiting or diarrhoea. Malnutrition is, therefore, a common
consequence of the oral complications. Other side effects include
monoliasis, dysphagia, tooth hypersensitivity and rampant dental
caries.
[0067] For example, bone marrow transplantation (BMT) has been
found to be successful in the treatment of leukaemia, lymphoma and
some solid mass tumours. Prior to a bone marrow transplant,
intensive chemotherapy and total body irradiation (for allogenic
BMT patients) is administered to the patient in an effort to
destroy all cancer cells. The dosages must be so high that the bone
marrow is destroyed, leaving the patient wholly dependent on
supportive care for defence against infection until the new marrow
engrafts and starts to function.
[0068] This intensive treatment places the BMT patient in need of
dental intervention, since it depresses the patient's immune
system. The majority of BMT patients who die do so as a result of
an infection. Reverse isolation and prophylactic antibiotics are
effective in preventing microbial infections except for those
infections originating. in the mouth. Thus, microorganisms can
enter the bloodstream through ulcerations of the oral mucosa,
resulting in septicemia and, in many cases, death. Studies have
shown that 25% of the deaths from infections were of oral origin
(as evidenced by, for example, Research Report on Leukaemia,
prepared by the Office of Cancer Communications, National Cancer
Institute, NIH Publication No. 88-329, 1988; and Epstein, J. B. in
Infection prevention in bone marrow transplantation and radiation
patients, NCI Monogr. 9 7385, 1990).
[0069] Mucositis is therefore a common consequence not only of
(high dose) radiation therapy but also in patients undergoing bone
marrow transplantation. This painful condition appears three days
post-induction therapy and usually continues until engraftment
occurs, The pain is often so great that patients cannot eat and
require high-ose morphine. This further debilitates the patient so
that total parenteral nutrition is necessary to maintain
nutritional levels. Mucositis is caused by non-specific inhibitory
effects of the chemotherapeutic agent and radiation on mitosis of
the rapidly-ividing basal epithelial cells. Atrophic changes and,
eventually, ulceration are a result of this reduction in the
renewal rate of basal epithelial cells. The loss of integrity of
the epithelium provides a portal for the entry of oral
micro-organisms at the time of maximum myelosuppression (the
nadir). Oral flora have been found to be the most frequent source
of sepsis in granulocytopaenic cancer patients. (NIH, ibid).
Non-keratinized mucosa is more vulnerable to chemotherapeutic
agents than keratinized mucosa; thus, the highly vascular lining of
the floor of the mouth is a common site of entry for oral
flora.
[0070] Additionally, degenerative and vascular changes in the
submucosa, xerostomia and reactivation of latent viruses directly
affect the epithelium. Local irritants such as ill-fitting dental
appliances, cracked or rough restorations may further compromise
the oral mucosa.
[0071] Although chlorhexidine has been shown to be useful in the
prevention of bacterial and fungal infection, there are no
consistent findings in the value of chlorhexidine in reducing
mucositis in cancer patients. It probably works on the secondary
microbial initiation of already-affected tissue. The problem with
its use is that, once mucqsitis starts, the alcohol content of
chlorhexidine preparations makes it difficult for the patient to
use even at one-half strength. It is difficult to force the
patients who are experiencing severe pain and who are already on
morphine to use something that increases their pain.
[0072] Many of these side-effects can be minimised with a rigorous
preventative regime. In conjunction with oral preventative care,
chemical enhancement of the oral environment is essential to
maintain the mucosal barrier intact. It has now surprisingly been
found that chemical enhancement with the supersaturated solution of
the present invention, preferably in conjunction with a
multi-component treatment programme such as described above, is
effective in decreasing mucositis and increasing survival and
recovery. The present supersaturated solutions are effective in
treating or preventing both the soft tissue and hard tissue
problems or side effects mentioned above.
[0073] The supersaturated solutions of the present invention are
therefore useful in the treatment or prevention of any disease,
patient or condition which requires (a) remineralisation or
maturation of oral hard tissue (since these solutions substantially
enhance the natural, ongoing remineralisation process); and (b)
anti-inflammatory, including anti-mucositis, and anti-infective,
including anti-septicaemic, treatment of periodontal, soft tissue.
