U.S. patent application number 15/955798 was filed with the patent office on 2018-08-16 for amino acid derivatives and their uses.
The applicant listed for this patent is Johnson & Johnson Consumer Inc.. Invention is credited to Robert J. Gambogi, Anthony R. Geonnotti, III, Michael C. Giano, Latrisha Petersen.
Application Number | 20180230089 15/955798 |
Document ID | / |
Family ID | 54705836 |
Filed Date | 2018-08-16 |
United States Patent
Application |
20180230089 |
Kind Code |
A1 |
Gambogi; Robert J. ; et
al. |
August 16, 2018 |
Amino Acid Derivatives and Their Uses
Abstract
Provided are compounds described by the Formula I: ##STR00001##
wherein: R.sub.1 is a linear or branched, saturated or unsaturated
aliphatic group having from 5 to 22 carbon atoms; R.sub.2 is
selected from the group consisting of the functional groups:
--NH.sub.2; ##STR00002## and salts thererof; n is from 0 to 4; and
R.sub.3 is a linear or branched, saturated or unsaturated aliphatic
group having from 1 to 6 carbon atoms. Also provided are
compositions comprising, and methods of use of, the compounds of
the present invention.
Inventors: |
Gambogi; Robert J.;
(Hillsborough, NJ) ; Geonnotti, III; Anthony R.;
(Princeton, NJ) ; Giano; Michael C.; (Southampton,
NJ) ; Petersen; Latrisha; (Highland Park,
NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Johnson & Johnson Consumer Inc. |
Skillman |
NJ |
US |
|
|
Family ID: |
54705836 |
Appl. No.: |
15/955798 |
Filed: |
April 18, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
14938334 |
Nov 11, 2015 |
9975847 |
|
|
15955798 |
|
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|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 8/43 20130101; A61K
8/44 20130101; A61Q 11/00 20130101; C07C 279/12 20130101; C07C
237/22 20130101 |
International
Class: |
C07C 279/12 20060101
C07C279/12; C07C 237/22 20060101 C07C237/22; A61K 8/43 20060101
A61K008/43; A61K 8/44 20060101 A61K008/44; A61Q 11/00 20060101
A61Q011/00 |
Claims
1. A method of inhibiting plaque in the oral cavity comprising
contacting a surface of the oral cavity with a compound Formula I:
##STR00034## wherein: R.sub.1 is a linear or branched, saturated or
unsaturated aliphatic group having from 5 to 22 carbon atoms;
R.sub.2 is selected from the group consisting of the functional
groups: --NH.sub.2; ##STR00035## and salts thererof, said salts
having an anion X.sup.- preferably selected from the group
consisting of acetate, benzoate, besylate, bromide, chloride,
chlortheophyllinate, citrate, ethandisulfonate, fumarate,
gluconate, hippurate, iodide, fluoride, lactate, laurylsulfate,
malate, laeate, mesylate, methysulfate, napsylate, nitrate,
octadecanoate, oxalate, pamoate, phosphate, polygalacturonate,
succinate, sulfate, tartrate, and tosylate; n is from 0 to 4; and
R.sub.3 is a linear or branched, saturated or unsaturated aliphatic
group having from 1 to 6 carbon atoms.
2. The method of claim 1 wherein R.sub.1 is a C.sub.7-C.sub.17
alkyl group.
3. The method of claim 2 wherein R.sub.3 is a C.sub.1-C.sub.6 alkyl
group
4. The method of claim 1 having a formula selected from the group
consisting of: ##STR00036##
[amino({[4-(methylcarbamoyl)-4-octanamidobutyl]amino})methylidene]azanium
##STR00037##
[amino({[4-(ethylcarbamoyl)-4-octanamidobutyl]amino})methylidene]azanium
##STR00038##
[amino({[4-(hexylcarbamoyl)-4-octanamidobutyl]amino})methylidene]azanium
##STR00039##
[amino({[4-dodecanamido-4-(methylcarbamoyl)butyl]amino})methylidene]azani-
um ##STR00040##
[amino({[4-dodecanamido-4-(ethylcarbamoyl)butyl]amino})methylidene]azaniu-
m ##STR00041##
[amino({[4-dodecanamido-4-(hexylcarbamoyl)butyl]amino})methylidene]azaniu-
m ##STR00042##
[amino({[4-(methylcarbamoyl)-4-octadecanamidobutyl]amino})methylidene]aza-
nium ##STR00043##
[amino({[4-(ethylcarbamoyl)-4-octadecanamidobutyl]amino})methylidene]azan-
ium ##STR00044##
[amino({[4-(hexylcarbamoyl)-4-octadecanamidobutyl]amino})methylidene]azan-
ium ##STR00045##
[amino({[5-dodecanamido-5-(ethylcarbamoyl)pentyl]amino})methylidene]azani-
um ##STR00046## N-[5-amino-1-(ethylcarbamoyl)pentyl]dodecanamide
##STR00047## N-[4-amino-1-(ethylcarbamoyl)butyl]dodecanamide
##STR00048## N-[2-amino-1-(ethylcarbamoyl)ethyl]dodecanamide and
##STR00049##
5. The method of claim 4 having the formula: ##STR00050##
6. The method of claim 1 wherein R.sub.2 is a guanidinyl functional
group in its free base form or a salt thereof; n is 3 or 4; R.sub.3
is an ethyl group; and R.sub.1 is a linear or branched, saturated
or unsaturated aliphatic group having from 9 to 16 carbon
atoms.
7. The method of claim 6 wherein n is 3 and R.sub.1 is an alkyl
group having from about 11 to about 13 carbon atoms.
8. The method of claim 1 wherein R.sub.2 is a guanidinyl functional
group in its free base form or a salt thereof; n is 3; R.sub.1 is a
linear or branched, saturated or unsaturated aliphatic group having
about 11 carbon atoms; and R.sub.3 is a linear or branched,
saturated or unsaturated aliphatic group having a carbon chain
length of about 1 to 11 carbon atoms.
9. The method of claim 8 wherein R.sub.1 is an alkyl group having
about 11 carbon atoms and R.sub.3 is an alkyl group having a carbon
chain length of about 2 to 8 carbon atoms.
10. The c method of claim 1 wherein R.sub.2 is a guanidinyl
functional group in its free base form or a salt thereof; n is 3;
R.sub.1 is a linear or branched, saturated or unsaturated aliphatic
group having about 7 carbon atoms; and R.sub.3 is a linear or
branched, saturated or unsaturated aliphatic group having a carbon
chain length of about 7 to 16 carbon atoms.
11. The method of claim 10 wherein R.sub.1 is an alkyl group having
about 7 carbon atoms and R.sub.3 is an alkyl group having a carbon
chain length of about 7 to 11 carbon atoms.
12. The method of claim 1 wherein R.sub.2 is an amine group in its
free base form (--NH.sub.2) or a salt thereof; and n is 1, 3, or
4.
13. The method of claim 12 wherein n is 3; R.sub.1 is a linear or
branched, saturated or unsaturated aliphatic group having about 7
carbon atoms; and R.sub.3 is a linear or branched, saturated or
unsaturated aliphatic group having a carbon chain length of about 1
to 11 carbon atoms.
14. The method of claim 13 wherein R.sub.1 is an alkyl group having
about 7 carbon atoms and R.sub.3 is an alkyl group having a carbon
chain length of about 8 to 11 carbon atoms.
15. The method of claim 12 wherein n is 3; R.sub.1 is a linear or
branched, saturated or unsaturated aliphatic group having about 11
carbon atoms; and R.sub.3 is a linear or branched, saturated or
unsaturated aliphatic group having a carbon chain length of about 1
to 11 carbon atoms.
16. The method of claim 15 wherein R.sub.1 is an alkyl group having
about 11 carbon atoms and R.sub.3 is an alkyl group having a carbon
chain length of about 2 to 6 carbon atoms.
17. The method of claim 1 wherein the compound is selected from the
group consisting of: ##STR00051##
[amino({[4-(methylcarbamoyl)-4-octanamidobutyl]amino})methylidene]azanium
##STR00052##
[amino({[4-(ethylcarbamoyl)-4-octanamidobutyl]amino})methylidene]azanium
##STR00053##
[amino({[4-(hexylcarbamoyl)-4-octanamidobutyl]amino})methylidene]azanium
##STR00054##
[amino({[4-dodecanamido-4-(methylcarbamoyl)butyl]amino})methylidene]azani-
um ##STR00055##
[amino({[4-dodecanamido-4-(ethylcarbamoyl)butyl]amino})methylidene]azaniu-
m ##STR00056##
[amino({[4-dodecanamido-4-(hexylcarbamoyl)butyl]amino})methylidene]azaniu-
m ##STR00057##
[amino({[4-(methylcarbamoyl)-4-octadecanamidobutyl]amino})methylidene]aza-
nium ##STR00058##
[amino({[4-(ethylcarbamoyl)-4-octadecanamidobutyl]amino})methylidene]azan-
ium ##STR00059##
[amino({[4-(hexylcarbamoyl)-4-octadecanamidobutyl]amino})methylidene]azan-
ium ##STR00060##
[amino({[5-dodecanamido-5-(ethylcarbamoyl)pentyl]amino})methylidene]azani-
um; and ##STR00061##
N-(5-guanidino-1-oxo-1-(undecylamino)pentan-2-yl)octanamide.
18. The method of claim 1 wherein the compound is selected from the
group consisting of: ##STR00062##
N-[5-amino-1-(ethylcarbamoyl)pentyl]dodecanamide ##STR00063##
N-[2-amino-1-(ethylcarbamoyl)ethyl]dodecanamide ##STR00064##
N-[4-amino-1-(ethylcarbamoyl)butyl]dodecanamide ##STR00065##
N-(5-amino-1-(hexylamino)-1-oxopentan-2-yl)dodecanamide
##STR00066##
N-(5-amino-1-oxo-1-(undecylamino)pentan-2-yl)octanamide; and
##STR00067##
N-(5-amino-1-(octylamino)-1-oxopentan-2-yl)octanamide.
19. The method of claim 1 wherein R.sub.1 is a C.sub.7-C.sub.11
alkyl group.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This is a divisional application which claims the benefit of
U.S. patent application Ser. No. 14,938,334 filed Nov. 11, 2015,
which application claims the benefit of U.S. Provisional
Application Ser. No. 62/078,187, filed Nov. 11, 2014.
BACKGROUND
[0002] A variety of amino acid derivatives are known in the art for
a variety of uses. For example, U.S. Pat. No. 5,874,068,
WO2003/013454, and US2010/0330136 disclose the use of Lauryl
arginine ethyl ester ("LAE"), and certain related compounds, for
use in oral compositions. In addition, LAE is currently used in
hydroalcoholic mouth rinses to prevent bacterial attachment.
However, applicants have recognized that LAE tends to lack
sufficient stability to be useful in low-alcohol or alcohol-free
mouth rinses.
[0003] In addition, other documents such as WO2008/137758A2 and
WO2000/011022 disclose broad classes of compounds, which may
include certain amino acid derivatives, for uses such as for drug
delivery or anti-tumor end benefits, respectively.
BRIEF DESCRIPTION OF THE DRAWINGS
[0004] FIG. 1 is an HPLC chromatograph and a mass spectrometry
graph of
[amino({[4-dodecanamido-4-(ethylcarbamoyl)butyl]amino})methylidene]azaniu-
m.
[0005] FIG. 2 is a drawing of the chemical structure and mass
spectrometry graph of
[amino({[4-dodecanamido-4-(ethylcarbamoyl)butyl]amino})methylide-
ne]azanium.
[0006] FIG. 3: is a .sup.1H-NMR graph of
[amino({[4-dodecanamido-4-(ethylcarbamoyl)butyl]amino})methylidene]azaniu-
m.
