U.S. patent application number 13/319809 was filed with the patent office on 2012-03-01 for borinic compositions.
This patent application is currently assigned to Colgate-Palmolive Company. Invention is credited to Jennifer Gronlund, Stanislav Jaracz, Andre Morgan, Venda Porter, Michael Prencipe, Ravi Subramanyam, Donghui Wu, Guofeng Xu.
Application Number | 20120052025 13/319809 |
Document ID | / |
Family ID | 43298506 |
Filed Date | 2012-03-01 |
United States Patent
Application |
20120052025 |
Kind Code |
A1 |
Porter; Venda ; et
al. |
March 1, 2012 |
BORINIC COMPOSITIONS
Abstract
A stabilized topical composition comprising a borinic acid
derivative, e.g., a borinic ester.
Inventors: |
Porter; Venda; (Piscataway,
NJ) ; Morgan; Andre; (Robbinsville, NJ) ;
Jaracz; Stanislav; (Somerset, NJ) ; Gronlund;
Jennifer; (Flemington, NJ) ; Xu; Guofeng;
(Plainsboro, NJ) ; Wu; Donghui; (Bridgewater,
NJ) ; Prencipe; Michael; (Princeton Junction, NJ)
; Subramanyam; Ravi; (Belle Mead, NJ) |
Assignee: |
Colgate-Palmolive Company
Piscataway
NJ
|
Family ID: |
43298506 |
Appl. No.: |
13/319809 |
Filed: |
June 3, 2010 |
PCT Filed: |
June 3, 2010 |
PCT NO: |
PCT/US10/37223 |
371 Date: |
November 10, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61183792 |
Jun 3, 2009 |
|
|
|
61183788 |
Jun 3, 2009 |
|
|
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Current U.S.
Class: |
424/52 ; 424/54;
514/64 |
Current CPC
Class: |
Y10S 514/835 20130101;
A61P 29/00 20180101; A61Q 11/00 20130101; A61P 17/00 20180101; A61P
31/04 20180101; A61Q 17/005 20130101; A61K 31/69 20130101; A61K
8/58 20130101; A61P 1/02 20180101; A61P 17/10 20180101; A61P 31/02
20180101; A61P 17/02 20180101; A61P 31/00 20180101 |
Class at
Publication: |
424/52 ; 514/64;
424/54 |
International
Class: |
A61K 31/69 20060101
A61K031/69; A61P 31/00 20060101 A61P031/00; A61P 17/02 20060101
A61P017/02; A61P 31/04 20060101 A61P031/04; A61P 29/00 20060101
A61P029/00; A61Q 19/10 20060101 A61Q019/10; A61Q 5/02 20060101
A61Q005/02; A61Q 11/00 20060101 A61Q011/00; A61K 8/58 20060101
A61K008/58; A61P 17/10 20060101 A61P017/10 |
Claims
1. A topical composition having a pH of at least 8, or buffered to
provide a pH of at least 7, comprising a compound of formula A:
##STR00008## wherein R.sub.1 and R.sub.2 are the same or different,
and are selected from aralkyl, aryl, cycloalkyl, or heterocycle;
and R.sub.3 is hetetoaryl, heteroarylalkyl, heteroarylcarbonyl, or
heteroarylalkylcarbonyl, in free or pharmaceutically acceptable
salt form; in combination or association with an orally or
topically acceptable carrier.
2. A composition according to claim 1 wherein the compound of
Formula A is a compound of Formula (I) ##STR00009## wherein R* and
R** are independently substituted or unsubstituted aralkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
cycloalkyl, or substituted or unsubstituted heterocycle; z is 0 or
1, with the proviso, that if z is 1, then A is CR.sup.10 or N, and
D is N or CR.sup.12, and with the further proviso that if z is 0
then D is O, S or NR.sup.12a; E is hydrogen, hydroxy, alkoxy,
(cycloalkyl)oxy, (cycloheteroalkyl)oxy, carboxy, or
alkyloxycarbonyl; m is 0 or 1; R.sup.12 is hydrogen, hydroxyalkyl,
aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxy,
alkyloxycarbonyl, amido, hydroxy, alkoxy, aryloxy, thio, alkylthio,
arylthio, alkylsulfonyl, dialkylaminosulfonyl, alkylaminosulfonyl,
aminosulfonyl, sulfo, cyano, halo, nitro, amino, dialkylamino,
alkylamino, arylamino, diarylamino, aralkylamino, or
diaralkylamino; R.sup.12a is hydrogen, substituted or unsubstituted
alkyl, substituted or unsubstituted heteroalkyl, substituted or
unsubstituted aralkyl, substituted or unsubstituted aryl,
substituted or unsubstituted cycloalkyl, or substituted or
unsubstituted heterocycle; and R.sup.9 and R.sup.10 are
independently hydrogen, alkyl, cycloalkyl, hydroxyalkyl,
aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, halo, carbonyl,
hydroxyimino, carboxy, alkyloxycarbonyl, alkylthio, alkylsulfonyl,
arylthio, dialkylaminosulfonyl, alkylaminosulfonyl, aminosulfonyl,
amino, alkoxy, nitro, sulfo, or hydroxy; in free or
pharmaceutically acceptable salt form.