The soft tissue effects of these solutions are particularly
unexpected and include positive effects on the gums, soft and hard
palates, tongue and mouth floor. Inflammation, ulceration, erythema
and eruptions of the mucous membrane may all be treated or
prevented with these supersaturated solutions.
[0074] It is therefore visuaksed that the following patient groups
will benefit from the use of the supersaturated solutions aacording
to the invention:
[0075] Oncology patients undergoing radiation therapy and/or
chemotherapy both during treatment and after treatment for as long
as salivary function is impaired (months to years);
[0076] Bone marrow transplant patients who often develop fatal
infections in the oral cavity during and after treatment. The
supersaturated calciumiphosphate mouthwash decreases mucositis. and
increases survival and recovery, sparing the patient pain and
discomfort and decreasing hospital stay. In patients suffering from
graft versus host disease, the changes to the salivary glands and
oral mucosa can last for years and are very painful;
[0077] Patients suffering from medical conditions in which salivary
secretion is reduced or absent (xerostomia). Specific examples
include Sjogrens syndrome, various connective tissue degenerative
diseases, and congenital absence of salivary glands;
[0078] Patients with decreased salivary functions resulting from
the administration of various medications, which as a side-reaction
causes impairment of salivary function (psychiatric conditions,
high blood pressure, `dry-mouth` reactions to medicines etc.);
[0079] AIDS patients--to manage their severe mucositis and
monoliasis which occur in advanced stages of the disease;
[0080] Patients with high susceptibility to dental caries without
specific systemic disease;
[0081] Patients with inflammatory and/or ulcerative lesions in the
oral cavity--either acute, chronic or recurrent; and
[0082] Any other patient, including patients with sensitive teeth,
and those who wish to strengthen the teeth against dental caries
and promote better oral health--by combining a fluoride treatment
with the supersaturated solution mouthwash.
[0083] For remineralising use, the supersaturated solutions should
be used at least twice and up to ten times per day at a time when
no food or drink is to be taken for at least 30 minutes after
rinsing. If in combination with fluoride gel, the supersaturated
solution is to be used after the fluoride treatment. In use, the
preferred supersaturated solutions of this invention are believed
to form, in the oral cavity with saliva when present, a mixture
having 4.7-5 mM calcium; and 3-3. SmM phosphate; at pH 6.97.1.
[0084] Cancer or BMT patients may require around five treatments
per day. In cases of severe mucositis, the supersaturated solutions
may be used as often as twelve times per day. Usually from 15 to 40
ml of the final, supersaturated solution is required per treatment
comprising two-part rinsing. For example, in the case of a 20 ml
treatment, the patient rinses first with about 10 ml of the
supersaturated solution for about one minute, expectorates, and
then repeats this procedure.
[0085] Remineralisation following the preventative treatment
program mentioned before may be complete in `normal` patients after
approximately 2 weeks of twice-aily treatments followed by about
one week of once-daily treatments; however, treatment may be
continued thereafter. Cancer or BMT patients may need to continue
treatment indefinitely or at least until resumption of normal
salivary function after which treatment would follow the pattern
for `normal` patients.
[0086] Therefore, the present invention yet further provides a
method of (a) remineraizing teeth; (b) preventing or relieving
mucositis in subjects in need of such treatment; and (c) preventing
oral cavity infection in a patient with an impaired immune system,
which method comprises periodically rinsing the oral cavity with a
supersaturated solution as described hereinbefore.
EXAMPLES
[0087] The present invention will now be illustrated with reference
to the following examples.
Example 1
Saliva Substitute Formulation
[0088] The following formulation is suitable for use in
patients/individuals having a decreased salivary outputtexcretion
(i.e. to moisten and lubricate the oral cavity and to act as a
salivary substitute or replacement solution).