DESCRIPTION OF THE INVENTION
[0007] The present invention relates to new amino acid derivatives
developed by applicants that are described by the Formula I:
##STR00003##
wherein:
[0008] R.sub.1 is a linear or branched, saturated or unsaturated
aliphatic group having from 5 to 22 carbon atoms;
[0009] R.sub.2 is selected from the group consisting of the free
base and corresponding salt forms of the functional groups: [0010]
--NH.sub.2;
[0010] ##STR00004## [0011] said salt versions having an anion
X.sup.- preferably selected from the group consisting of acetate,
benzoate, besylate, bromide, chloride, chlortheophyllinate,
citrate, ethandisulfonate, fumarate, gluconate, hippurate, iodide,
fluoride, lactate, laurylsulfate, malate, laeate, mesylate,
methysulfate, napsylate, nitrate, octadecanoate, oxalate, pamoate,
phosphate, polygalacturonate, succinate, sulfate, tartrate, and
tosylate;
[0012] n is from 0 to 4; and
[0013] R.sub.3 is a linear or branched, saturated or unsaturated
aliphatic group having from 1 to 6 carbon atoms.
[0014] The compositions of Formula I may have any suitable linear
or branched, saturated or unsaturated aliphatic group having from 5
to 22 carbons for R.sub.1. Examples of suitable linear or branched,
saturated or unsaturated aliphatic groups having from 5 to 22
carbons include, C.sub.5 to C.sub.22 linear or branched alkyl
groups, such as, pentyl, hexyl, heptyl, octyl, nonyl, decyl,
undecyl, dodecyl, up to docosanyl, and the like; as well as,
C.sub.5 to C.sub.22 linear or branched alkylene groups such as
myristolyl up to docasanhexayl, and the like.
[0015] In certain embodiments, R.sub.1 is linear or branched alkyl
group having a carbon chain of from 5 to 22 carbons atoms,
including for example, pentyl, hexyl, heptyl, octyl, nonyl, decyl,
undecyl, dodecyl up to docasonyl. In certain other embodiments,
R.sub.1 is linear or branched alkyl group having a carbon chain of
from 7 to 18 carbons atoms, including for example, heptyl, octyl,
nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl,
hexadecyl, heptadecyl and octadecyl. In still other embodiments,
R.sub.1 is linear or branched alkyl group having a carbon chain of
from 9 to 14 carbons atoms, including for example, decyl, undecyl,
dodecyl up to tetradecyl. In certain embodiments, R.sub.1 is an
undecyl group. In certain embodiments, R.sub.1 is a heptyl group.
In certain embodiments, R.sub.1 is a heptadecyl group.
[0016] In certain embodiments, R.sub.1 is linear or branched
alkenyl group having a carbon chain of from 5 to 22 carbons atoms,
including for example, 9-hexadecenyl, 9-octadecenyl, 11-decenyl,
9,12-octadecandienyl, 9,12,15-octadecatrienyl,
6,9,12-octadecatrienyl, 9-eicosenyl, 5,8,11,14-eicosatetraenyl,
13-docosenyl and 4,7,10,13,16,19-docosaheaenyl. In certain other
embodiments, R.sub.1 is linear or branched alkenyl group having a
carbon chain of from 16 to 20 carbons atoms, including for example,
9-hexadecenyl, 9-octadecenyl, 11-decenyl, 9,12-octadecandienyl,
9,12,15-octadecatrienyl, and 6,9,12-octadecatrienyl.
[0017] In certain embodiments, R.sub.1 is a branched alkyl group
having a carbon chain of from 5 to 22 carbons atoms, including for
example, 2-decyldodecanyl, 2-nonyltridecanyl, 2-octyltetradecanyl,
2-heptylpentadecanyl, 2-hexylhexadecanyl, 2-pentylheptadecanyl,
21-methylicosanyl, 18-ethylicosanyl, 16-propylnonadecyl, and
14-butyloctadecyl.
[0018] The compositions of Formula I may comprise an R.sub.2 group
that is an amine group in its free base form (--NH.sub.2) or a salt
thereof, or a guanidinyl functional group in its free base form
(--NH(CNH)NH.sub.2) or a salt thereof. Examples of suitable amine
salts and guanidinyl salts include salts of such groups having an
anion (X--) selected from the group consisting of acetate,
benzoate, besylate, bromide, chloride, chlortheophyllinate,
citrate, ethandisulfonate, fumarate, gluconate, hippurate, iodide,
fluoride, lactate, laurylsulfate, malate, laeate, mesylate,
methysulfate, napsylate, nitrate, octadecanoate, oxalate, pamoate,
phosphate, polygalacturonate, succinate, sulfate, tartrate, and
tosylate. In certain embodiments, the composition of the present
invention has an R.sub.2 group that is an amine group in its free
base form (--NH.sub.2). In certain other embodiments, the
composition of the present invention has an R.sub.2 group that is
an a guanidinyl group in its free base form (--NH(CNH)NH.sub.2). In
certain embodiments, the composition of the present invention has
an R.sub.2 group that is an amine salt having an anion selected
from the group consisting of acetate, benzoate, besylate, bromide,
chloride, chlortheophyllinate, citrate, ethandisulfonate, fumarate,
gluconate, hippurate, iodide, fluoride, lactate, laurylsulfate,
malate, laeate, mesylate, methysulfate, napsylate, nitrate,
octadecanoate, oxalate, pamoate, phosphate, polygalacturonate,
succinate, sulfate, tartrate, and tosylate. In certain other
embodiments, the R.sub.2 amine salt has an anion selected from the
group consisting of acetate, benzoate, bromide, chloride, citrate,
fumarate, gluconate, iodide, fluoride, lactate, malate, nitrate,
oxalate, phosphate, sulfate, and in certain other embodiments an
anion selected from the group consisting of bromide, chloride,
iodide, fluoride, oxalate, and phosphate. In addition, in certain
embodiments, the composition of the present invention has an
R.sub.2 group that is a guanidinyl salt having an anion selected
from the group consisting of acetate, benzoate, besylate, bromide,
chloride, chlortheophyllinate, citrate, ethandisulfonate, fumarate,
gluconate, hippurate, iodide, fluoride, lactate, laurylsulfate,
malate, laeate, mesylate, methysulfate, napsylate, nitrate,
octadecanoate, oxalate, pamoate, phosphate, polygalacturonate,
succinate, sulfate, tartrate, and tosylate. In certain other
embodiments, the R.sub.2 guanidinyl salt has an anion selected from
the group consisting of acetate, benzoate, bromide, chloride,
citrate, fumarate, gluconate, iodide, fluoride, lactate, malate,
nitrate, oxalate, phosphate, sulfate, and in certain other
embodiments an anion selected from the group consisting of bromide,
chloride, iodide, fluoride, oxalate, and phosphate.
[0019] The compositions of Formula I may have any suitable linear
or branched, saturated or unsaturated aliphatic group having from 1
to 6 carbons for R.sub.3. Examples of suitable linear or branched,
saturated or unsaturated aliphatic groups having from 1 to 6
carbons include, C.sub.1 to C.sub.6 linear or branched alkyl
groups, such as, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl, pentyl, tert-pentyl, neopentyl, isopentyl,
hexyl, isohexyl, neohexyl; as well as, C.sub.2 to C.sub.6 linear or
branched alkenyl groups such as vinyl, allyl, propenyl, butenyl,
pentenyl, hexenyl, and the like. In certain embodiments, R.sub.3 is
linear or branched alkyl group having a carbon chain of from 1 to 4
carbons atoms, including for example, methyl, ethyl, propyl,
isopropyl, butyl, sec-butyl, isobutyl, and tert-butyl. In certain
other embodiments, R.sub.3 is linear or branched alkyl group having
a carbon chain of from 1 to 3 carbons atoms, including for example,
methyl, ethyl, propyl and isopropyl. In certain embodiments,
R.sub.3 is an ethyl group.
[0020] In certain embodiments, R.sub.3 is linear or branched
alkenyl group having a carbon chain of from 2 to 6 carbons atoms,
including for example, vinyl, allyl, propenyl, butenyl, pentenyl,
hexenyl, and the like as well as mixture thereof. In certain other
embodiments, R.sub.3 is linear or branched alkylene group having a
carbon chain of from 2 to 4 carbons atoms, including for example,
vinyl, allyl, propenyl, and butenyl.
[0021] In the compounds of Formula I, n can be from zero to four.
In certain embodiments, n is from 1 to 4, in certain embodiments
from 2 to 4, in certain embodiments 3 to 4. In certain particular
embodiments, n is 0. In certain other embodiments n is 1, in other
embodiments n is 2 in other embodiments n is 3 and in other
embodiments n is 4.
[0022] According to certain embodiments of the invention, the
compounds of Formula I are compounds wherein R.sub.2 is a
guanidinyl functional group in its free base form
(--NH(CNH)NH.sub.2) or a salt thereof; n is 3 or 4, preferably 3;
R.sub.3 is an aliphatic group having a carbon chain of about 2
carbons atoms, for example an ethyl group; and R.sub.1 is a linear
or branched, saturated or unsaturated aliphatic group, including
for example an alkyl group, having from 9 to 16 carbon atoms,
including from about 10 to about 16 carbon atoms, about 10 to about
15 carbon atoms, about 10 to about 14 carbon atoms, about 10 to
about 13 carbon atoms, about 11 to about 14 carbon atoms, about 11
to about 15 carbon atoms, about 11 to about 16 carbon atoms, and
about 11, and/or about 13 carbon atoms.
[0023] In certain other embodiments, the compounds of Formula I are
compounds wherein R.sub.2 is a guanidinyl functional group in its
free base form (--NH(CNH)NH.sub.2) or a salt thereof; n is 3;
R.sub.1 is a linear or branched, saturated or unsaturated aliphatic
group, including for example an alkyl group, having about 11 carbon
atoms; and R.sub.3 is a linear or branched, saturated or
unsaturated aliphatic group, including for example an alkyl group,
having a carbon chain length of about 1 to 11 carbons atoms,
including from about 2 to about 10 carbon atoms, about 2 to about 9
carbon atoms, about 2 to about 8 carbon atoms, about 3 to about 11
carbon atoms, about 3 to about 10 carbon atoms, about 3 to about 9
carbon atoms, about 3 to about 8 carbon atoms, and about 2, about
6, and/or about 8 carbon atoms.
[0024] In certain other embodiments, the compounds of Formula I are
compounds wherein R.sub.2 is a guanidinyl functional group in its
free base form (--NH(CNH)NH.sub.2) or a salt thereof; n is 3;
R.sub.1 is a linear or branched, saturated or unsaturated aliphatic
group, including for example an alkyl group, having about 7 carbon
atoms; and R.sub.3 is a linear or branched, saturated or
unsaturated aliphatic group, including for example an alkyl group,
having a carbon chain length of about 7 to 16 carbons atoms,
including from about 7 to about 15 carbon atoms, about 7 to about
14 carbon atoms, about 7 to about 13 carbon atoms, about 7 to about
12 carbon atoms, about 7 to about 11 carbon atoms, and about 7,
and/or about 11 carbon atoms.
[0025] In certain other embodiments, the compounds of Formula I are
compounds wherein R.sub.2 is an amine group in its free base form
(--NH.sub.2) or a salt thereof; and n is 1, 3, or 4. Examples of
such compounds include those wherein n is 3; R.sub.1 is a linear or
branched, saturated or unsaturated aliphatic group, including for
example an alkyl group, having about 7 carbon atoms; and R.sub.3 is
a linear or branched, saturated or unsaturated aliphatic group,
including for example an alkyl group, having a carbon chain length
of about 1 to 11 carbons atoms, including from about 2 to about 10
carbon atoms, about 2 to about 9 carbon atoms, about 2 to about 8
carbon atoms, about 3 to about 11 carbon atoms, about 3 to about 10
carbon atoms, about 3 to about 9 carbon atoms, about 3 to about 8
carbon atoms, and about 8, and/or about 11 carbon atoms. Other
Examples include compounds wherein n is 3; R.sub.1 is a linear or
branched, saturated or unsaturated aliphatic group, including for
example an alkyl group, having about 11 carbon atoms; and R.sub.3
is a linear or branched, saturated or unsaturated aliphatic group,
including for example an alkyl group, having a carbon chain length
of about 1 to 11 carbons atoms, including from about 1 to about 10
carbon atoms, about 1 to about 9 carbon atoms, about 1 to about 8
carbon atoms, about 1 to about 7 carbon atoms, about 1 to about 6
carbon atoms, about 2 to about 11 carbon atoms, about 2 to about 10
carbon atoms, about 2 to about 9 carbon atoms, about 2 to about 8
carbon atoms, about 2 to about 7 carbon atoms, about 2 to about 6
carbon atoms, and about 2 and/or about 6 carbon atoms.