3. The composition of claim 1 comprising
3-hydroxypyridine-2-carbonyloxy-bis(3-chloro-4-methylphenyl)-borane.
4. The composition of claim 1 further comprising a buffer.
5. The composition of claim 11 further comprising arginine in free
or pharmaceutically acceptable salt form.
6. The composition of claim 1 further comprising an
antioxidant.
7. The composition of claim 1 further comprising a solubilizing
agent.
8. The composition of claim 1 further comprising a chelator.
9. A composition according to claim 1 having a pH of at least 8
comprising an antibacterially effective amount of a compound of
Formula (A); an antioxidant in an amount effective to inhibit the
oxidation of the compound of Formula (A); a solubilizing agent; and
a pharmaceutically acceptable carrier.
10. The composition of claim 1 wherein the compound of formula (A)
is present in an amount of 0.05% to 20% by weight.
11. The composition of claim 1 wherein the antioxidant is selected
from ascorbic acid, sodium ascorbyl phosphate, butylated
hydroxytoluene (BHT), alpha tocopherol, citric acid, or a mixture
thereof.
12. The composition of claim 1 wherein the solubilizing agent is a
nonionic surfactant.
13. The composition of claim 1 having a pH of 8.5-10.
14. The composition of claim 1 in the form of a dentifrice,
comprising an orally acceptable carrier, wherein the orally
acceptable carrier comprises water and a humectant.
15. The composition of claim 1 wherein the compound of Formula A is
in aqueous solution.
16. The composition of claim 4 wherein the buffer is a phosphate
buffer.
17. The composition of claim 14, further comprising a fluoride ion
source and an abrasive.
18. A method for preparing a topical composition according to claim
1 comprising mixing a compound of Formula A with an orally or
topically acceptable carrier and adjusting or maintaining the pH at
a level of at least 7.
19. A method to reduce, inhibit, or treat oral microbial infections
comprising applying the composition of claim 1 to the oral cavity
of a patient in need thereof.
20. A method to reduce or inhibit formation of dental caries, to
treat, reduce or inhibit gingivitis, to reduce levels of oral
bacteria, to inhibit microbial biofilm formation in the oral
cavity, to reduce plaque accumulation, and/or clean the teeth and
oral cavity, comprising applying a composition according to claim 1
to the teeth and gums of a subject in need thereof.
21. A topical composition according to claim 1, suitable for
application to the skin or nails, having a pH of at least 8, or
buffered to at least pH 7, comprising an antibacterially effective
amount of a compound of Formula (A); an antioxidant in an amount
effective to inhibit the oxidation of the compound of Formula (A);
a solubilizing agent; and a pharmaceutically acceptable
carrier.
22. The composition of claim 21 wherein the compound of formula (A)
is present in an amount of 0.05% to 20% by weight.
23. The composition of claim 21 wherein the antioxidant is selected
from ascorbic acid, sodium ascorbyl phosphate, butylated
hydroxytoluene (BHT), alpha tocopherol, citric acid, or a mixture
thereof.
24. The composition of claim 21 wherein the solubilizing agent is a
nonionic surfactant.
25. The composition of claim 21 having a pH of 8.5-10.
26. The composition of claim 21 in the form of a topical cream,
gel, spray or ointment.
27. The composition of claim 21 in the form of an antimicrobial
soap, shampoo, or hand wash.
28. A method for preparing a topical composition of claim 21
comprising mixing a compound of Formula A with a pharmaceutically
acceptable carrier and adjusting or maintaining the pH at a level
of at least 7.
29. A method to reduce, inhibit, or treat topical microbial
infections comprising applying the composition of claim 21 to the
skin of a patient in need thereof.
30. The method of claim 29, wherein the condition to be treated is
selected from acne, superficial skin infections, minor cuts,
pathogen colonization, and inflammatory skin conditions.
Description
[0001] This application claims the benefit of U.S. Provisional
Application 61/183,788, filed Jun. 3, 2009 and U.S. Provisional
Application 61/183,792, also filed Jun. 3, 2009, the contents of
which are incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] The present invention relates to antimicrobial compositions
containing a borinic acid derivative, e.g. a borinic ester. In
particular embodiments, the invention covers topical antimicrobial
compositions, for example topical compositions for treating fungal
or bacterial infections of the skin or nails, and oral
compositions, for example dentifrice, for reducing bacteria in the
mouth, e.g. for inhibiting and reducing plaque, gingivitis and
dental caries.
[0003] Although some borinic esters are effective as antibacterial
agents, incorporating borinic esters into oral care compositions
presents difficulties, as borinic esters have proven to be unstable
when added to aqueous compositions. For example, borinic esters may
hydrolyze and decompose, e.g., in oral care compositions.