[0089] The saliva substitute is comprised of two separate
concentrate solutions each of which is diluted with water and
stored separately. Approximately equal volumes of the two solutions
are mixed just prior to introduction into the oral cavity. The two
solutions are:
[0090] A. A fresh mint-flavoured calcium concentrate; and
[0091] B. A fresh mint-flavoured phosphate concentrate, made up as
follows:
1 A. Calcium concentrate Calcium Chloride Dihydrate, USP 52.9 g/l
(360 mM) Sodium Chloride, USP 217 g/l (3.71M) Sodium Benzoate, USP
1.0 gm/l Fresh Mint Colouring 1.5 ml/l Fresh Mint Flavouring 2.0
ml/l Water for injection q.s. to 1000 ml B. Phosphate concentrate
Disodium Phosphate, USP 24.1 g/l (170 mM) Monosodium Phosphate
Monohydrate, USP 7.6 g/l (55.1 mM) Sodium Chloride, USP 217 g/l
(3.71M) Sodium Benzoate, USP 1 g/l Fresh Mint Flavouring 2.0 ml
Fresh Mint Colouring 1.5 ml Water for Injection q.s. to 1000 ml
[0092] Each of these two concentrates is filled in a separate 25.0
ml container comprising high density polyethylene. Each container
is sealed with a tamper-evident shrink film and placed in a
cardboard container. The package and/or container(s) is/are
labelled with the following directions: Remove the protective
shrink film and cap. The entire contents of this container is to be
mixed with one U.S. quart (925 ml) of water prior to use. A
measuring cup (included in the package) should be used to mix
together equal volumes of the diluted calcium solution (12.5 ml)
and diluted phosphate solution (12.5 ml). Immediately after mixing,
one half of the contents of the measuring cup should be rinsed in
the mouth for 1 minute and this repeated with the remaining
contents of the measuring cup, For best results it is recomrimended
that the following rinsing schedule be followed:
2 Weeks 1-2 Rinse mouth twice per day (morning and evening) for 2
minutes Weeks 4-6 Rinse mouth once per day (morning and or evening)
for 2 minutes. Thereafter- Rinse mouth twice per week for 2
minutes.
[0093] The supersaturated solution may be (insed in the mouth as
often as needed to moisten and lubricate the mouth as a means of
replacing decreased salivary excretions. When rinsing is completed,
the solution is expectorated.
[0094] The chemical composition of these final, diluted stock
solutions will be as follows:
3 Calcium Stock Solution (25.0 ml concentrate + 925 ml Water)
Calcium chloride dihydrate, USP 1.39 g/950 ml (9.5 mM) Sodium
Chloride, USP 5.71 g/950 ml (97.7 mM) Sodium Benzoate, USP 0.025
g/950 ml Fresh Mint Colouring 0.038 ml/950 ml Fresh Mint Flavouring
0.050 ml/950 ml Water q.s. to 950 ml Phosphate Stock Solution (25.0
ml concentrate + 925 ml Water) Disodium Phosphate, USP 0.634 g/950
ml (4.47 mM) Monosodium Phosphate Monohydrate, USP 0.200 g/950 ml
(1.45 mM) Sodium Chloride, USP 5.71 g/950 ml (97.7 mM) Sodium
Benzoate, USP 0.025 g/950 ml Fresh Mint Flavouring 0.038 ml/950 ml
Fresh Mint Colouring 0.050 ml/950 ml Water q.s. to 950 ml
Example 2
Remineralising Solution
[0095] Alternatively, supersaturated solutions according to this
invention may be prepared by:
4 A. Calcium concentrate (1 US gallon) Calcium chloride dihydrate
200 g (360 mM) Sodium chloride 821 g (3.71M) Sterile water q.s. ad
3785 ml B. Phosphate concentrate (1 US gallon) Monobasic sodium
phosphate (NaH.sub.2PO.sub.4) 25 g (55.1 mM) Dibasic sodium
phosphate (Na.sub.2HPO.sub.4.7H.sub.2O) 172 g (170 mM) Sodium
chloride 821 g (3.71 m) Sterile water q.s. ad 3785 ml
[0096] In each case, the salts are sifted together in a 4000 ml
stainless steel container. They are then added gradually to 2000 ml
water for irrigation in a 4000 ml Erlenmeyer flask. Once the
reaction has subsided, sufficient water is added to make 1 U.S.
gallon (3785 ml). The concentrate is then passed through a large 40
cm filter paper into a plastic gallon. Thereafter, it is packaged
in 25 ml volumes into 30 ml plastic squeeze containers.
[0097] To make the remineralising solution, 25 ml of each
concentrate is separately diluted with one U.S. quart (925 ml) of
tap water to form stock solutions. 30 ml of each stock solution are
mixed together to form the remineralising solution.
