U.S. patent number RE31,181 [Application Number 06/162,102] was granted by the patent office on 1983-03-15 for means and method for improving natural defenses against caries.
Invention is credited to Israel Kleinberg.
United States Patent |
RE31,181 |
Kleinberg |
March 15, 1983 |
Means and method for improving natural defenses against caries
Abstract
Destruction of tooth tissues due to various microorganisms is
slowed or prevented by introducing into the mouth arginine or an
arginine precursor, especially peptides having from 2-4 amino acid
units at least one of which is arginine.
Inventors: |
Kleinberg; Israel (Smithtown,
NY) |
Family
ID: |
26858454 |
Appl.
No.: |
06/162,102 |
Filed: |
June 23, 1980 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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697538 |
Jun 18, 1976 |
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Reissue of: |
868933 |
Jan 12, 1978 |
04154813 |
May 15, 1979 |
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Current U.S.
Class: |
424/48; 260/1;
424/49; 424/52; 424/54; 514/16.7; 514/21.9; 514/21.91; 530/330;
530/331 |
Current CPC
Class: |
A61Q
11/00 (20130101); A61K 8/64 (20130101) |
Current International
Class: |
A61K 009/68 ();
A61K 007/16 (); A61K 007/18 (); A61K 007/22 (); A61K
037/00 (); C07C 103/52 () |
Field of
Search: |
;424/52,54,48,49,177
;260/112.5R |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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270399 |
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Nov 1963 |
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AU |
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269188 |
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Jan 1965 |
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AU |
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272332 |
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Apr 1965 |
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AU |
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Other References
Kleinberg, J. of Dental Research 49, (1970), 1300-1316. .
Kleinberg, Archs Oral Biol. 18, 787-798 (1973). .
Kleinberg, Biochemistry of the Dental Plaque, 1970, pp. 43-89, vol.
4. .
Kleinberg, et al., Microbial Aspects of Dental Caries, pp. 433-464
(1977). .
Fosdick, J. Dental Res., vol. 38, No. 3, 519-524, (1959). .
Calandra, S. Dental Res., vol. 26, pp. 303-308, 1947. .
Science, vol. 122, pp. 557-558. .
Kleinberg, et al., Caries Research 11, 1977, 292-320. .
Kleinberg, Oral Microbiology, 3 ed., 1977, chapter 19, 515-534.
.
Pettit, Synthetic Peptides, vol. I, pp. 82-83, 88-89,
190-191..
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Primary Examiner: Phillips; Delbert R.
Parent Case Text
RELATED APPLICATION
The present application is a continuation in-part of applicant's
Application Ser. No. 697,538 filed June 18, 1976 now abandoned.
Claims
What is claimed is
1. A method for supplementing the body's resistance to caries which
comprises providing to the mouth an effective amount of a caries
combatting pH rise factor which is .[.a peptide.]. .Iadd.a source
of pH adjusting compound or precursor thereof .Iaddend.having 2-4
amino acid units at least one of which is arginine.
2. A method as set forth in claim 1 wherein the pH rise factor is
provided in concentrations of from about 0.05 mM to about 3 mM.
3. A method as set forth in claim 1 wherein the pH rise factor is
provided in combination with a dental care product.
4. A method as set forth in claim 1 wherein the pH rise factor is
provided in a food product.
5. A method as set forth in claim 1 wherein the pH rise factor is
provided in combination with chewing gum. .Iadd. 6. The method
according to claims 1, 3, 4 or 5 wherein said pH-rise factor is
applied to the mouth in association with fluoride ions.
.Iaddend..Iadd. 7. The method according to claim 1 wherein said
pH-rise factor is provided to the mouth in a mouth wash.
.Iaddend..Iadd. 8. The method according to claim 1 wherein said
pH-rise factor is provided to the mouth in tooth paste.
.Iaddend..Iadd. 9. The method according to claim 1 wherein said
pH-rise factor is provided in tooth powder..Iaddend.
Description
BACKGROUND OF THE INVENTION
The present invention salutary based on two well accepted
observations. Caries is more likely to occur when the pH of the
mouth falls below a certain critical level depending on the
resistance of the individual and on the duration for which the
critical level is exceeded. The second observation is the
recognition that saliva itself has a satutary effect on the
aforementioned caries causing factors which include some means for
raising oral pH.
THE PRESENT INVENTION
It has been clear for some time that when an abundance of
carbohydrates, particularly sugar, is present in the mouth,
conditions favoring the production of an acid pH in plaque are sure
to be present. The plaque microflora form acid from exogenous or
endogenous carbohydrate. The balancing of this acid production has
been observed to be my means of producing alkaline substances which
neutralize the cariogenic acids derived from the carbohydrates and
return the pH of tooth surfaces to a level above that at which
caries will occur.