Additionally, borinic esters may be insoluble in aqueous
compositions. For example, the solubility of
3-hydroxypyridine-2-carbonyloxy-bis(3-chloro-4-methylphenyl)-borane
in water is only 100 ppm, and its solubility in various oils may be
less than 0.5%. There remains a need to develop compositions and
methods to incorporate borinic acid derivatives stably in oral care
compositions.
SUMMARY OF THE INVENTION
[0004] The present invention is directed to the surprising
discovery that certain borinic esters are stable, soluble, and
retain antimicrobial activity when incorporated into an topical or
oral care composition, e.g., a topical pharmaceutical composition
or a dentifrice or mouthwash.
[0005] In one embodiment, the borinic acid derivatives of the
present invention are borinic esters, e.g. of formula A:
##STR00001##
wherein R.sub.1 and R.sub.2 are the same or different (e.g. the
same), and are selected from arylalkyl, aryl, cycloalkyl, or
heterocycle (e.g. substituted or unsubstituted aryl or heteroaryl,
for example phenyl, chlorophenyl, methylphenyl, or
methylchlorophenyl); and R.sub.3 is heteroaryl, heteroarylalkyl,
heteroarylcarbonyl, or heteroarylalkylcarbonyl (e.g., substituted
or unsubstituted heteroaryl, for example quinolinyl or
hydroxypyridinylcarbonyl), in free or pharmaceutically acceptable
salt form, in combination with a pharmaceutically acceptable
carrier. For example, in one embodiment R.sub.1 and R.sub.2 are the
same and are both aryl, e.g., phenyl, chlorophenyl, methylphenyl,
or methylchlorophenyl.
[0006] Heteroaryl is for example an aryl group containing 1, 2 or 3
nitrogen atoms, for example pyridinyl, quinolinyl,
hydroxypyridinyl, or hydroxyquinolinol. Alkyl is for example
C.sub.1-4 alkyl. Substitutions are for example halogen, e.g.,
chloro or fluoro, hydroxy, or C.sub.1-4 alkyl.
[0007] The borinic esters useful in the present invention thus
include, for example, (i) boron picolinates, e.g. diaryl boron
picolinates, for example
3-hydroxypyridine-2-carbonyloxy-bis(3-chloro-4-methylphenyl)-bora-
ne or
3-hydroxypyridine-2-carbonyloxy-bis(2-methyl-4-chlorophenyl)-borane,
as well as (ii) diaryl borinic esters, for example
diphenylborane-8-hydroxyquinolinate (PBHQ).
[0008] In one embodiment, the borinic esters are compounds as
described in WO 2006/102604, incorporated herein by reference,
e.g., of Formula (I)
##STR00002##
wherein R* and R** are independently substituted or unsubstituted
aralkyl, substituted or unsubstituted aryl, substituted or
unsubstituted cycloalkyl, or substituted or unsubstituted
heterocycle; z is 0 or 1, with the proviso, that if z is 1, then A
is CR.sup.10 or N, and D is N or CR.sup.12, and with the further
proviso that if z is 0 then D is O, S or NR.sup.12a; E is hydrogen,
hydroxy, alkoxy, (cycloalkyl)oxy, (cycloheteroalkyl)oxy, carboxy,
or alkyloxycarbonyl; m is 0 or 1; R.sup.12 is hydrogen,
hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,
carboxy, alkyloxycarbonyl, amido, hydroxy, alkoxy, aryloxy, thio,
alkylthio, arylthio, alkylsulfonyl, dialkylaminosulfonyl,
alkylaminosulfonyl, aminosulfonyl, sulfo, cyano, halo, nitro,
amino, dialkylamino, alkylamino, arylamino, diarylamino,
aralkylamino, or diaralkylamino; R.sup.12a is hydrogen, substituted
or unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted aralkyl, substituted or unsubstituted
aryl, substituted or unsubstituted cycloalkyl, or substituted or
unsubstituted heterocycle; and
[0009] R.sup.9 and R.sup.10 are independently hydrogen, alkyl,
cycloalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl,
dialkylaminoalkyl, halo, carbonyl, hydroxyimino, carboxy,
alkyloxycarbonyl, alkylthio, alkylsulfonyl, arylthio,
dialkylaminosulfonyl, alkylaminosulfonyl, aminosulfonyl, amino,
alkoxy, nitro, sulfo, or hydroxy;
in free or pharmaceutically acceptable salt form.
[0010] "Aralkyl" and "alkaryl" are sometimes used to refer to
arylalkyl and alkylaryl respectively. The alkyl or aryl portion of
any moiety recited for R.sup.9, R.sup.19, or R.sup.12 is optionally
substituted, for example with hydroxy, halogen, or C.sub.1-4
alkyl.
[0011] Alkyl is preferably C.sub.1-4 alkyl. Cycloalkyl is
preferably C.sub.3-7 cycloalkyl. Aryl is preferably phenyl.
[0012] In some embodiments, E is a member selected from hydrogen,
hydroxy, or (cycloheteroalkyl)oxy such as 2-morpholinoethoxy.