Example 3
Remineralisation of Caniouc Lesions in Elderly Patients
[0098] Two studies were carried out independently of each
other.
[0099] Study 1
[0100] A total of 171 patients were stLudied. The ages of the
patients ranged from 2 1/2 to 76 years old, Data or. 30 patients,
45 years old and older, are included in this example. The patients
were selected because of existing extensive caries and/or
documented histories of high caries susceptibility over several
years.
[0101] On the basis of general health status, the 30 participating
subjects were divided into two groups. The 18 patients included in
Group A suffered from various diagnosed illnesses including
diabetes, high blood pressure, Parkinson's disease and cancer, andi
received various types of medications. In contrast, Group B
consisted of 12 healthy individuals who were not on any medication.
This example covers only the first 4 years of treatment.
[0102] Study 2
[0103] More than 500 patients of all ages participated in this
study, but this example includes only the findings on 94 patients
aged 45 years and older.
[0104] In both studies, the preventative procedures were explained
and demonstrated to each patient either individually or in small
groups, and written instructions were also provided. Briefly
stated, the preventative procedures were as follows:
[0105] 1. Oral hygiene: Flossing, standardised tooth brushing with
fluoride toothpaste, and cleaning of tooth surfaces with cotton
swabs.
[0106] 2. Topical fluoride applications: Self-administration of
fluoride gel by means of custom-made trays of soft plastic
(Mouthguard.RTM. material). Neutral sodium fluoride gel containing
1% F was prescribed for most patients. In some instances, gel with
only half the F concentration was used. The initial home treatment
schedule consisted of two 5-minute applications per day for 2 weeks
followed by sing!e daily applications for an additional 2 weeks.
Following each treatment, the mouth was to be thoroughly rinsed
with water to remove residual gel and prevent swallowing of
fluoride. For some patients, a limited number of booster treatments
were prescribed on an individual basis at different times during
the period of study. 3. Remineralising mouthwash: The composition
of the remineralising supersaturated solution at pH 7.0 (.+-.0.2)
was 4.74 mM Ca, 2.96 mM PO4, 0.107 M Na, 0.103 M Cl and 0.25 mM
fluoride.
[0107] The remineralising solution was prepared substantially in
accordance with Example 2 but with the addition of 19 mM fluoride
in the phosphate concentrate; resulting in 0.5 mM fluoride in the
phosphate stock solution (hence 0.25 mM in the supersaturated
solution). The two stock solutibns (which were stored separately
and mixed as described in Examples 1 and 2 immediately prior to
use) comprised:
5 Calcium stock solution (a) Na.sup.+ 0.098M Cl.sup.- 0.117M
Ca.sup.++ 9.47 mM pH 4-6 Phosphate stock solution (b) Na.sup.+
0.108M Cl.sup.- 0.098M H.sub.xPO.sub.4 5.92 mM (4.47 mM dibasic +
1.45 mM monobasic) F 0.5 mM pH 7-7.3
[0108] A 2-minute rinse was prescribed after each topical fluoride
application. When the fluoride gel treatment was completed,
patients with limited salivary secretion were asked to continue
using the rinse solutions twice a day after toothbrushing.
[0109] 4. Salivary gland stimulation: A non-sweetened gum was
prepared and prescribed for patients with xerostomia to stimulate
salivary secretion.
[0110] The two studies described differ in several respects. In
study 1, the patients were not under close observation after the
initial 4-6 weeks, when the preventative treatment procedures had
been completed. Some patients were only recalled at 6- to 12-month
intervals for reexamination, while others were seen at shorter
intervals for the rendering of restorative or periodontal
treatment. At all appointments, the maintenance of good oral
hygiene was emphasized. Additional supplies of rinse solution were
made available to all participants during the first year, but
subsequently fluoride gel and remineralizing solution were given
primarily to patients with impaired salivary function. Thus, not
all of the participants followed the same routine after the
original preventative treatment. In contrast, the participants in
study 2 were monitored carefully and given remineralising solutions
as requested and fluoride as deemed necessary. Patients with
apparently stable oral health conditions were recalled less
frequently than the oncology patients who were at greater risk of
losing their teeth.