The present invention relates to providing a means to enhance the
natural defenses of the body against tooth caries when the latter
are by cariogenic acids. If further is directed to replacing or
supplementing the natural protective function of saliva when it is
diminished by atrophy of the salivary glands or other impairments
which diminish the secretion of saliva or the protective capability
thereof.
It is an object of the present invention to provide a replacement
or supplement to the caries protective portion of saliva.
It is a further object to diminish or eliminate caries in otherwise
susceptible individuals by supplying suitable sources of pH
adjusting compound or precursors thereof.
Another object of the present invention is the utilization of
arginine precursors particularly peptides having 2-4 amino acid
units, one or more of which is arginine as the pH adjusting
means.
It has been observed that plaque, the closely adhering spongy
organic material found on tooth surfaces accepts within its matrix
molecules of certain size and shape. Peptides are among those
compounds which can penetrate plaque. It has been shown that these
compounds penetrate bacteria present in the mouth. It has been
discovered that the material which most readily counteracts the
acid produced when an abundance of carbohydrate, particularly
sugar, is present is arginine. Surprisingly, it has been determined
that peptide of 2-4 amino acid units, one or more of which is
arginine, is effective in restoring mouth pH to a non-carious
level.
It has been determined that generally, caries resulting from an
acidic pH nearly invariably occurs when a pH of about 5 or 5.1
occurs for a sufficient time while with only rare exceptions will
caries occur if the pH is maintained at 6.1 or higher.
The question of duration of exposure of enamel to a pH lower than
about pH 5 varies with individuals but certain generalities have
been determined. Two schemes of activity may be posited. In the
first, the mouth is exposed to a limited amount of fermentable
carbohydrate, usually sugar, after which the bacteria present in
plaque convert the carbohydrate to acids, mainly acetic, lactic and
propionic. In this case the pH drops as the above indicated acids
are produced and a slow countering production of alkaline amines
occurs as susceptible peptides or proteins give up amino acids
which are decarboxylated by other oral bacteria. The two
antagonistic reactions occur at rates such that the pH drop which
is achieved between about 5 and 15 minutes will usually reach the
pH level critical to the formation of caries unless the pH rise
factor which has been found to be arginine and its precursors is
present and is acted upon by oral bacteria so that the pH fall is
reduced and the pH begins to return to the normal by the end of
about 45 minutes to 1 hour depending upon the particular mouth.
A second situation is represented by an availability of greater
amounts of fermentable carbohydrate available for a longer time.
The mouth pH in this case goes below pH 5 which is conducive to the
formation of caries after about 15 minutes and remains there while
the excess of fermentable carbohydrate is available. This can be
for a period of 2 or more hours. It is under these conditions that
a more serious carious attack occurs but in the presence of the pH
rise factor the duration is reduced.
Experiments were performed in vitro using supernatant saliva. The
saliva was obtained from random donors whose salivary secretions
were paraffin block stimulated. The saliva donations were pooled
before and after sediment removal.
A naturally occurring effective peptide in saliva has the
arrangement H-glycine-glycine-lysine-arginine-OH with amino and
carboxyl termini. This compound was synthesized by conventional
methods and has proven effective for the purposes of this invention
and is a preferred pH rise factor. It being a compound which occurs
naturally, it is a first choice, but the possibility of peptides
having two or more arginine units might prove even more
effective.
The arginine containing peptide rapidly enters plaque and also
enters bacteria itself. The peptide is stored there protected from
dilution providing a potential source of alkaline material to
counter-act acid formation activated by the presence of dietary
carbohydrate. This storage capability suggests inclusion of the
peptide pH rise factor in common dental products such as tooth
pastes, tooth powders, mouthwashes, chewing gum and the like.
It has further been found that the oligomeric peptide pH rise
factor is effective even when provided to the mouth simultaneously
with carbohydrate substances which are operated upon by plaque
bacteria to produce acids. The addition of the pH rise factor to
carbohydrate containing substances such as sugared cereals, candy
or chewing gum is an effective means for supplementing the natural
defenses of the body against caries.
The arginine containing peptides are particularly suited as food
additives in that many occur in nature, particularly the preferred
one of the present invention.
They are generally heat stable, tasteless, odorless and soluble in
amounts beyond their effective level. They are esthetically
acceptable as used.
The pH differences in the mouths of caries prone and caries free
subjects can be minimized by adding pH rise factor supplement to
the former. This is effective in proportion to the amounts of an
arginine containing peptide provided. A significant effect is
produced with as little as 0.05 mM while as such as 3 mM and more
continued to show improvement.