[0026] One example of a compound of Formula I of the present
invention is
[amino({[4-dodecanamido-4-(ethylcarbamoyl)butyl]amino})methylidene]azaniu-
m (compound 9) as shown below.
##STR00005##
As shown in the formula above, compound 9 represents a compound of
Formula I wherein R.sub.1 is an undecyl group, R.sub.2 is a
guanidinyl group in its free base form, R.sub.3 is an ethyl group,
and n is 3.
[0027] Other examples of compounds of the present invention
include, but are not limited to compounds described by the
formulae:
##STR00006##
[amino({[4-(methylcarbamoyl)-4-octanaidobutyl]amino})methyidene]azanium
##STR00007##
[0028]
[amino({[4-(ethylcarbamoyl)-4-octanamidobutyl]amino})methylidene]az-
anium
##STR00008##
[0029]
[amino({[4-(hexylcarbamoyl)-4-octanamidobutyl]amino})methylidene]az-
anium
##STR00009##
[0030]
[amino({[4-dodecanamido-4-(methylcarbamoyl)butyl]amino})methylidene-
]azanium
##STR00010##
[0031]
[amino({[4-dodecanamido-4-(hexylcarbamoyl)butyl]amino})methylidene]-
azanium
##STR00011##
[0032]
[amino({[4-dodecanamido-4-(hexylcarbamoyl)butyl]amino})methylidene]-
azanium
##STR00012##
[0033]
[amino({[4-(ethylcarbamoyl)-4-octadecanamidobutyl]amino})methyliden-
e]azanium
##STR00013##
[0034]
[amino({[4-(hexylcarbamoyl)-4-octadecanamidobutyl]amino})methyliden-
e]azanium
##STR00014##
[0035]
[amino({[5-dodecanamido-5-(ethylcarbamoyl)pentyl]amino})methylidene-
]azanium
##STR00015##
[0036] N-[5-amino-1-(ethylcarbamoyl)pentyl]dodecanamide
##STR00016##
[0037] N-[4-amino-1-(ethylcarbamoyl)butyl]dodecanamide
##STR00017##
[0038] N-[2-amino-1-(ethylcarbamoyl)ethyl]dodecanamide
##STR00018##
[0039] 3-dodecanamido-4-(ethylamino)-4-oxobutanoic acid
##STR00019##
[0040]
N-(1-(ethylamino)-3-hydroxy-1-oxopropan-2-yl)dodecanamide
##STR00020##
[0041] 2-dodecanamido-3-(ethylamino)-3-oxopropyl dihydrogen
phosphate
##STR00021##
[0042] N-(5-amino-1-(hexylamino)-1-oxopentan-2-yl)dodecanamide
##STR00022##
[0043] N-(5-amino-1-oxo-1-(undecylamino)pentan-2-yl)octanamide
##STR00023##
[0044] N-(5-amino-1-(octylamino)-1-oxopentan-2-yl)octanamide
##STR00024##
[0045]
N-(1-(ethylamino)-5-guanidino-1-oxopentan-2-yl)tetradecanamide
##STR00025##
[0046]
N-(5-guanidino-1-(octylamino)-1-oxopentan-2-yl)octanamide
##STR00026##
[0047]
N-(5-guanidino-1-(octylamino)-1-oxopentan-2-yl)dodecanamide
##STR00027##
[0048]
N-(1-(decylamino)-5-guanidino-1-oxopentan-2-yl)dodecanamide
##STR00028##
[0049]
N-(1-(ethylamino)-5-guanidino-1-oxopentan-2-yl)decanamide
##STR00029##
[0050]
N-(5-guanidino-1-oxo-1-(undecylamino)pentan-2-yl)dodecanamide
##STR00030##
[0051]
N-(5-guanidino-1-oxo-1-(undecylamino)pentan-2-yl)octanamide
[0052] Any of a variety of suitable methods for synthesizing the
compounds of the present invention may be used. For example, on
particular method for synthesizing
[amino({[4-dodecanamido-4-(ethylcarbamoyl)butyl]amino})methylidene]azaniu-
m is described in Example 1. As will be recognized by those of
skill in the art, other similar compounds of Formula I may be
synthesized in a similar manner using the appropriate starting
materials to achieve the appropriate R.sub.1, R.sub.2, R.sub.3 and
n substitution on the molecule without undue experimentation.
[0053] Applicants have recognized that the compounds of the present
invention provide a wide variety of benefits, including, for
example, in compositions for use in healthcare applications.
Accordingly, in certain embodiments, the present invention is
directed to healthcare compositions comprising at least one
compound of Formula I. Such healthcare compositions may be in any
suitable form for use as, in, or on personal care, cosmetic,
pharmaceutical, and medical device products, and the like. In
certain preferred embodiments, the compositions of the present
invention are compositions for oral care, including, for example,
oral care compositions in the form of a solution, mouthwash, mouth
rinse, mouth spray, toothpaste, tooth gel, sub-gingival gel,
mousse, foam, denture care product, dentifrice, lozenge, chewable
tablet, dissolvable tablet, dry powder and the like. The oral care
composition may also be incorporated into or onto floss,
dissolvable strips or films or integrated into or onto a device or
applicator for oral use.
[0054] In certain embodiments, the compositions of the invention
comprise at least one composition of Formula I and a vehicle. Any
suitable vehicle may be used in the compositions of the present
invention. Preferably, the vehicle is selected from the group
consisting of cosmetically-acceptable and
pharmaceutically-acceptable vehicles. As used herein,
"cosmetically-acceptable" and "pharmaceutically-acceptable"
vehicles are liquid, solid, or other ingredients suitable for use
as vehicles in products for mammals, including humans without undue
toxicity, incompatibility, instability, irritation, allergic
response, and the like.
[0055] For liquid compositions, the vehicle may be any suitable
aqueous or non-aqueous liquid vehicle. In certain embodiments, the
liquid vehicle comprises water. For example, in many compositions,
as will be understood by those of skill in the art, water is added
to q.s. (Quantum Sufficit, Latin for "as much as needed") the
composition. In certain embodiments, the composition comprises from
about 60% to about 99.99% water, including from about 70% to about
95% water, from about 80% to 95% water, from about 60% to about 90%
water, from about 60% to about 80% water, or from about 60% to
about 75% water.
[0056] In certain embodiments, alcohol may be added to the
composition. Any of a variety of alcohols represented by the
formula R.sub.4--OH, wherein R.sub.4 is an alkyl group having from
2 to 6 carbons, may be used in the present invention. Examples of
suitable alcohols of formula R.sub.4--OH include ethanol;
n-propanol, iso-propanol; butanols; pentanols; hexanols, and
combinations of two or more thereof, and the like. In certain
embodiments, the alcohol is, or comprises, ethanol.
[0057] In some embodiments, the alcohol may be present in the
composition in an amount of at least about 10.0% v/v of the total
composition, or from about 10% to about 35% v/v of the total
composition, or from about 15% to about 30% v/v of the total
composition and may be from about 20% to about 25% v/v of the total
composition.
[0058] Applicants have discovered that the compounds of the present
invention exhibit increased stability in low-alcohol or alcohol
free formulations, while maintaining other oral care benefits, as
compared to previously known amino acid derivative compounds.
Accordingly, in some embodiments, the composition may comprise a
reduced level of alcohol. The phrase "reduced level" of alcohol
means an amount of a R.sub.4--OH alcohol of about 10% v/v or less,
optionally of about 5% v/v or less, optionally of about 1% v/v or
less, optionally of about 0.1% v/v or less by volume of the total
composition. In certain embodiments, the compositions of the
present invention are free of R.sub.4--OH alcohols.
[0059] Alternatively, the compositions of the present invention may
be formulated in a dissolvable tablet, dry powder, chewing gum,
film, semi-solid, solid or liquid concentrate form. In such
embodiments, for example, water is added to q.s. as necessary in
the case of liquid dissolvable tablet, concentrates or powdered
formulations, or water may be removed using standard evaporation
procedures known in the art to produce a composition in dry powder
form. Evaporated, or freeze dried forms are advantageous for
storage and shipping.
[0060] Any suitable amounts of one or more compounds of Formula I
may be used in the compositions of the present invention. In
certain embodiments, the compositions comprise a total amount of
compounds of Formula I (whether the composition comprises only one
compound of Formula I or a combination of two or more thereof) of
about 0.0001% to about 50% w/w of active/solid amount of total
compounds of Formula I based on the total weight of the
composition. In certain embodiments, the percent of total
compound(s) of Formula I is from about 0.001% to about 10%, or from
about 0.01% to about 1%, or from about 0.05% to about 0.5% w/w of
active/solid amount of total compounds of Formula I based on the
total weight of the composition.
[0061] In certain embodiments, as will be recognized by those of
skill in the art, compounds made in accord with the present
invention may be purified and/or may comprise a mixture of two or
more compounds of Formula I. In certain embodiments, the
compositions of the present invention comprise a combination of at
least two compounds of Formula I. In certain embodiments, the
compositions of the present invention comprise a combination of at
least three compounds of Formula I.
[0062] The compositions of the present invention may further
comprise any of a variety of optional ingredients therein,
including, but not limited to oily components, active ingredients,
additional surfactants, humectants, solvents, flavors, sweeteners,
colorants, preservatives, pH adjusters, pH buffers, and the
like.
[0063] Any of a variety of oily components may be used in the
present compositions. The oily component may comprise any one or
more oils, or other materials that are water insoluble, or
substantially water-insoluble, meaning that its solubility is less
than about 1% by weight in water at 25.degree. C. or, optionally,
less than about 0.1%. In certain embodiments, the oily component of
the present invention comprises, consists essentially of, or
consists of, at least one essential oil, i.e. a natural or
synthetic (or combination thereof) concentrated hydrophobic
material of vegetable origin, generally containing volatile
compounds, at least one flavor oil, or a combination of two or more
thereof. Examples of suitable essential oils, flavor oils, and
their amounts are described below. In certain embodiments, the
composition comprises a total amount of oily component of about
0.05% w/w or more, about 0.1% w/w or more, or about 0.2% w/w or
more of oily component.
[0064] In certain embodiments, compositions of the present
invention comprise essential oils. Essential oils are volatile
aromatic oils which may be synthetic or may be derived from plants
by distillation, expression or extraction, and which usually carry
the odor or flavor of the plant from which they are obtained.
Useful essential oils may provide antiseptic activity. Some of
these essential oils also act as flavoring agents. Useful essential
oils include but are not limited to citra, thymol, menthol, methyl
salicylate (wintergreen oil), eucalyptol, carvacrol, camphor,
anethole, carvone, eugenol, isoeugenol, limonene, osimen, n-decyl
alcohol, citronel, a-salpineol, methyl acetate, citronellyl
acetate, methyl eugenol, cineol, linalool, ethyl linalaol, safrola
vanillin, spearmint oil, peppermint oil, lemon oil, orange oil,
sage oil, rosemary oil, cinnamon oil, pimento oil, laurel oil,
cedar leaf oil, gerianol, verbenone, anise oil, bay oil,
benzaldehyde, bergamot oil, bitter almond, chlorothymol, cinnamic
aldehyde, citronella oil, clove oil, coal tar, eucalyptus oil,
guaiacol, tropolone derivatives such as hinokitiol, avender oil,
mustard oil, phenol, phenyl salicylate, pine oil, pine needle oil,
sassafras oil, spike lavender oil, storax, thyme oil, tolu balsam,
terpentine oil, clove oil, and combinations thereof.
[0065] In certain embodiments, the essential oils are selected from
the group consisting of thymol
((CH.sub.3).sub.2CHC.sub.6H.sub.3(CH.sub.3)OH, also known as
isopropyl-m-cresol), eucalyptol (C.sub.10H.sub.18O, also known as
cineol), menthol (CH.sub.3C.sub.6H.sub.9(C.sub.3H.sub.7)OH), also
known as hexahydrothymol), methyl salicylate
(C.sub.6H.sub.4OHCOOCH.sub.3, also known as wintergreen oil),
isomers of each of these compounds, and combinations of two or more
thereof. In some embodiments, the compositions of the present
invention contain thymol. In some embodiments, the compositions of
the present invention contain menthol. In some embodiments, the
composition contains all four of these essential oils.