[0111] The findings in both studies confirm the ability of the
treatment system to remineralize active carious lesions. The
greatest success was obtained with root surface lesions.
[0112] The incidence of new carious lesions in both groups dropped
close to zero. The fluoride levels of enamel, dentin and cementum
increased markedly, to a level where the crystallites apparently
become more resistant to demineralisation, The fact that the caries
resistance persists over several years adds further credence to
this explanation. Some of these patients have had no cavity now for
up to 16 years; and several for up to 10 years. The benefit is
clearly not a temporary phenomenon, but represents a permanent
increase in tooth resistance to caries.
Example 4
Clinical Studies on BMT Patients --Soft Tissue Effects
[0113] In order to stimulate salivary secretion, BMT patients were
supplied with inert chewing gum. They were also given individual
instructions on proper oral hygiene, as well as nutritional
counselling.
[0114] In order to minimise the dangers of septicemia, a rigorous
oral management regimen was instituted. This example presents the
findings from a retrospective study comparing patients who received
an intensive oral preventative regimen (including the solution of
the present invention) during hospitalisation with those who did
not receive such treatment.
[0115] The bone marrow transplant protocols were the same for all
patients, The treatment regimens for autologous bone marrow
transplant patients were:
6 Cytoxan 12,000 mg/m.sup.2 4 times per day Carboplatin 1,600
mg/m.sup.2 4 times per day VP16 (Etoposide) 1,600 mg 4 times per
day
[0116]
7TABLE 1A Study 1: Remineralization of active carious lesions
Patient Population Mean Group* No. Age DMFT No. of Teeth Present A.
12 50 25 22 B. 18 58 27 21 Post-treatment Remineralized Lesions
Pre-treatment Year Active Lesions 1 2 3 4 No. % No. % No. % No. %
No. % 77 100 66 86 55 71 53 69 47 61 129 100 90 70 75 58 71 55 69
53 Totals 206 100 156 76 130 63 124 60 116 58 *A - Patients without
diagnosed medical problems B - Patients with medical problems
[0117]
8TABLE 1B Study 2: Remineralization of active carious lesions
Pre-treatment: Types and No. of Lesions Post-treatment:
Remineralized Surfaces No. of Root Caries Coronal Caries Root
Caries Coronal Caries No. of Carious No. of No. of No. of % of No.
of % of Group Teeth Teeth Surfaces Surfaces Surfaces Surfaces
Surfaces Surfaces Radiation Therapy 1002 448 490 277 354 72* 144 52
Xerostomia 182 87 139 18 125 90 13 72 Sjogren's Syndrome 210 116
166 50 144 87 26 52 High Caries Susceptibility 308 114 149 23 102
68 5 22 TOTALS 1702 765 944 368 725 77 188 51 *In 23 patients of
the Radiation Therapy group, 100% of the 243 carious surfaces were
remineralized.
[0118] For allogenic bone marrow transplant patients, the treatment
regimens were:
9 Cytoxan 60 mg/kg/day .times. 2 Total Body Irradiation 300
Rads/QDX given twice per day
[0119] All patients received prevention education and comprehensive
dental care before therapy. All patients completed their dental
treatment before going in for therapy. Before therapy began, the
patients maintained a daily regimen of using custom fluoride trays
with 2% sodium fluoride. (Fluoride gel is placed in the custom tray
and inserted in the mouth for approximately five minutes twice per
day.) Chlorhexidine was used as long as the patient could tolerate
it--usually until the onset of mucositis.
[0120] All BMT recipients were referred from the
Hematology-Oncology Division of New England Medical Center, Boston,
Mass. U.S.A.
[0121] Group 1 19 BMT patients who had received comprehensive
dental care before entering therapy, custom fluoride trays with 2%
sodium fluoride and Peridex (Registered Trademark) rinse b.i.d.
were administered with no follow-up dental care. Saline and
peroxide rinses, 2-2-2 solutions, Peridex (Registered Trademark)
and Nystantin (Registered Trademark) were used. Prophylactic
antibiotics and acyclovir were used.