Particularly interesting cooperation between the pH rise factor and
fluoride ions has been observed. Fluoride ions in minor amounts
such as about 5 ppm reduces tooth solubility generally. It further
inhibits the pH fall when the pH drops below about 5. The pH fall
in the case of high sugar availability to 4.8 is held to 5.1 when 5
ppm of fluoride is present. This is about as high as fluoride ions
alone can return the pH. When the pH rise factor of the present
invention is also present, fluoride still inhibits the pH fall but
the pH recovers earlier to safe levels of pH than when no factor is
present.
The following are given by way of exemplification and not by way of
limitation.
Four sets of three 10.times.75 mm test tubes were provided with 0.2
ml of 8.4 mM (millimolar) of aqueous glucose solution. Set I was
provided with 0.2 ml of pooled supernatant saliva. Set II was
provided with 0.2 ml of 9.9 mM of the peptide
glycine-glycine-arginine. Set III was provided with 0.2 ml of 9.9
mM arginine. Set IV was provided with 0.2 ml of distilled water.
Sequentially 0.2 ml of a 50:50 aqueous suspension of oral bacteria
was added to each test tube. The concentration of the peptide in
the combined composition was 3.3 mM. The prepared test tubes were
kept at 37.degree. C. in a water bath. pH readings were taken at 0
time when the bacteria were added and at 15, 30, 45, 60, 90, 120,
180 and 240 minutes. The pH values are as follows:
______________________________________ TIME (minutes) 0 15 30 45 60
90 120 180 240 ______________________________________ Set I 7.4 6.2
5.9 6.1 6.3 6.4 6.5 6.6 6.6 Set II 7.4 6.8 6.6 6.4 6.6 6.6 6.7 7.2
7.6 Set III 7.3 5.8 5.4 5.2 4.9 5.0 5.0 5.3 5.8 Set IV 7.3 5.8 5.2
4.9 4.7 4.6 4.5 4.5 4.5 ______________________________________
It is clear that supernatant saliva and an arginine providing
supplement slows the pH fall in a carbohydrate rich environment. It
is also evident that an arginine providing peptide is preferred to
arginine alone. In similar experiments, an arginine providing
peptide supplement acts to moderate the pH drop more than either
saliva alone or arginine alone and restores the pH to its initial
level or better.
The identification of the arginine providing peptide pH rise factor
suggests other areas wherein arginine containing peptides could be
utilized. These compounds could be used in the regulation of many
processes involving microorganisms such as bacterial fermentations,
wine making, antibiotic production, citric acid formation and
others.
Extensive testing of individual peptides of 2-4 amino acid units as
could reasonably be obtained or synthesized was done. The tests
were carried out under the same conditions as Sets I-IV. The
salivary sediment was present in an amount of 16.7% (v/v), glucose
2.8 mM and the peptide 3.3 mM in the final composition.
Duplicate runs without peptide were run parallel to the others as a
double check. The pH starts at slightly above 7 and falls rapidly
to between 4.5-5. An effective pH rise factor begins to reverse the
fall within the first hour. Measurement continues through the
fourth hour. The results were as follows:
______________________________________ Arg--Leu pH drop to 5.5,
rising to about 7-8 Lys--Leu pH drop to 5.2 rising to about 5.5
Pro--Pro no significant pH rise Pro--Pro--Pro no significant pH
rise Pro--Ala no significant pH rise Meth--Pro no significant pH
rise Arg--Ser pH drop to about 5.5, rising to about 7. Lys--Ser pH
drop to about 5.3, rising to about 5.6 His--Meth pH drop to about
5.4, rising to about 5.5 Asp-Arg pH drop to about 5.4, rising to
about 6.8 Phe--Arg pH drop to about 5, rising to 6.8-7.8 Gly--Arg
pH drop to about 5.2, rising to 7.5 Arg--Gly pH drop to about 5.5,
rising to 7-7.9 Arg--Lys pH drop to about 6-6.7, rising to 7.2-8
Gly--Gly--Pro no significant pH rise Gly--Gly--Gly no significant
pH rise Gly--Gly--Arg pH drop to 5.5, rising to 7.5
Gly--Gly--Lys--Arg pH drop to 6.4, rising to 8.4
______________________________________
It is clear from the representative results that peptides of 2-4
amino acid units one or more of which is arginine constitute
providers of a pH rise factor. This is so whether the arginine
moiety is linked to the other amino acids of the peptide by the
carboxyl or amino group.
The invention has been described with respect to certain preferred
embodiments but it will be understood that variations and
modifications may be made therein without departing from the spirit
of this invention and the scope of the appended claims.
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