[0066] In certain embodiments, thymol is employed in amounts of
from about 0.0001% to about 0.6% w/v, or from about 0.005% to about
0.07% w/v of the composition. In certain embodiments, eucalyptol
may be employed in amounts of from about 0.0001% to about 0.51 w/v,
or from about 0.0085% to about 0.10% w/v of the composition. In
certain embodiments, menthol is employed in amounts of from about
0.0001% to about 0.25% w/v, or from about 0.0035% to about 0.05%
w/v of the composition. In certain embodiments, methyl salicylate
is employed in amounts of from about 0.0001% to about 0.28% w/v, or
from about 0.004% to about 0.07% w/v of the composition. In certain
embodiments, the total amount of all of such essential oils present
in the disclosed compositions can be from about 0.0004% to about
1.64% w/v, or from about 0.0165% to about 0.49% w/v of the
composition.
[0067] In certain embodiments, fluoride providing compounds may be
present in the mouth rinse compositions of this invention. These
compounds may be slightly water soluble or may be fully water
soluble and are characterized by their ability to release fluoride
ions or fluoride containing ions in water. Typical fluoride
providing compounds are inorganic fluoride salts such as soluble
alkali metal, alkaline earth metal, and heavy metal salts, for
example, sodium fluoride, potassium fluoride, ammonium fluoride,
cupric fluoride, zinc fluoride, stannic fluoride, stannous
fluoride, barium fluoride, sodium hexafluorosilicate, ammonium
hexafluorosilicate, sodium fluorozirconate, sodium
monofluorophosphate, aluminum mono- and difluorophosphate and
fluorinated sodium calcium pyrophosphate. Amine fluorides, such as
N'-octadecyltrimethylendiamine-N,N,N'-tris(2-ethanol)-dihydrofluoride
and 9-octadecenylamine-hydrofluoride), may also be used. In certain
embodiments, the fluoride providing compound is generally present
in an amount sufficient to release up to about 5%, or from about
0.001% to about 2%, or from about 0.005% to about 1.5% fluoride by
weight of the composition.
[0068] In certain embodiments, sensitivity reducing agents, such as
potassium salts of nitrate and oxalate in an amount from about 0.1%
to about 5.0% w/v of the composition may be incorporated into the
present invention. Other potassium releasing compounds are feasible
(e.g. KCl). High concentrations of calcium phosphates may also
provide some added sensitivity relief. These agents are believed to
work by either forming an occlusive surface mineral deposit on the
tooth surface or through providing potassium to the nerves within
the teeth to depolarize the nerves. A more detailed discussion of
suitable sensitivity reducing agents can be found in US
2006/0013778 to Hodosh and U.S. Pat. No. 6,416,745 to Markowitz et
al., both of which are herein incorporated by reference in their
entirety.
[0069] In certain embodiments, compounds with anti-calculus
benefits (e.g. various carboxylates, polyaspartic acid, etc.) may
be incorporated into the present invention. Also useful as an
anticalculus agent are the anionic polymeric polycarboxylates. Such
materials are well known in the art, being employed in the form of
their free acids or partially or preferably fully neutralized water
soluble alkali metal (e.g. potassium and preferably sodium) or
ammonium salts. Preferred are 1:4 to 4:1 by weight copolymers of
maleic anhydride or acid with another polymerizable ethylenically
unsaturated monomer, preferably methyl vinyl ether
(methoxyethylene) having a molecular weight (M.W.) of about 30,000
to about 1,000,000. These copolymers are available, for example, as
Gantrez 25 AN 139 (M.W. 500,000), AN 119 (M.W. 250,000) and
preferably S-97 Pharmaceutical Grade (M.W. 70,000), of GAF
Chemicals Corporation.
[0070] Additional anti-calculus agents may be selected from the
group consisting of polyphosphates (including pyrophosphates) and
salts thereof polyamino propane sulfonic acid (AMPS) and salts
thereof; polyolefin sulfonates and salts thereof, polyvinyl
phosphates and salts thereof; polyolefin phosphates and salts
thereof; diphosphonates and salts thereof; phosphonoalkane
carboxylic acid and salts thereof; polyphosphonates and salts
thereof; polyvinyl phosphonates and salts thereof; polyolefin
phosphonates and salts thereof; polypeptides; and mixtures thereof;
carboxy-substituted polymers; and mixtures thereof. In one
embodiment, the salts are alkali metal or ammonium salts.
Polyphosphates are generally employed as their wholly or partially
neutralized water-soluble alkali metal salts such as potassium,
sodium, ammonium salts, and mixtures thereof. The inorganic
polyphosphate salts include alkali metal (e.g. sodium)
tripolyphosphate, tetrapolyphosphate, dialkyl metal (e.g. disodium)
diacid, trialkyl metal (e.g. trisodium) monoacid, potassium
hydrogen phosphate, sodium hydrogen phosphate, and alkali metal
(e.g. sodium) hexametaphosphate, and mixtures thereof.
Polyphosphates larger than tetrapolyphosphate usually occur as
amorphous glassy materials. In one embodiment the polyphosphates
are those manufactured by FMC Corporation, which are commercially
known as Sodaphos (n.apprxeq.6), Hexaphos (n.apprxeq.13), and Glass
H (n.apprxeq.21, sodium hexametaphosphate), and mixtures thereof.
The pyrophosphate salts useful in the present invention include,
alkali metal pyrophosphates, di-, tri-, and mono-potassium or
sodium pyrophosphates, dialkali metal pyrophosphate salts,
tetraalkali metal pyrophosphate salts, and mixtures thereof. In one
embodiment the pyrophosphate salt is selected from the group
consisting of trisodium pyrophosphate, disodium dihydrogen
pyrophosphate (Na.sub.2H.sub.2P.sub.2O.sub.7), dipotassium
pyrophosphate, tetrasodium pyrophosphate (Na.sub.4P.sub.2O.sub.7),
tetrapotassium pyrophosphate (K.sub.4P.sub.2O.sub.7), and mixtures
thereof. Polyolefin sulfonates include those wherein the olefin
group contains 2 or more carbon atoms, and salts thereof.
Polyolefin phosphonates include those wherein the olefin group
contains 2 or more carbon atoms. Polyvinylphosphonates include
polyvinylphosphonic acid. Diphosphonates and salts thereof include
azocycloalkane-2,2-diphosphonic acids and salts thereof, ions of
azocycloalkane-2,2-diphosphonic acids and salts thereof,
azacyclohexane-2,2-diphosphonic acid,
azacyclopentane-2,2-diphosphonic acid,
N-methyl-azacyclopentane-2,3-diphosphonic acid, EHDP
(ethane-1-hydroxy-1,1-diphosphonic acid), AHP
(azacycloheptane-2,2-diphosphonic acid),
ethane-1-amino-1,1-diphosphonate, dichloromethane-diphosphonate,
etc. Phosphonoalkane carboxylic acid or their alkali metal salts
include PPTA (phosphonopropane tricarboxylic acid), PBTA
(phosphonobutane-1,2,4-tricarboxylic acid), each as acid or alkali
metal salts. Polyolefin phosphates include those wherein the olefin
group contains 2 or more carbon atoms. Polypeptides include
polyaspartic and polyglutamic acids.
[0071] In certain embodiments, zinc salts such as zinc chloride,
zinc acetate or zinc citrate may be added as an astringent for an
"antiseptic cleaning" feeling, as a breath protection enhancer or
as anti-calculus agent in an amount of from about 0.0025% w/v to
about 0.75% w/v of the composition.
[0072] Any of a variety of additional surfactants may be used in
the present invention. Suitable surfactants may include anionic,
non-ionic, cationic, amphoteric, zwitterionic surfactants, and
combinations of two or more thereof. Examples of suitable
surfactants are disclosed, for example, in U.S. Pat. No. 7,417,020
to Fevola, et al which is incorporated in its entirety herein by
reference.
[0073] In certain embodiments, the compositions of the present
invention comprise a non-ionic surfactant. Those of skill in the
art will recognize that any of a variety of one or more non-ionic
surfactants include, but are not limited to, compounds produced by
the condensation of alkylene oxide groups (hydrophilic in nature)
with an organic hydrophobic compound which may be aliphatic or
alkyl-aromatic in nature. Examples of suitable nonionic surfactants
include, but are not limited to, alkyl polyglucosides; alkyl
glucose amines, block copolymers such as ethylene oxide and
propylene oxide copolymers e.g. Poloxamers; ethoxylated
hydrogenated castor oils available commercially for example under
the trade name CRODURET (Croda Inc., Edison, N.J.); alkyl
polyethylene oxide e.g. Polysorbates, and/or; fatty alcohol
ethoxylates; polyethylene oxide condensates of alkyl phenols;
products derived from the condensation of ethylene oxide with the
reaction product of propylene oxide and ethylene diamine; ethylene
oxide condensates of aliphatic alcohols; long chain tertiary amine
oxides; long chain tertiary phosphine oxides; long chain dialkyl
sulfoxides; and mixtures thereof.
[0074] Exemplary non-ionic surfactants are selected from the group
known as poly(oxyethylene)-poly(oxypropylene) block copolymers.
Such copolymers are known commercially as poloxamers and are
produced in a wide range of structures and molecular weights with
varying contents of ethylene oxide. These non-ionic poloxamers are
non-toxic and acceptable as direct food additives. They are stable
and readily dispersible in aqueous systems and are compatible with
a wide variety of formulations and other ingredients for oral
preparations. These surfactants should have an HLB
(Hydrophilic-Lipophilic Balance) of between about 10 and about 30
and preferably between about 10 and about 25. By way of example,
non-ionic surfactants useful in this invention include the
poloxamers identified as poloxamers 105, 108, 124, 184, 185, 188,
215, 217, 234, 235, 237, 238, 284, 288, 333, 334, 335, 338, 407,
and combinations of two or more thereof. In certain preferred
embodiments, the composition comprises poloxamer 407.
[0075] In certain embodiments, the compositions of the claimed
invention comprise less than about 9% of non-ionic surfactant, less
than 5%, or less than 1.5%, or less than 1%, or less than 0.8, less
than 0.5%, less than 0.4%, or less than 0.3% of non-ionic
surfactants. In certain embodiments, the composition of the present
invention is free of non-ionic surfactants.
[0076] In certain embodiments, the compositions of the present
invention also contain at least one alkyl sulfate surfactant. In
certain embodiments, suitable alkyl sulfate surfactants include,
but are not limited to sulfated C.sub.8 to C.sub.18, optionally
sulfated C.sub.10 to C.sub.16 even numbered carbon chain length
alcohols neutralized with a suitable basic salt such as sodium
carbonate or sodium hydroxide and mixtures thereof such that the
alkyl sulfate surfactant has an even numbered C.sub.8 to C.sub.18,
optionally C.sub.10 to C.sub.16, chain length. In certain
embodiments, the alkyl sulfate is selected from the group
consisting of sodium lauryl sulfate, hexadecyl sulfate and mixtures
thereof. In certain embodiments, commercially available mixtures of
alkyl sulfates are used. A typical percentage breakdown of alkyl
sulfates by alkyl chain length in commercially available sodium
lauryl sulfate (SLS) is as follows:
TABLE-US-00001 Alkyl Component Chain Percentage Length in SLS
C.sub.12 >60% C.sub.14 20%-35% C.sub.16 <10% C.sub.10 <1%
C.sub.18 <1%
[0077] In certain embodiments, the alkyl sulfate surfactant is
present in the composition from about 0.001% to about 6.0% w/v, or
optionally from about 0.1% to about 0.5% w/v of the
composition.
[0078] Another suitable surfactant is one selected from the group
consisting of sarcosinate surfactants, isethionate surfactants and
taurate surfactants. Preferred for use herein are alkali metal or
ammonium salts of these surfactants, such as the sodium and
potassium salts of the following: lauroyl sarcosinate, myristoyl
sarcosinate, palmitoyl sarcosinate, stearoyl sarcosinate and oleoyl
sarcosinate. The sarcosinate surfactant may be present in the
compositions of the present invention from about 0.1% to about
2.5%, or from about 0.5% to about 2% by weight of the total
composition.
[0079] Zwitterionic synthetic surfactants useful in the present
invention include derivatives of aliphatic quaternary ammonium,
phosphonium, and sulfonium compounds, in which the aliphatic
radicals can be straight chain or branched, and wherein one of the
aliphatic substituents contains from about 8 to 18 carbon atoms and
one contains an anionic water-solubilizing group, e.g., carboxy,
sulfonate, sulfate, phosphate or phosphonate.