[0122] Group 2 39 BMT patients who had received comprehensive
dental care before entering therapy and throughout their hospital
stay, custom fluoride trays with 2% sodium fluoride and Peridex
(Registered Trademark) rinse b.i.d. and supersaturated
calcium/phosphate remineralising rinses according to Example 3. (2
U.S. fl. oz. (59 ml) used 4-5 times per day). Peridex (Registered
Trademark) and Nystantin (Registered Trademark) were used.
Prophylactic antibiotics and acyclovir were used.
10TABLE 2A PATIENT POPULATION BY DIAGNOSIS Dental Preventative
Treatment? NO YES N = 19 N = 39 LEUKAEMIA 8 12 HODGKINS DISEASE 4
10 LYMPHOMA 4 14 OTHER 3 3
[0123] The records of 58 bone marrow transplant patients (19
allogenic; 39 autologous) ages 2057 were reviewed for length of
stay (post transplantation), days of neutropaenia, days of
morphine, days of fever, days of infection, total parenteral
nutrition (TPN) and duration of mucositis.
11TABLE 2B RESULTS FOR All BMT PATIENTS Dental Preventative
Treatment? NO YES N = 19 N = 39 LENGTH OF STAY POST TRANSPLANTATION
30.2 28.7 DAYS OF NEUTROPAENIA 16.0 10.9 (White blood cell count
below 500) DAYS OF FEVER 7.70 7.05 DAYS OF INFECTION 8.6 4.5 DAYS
OF MUCOSITIS 13.3 9.5 DAYS OF MORPHINE 5.15 3.38
[0124] When allogenic and autologous transplantations were
separated, allogenic transplantation patients had more difficulty
in all the measures than the autologous ones. All the cases which
did not have the dental preventative treatment developed severe and
prolonged mucositis; in one of these cases, a systemic infection
originating in the mouth led to the patient's death. The allogenic
patients who had the dental preventive treatment had very mild
mucositis except for those who developed graft vs. host disease and
died.
[0125] The results of this retrospective study demonstrate that a
preventative regimen using a supersaturated calcium/phosphate
solution of this invention can protect the oral mucosa, treat and
prevent mucositis and reduce the severity of infection and lgngth
of stay in reverse isolation.
Examples 5 & 6
Zinc--containing Mouthninses
[0126] According to the methods of Examples 1 and 2, the following
stock solutions were prepared from the following concentrates, and
mixed (component (a);component (b)=1:1) to form a supersaturated
solution having pH.sup..about.7 containing (5) zinc but
substantially no fluoride; and (6) fluoride and zinc:
12 Stock Concentrate Component(a) Concentrate Stock 0.1166M 4.43M
Cl.sup.- 4.43M 0.1166M 0.0977M 3.71M Na.sup.+ 3.71M 0.0977M 9.474
mM 360 mM Ca.sup.++ 360 mM 9.474 mM 0.05 mM 1.9 mM Zn.sup.++ 1.9 mM
0.05 mM 4-6 -- pH -- 4-6 Component(b) 0.0977M 3.71M Cl.sup.- 3.71M
0.0977M 0.1081M 4.11M Na.sup.+ 4.11M 0.1081M 1.45 mM 55.1 mM
H.sub.2PO.sub.4.sup.- 55.1 mM 1.45 mM 4.47 mM 169.9 mM
HPO.sub.4.sup.- 169.9 mM 4.47 mM 0 0 F 19 mM 0.50 mM 7-7.3 -- pH --
7-7.3
[0127] In these examples, ions were supplied as follows:
13 Stock Concentrate Component(a) Concentrate Stock 0.098 M 3.71 M
NaCl 3.71 M 0.098 M 9.474 mM 360 mM CaCl.sub.2 360 mM 9.474 mM 0.05
mM 1.90 mM ZnCl.sub.2 1.90 mM 0.05 mM
[0128]
14 Example 5 Component(b) Example 6 0.098 M 3.71 M NaCl 3.71 M
0.095 M 1.45 mM 55.1 mM NaH.sub.2PO.sub.4 55.1 mM 1.45 mM 4.47 mM
169.9 mM Na.sub.2HPO.sub.4 169.9 mM 4.47 mM .O slashed. .O slashed.