[0013] In other embodiments, R.sup.12 is (CH.sub.2).sub.kOH (where
k=1, 2 or 3), CH.sub.2NH.sub.2, CH.sub.2NH-alkyl,
CH.sub.2N(alkyl).sub.2, CO.sub.2H, CO.sub.2alkyl, CONH.sub.2, OH,
alkoxy, aryloxy, SH, S-alkyl, S-aryl, SO.sub.2alkyl,
SO.sub.2N(alkyl).sub.2, SO.sub.2NHalkyl, SO.sub.2NH.sub.2,
SO.sub.3H, SCF.sub.3, CN, halogen, CF.sub.3, NO.sub.2, NH.sub.2,
2.degree.-amino, 3.degree.-amino, NH.sub.2SO.sub.2 or
CONH.sub.2.
[0014] In still other embodiments, R.sup.9 and R.sup.19 are
independently hydrogen, alkyl, cycloalkyl, (CH.sub.2).sub.nOH (n=1
to 3), CH.sub.2NH.sub.2, CH.sub.2NHalkyl, CH.sub.2N(alkyl).sub.2,
halogen, CHO, CH.dbd.NOH, CO.sub.2H, CO.sub.2-alkyl, S-alkyl,
S0.sub.2-alkyl, S-aryl, SO.sub.2N(alkyl).sub.2, SO.sub.2NHalkyl,
SO.sub.2NH.sub.2, NH.sub.2, alkoxy, CF.sub.3, SCF.sub.3, NO.sub.2,
SO.sub.3H or OH;
[0015] Compounds of Formula 1 may exist in rotameric form, and the
illustrated dative bond (arrow) may or may not be present, i.e.,
the present invention includes those compounds in which
coordination between the boron atom and the nitrogen or hydroxy of
the picolinate is present and those compounds where such
coordination is missing. The present invention also includes those
compounds of Formula 1 in which a dative bond is formed between the
boron and another atom of the molecule. In addition, those of skill
in the art, e.g., organic and medicinal chemistry, will appreciate
that the large difference in atomic radius between carbon and boron
can allow for the formation of solvent coordination complexes in
which a solvent molecule, such as water, can be inserted between
the boron atom and the nitrogen atom of the picolinate ring. The
present invention includes such adducts of the compounds of Formula
1.
[0016] In one embodiment of the invention in which z is 1, the
compound of Formula 1 has a structure according to the following
formula:
##STR00003##
wherein D is selected from N and CR.sup.12.
[0017] In another embodiment of the invention, in which z is 0, the
compound of Formula 1 has a structure according to the following
formula:
##STR00004##
wherein D is a member selected from O, S and NR.sup.12a.
[0018] In one embodiment of the invention, R* and R** are the same.
In a more specific embodiment, R* and R* * are substituted or
unsubstituted aryl. In a still more specific embodiment, R* and R**
are substituted or unsubstituted phenyl, wherein said substituted
or unsubstituted phenyl has the structure:
##STR00005##
and further wherein each of R.sup.4-R.sup.8 is a member
independently selected from hydrogen, alkyl, cycloalkyl, aryl,
substituted aryl, aralkyl, substituted aralkyl, hydroxyalkyl,
aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxy,
alkylcarbonyl, aminocarbonyl, alkylaminocarbonyl,
dialkylaminocarbonyl, hydroxy, alkoxy, aryloxy, thio, alkylthio,
arylthio, alkylsulfonyl, diaminosulfonyl, alkylaminosulfonyl,
aminosulfonyl, sulfo, cyano, halo, nitro, amino, 2.degree.-amino,
3.degree.-amino, aminosulfonyl, aminoalkyloxy,
(alkylamino)alkyloxy, (dialkylamino)alkyloxy, and cycloheteroalkyl.
Each alkyl or aryl portion of each moiety recited for
R.sup.4-R.sup.8 is optionally substituted.
[0019] In more specific embodiments of the invention in which R*
and R** are both optionally substituted phenyl as just described,
each of R.sup.4-R.sup.8 is a member independently selected from the
group consisting of: hydrogen, alkyl, cycloalkyl, aryl, substituted
aryl, aralkyl, substituted aralkyl, (CH.sub.2).sub.kOH (where k=1,
2 or 3), CH.sub.2NH.sub.2, CH.sub.2NH-alkyl,
CH.sub.2N(alkyl).sub.2, CO.sub.2H, CO.sub.2alkyl, CONH.sub.2,
CONHalkyl, CON(alkyl).sub.2, OH, alkoxy, aryloxy, SH, S-alkyl,
S-aryl, SO.sub.2alkyl, S0.sub.2N(alkyl).sub.2, SO.sub.2NHalkyl,
SO.sub.2NH.sub.2, SO.sub.3H, SCF.sub.3, CN, halogen, CF.sub.3,
NO.sub.2, NH.sub.2, 2.degree.-amino, 3.degree.-amino,
NH.sub.2SO.sub.2, OCH.sub.2CH.sub.2NH.sub.25
OCH.sub.2CH.sub.2NHalkyl, OCH.sub.2CH.sub.2N(alkyl).sub.2,
oxazolidin-2-yl, and alkyl substituted oxazolidin-2-yl.