[0080] The amphoteric surfactants useful in the present invention
include, but are not limited to, derivatives of aliphatic secondary
and tertiary amines in which the aliphatic radical can be a
straight chain or branched and wherein one of the aliphatic
substituents contains from about 8 to about 18 carbon atoms and one
contains an anionic water-solubilizing group, e.g., carboxylate,
sulfonate, sulfate, phosphate, or phosphonate. Examples of suitable
amphoteric surfactants include, but are not limited
alkylimino-diproprionates, alky lamphoglycinates (mono or di),
alkylamphoproprionates (mono or di), alkylamphoacetates (mono or
di), N-alkyl [3-aminoproprionic acids, alkylpolyamino carboxylates,
phosphorylated imidazolines, alkyl betaines, alkylamido betaines,
alkylamidopropyl betaines, alkyl sultaines, alkylamido sultaines,
and mixtures thereof. In certain embodiments, the amphoteric
surfactant is selected from the group consisting of
alkylamidopropyl betaines, amphoacetates such as sodium
auroamphoacetate and mixtures thereof. Mixtures of any of the above
mentioned surfactants can also be employed. A more detailed
discussion of anionic, nonionic and amphoteric surfactants can be
found in U.S. Pat. No. 7,087,650 to Lennon; U.S. Pat. No. 7,084,104
to Martin et al.; U.S. Pat. No. 5,190,747 to Sekiguchi et al.; and
U.S. Pat. No. 4,051,234, Gieske, et al., each of which patents are
herein incorporated by reference in their entirety.
[0081] In certain embodiments, the compositions of the claimed
invention comprise less than about 9% of amphoteric surfactant,
less than 5%, or less than 1.5%, or less than 1%, or less than 0.8,
less than 0.5%, less than 0.4%, or less than 0.3% of amphoteric
surfactants. In certain embodiments, the composition of the present
invention is free of amphoteric surfactants.
[0082] Additional surfactants may be added with the alkyl sulfate
surfactant to aid in solubilization of the essential oils provided
such surfactants do not affect the bioavailability of the essential
oils. Suitable examples include additional anionic surfactants,
nonionic surfactants, amphoteric surfactants and mixtures thereof.
However, in certain embodiments, the total surfactant concentration
(including the alkyl sulfate surfactant alone or in combination
with other surfactants) for mouth rinses of the present invention
should not exceed or should about 9% or less, optionally, the total
surfactant concentration should be about 5% or less, optionally
about 1% or less, optionally about 0.5% or less w/w % of active
surfactant by weight of the composition.
[0083] In certain embodiments, a sugar alcohol (humectant) is also
added to the oral compositions of the present invention. The sugar
alcohol solvent(s) may be selected from those
multi-hydroxy-functional compounds that are conventionally used in
oral and ingestible products. In certain embodiments, the sugar
alcohol (s) should be nonmetabolized and non-fermentable sugar
alcohol (s). In specific embodiments, the sugar alcohols include,
but are not limited to sorbitol, glycerol, xylitol, mannitol,
maltitol, inositol, allitol, altritol, dulcitol, galactitol,
glucitol, hexitol, iditol, pentitol, ribitol, erythritol and
mixtures thereof. Optionally, the sugar alcohol is selected from
the group consisting of sorbitol and xylitol or mixtures thereof.
In some embodiments, the sugar alcohol is sorbitol. In certain
embodiments, the total amount of sugar alcohol (s), which are added
to effectively aid in the dispersion or dissolution of the mouth
rinse or other ingredients, should not exceed about 50% w/of the
total composition. Or, total amount of sugar alcohol should not
exceed about 30% w/v of the total composition. Or, total amount of
sugar alcohol should not exceed 25% w/v of the total composition.
The sugar alcohol can be in an amount of from about 1.0% to about
24% w/v, or from about 1.5% to about 22% w/v, or from about 2.5% to
about 20% w/v of the total composition.
[0084] In certain embodiments, a polyol solvent is added to the
composition. The polyol solvent comprises a polyol or polyhydric
alcohol selected from the group consisting of polyhydric alkanes
(such as propylene glycol, glycerin, butylene glycol, hexylene
glycol, 1,3-propanediol); polyhydric alkane esters (dipropylene
glycol, ethoxydiglycol); polyalkene glycols (such as polyethylene
glycol, polypropylene glycol) and mixtures thereof. In certain
embodiments, the polyol solvent can be present in an amount of from
0% to about 40% w/v, or from about 0.5% to about 20% w/v, or from
about 1.0% to about 10% w/v of the composition.
[0085] In certain embodiments, the compositions of the present
invention have a pH of about 11 or less. In some embodiments, the
compositions have a pH of from about 3 to about 7, or from about
3.5 to about 6.5, or from about 3.5 to about 5.0.
[0086] As will be recognized by those of skill in the art, the pH
of the composition may be adjusted or maintained using a buffer in
an amount effective to provide the composition with a pH at or
below 11. The composition can optionally comprise at least one pH
modifying agents among those useful herein include acidifying
agents to lower pH, basifying agents to raise pH, and buffering
agents to maintain pH within a desired range. For example, one or
more compounds selected from acidifying, basifying and buffering
agents can be included to provide a pH of about 2 to about 7, or in
various embodiments from about 3 to about 6, or from about 4 to
about 5. Any orally acceptable pH modifying agent can be used
including without limitation hydrochloric, carboxylic and sulfonic
acids, acid salts (e.g., monosodium citrate, disodium citrate,
monosodium malate, etc.), alkali metal hydroxides such as sodium
hydroxide, borates, silicates, imidazole and mixtures thereof. One
or more pH modifying agents are optionally present in a total
amount effective to maintain the composition in an orally
acceptable pH range. In certain embodiments, inorganic acids may be
used as the buffer added to the composition.
[0087] In certain embodiments, organic acids may be used as the
buffer added to the composition. Organic acids suitable for use in
the compositions of the present invention include, but are not
limited to, ascorbic acid, sorbic acid, citric acid, glycolic acid,
lactic acid and acetic acid, benzoic acid, salicylic acid, phthalic
acid, phenolsulphonic acid, and mixtures thereof, optionally, the
organic acid is selected from the group consisting of benzoic acid,
sorbic acid, citric acid and mixtures thereof, or optionally, the
organic acid is benzoic acid.
[0088] Generally the amount of buffering compound is from about
0.001% to about 20.0% of the composition. In certain embodiment,
the organic acid buffer is present in amounts of from about 0.001%
to about 10% w/v of the composition, or from about 0.01% to about
1% of the composition.
[0089] In certain embodiments, additional conventional components
may be added as in mouthwashes and mouth rinses of the prior art.
Whereas some alcohol containing mouth rinses have a pH of about
7.0, reduction of the alcohol level may require the addition of
acidic preservatives, such as sorbic acid or benzoic acid, which
reduce pH levels. Buffer systems are then necessary to control the
pH of the composition at optimal levels. This is generally
accomplished through the addition of a weak acid and its salt or a
weak base and its salt. In some embodiments, useful systems have
been found to be sodium benzoate and benzoic acid in amounts of
from 0.01% (or about 0.01% w/v) to 1.0% w/v (or about 1.0% w/v) of
the composition, and sodium citrate and citric acid in amounts of
from 0.001% (or about 0.001% w/v) to 1.0% w/v (or about 1.0% w/v)
of the composition, phosphoric acid and sodium/potassium phosphate
of amounts from 0.01% (or about 0.01%) to 1.0% (or about 1.0%) by
weight of the composition. In certain embodiments, the buffers are
incorporated in amounts that maintain the pH at levels of from 3.0
(or about 3.0) to 8.0 (or about 8.0), optionally from 3.5 (or about
3.5) to 6.5 (or about 6.5), optionally from 3.5 (or about 3.5) to
5.0 (or about 5.0).
[0090] Additional buffering agents include alkali metal hydroxides,
ammonium hydroxide, organic ammonium compounds, carbonates,
sesquicarbonates, borates, silicates, phosphates, imidazole, and
mixtures thereof. Specific buffering agents include monosodium
phosphate, trisodium phosphate, sodium hydroxide, potassium
hydroxide, alkali metal carbonate salts, sodium carbonate,
imidazole, pyrophosphate salts, sodium gluconate, sodium lactate,
citric acid, and sodium citrate.
[0091] Sweeteners such as aspartame, sodium saccharin (saccharin),
sucralose, stevia, acesulfame K and the like may be added for
better taste in amounts of from about 0.0001% w/v to about 1.0%
w/v. In certain preferred embodiments, the sweetener comprises
sucralose.
[0092] In certain embodiments, the composition further comprises
flavors or flavorants to modify or magnify the taste of the
composition, or reduce or mask the sharp "bite" or "burn" of
ingredients such as thymol. Suitable flavors include, but are not
limited to, flavor oils such as oil of anise, anethole, benzyl
alcohol, spearmint oil, citrus oils, vanillin and the like may be
incorporated. Other flavors such as citrus oils, vanillin and the
like may be incorporated to provide further taste variations. In
these embodiments, the amount of flavor oil added to the
composition can be from about 0.001% to about 5% w/v, or from about
0.01% to about 0.3% w/v of the total composition. The particular
flavors or flavorants, and other taste improving ingredients,
employed will vary depending upon the particular taste and feel
desired. Those skilled in the art can select and customize these
types of ingredients to provide the desired results.
[0093] In certain embodiments, acceptably approved food dyes may be
used to provide a pleasing color to the compositions of the
invention. These may be selected from, but not limited to, the long
list of acceptable food dyes. Suitable dyes for this purpose
include FD&C yellow #5, FD&C yellow #10, FD&C blue #1
and FD&C green #3. These are added in conventional amounts,
typically in individual amounts of from about 0.00001% w/v to about
0.0008% w/v, or from about 0.000035% w/v to about 0.0005% w/v of
the composition.
[0094] Other conventional ingredients may be used in the liquid or
mouth rinse compositions of this invention, including those known
and used in the art. Examples of such ingredients include
thickeners, suspending agents and softeners. Thickeners and
suspending agents useful in the compositions of the present
invention can be found in U.S. Pat. No. 5,328,682 to Pullen et al.,
herein incorporated by reference in its entirety. In certain
embodiments, these are incorporated in amounts of from about 0.1%
w/v to about 0.6% w/v, or about 0.5% w/v of the composition.
[0095] In some embodiments, antimicrobial preservatives may be
added to the composition. Some antimicrobial preservatives which
may be used include, but are not limited to cationic
antibacterials, such as sodium benzoate, polyquatemium polycationic
polymers (i.e polyquaternium-42: Poly
[oxyethylene(dimethylimino)ethylene (dimethylimino)ethylene
dichloride]), quaternary ammonium salts or quaternary ammonium
compounds, parabens (i.e. parahydroxybenzoates or esters of
parahydroxybenzoic acid), hydroxyacetophenone, 1,2-Hexanediol,
Caprylyl Glycol, chlorhexidine, alexidine, hexetidine, benzalkonium
chloride, domiphen bromide, cetylpyridinium chloride (CPC),
tetradecylpyridinium chloride (TPC), N-tetradecyl-4-ethylpyridinium
chloride (TDEPC), octenidine, bisbiguanides, zinc or stannous ion
agents, grapefruit extract, and mixtures thereof. Other
antibacterial and antimicrobial agents include, but are not limited
to: 5-chloro-2-(2,4-dichlorophenoxy)-phenol, commonly referred to
as triclosan; 8-hydroxyquinoline and its salts, copper II
compounds, including, but not limited to, copper(II) chloride,
copper(II) sulfate, copper(II) acetate, copper(II) fluoride and
copper(II) hydroxide; phthalic acid and its salts including, but
not limited to those disclosed in U.S. Pat. No. 4,994,262,
including magnesium monopotassium phthalate; sanguinarine;
salicylanilide; iodine; sulfonamides; phenolics; delmopinol,
octapinol, and other piperidino derivatives; niacin preparations;
nystatin; apple extract; thyme oil; thymol; antibiotics such as
augmentin, amoxicillin, tetracycline, doxycycline, minocycline,
metronidazole, neomycin, kanamycin, cetylpyridinium chloride, and
clindamycin; analogs and salts of the above; methyl salicylate;
hydrogen peroxide; metal salts of chlorite; pyrrolidone ethyl
cocoyl arginate; lauroyl ethyl arginate monochlorohydrate; and
mixtures of all of the above. In another embodiment, the
composition comprises phenolic antimicrobial compounds and mixtures
thereof. Antimicrobial components may be present from about 0.001%
to about 20% by weight of the oral care composition. In another
embodiment the antimicrobial agents generally comprise from about
0.1% to about 5% by weight of the oral care compositions of the
present invention.