NaF 19 mM 0.5 mM
Examples 7-9
Mouthrinses Having Non-Neutral pH
[0129] According to the methods of Examples 1 and 2, the following
stock solutions were prepared from the following concentrates, and
mixed (component (a):component (b)=1:1) to form a supersaturated
solution having non-neutral pH:
Example 7
Supersaturated Solution pH.sup..about.6-5
[0130]
15 Stock Concentrate Component(a) 0.1333 M Cl.sup.- 5.07 M 0.0977 M
Na.sup.+ 3.71 M 17.5 mM Ca.sup.++ 676.4 mM 4-6 pH -- Component(b)
0.0977 M Cl.sup.- 3.71 M 0.1134 M Na.sup.+ 4.31 M 6.68 mM
H.sub.2PO.sub.4.sup.- 253.8 mM 4.53 mM HPO.sub.4.sup.- 172.1 mM
0.50 mM F.sup.- 19 mM 6.6-6.7 pH --
[0131] In this example, ions were supplied as follows:
16 Stock Concentrate Component(a) 0.098 M NaCl 3.71 M 17.8 mM
CaCl.sub.2 676.4 mM .O slashed. ZnCl.sub.2 .O slashed. Component(b)
0.098 M NaCl 3.71 M 6.68 mM NaH.sub.2PO.sub.4 253.8 mM 4.53 mM
Na.sub.2HPO.sub.4 172.1 mM 0.50 mM NaF 19.00 mM
[0132]
17 Example 8 Example 9 Supersaturated Solution Supersaturated
Solution pH .about. 7.5 pH .about. 6.0 Stock Concentrate
Concentrate Stock Component(a) 0.1099 M 4.17 M Cl.sup.- 6.44 M 0.17
M 0.0977 M 3.71 M Na.sup.+ 3.71 M 0.098 M 6.08 mM 231 mM Ca.sup.++
1364 mM 35.9 mM 0.05 mM 1.9 mM Zn.sup.++ 3.8 mM 0.10 mM 4-6 -- pH
-- 4-6 Component(b) 0.0977 M 3.71 M Cl.sup.- 3.71 M 0.0977 M 0.105
M 3.99 M Na.sup.+ 4.72 M 0.1241 M 0.319 mM 12.12 mM
H.sub.2PO.sub.4.sup.- 699 mM 18.4 mM 3.48 mM 132.2 mM
HPO.sub.4.sup.- 152.4 mM 4.01 mM .O slashed. .O slashed. F.sup.- 19
mM 0.50 mM 7.7-7.9 -- pH -- 6-6.2
[0133] In these examples, ions were supplied as follows:
18 Stock Concentrate Concentrate Stock Component(a) 0.098 M 3.71 M
NaCl 3.71 M 0.098 M 6.08 mM 231.0 mM CaCl.sub.2 1364 mM 35.9 mM
0.05 mM 1.90 mM ZnCl.sub.2 3.80 mM 0.1 mM Component(b) 0.098 M 3.71
M NaCl 3.71 M 0.098 M 0.319 mM 12.12 mM NaH.sub.2PO.sub.4 699 mM
18.4 mM 3.48 mM 132.2 mM Na.sub.2HPO.sub.4 152.4 mM 4.01 mM .O
slashed. .O slashed. NaF 19 mM 0.5 mM
Example 10
[0134] The supersaturated solution formed in accordance with
Example 7 could alternatively be formulated from the calcium
(component (a)) stock and concentrate solutions described therein,
but replacing the phosphate (component (b)) stock and concentrate
solutions with:
19 Stock Concentrate Component(b) 0.098 M NaCl 3.71 M 6.68 mM
H.sub.3PO.sub.4 253.8 mM 453 mM Na.sub.3PO.sub.4 172.1 mM 0.50 mM
NaF 19 mM 6.6-6.7 pH --
Example
[0135] The following concentrates were prepared in accordance with
the method of Example 1
20 A B Calcium chloride dihydrate 52.9 g 55.7 g Sodium chloride
217.0 g 228.3 g Monosodium phosphate dihydrate 8.6 g 9.1 g Disodium
phosphate dodecahydrate 60.8 g 84.0 g Sodium chloride 217.0 g 228.3
g
[0136] In the case of solution A, the dilution from concentrate to
stock solution was 38-fold as in Example 1, whereas in the case of
solution B, the dilution from concentrate to stock solution was
40-fold.
* * * * *