[0020] In one embodiment of the invention in which R* and R** are
both optionally substituted phenyl as described, R.sup.9 is H, z is
1, A is CH, D is CH, E is OH, and m is O. In a more specific
embodiment of the foregoing, R* and R** are both
3-chloro-4-methylphenyl. In another specific embodiment, R* and R**
are both 2-methyl-4-chlorophenyl.
[0021] Particularly useful compounds include
3-hydroxypyridine-2-carbonyloxy-bis(3-chloro-4-methylphenyl)-borane
and
3-hydroxypyridine-2-carbonyloxy-bis(2-methyl-4-chlorophenyl)-borane,
in free or pharmaceutically acceptable salt form.
[0022] It has surprisingly been discovered that in formulations,
the borinic ester compounds may exist in rotameric form, wherein
the form is largely pH dependent, and the boron may be linked by a
coordinate covalent bond (dative bond) to the nitrogen in the
heteroaryl. The rotamer wherein the boron is nonpolar or associated
with the hydroxy group on the picolinate moiety is predominantly or
exclusively present at basic pH, while the more polar rotamer,
wherein the boron is associated with the nitrogen on the picolinate
or other heterocycle predominates at acidic pH. For example,
##STR00006##
It has also been discovered that the nonpolar rotamer or rotamer
wherein the boron is associated with hydroxy is more stable in
formulation. Without intending to be bound by theory, it is
believed that the shift in electron density that occurs upon the
formation of the dative bond with nitrogen makes the polar isomer
more susceptible to hydrolysis at the ester bond.
[0023] To favor the more stable rotamer, we have discovered that it
is advantageous that the pH of the formulation be maintained above
7, e.g., by using a buffer to prevent a drop in pH which would
result in formation of the more polar rotamer, and/or that the pH
be maintained even at a higher level, e.g., 8-9.5, it having been
surprisingly shown that the compounds are stable at higher pH, and
not (as might be suspected) highly vulnerable to degradation by
OH.sup.- ions. This discovery allows preparation of stable aqueous
formulations of the compounds. We note that this discovery is
somewhat in contrast to the examples of WO 2006/102604 which
describe topical emulsions, with the borinic ester in the oil
phase, or else compositions having relatively low pH, e.g.,
5.5.
[0024] Thus, the invention provides Composition 1.0, a composition,
e.g., a topical composition, e.g., an oral care or topical
pharmaceutical composition, comprising an antibacterially effective
amount of a borinic acid derivative, e.g., of Formula A, for
example a compound of Formula (I), having a pH of at least 8, e.g.
8.5-11, for example about 9, or buffered to at least pH 7, and
optionally further comprising one or more antioxidants, surfactants
and solubilizing agents.
[0025] The present invention includes Composition 2.0, a
dentifrice, comprising Composition 1.0 and a dentifrice vehicle,
having a pH of at least 8, e.g. 8.5-11, for example about 9, or
buffered to at least pH 7, and optionally further comprising one or
more antioxidants, surfactants and/or solubilizing agents.
[0026] In another aspect, it has been discovered that borinic acid
derivatives, e.g. of Formula A, which are often difficult to
solubilize, are highly soluble in polymers comprising
polyoxyethylene or polyoxyethylene and polyoxypropylene. Thus in
another embodiment the present invention comprises Composition 3.0,
a topical composition, for example a topical pharmaceutical or oral
care formulation, e.g., according to any of Compositions 1.0 to
2.0, comprising borinic acid derivatives, e.g. of Formula A, for
example a Compound of Formula I, and a solubilizing agent, e.g.,
selected from polymers of polyoxyethylene and
polyoxyethylene/polyoxypropylene.
[0027] It has also been found that buffering the formulation to a
pH of at least 7 enhances stability. The invention thus provide
provides Composition 4.0, a topical composition, for example a
topical pharmaceutical or oral care formulation, comprising an
antibacterially effective amount of a borinic acid derivative,
e.g., of Formula A, for example a compound of Formula (I), for
example any of Compositions 1.0 et seq.--3.0 et seq. more fully
described below, in combination with a suitable buffer, for example
a phosphate buffer.
[0028] The present invention also includes Composition 5.0, a
topical composition (for example a topical antimicrobial product or
an antimicrobial soap), comprising Composition 1.0, 3.0 or 4.0 and
a pharmaceutically (including cosmetically) acceptable vehicle,
having a pH of at least 8, e.g. 8.5-11, for example about 9, or
buffered to at least 7, and optionally further comprising one or
more antioxidants, surfactants and/or solubilizing agents.
[0029] The present invention also includes Method 6.0, a method for
preparing a topical composition comprising mixing Composition 1.0,
3.0 or 4.0 with a pharmaceutically acceptable vehicle and adjusting
or maintaining the pH at a level of at least 7, preferably at least
8, e.g., 8.5-11.
[0030] The present invention also includes Method 7.0, a method to
reduce, inhibit, or treat topical microbial infections, for example
to treat, reduce or inhibit topical skin infections, e.g., acne,
superficial skin infections, minor cuts, pathogen colonization, and
inflammatory skin conditions, comprising applying a Composition of
the Invention to the affected skin or nails of a subject in need
thereof.