[0096] Other antibacterial agents may be basic amino acids and
salts. Other embodiments may comprise arginine.
[0097] Other useful oral care actives and/or inactive ingredients
and further examples thereof can be found in U.S. Pat. No.
6,682,722 to Majeti et al. and U.S. Pat. No. 6,121,315 to Nair et
al., each of which are herein incorporated by reference in its
entirety.
[0098] The compositions of the present invention may be made
according to any of a variety of methods disclosed herein and known
in the art. In particular, applicants have discovered for certain
oral care compositions, that the present compounds may be
incorporated into oral care compositions to produce compositions
that tend to be relatively more stable than prior compositions,
including, for example, similar compositions comprising LAE.
[0099] According to certain embodiments, the compositions of the
present invention may be made according to the following
method(s).
[0100] The compounds and compositions of the present invention may
be used in a variety of methods of treating a mammalian body. Such
methods generally comprise introducing a compound or composition of
the present invention into or onto the mammalian body to be
treated. For example, certain methods of the present invention
comprise treating a condition or disease of the skin, mucosal
membrane, hair, eye, or other part of the mammalian body by
applying to the skin, mucosal membrane, hair, eye, or other part of
the body, respectively, or injecting into the mammalian body, a
compound or composition of the claimed invention. Certain methods
of the present invention comprise treating a condition or disease
of the oral cavity, including the teeth, mucosal membranes/gums,
and the like, by applying to the oral cavity, or injecting into the
oral cavity or otherwise into the mammalian body, a compound or
composition of the claimed invention.
[0101] The compounds and compositions of the present invention may
be used in a variety of methods of treating a mammalian body, in
particular for disrupting a biofilm on a surface of the oral
cavity. According to certain embodiments, the present invention
comprises disrupting biofilm on a surface by contacting the surface
comprising biofilm with a composition of the present invention. In
certain embodiments, the present invention comprises removing
biofilm from a surface by contacting the surface comprising biofilm
with a composition of the present invention. In certain
embodiments, the present invention comprises reducing bacterial
attachment to a surface by contacting the surface with a
composition of the present invention. In certain embodiments, the
present method comprises inhibiting plaque by contacting a surface
of the oral cavity with a compound or composition of the present
invention.
[0102] Any suitable surface of the oral cavity may be contacting in
accord with the methods of the present invention including one or
more surfaces selected from the group consisting of surfaces of one
or more teeth, surfaces of the gums, combinations of two or more
thereof, and the like.
[0103] In each of the above methods, the composition of the claimed
method may be introduced to the surface to be contacted via any of
a variety of methods. In certain embodiments, the composition is
introduced into the oral cavity and applied to the surface by a
user as a mouthwash or mouth rinse. In certain embodiments, the
composition is introduced to the oral cavity and applied to the
surface as a toothpaste on an article for cleaning the teeth, e.g.
a toothbrush. The compositions of the present invention may be
further introduced via the mouth and applied to the surface as a
gum, lozenge, dissolvable strip, or the like.
[0104] Furthermore, the contacting step of the methods of the
present invention may comprise contacting the surface with the
composition for any suitable amount of time. In certain
embodiments, the contacting step comprises contacting the surface
for less than thirty seconds. In certain embodiments, the
contacting step comprises contacting the surface with the
composition for thirty seconds or more, for example, for about
thirty seconds, for about 40 seconds, for about one minute, or for
greater than one minute.
EXAMPLES
Example 1: Synthesis of
[amino({[4-dodecanamido-4-(ethylcarbamoyl)butyl]amino})methylidene]azaniu-
m (compound 9)
##STR00031## ##STR00032##
[0105]
[amino({[4-dodecanamido-4-(ethylcarbamoyl)butyl]amino})methylidene]-
azanium was synthesized in accord with the following procedure:
Condensation of Protected Arginine with Ethylamine:
[0106] A mass of 19.72 g of
N-.alpha.-(9-fluorenylmethyloxycarbonyl)-N-.omega.',N-.omega..omega.''-bi-
s-tert-butyloxycarbonyl-L-argine (Fmoc-Arg(Boc).sub.2-OH; 0.033050;
1.0 equivalents) and 12.80 g of
1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium
3-oxid hexafluorophosphate (HATU; 0.033663 moles; 1.0 equivalents)
was dissolved in in 120 mL of dichloromethane (DCM). To this, 19.0
mL (0.038000 moles; 1.1 equivalents) of 2.0 M ethylamine in
tetrahydrofuran (THF) was added to the reaction mixture. To promote
the condensation reaction, 18.0 mL of diisopropylethylamine (DIEA;
0.10334 moles; 3.0 equivalents) was added to the reaction mixture
and allowed to stir for 24 hours at room temperature under argon
gas (Ar(g)). The reaction was followed by thin-layer chromatography
by monitoring the consumption of reactants and production of
product 1. Upon completion, the reaction mixture was concentrated
under vacuum and product 1 was purified over silica employing a
methanol (MeOH) gradient with DCM. The purified mass of product 1
was 16.5 g, a yield of 80%.
Fmoc-Deprotection of Product 1:
[0107] A mass of 16.5 g of product 1 (0.026453 moles; 1.0
equivalents) was dissolved in 80 mL of DCM. After which 20 mL of
piperidine (0.23488 moles; 8.9 equivalents) was added to the
reaction mixture and allowed to stir at room temperature under
Ar(g). The reaction was monitored by TLC until completion. Product
2 was concentrated under vacuum and purification was attempted over
silica. The impure mass of product 2 was 10.83 g.
Condensation of Product 2 with Lauric Acid:
[0108] A mass of 10.83 g of product 2 (0.026973 moles; 1.0
equivalents) and 11.29 g of HATU (0.029692 moles; 1.1 equivalents)
was dissolved in 120 mL of DCM. To this a mass of 5.95 g of lauric
acid (0.029702 moles; 1.1 equivalents) was added to the reaction
mixture. To promote the condensation reaction, 14.0 mL of DIEA
(0.080377 moles; 3.0 equivalents) was added to the reaction mixture
and allowed to stir for 24 hours at room temperature under Ar(g).
The reaction was followed by thin-layer chromatography by
monitoring the consumption of reactants and production of product
3. Upon completion, the reaction mixture was concentrated under
vacuum and product 3 was purified over silica employing a ethyl
acetate (EtOAc) gradient with heptane. The purified mass of product
3 was 7.0 g, a yield of 44%.
Boc-Group Deprotection of Product 3:
[0109] A mass of 7.0 g of product 3 (0.011990 moles; 1.0
equivalents) was dissolved in dioxane. To this, 50 mL of 12.1 M
concentration hydrochloridic acid (HCl; 0.60500 moles; 50.1
equivalents) was added to the reaction mixture. The reaction was
stirred for 2 hours at room temperature under Ar(g). Upon
completion of the reaction a significant amount of product3
remained with respect to product 4. Therefore, the reaction mixture
was concentrated and the reaction was repeated for 30 minutes to
ensure complete conversion of product3 to product4. After near
complete conversion was observed, the reaction was concentrated
under vacuum and purified over silica employing a MeOH gradient
with DCM. The final purified mass of product 4, the desired
product, was 2.77 g, a yield of 60%. Complete .sup.1H-NMR, LC/MS
and flow injection positive mode ESI-MS was performed to confirm
the identity of the product.
[0110] In general the reaction scheme that can be employed is shown
below. Here, the Fmoc-protect amino acid can be couple to any
primary (or secondary amine) with any one of the various coupling
agents to amidate the carboxylic acid. Following deprotection of
the Fmoc-group with piperidine, the amine on the amino acid can be
acetylated with any carboxylic acid employing any one of the
plethora of coupling agents. Finally, deprotection of any side
chain protection groups can be performed by utilizing a strong
acid.
##STR00033##
[0111] As further illustrated in FIGS. 1-3, the resulting purified
product was measured using HPLC monitoring absorbance at 220 nm
wavelength, mass spectrometry, and proton NMR in D.sub.2O using a
400 MHz Bruker instrument with 16 scans and identified as
[amino({[4-dodecanamido-4-(ethylcarbamoyl)butyl]amino})methylidene]azaniu-
m. Shown in in FIG. 1 is the LC/MS of purified compound 9. (A) HPLC
chromatogram monitoring absorbance at 220 nm wavelength. (B) The
corresponding positive mode electrospary ionization mass
spectrometery of the primary peak highlighted in the red dotted
line box. The calculated m/z for the [M+H].sup.+ of compound 9 is
calculated to be 384.58727. Shown in FIG. 2 is: (A) The chemical
structure and corresponding [M+H].sup.+ m/z for compound 9. (B)
Positive mode ESI-MS of compound 9 final product. Shown in FIG. 3
is: .sup.1H-NMR of compound 9 in D.sub.2O on 400 MHz Bruker
instrument with 16 scans.
Example 2: Dose Response of Compound 9 Prevention of Bacterial
Attachment
[0112] Compositions A-F comprising different concentrations of
compound 9 in water are shown in Table 1.
TABLE-US-00002 TABLE 1 Formulation compositions used in Example 2
Composition A B C D E F Compound 9 (w/w %) 0.4 0.3 0.15 0.1 0.05
0.01 Purified Water (w/w %) 99.6 99.7 99.85 99.9 99.95 99.99
[0113] Initial studies evaluated the concentration effect of
compound 9 in a simple water solution (Table 1 compositions) on
prevention of bacterial attachment to pellicle coated HA pegs.
Compound 9 in water demonstrated a dose dependent response and the
most effective concentration was identified to be 0.3 wt % (Table
2). However, 0.15 wt % compound 9 also demonstrated efficacy at
preventing bacterial attachment and was evaluated at that
concentration further to match the concentration of LAE in the
current commercial product, Listerine Advanced Defense Gum Health
(positive control).
TABLE-US-00003 TABLE 2 Prevention assay efficacy results for
compositions in Table 1 Compo- Positive Negative sition A B C D E F
Control Control Average 3.44 3.25 4.86 5.59 5.52 5.95 4.09 6.20 Log
RLU Std Error -- -- -- -- -- -- 0.14 0.15
Example 3: Compound 9 Prevents Bacterial Attachment Equivalent to
LAE
[0114] The optimal concentration of compound 9 (0.15 wt %) was
compared to the same concentration of LAE for prevention of
bacterial attachment when formulated into a simple water or alcohol
solution (Table 3).
TABLE-US-00004 TABLE 3 Formulation compositions used in Example 3
Compositions G H I J Compound 9 (w/w %) 0.00 0.15 0.00 0.15 LAE
(w/w %) 0.15 0.00 0.15 0.00 Alcohol, 190 proof (w/w %) 18.2 18.2 0
0 Purified Water (w/w %) 81.65 81.65 99.85 99.85
[0115] Table 4 suggests that compound 9 (0.15 wt %) is equally as
efficacious as LAE (0.15 wt %) at preventing bacterial attachment
in both a 21.6% alcohol and water based solution. LAE concentration
in Listerine Advanced Defense Gum Treatment (LAGDT) is 0.15 wt %
which was the positive control with water as the negative
control.
TABLE-US-00005 TABLE 4 Comparison between LAE and compound 9 in the
prevention of bacterial attachment 21.6% Alcohol (Positive
(Negative Compositions G H I J Control Control) Control) Average
Log 4.35 4.75 4.85 4.59 5.96 4.09 6.20 RLU Std Error -- -- 0.26
0.47 -- 0.14 0.15
Example 4: Compound 9 Prevents Bacterial Attachment in Full
Formula
[0116] Following confirmation that LAE prevents bacterial
attachment to the same degree as LAE by the same mechanism of
action, full formulas with compound 9 were optimized. Compound 9
compositions K-R include 0.15 wt % compound 9 in alcohol free base
(Table 5).