[0031] The present invention also includes Method 8.0, a method for
preparing a topical, e.g., oral care composition comprising mixing
any of Compositions 1.0-4.0 with an orally or topically acceptable
vehicle and adjusting or maintaining the pH at a level of at least
7, preferably at least 8, e.g., 8.5-11.
[0032] The present invention also includes Method 9.0, a method to
reduce, inhibit, or treat oral microbial infections, for example to
reduce or inhibit formation of dental caries, to treat, reduce or
inhibit gingivitis, to reduce levels of oral bacteria, to inhibit
microbial biofilm formation in the oral cavity, to reduce plaque
accumulation, and/or clean the teeth and oral cavity, comprising
applying a Composition of the Invention to the oral cavity of a
subject in need thereof.
DESCRIPTION OF DRAWINGS
[0033] FIG. 1 depicts percent of COMPOUND 1 recovery after two
weeks at 60.degree. C. as a function of formula pH in the (a)
G-series base and (b) the low water base, as further described in
the examples.
[0034] FIG. 2 shows the percentage of COMPOUND 1 recovery in a
50/50 acetonitrile/water solution as a function of pH after 1 day
at 70.degree. C., as further described in the examples.
DETAILED DESCRIPTION
[0035] As used throughout, ranges are used as a shorthand for
describing each and every value that is within the range. Any value
within the range can be selected as the terminus of the range. In
addition, all references cited herein are hereby incorporated by
reference in their entireties. In the event of a conflict in a
definition in the present disclosure and that of a cited reference,
the present disclosure controls.
[0036] Unless otherwise specified, all percentages and amounts
expressed herein and elsewhere in the specification should be
understood to refer to percentages by weight. The amounts given are
based on the active weight of the material.
[0037] The oral compositions of the present invention may include a
dentifrice, mouth rinse, dental floss, dental paint, dental film,
lozenge, or confectionery. Dentifrice compositions may include a
toothpaste, gel, or powder.
[0038] "Orally acceptable salts" are pharmaceutically acceptable
acid or base addition salts that are safe for use in an oral care
product such as a dentifrice in the amounts and concentrations
provided by normal use of the product.
[0039] Compounds of Formula (I) which may be useful in the present
invention include:
3-hydroxypyridine-2-carbonyloxy-bis(3-chloro-4-methylphenyl)-borane
(or bis(3-chloro-4-methylphenyl)borinic acid 3-hydroxypicolinate
ester), e.g. of Formula (II):
##STR00007##
[0040] Thus, in one aspect of the present invention, Composition 1,
e.g., a composition, e.g., an oral care composition or topical
pharmaceutical formulation, comprising an antibacterially effective
amount of a borinic acid derivative, e.g., of Formula A, for
example a compound of Formula (I), having a pH of at least 7,
preferably at least 8, e.g. 8.5-11, for example about 9, and
optionally further comprising one or more antioxidants, surfactants
and solubilizing agents, includes, for example, any of the
following compositions: [0041] 1.1 Composition 1 comprising a
borinic ester. [0042] 1.2 Composition 1.1 comprising a borinic
ester of Formula 1. [0043] 1.3 Composition 1.1 or 1.2 comprising a
diaryl boron picolinate. [0044] 1.4 Composition 1.1, 1.2 or 1.3
comprising
3-hydroxypyridine-2-carbonyloxy-bis(3-chloro-4-methylphenyl)-borane
or
3-hydroxypyridine-2-carbonyloxy-bis(2-methyl-4-chlorophenyl)-borane.
[0045] 1.5 Composition 1.4 comprising
3-hydroxypyridine-2-carbonyloxy-bis(3-chloro-4-methylphenyl)-borane.
[0046] 1.6 Composition 1 comprising a diaryl borinic ester. [0047]
1.7 Composition 1.6 wherein the diaryl borinic ester is
diphenylborane-8-hydroxyquinolinate (PBHQ). [0048] 1.8 Any of
compositions 1.0-1.7, wherein the compound of formula (A) is
present in an amount of 0.05% to 20% by weight, e.g., 0.1% to 10%.
[0049] 1.9 Any of compositions 1-1.8 comprising buffering agents to
raise and maintain the pH at the desired level. [0050] 1.10
Composition 1.9 wherein the buffering agent includes a basic amino
acid in free or pharmaceutically acceptable salt form [0051] 1.11
Composition 1.10 wherein the basic amino acid is selected from
arginine, lysine, citrulline, ornithine, creatine, histidine,
diaminobutanoic acid, diaminoproprionic acid and mixtures thereof,
in free or pharmaceutically acceptable salt form. [0052] 1.12
Composition 1.12 wherein the basic amino acid is arginine in free
or pharmaceutically acceptable salt form.
[0053] Without intending to be bound by theory, it is believed that
compounds of Formula A, e.g., the borinic esters of Formula (I) may
be oxidized by oxygen, peroxides, or by peroxides that can be
formed in oral and topical compositions, e.g., from ethers such as
polyethylene glycol reacting with oxygen. Such oxygen and/or
peroxides may react with the borinic ester at the carbon-boron
bond, leading to cleavage and formation of boronic acid derivatives
and phenol derivatives, which are ineffective antibacterial agents.
It is believed that the addition of antioxidants reduces the
peroxides and other oxidizing agents that may be present or form in
the oral compositions.
[0054] Thus, in one aspect of the present invention, Composition
1.0 thus includes for example, any of the following compositions:
[0055] 1.13 Any of Compositions 1.0-1.8 further comprising an
antioxidant. [0056] 1.14 Composition 1.9 wherein the antioxidant is
selected from ascorbic acid, sodium ascorbyl phosphate, butylated
hydroxytoluene (BHT), alpha tocopherol, citric acid, and a mixture
thereof. [0057] 1.15 Any of Compositions 1.9-1.10 wherein the
antioxidant is present in an amount sufficient to inhibit oxidation
of the borinic acid derivative; [0058] 1.16 Any of compositions
1.9-1.11 wherein the antioxidant is present in an effective amount
to prevent or inhibit oxidation of the compound of formula (I).
[0059] In one embodiment of the present invention, the compounds of
formula (I) are solubilzed in the compositions of the present
invention with a solubilizing agent, which may include for example
polyethylene glycol, glycerin, co-polymers of polyethylene glycol
and polypropylene glycol (e.g., Pluraflo L4370), or Triblock
Copolymer Surfactant F127. The amounts of solubilizing agent
required will be dependent upon the amount of the compounds of
Formula (I) in the composition, and the particular solubilizing
agent selected. Thus, the present invention includes the following
compositions: [0060] 1.17 Any of compositions 1.0-1.12 further
comprising a solubilizing agent. [0061] 1.18 Composition 1.13
wherein the solubilizing agent is a nonionic surfactant. [0062]
1.19 Composition 1.14 wherein the solubilizing agent comprises an
alkyl ether, for example a polyalkyleneglycol, for example
polyethylene glycol, polypropylene glycol, or co-polymers or
mixtures of any of these. [0063] 1.20 Any of compositions 1.13-1.15
wherein the compound of Formula A is solubilized in the
solubilizing agent prior to mixture with the other composition
ingredients. [0064] 1.21 Any of compositions 1.13-1.16 wherein the
solubilizing agent is present in an amount of from 1-30% by weight,
for example 5-10% by weight.
[0065] The compositions of the invention also may optionally
include one or more chelating agents which are able to complex
calcium found in the cell walls of the bacteria, which, it is
believed weakens the bacterial cell wall and augments bacterial
lysis. Chelating agents may further sequester ions that could
complex with and destabilize the borinic acid derivatives. Agents
suitable for use as chelating agents are known to those of skill in
the art, and include di- or tetra-acids and their salts, such as
the soluble pyrophosphates, polycarboxylic acids, and
polyaminocarboxylic acids. The pyrophosphate salts used in the
present compositions can be any of the alkali metal pyrophosphate
salts. In certain embodiments, salts include tetra alkali metal
pyrophosphate, dialkali metal diacid pyrophosphate, trialkali metal
monoacid pyrophosphate and mixtures thereof, wherein the alkali
metals are sodium or potassium. The salts are useful in both their
hydrated and unhydrated forms. An effective amount of pyrophosphate
salt useful in the present composition is generally enough to
provide at least about 1 wt. % pyrophosphate ions, about 1.5 wt. %
to about 6 wt. %, about 3.5 wt. % to about 6 wt. % of such ions.
Useful chelating agents include tetrasodium pyrophosphate,
tetrapotassium pyrophosphate, ethylene diamine tetraacetic acid,
ethylene glycol tetraacetic acid, sodium pyrophosphate, sodium
tripolyphosphate, potassium tripolyphosphate, sodium
hexametaphosphate, and citric acid. Accordingly, in a further
embodiment, the invention provides [0066] 1.22 Any of compositions
1.0-1.17 further comprising a chelator. [0067] 1.23 Composition
1.22 wherein the chelator is selected from tetrasodium
pyrophosphate, tetrapotassium pyrophosphate, ethylene diamine
tetraacetic acid, ethylene glycol tetraacetic acid, sodium
pyrophosphate, sodium tripolyphosphate, potassium tripolyphosphate,
sodium hexametaphosphate, and citric acid. [0068] 1.24 Any of
compositions 1.22 or 1.23 wherein the chelator provides ion in an
amount by weight of 1-6%
[0069] In one embodiment, Composition 2.0 of the present invention
is an oral care product, comprising an effective amount of
Composition 1.0 and an orally acceptable carrier. Acceptable
carriers suitable for use in an oral care product are known by
those of skill in the art, and may take the form of a paste, gel or
mouthwash which includes water and/or a humectant, or may take the
form of a powder, or a dental floss or dental device. The
components of the acceptable carrier may include Composition 1.0.