TABLE-US-00006 TABLE 5 Formulation compositions used in example 3.
Composition K L M N O P Q R Compound 9 (w/w %) 0.15 0.15 0.15 0.15
0.15 0.15 0.15 0.15 L-Menthol, USP (w/w %) 0.0039 0.0000 0.0039
0.0000 0.0039 0.0000 0.0039 0.0000 Thymol NF(w/w %) 0.0062 0.0000
0.0062 0.0000 0.0062 0.0000 0.0062 0.0000 Methyl Salicylate NF
0.0064 0.0000 0.0064 0.0000 0.0064 0.0000 0.0064 0.0000 (w/w %)
Eucalyptol USP (w/w %) 0.0090 0.0000 0.0090 0.0000 0.0090 0.0000
0.0090 0.0000 Pluracare F-127 NF Prill 0.20 0.20 0.20 0.20 0.00
0.00 0.00 0.00 (w/w %), Poly ethylene oxide co-propylene oxide
Mackam (w/w %) (31% 0.00 0.00 0.65 0.65 0.65 0.65 0.00 0.00
LAURAMIDOPROPYL BETAINE, 62.7% water, 5.4% sodium chloride) Benzoic
Acid (w/w %) 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 Sodium
Benzoate, NF/FCC 0.11 0.11 0.11 0.11 0.11 0.11 0.11 0.11 Dense Form
(w/w %) Sucralose(w/w %), 1,6- 0.01 0.01 0.01 0.01 0.01 0.01 0.01
0.01 Dichloro-1,6-dideoxy-.beta.-D- fructofuransyl-4-chloro-
4-deoxy-.alpha.-D- galactopyranoside Sorbitol 70%, USP 10.00 10.00
10.00 10.00 10.00 10.00 10.00 10.00 (w/w %), (2S,3R,4R,5R)-
Hexane-1,2,3,4,5,6-hexol Propylene Glycol, USP 7.00 7.00 7.00 7.00
7.00 7.00 7.00 7.00 (w/w %) Intensate Sweet Mint II, 0.02 0.00 0.02
0.00 0.02 0.00 0.02 0.00 SF MOD (w/w %) Purified Water (w/w %)
82.43 82.48 81.79 81.83 81.99 82.03 82.63 82.68 Final pH 4.20 4.20
4.20 4.20 4.20 4.20 4.20 4.20
[0117] The results in Table 6 suggest that the presence of
essential oils (EOs) has no effect on compound 9 (0.15 wt %)
prevention of bacterial attachment. However, surfactant has a major
effect with 0.645 wt % Mackam and no surfactant enabling the best
prevention of attachment. LAE concentration in Listerine Advanced
Defense Gum Treatment (LAGDT) is 0.15 wt % which is the positive
control with water as the negative control.
TABLE-US-00007 TABLE 6 Prevention efficacy of formulations in Table
5. Compositions Positive Negative K L M N O P Q R Control Control
Average Log 4.70 4.88 4.33 4.39 4.08 4.17 3.82 3.65 4.09 6.20 RLU
Std Error -- -- -- -- -- -- -- -- 0.14 0.15
Example 5
[0118] Compound 9 maintains stability in an alcohol-free
formulation while LAE does not Select formulations (Table 7) were
further evaluated for stability following incubation at 50.degree.
C. for 4 weeks by HPLC.
TABLE-US-00008 TABLE 7 Formulation compositions for Example 5.
Composition S L I J L-Menthol, USP (w/w %) 0.0039 0.0039 0 0 Thymol
NF (w/w %) 0.0062 0.0062 0 0 Methyl Salicylate NF (w/w %) 0.0064
0.0064 0 0 Eucalyptol USP (w/w %) 0.0090 0.0090 0 0 Pluracare F-127
NF Prill 0.20 0.20 0 0 (w/w %), Poly ethylene oxide co-propylene
oxide Benzoic Acid (w/w %) 0.05 0.05 0 0 Sodium Benzoate, NF/FCC
0.11 0.11 0 0 Dense Form (w/w %) Sucralose(w/w %), 1,6-Dichloro-
0.01 0.01 0 0 1,6-dideoxy-.beta.-D- fructofuranosyl-4-chloro-4-
deoxy-.alpha.-D-galactopyranoside Sorbitol 70%, USP (w/w %), 10.00
10.00 0 0 (2S,3R,4R,5R)-Hexane- 1,2,3,4,5,6-hexol Propylene Glycol,
USP (w/w %) 7.00 7.00 0 0 Intensate Sweet Mint II, SF 0.017 0.017 0
0 MOD (w/w %) LAE (w/w %) 0.15 0 0.15 0 Compound 9 (w/w %) 0 0.15 0
0.15 Purified Water (w/w %) 82.43 82.43 99.85 99.85 Final pH 4.37
4.37 -- --
[0119] Table 8 shows that compound 9 containing formulations are
able maintain at least 90% compound 9 out to 8 weeks when stored at
50.degree. C. as opposed to LAE which shows only 46 and 73%
stability of the molecule after that length of storage (determined
by HPLC).
TABLE-US-00009 TABLE 9 Compound 9 is stable in alcohol free
formulation compositions. % of Compound Remaining Following Storage
at 50.degree. C. Week 0 Week 2 Week 4 Week 8 Composition S 99 85 69
46 Composition L 104 95 93 92 Composition I 99 73 72 73 Composition
J 100 90 98 106
Example 6: Compounds 1, 2, 3, 4, 6, 9, 11, 12, 16, 17, 18, 19, 20,
21, 22, 23, 24, 25, and 26 Prevent Bacterial Attachment
[0120] A broader set of compounds (compounds 1-26) were evaluated
for their ability to prevent bacterial attachment on a pellicle
coated hydroxyapatite pegs. The results in Table 10 suggest that
compounds 1, 2, 3, 4, 6, 9, 11, 12, 16, 17, 18, 19, 20, 21, 22, 23,
24, 25, and 26 have the ability to prevent bacterial attachment
with compounds 1, 2, 3, 6, 9, 12, 17, 18, 19, 21, 22, and 26
preventing bacterial attachment the best. All tests were done in
simple solution solvent base formulas (Table 11). Listerine
Advanced Defense Gum Treatment (LAGDT) is the positive control with
water as the negative control.
TABLE-US-00010 TABLE 10 Prevention efficacy of formulations in
Table 11. Compositions T U V W X Y Z A1 B1 C1 Average Log RLU 3.88
3.96 4.00 5.61 6.29 4.41 6.47 6.68 4.98 6.55 Compositions D1 E1 F1
G1 H1 I1 J1 K1 L1 M1 Average Log RLU 5.77 4.40 6.13 5.97 5.82 5.74
3.50 3.86 3.51 5.00 Compositions Positive Negative N1 O1 P1 Q1 R1
S1 Control Control Average Log RLU 3.57 4.64 5.64 5.67 5.36 3.83
4.44 6.42
TABLE-US-00011 TABLE 11 Formulation compositions used in Example 6.
Composition (w/w %) T U V W X Y Z Compound 1 Compound 2 Compound 3
Compound 4 Compound 5 Compound 6 Compound 7 Compound 0.3 0.1 0.3
0.1 0.3 0.15 0.15 Purified Water 99.70 99.90 99.70 99.90 99.70
99.85 79.85 Ethanol 0 0 0 0 0 0 20 Propylene Glycol 0 0 0 0 0 0 0
Composition (w/w %) A1 B1 C1 D1 E1 F1 G1 Compound 8 Compound 9
Compound 10 Compound 11 Compound 12 Compound 13 Compound 14
Compound 0.3 0.15 0.15 0.3 0.15 0.15 0.15 Purified Water 79.70
79.85 79.85 99.70 99.85 49.85 49.85 Ethanol 20 20 0 0 0 0 0
Propylene Glycol 0 0 20 0 0 50 50 Composition (w/w %) H1 I1 J1 K1
L1 M1 N1 Compound 15 Compound 16 Compound 17 Compound 18 Compound
19 Compound 20 Compound 21 Compound 0.15 0.15 0.15 0.15 0.15 0.15
0.15 Purified Water 49.85 99.85 99.85 99.85 99.85 79.85 99.85
Ethanol 0 0 0 0 0 20 0 Propylene Glycol 50 0 0 0 0 0 0 Composition
(w/w %) O1 P1 Q1 R1 S1 Compound 22 Compound 23 Compound 24 Compound
25 Compound 26 Compound 0.15 0.15 0.15 0.15 0.15 Purified Water
99.85 99.85 99.85 79.85 99.85 Ethanol 0 0 0 20 0 Propylene Glycol 0
0 0 0 0
Example 7: Compounds 1 and 3-13 are Stable in Simple Solution
Formulations (Table 13) and Compounds 1, 2, 3, 4, 6, 7, 9, 11 and
12 do not Result in More than a One Log Reduction in S. mutans
[0121] Compounds 1, 2, 3, 4, 6, 7, 9, 11 and 12 were evaluated in
an in-vitro single species S. mutans biofilm model (Table 12 row
2). All compounds tested do not result in more than a one log
reduction in S. mutans. Listerine Cool Mint was the positive
control with water as the negative control. Compounds 1-13 were
evaluated for structural stability via HPLC after storage at
50.degree. C. for 4 and 8 weeks (Table 12 rows 3 and 4). All
compounds tested maintained stability with only compound 2 showing
a significant decrease in peak area. All tests were done in simple
solution solvent base formulas (Table 13).
TABLE-US-00012 TABLE 12 S. mutans biofilm efficacy (row 2),
compound stability after 4 weeks of storage at 50.degree. C. (row
3), and compound stability after 8 weeks of storage at 50.degree.
C. (row 4) of formulations in Table 13. Compositions T1 U1 V1 W1 X1
Y1 Z1 A2 B2 C2 S. Mutans Average 5.90 5.84 6.13 6.16 NT 6.20 6.51
NT 6.12 NT Log RLU % Stable Derivative at 98.80 76.30 103.08 97.35
105.21 104.56 94.20 98.74 102.35 97.65 4 weeks storage at
50.degree. C. % Stable Derivative at 91.39 63.46 106.34 96.06 96.54
106.43 93.84 100.18 104.39 93.95 8 weeks storage at 50.degree. C.
Compositions Positive Negative D2 E2 F2 G2 H2 I2 Control Control S.
Mutans Average 5.56 6.02 NT NT NT NT 3.86 6.43 Log RLU % Stable
Derivative at 98.38 119.74 123.65 NT NT NT -- -- 4 weeks storage at
50.degree. C. % Stable Derivative at 100.69 90.48 121.83 NT NT NT
-- -- 8 weeks storage at 50.degree. C. NT = composition not
tested.
TABLE-US-00013 TABLE 13 Formulation compositions used in Example 7.
Composition (w/w %) T1 U1 V1 W1 X1 Y1 Z1 Compound 1 Compound 2
Compound 3 Compound 4 Compound 5 Compound 6 Compound 7 Compound
0.30 0.10 0.30 0.10 0.30 0.15 0.15 Purified Water 99.70 99.90 99.70
99.90 99.70 99.85 79.85 Ethanol 0 0 0 0 0 0 20 Propylene Glycol 0 0
0 0 0 0 0 Composition (w/w %) A2 B2 C2 D2 E2 F2 G2 Compound 8
Compound 9 Compound 10 Compound 11 Compound 12 Compound 13 Compound
14 Compound 0.30 0.15 0.15 0.30 0.15 0.15 0.15 Purified Water 99.70
79.85 79.85 99.70 99.85 49.85 49.85 Ethanol 0 20 0 0 0 0 0
Propylene Glycol 0 0 20 0 0 50 50 Composition (w/w %) H2 I2
Compound 15 Compound 16 Compound 0.15 0.15 Purified Water 49.85
99.85 Ethanol 0 0 Propylene Glycol 50 0
Example 8: Compounds 1, 2, 3, 6, 9, 11 and 12 Prevent Bacterial
Attachment when Tested in Alcohol Free Full Formulations (Table
15)
[0122] Some of the lead candidates at preventing bacterial
attachment were further optimized in alcohol-free full formulations
with water as the only solvent (Table 15) for their ability to
prevent bacterial attachment with and without essential oils (EOs)
(Table 14: J2-Q2 without EOs and Q2-W2 with EOs). All formulations
tested prevent bacterial attachment better when formulated with
EOs. Listerine Advanced Defense Gum Treatment (LAGDT) is the
positive control with water as the negative control.
TABLE-US-00014 TABLE 14 Prevention efficacy of formulations in
Table 15. Compositions J2 K2 L2 M2 N2 O2 P2 Q2 R2 S2 Average Log
RLU 3.98 4.02 4.52 4.51 4.81 4.70 NT 3.68 3.60 3.61 Compositions
Positive Negative T2 U2 V2 W2 Control Control Average Log RLU 3.58
3.63 3.74 3.50 4.21 5.86
TABLE-US-00015 TABLE 15 Formulation compositions used in Example 8.
Composition (w/w %) J2 K2 L2 M2 N2 O2 P2 Compound Compound Compound
Compound Compound Compound Compound 1 2 3 6 9 11 12 Compound 0.15
0.15 0.15 0.15 0.15 0.15 0.15 Pluracare F-68 NF Prill 2.50 2.50
2.50 2.50 2.50 2.50 2.50 (w/w %), Poly ethylene oxide co-propylene
oxide Propylene glycol, USP 0.00 0.00 0.00 0.00 0.00 0.00 0.00
Sucralose(w/w %), 1,6- 0.059 0.059 0.059 0.059 0.059 0.059 0.059
Dichloro-1,6-dideoxy-.beta.-D- fructofuranosyl-4-chloro-4-
deoxy-.alpha.-D-galactopyranoside Benzoic Acid 0.086 0.086 0.086
0.086 0.086 0.086 0.000 Sodium Benzoate, NF/FCC 0.077 0.077 0.077
0.077 0.077 0.077 0.000 Dense Form L-Menthol, USP 0.000 0.000 0.000
0.000 0.000 0.000 0.000 Thymol NF 0.000 0.000 0.000 0.000 0.000
0.000 0.000 Methyl Salicylate NF 0.000 0.000 0.000 0.000 0.000
0.000 0.000 Eucalyptol USP 0.000 0.000 0.000 0.000 0.000 0.000
0.000 Garbanzo 8 EC MOD, 0.000 0.000 0.000 0.000 0.000 0.000 0.000
UT264932/00 Purified water 97.13 97.13 97.13 97.13 97.13 97.13
97.29 Composition (w/w %) Q2 R2 S2 T2 U2 V2 W2 Compound Compound
Compound Compound Compound Compound Compound 1 2 3 6 9 11 12
Compound 0.15 0.15 0.15 0.15 0.15 0.15 0.15 Pluracare F-68 NF Prill
2.50 2.50 2.50 2.50 2.50 2.50 2.50 (w/w %), Poly ethylene oxide
co-propylene oxide Propylene glycol, USP 0.00 0.00 0.00 0.00 0.00
0.00 0.00 Sucralose(w/w %), 1,6- 0.059 0.059 0.059 0.059 0.059
0.059 0.059 Dichloro-1,6-dideoxy-.beta.-D-
fructofuranosyl-4-chloro-4- deoxy-.alpha.-D- galactopyranoside
Benzoic Acid 0.086 0.086 0.086 0.086 0.086 0.086 0.000 Sodium
Benzoate, NF/FCC 0.077 0.077 0.077 0.077 0.077 0.077 0.000 Dense
Form L-Menthol, USP 0.020 0.020 0.020 0.020 0.020 0.020 0.020
Thymol NF 0.018 0.018 0.018 0.018 0.018 0.018 0.018 Methyl
Salicylate NF 0.070 0.070 0.070 0.070 0.070 0.070 0.070 Eucalyptol
USP 0.017 0.017 0.017 0.017 0.017 0.017 0.017 Garbanzo 8 EC MOD,
0.088 0.088 0.088 0.088 0.088 0.088 0.088 UT264932/00 Purified
water 96.92 96.92 96.92 96.92 96.92 96.92 97.08
Example 9: Compounds 1, 2, 3, 6, 9, 11 and 12 Prevent Bacterial
Attachment when Tested in Alcohol-Free Full Formulations (Table
17)
[0123] The lead candidates at preventing bacterial attachment were
further optimized in alcohol-free full formulations with water and
propylene glycol as the solvents (Table 17) for their ability to
prevent bacterial attachment with and without essential oils (EOs)
(Table 16: X2-D3 without EOs and E3-K3 with EOs). All formulations
tested prevent bacterial attachment better when formulated with
EOs. Listerine Advanced Defense Gum Treatment (LAGDT) is the
positive control with water as the negative control.
TABLE-US-00016 TABLE 16 Prevention efficacy of formulations in
Table 17. Compositions X2 Y2 Z2 A3 B3 C3 D3 E3 F3 G3 Average Log
RLU 4.67 3.50 5.18 4.65 4.94 5.23 3.51 3.49 3.38 3.53 Compositions
Positive Negative H3 I3 J3 K3 Control Control Average Log RLU 3.67
3.60 3.99 3.30 4.31 6.12
TABLE-US-00017 TABLE 17 Formulation compositions used in Example 9.
Composition (w/w %) X2 Y2 Z2 A3 B3 C3 D3 Compound Compound Compound
Compound Compound Compound Compound 1 2 3 6 9 11 12 Compound 0.15
0.15 0.15 0.15 0.15 0.15 0.15 Pluracare F-68 NF Prill 1.00 1.00
1.00 1.00 1.00 1.00 1.00 (P188), Poly ethylene oxide co-propylene
oxide Propylene glycol, USP 15.00 15.00 15.00 15.00 15.00 15.00
15.00 Sucralose(w/w %), 1,6- 0.059 0.059 0.059 0.059 0.059 0.059
0.059 Dichloro-1,6-dideoxy-.beta.- D-fructofuranosyl-4-
chloro-4-deoxy-.alpha.-D- galactopyranoside Benzoic Acid 0.086
0.086 0.086 0.086 0.086 0.086 0.011 Sodium Benzoate, 0.077 0.077
0.077 0.077 0.077 0.077 0.010 NF/FCC Dense Form L-Menthol, USP
0.000 0.000 0.000 0.000 0.000 0.000 0.000 Thymol NF 0.000 0.000
0.000 0.000 0.000 0.000 0.000 Methyl Salicylate NF 0.000 0.000
0.000 0.000 0.000 0.000 0.000 Eucalyptol USP 0.000 0.000 0.000
0.000 0.000 0.000 0.000 Garbanzo 8 EC MOD, 0.000 0.000 0.000 0.000
0.000 0.000 0.000 UT264932/00 Purified water 83.63 83.63 83.63
83.63 83.63 83.63 83.77 Composition (w/w %) E3 F3 G3 H3 I3 J3 K3
Compound Compound Compound Compound Compound Compound Compound 1 2
3 6 9 11 12 Compound 0.15 0.15 0.15 0.15 0.15 0.15 0.15 Pluracare
F-68 NF Prill 1.00 1.00 1.00 1.00 1.00 1.00 1.00 (P188), Poly
ethylene oxide co-propylene oxide Propylene glycol, USP 15.00 15.00
15.00 15.00 15.00 15.00 15.00 Sucralose(w/w %), 1,6- 0.059 0.059
0.059 0.059 0.059 0.059 0.059 Dichloro-1,6-dideoxy-.beta.-D-
fructofuranosyl-4-chloro- 4-deoxy-.alpha.-D- galactopyranoside
Benzoic Acid 0.086 0.086 0.086 0.086 0.086 0.086 0.011 Sodium
Benzoate, NF/FCC 0.077 0.077 0.077 0.077 0.077 0.077 0.010 Dense
Form L-Menthol, USP 0.020 0.020 0.020 0.020 0.020 0.020 0.020
Thymol NF 0.018 0.018 0.018 0.018 0.018 0.018 0.018 Methyl
Salicylate NF 0.070 0.070 0.070 0.070 0.070 0.070 0.070 Eucalyptol
USP 0.017 0.017 0.017 0.017 0.017 0.017 0.017 Garbanzo 8 EC MOD,
0.088 0.088 0.088 0.088 0.088 0.088 0.088 UT264932/00 Purified
water 83.57 83.57 83.57 83.57 83.57 83.57 83.71
Methods
Formulation Preparation
[0124] The formulations in Examples 2-9 were prepared using
conventional mixing technology. Briefly, benzoic acid and sodium
benzoate were dissolved in propylene glycol or water. Flavor and
essential oils were dissolved in propylene glycol or in surfactant
and water (in some compositions no EOs or flavor were added).
Sucralose was dissolved in water. Surfactant was dissolved/mixed
into water. The sodium benzoate and benzoic acid containing
solution was added to the mixing vessel followed by the essential
oil and flavor solutions and then the surfactant solution and
sorbitol. This was followed by addition of the solid compound.
Sonication or increase in temperature may or may not be used to
expedite the dissolution of the compounds. The pH of the
formulations was adjusted to about pH 4.2 with sodium hydroxide or
hydrochloric acid and then water added to q.s. the composition.
Prevention Assay Method
[0125] The formulations in Examples 2-4, 6, 8 and 9 were prepared
and test for prevention of bacterial attachment using the
prevention assay. In this assay hydroxyapatite-coated polystyrene
peg plate (96 pegs, N=8 per group) was exposed to saliva for one
minute to form a pellicle at a temperature of 35 C. Then, for each
formulation, eight pegs (N=8) were pre-treated for ten minutes with
the formulation using an orbital shaker set to 500 RPM at room
temperature. As a negative control, eight pegs (N=8) were
pre-treated for ten minutes with sterile water. Next, a 16-hour
salivary biofilm was grown on these polystyrene peg plates at a
temperature of 35 C.
[0126] After all treatments were complete, the biofilm from each
peg was neutralized and rinsed. The biofilm was harvested via
sonication using a Q-Sonica Q700 Ultrasonic Liquid Processor with
431MP4-00 microplate horn Damper and 0.5:1 reverse gain booster
(Q-Sonica, Newtown, Conn.). Using a Celsis Rapid Detection
RapiScreen kit (Celsis International PLC, Chicago, Ill.), the
bacteria were lysed with Celsis Luminex and then the adenosine
triphosphate (ATP) from the lysed bacteria was measured using the
bioluminescence marker Celcis Luminate and a Centro LB 960
Microplate Luminometer supplied by Berthold Technologies (Wildbad,
Germany). Data were reported in log RLU (relative light units)
where decreasing log RLUs indicated fewer viable bacteria remained
on the biofilm substrate. The log RLUs for the prevention assay are
shown on Tables 2, 4, 6, 10, 14, and 16.
S. Mutans Single Species Kill Assay
[0127] The formulations listed in Example 7 were prepared and
tested using an in-vitro single species S. mutans biofilm model. A
24-hour S. mutans biofilm is grown on a polystyrene peg plate (96
pegs, N=6 per test group). The pegs were subsequently treated for
thirty seconds with each of formulations H and I, as well as
positive and negative controls. The treatment is applied as a
single thirty (30) second treatment. The positive control is a
commercially available essential oil mouth rinse. The negative
control is sterile water. After treatment the biofilm is
neutralized and rinsed. The biofilm is harvested via sonication
using a Misonix Ultrasonic Liquid Processor (Farmingdale, N.Y.).
Using a Celsis Rapid Detection RapiScreen kit (Celsis International
PLC, Chicago), the bacteria are lysed with Celsis Luminex and then
the adenosine triphosphate (ATP) from the lysed bacteria is
measured using the bioluminescence marker LB960 Microplate
Luminometer supplied by Berthold (Wildbad, Germany). Data are
reported in log RLU (relative light units) where decreasing log
RLUs indicates fewer viable bacteria remaining on the biofilm
substrate.
HPLC Quantification of Compounds
[0128] Briefly, formulations containing either LAE or any of the 26
compounds and standards are diluted into a solution of 50%
acetonitrile and 50% water. They are evaluated on an Agilent HPLC
using a Zorbax ion exchange column. In the method, 10 uL of the
sample is withdrawn and ran through the HPLC with a 40% potassium
phosphate (molarity at pH 3.0) 60% acetonitrile mobile phase.
Sample retention time varies between 4 and 12 minutes, depending
upon the molecule. The molecule peak is auto-integrated using the
Online Agilent HPLC software. Comparisons are made to the standard
to identify the % of compound remaining following storage.
* * * * *