Humectants are known by those of skill in the art, and include
edible polyhydric alcohols such as glycerine, sorbitol, xylitol,
alkylene glycol such as polyethylene glycol or propylene glycol as
well as other polyols and mixtures of these humectants. The oral
compositions of the present invention may comprise from about 5% to
about 80% by weight of the humectant, with water and other
components making up the balance of the carrier.
2.1 Composition 2 in the form of a paste, gel or liquid comprising
any of compositions 1-1.24 in combination or association with water
and/or a humectant. 2.2 Composition 2.1 wherein the amount of water
is less than 10%. 2.3 Composition 2.1 or 2.2 wherein the amount of
humectant is greater than 50%. 2.4 Any of Compositions 2-2.3
wherein the humectant is selected from polyhydric alcohols (e.g.
glycerine, sorbitol, xylitol) and alkylene glycol (polyethylene
glycol or propylene glycol as well as other polyols and mixtures.
2.5. Any of Compositions 2-2.4 which is a dentifrice. 2.6
Composition 2.5 which is a toothpaste. 2.7 Composition 2.5 or 2.6
which further comprises an abrasive. 2.8 Composition 2.7 which
further comprises a fluoride ion source.
[0070] In another embodiment, the invention provides a topical or
oral care composition, Composition 3.0, e.g., according to
Composition 1.0 through 2.8, comprising borinic acid derivatives,
e.g. of Formula A, for example a compound of Formula I, and at
least one solubilizing agent selected from polymers of
polyoxyethylene and/or polyoxypropylene, e.g.
3.1 Composition 3.0 wherein the solubilizing agent comprises a
co-polymer of polyethylene glycol and polypropylene glycol, e.g.,
Fluraflo L4370 (BASF). 3.2 Composition 3.0 wherein the solubilizing
agent comprises a poloxamer, e.g. a tri-block co-polymer of formula
H--(O--CH.sub.2--CH.sub.2).sub.x--(O--CH(CH.sub.3)CH.sub.2).sub.y--(O--CH-
.sub.2--CH.sub.2).sub.z--OH. 3.3 Composition 3.2 wherein the
average molecular weight of the polyoxypropylene block in the
poloxamer is approximately 3-4 kD, the polyoxyethylene content is
approximately 65-75%, and the total average molecular weight of the
poloxamer is approximately 12-13 kD, for example wherein x and z
are each 90-110, e.g. about 101, and y is 50-65, e.g., about 56,
for example wherein the poloxamer is poloxamer 407 (e.g.,
Pluronic.RTM. F-127 from BASF). 3.3 Composition 3.0 wherein the
solubilizing agent comprises polyethylene glycol, e.g. having an
average molecular weight of 100 to 1000 daltons, for example, e.g.,
PEG 300 or PEG 600. 3.4 Composition 3.0 wherein the solubilizing
agent comprises an agent selected from co-polymers of polyethylene
glycol and polypropylene glycol, poloxamers, polyethylene glycols,
and mixtures thereof. It has also been discovered that the
stability of the borinic acid derivatives is significantly enhanced
by use of buffering agents, even to a large extent at neutral pH.
The invention provides in a further embodiment Composition 4, a
topical or oral care formulation, e.g., according to any of the
preceding Compositions 1.0 through 3.4, comprising an
antibacterially effective amount of a borinic acid derivative,
e.g., of Formula A, for example a compound of Formula (I), and a
buffer, having a pH of about 7 to about 11, for example a pH of at
e.g., at least 8, for example having a phosphate buffer providing a
pH of at least 7.2.
[0071] The oral care compositions of the present invention may also
contain one or more fluoride ion sources, e.g., fluoride salts
which may be soluble. Fluoride salts wherein the fluoride is
covalently bound to another atom and/or sequestered from calcium
are preferred. A wide variety of fluoride ion-yielding materials
can be employed as sources of soluble fluoride in the present
compositions. Representative fluoride ion sources include, but are
not limited to, stannous fluoride, sodium fluoride, potassium
fluoride, sodium monofluorophosphate, sodium fluorosilicate,
ammonium fluorosilicate, amine fluoride, ammonium fluoride, and
combinations thereof. In certain embodiments the fluoride ion
source includes stannous fluoride, sodium fluoride, sodium
monofluorophosphate as well as mixtures thereof.
[0072] In certain embodiments, the oral care composition of the
invention may also contain a source of fluoride ions or
fluorine-providing ingredient in amounts sufficient to supply about
25 ppm to about 25,000 ppm of fluoride ions, generally at least
about 500 ppm, e.g., about 500 to about 2000 ppm, e.g., about
1000--about 1600 ppm, e.g., about 1450 ppm.
[0073] Fluoride ion sources may be added to the compositions of the
invention at a level of about 0.01 wt. % to about 10 wt. % in one
embodiment or about 0.03 wt. % to about 5 wt. %, and in another
embodiment about 0.1 wt. % to about 1 wt. % by weight of the
composition in another embodiment. Weights of fluoride salts to
provide the appropriate level of fluoride ion will obviously vary
based on the weight of the counter ion in the salt.
[0074] The oral compositions of the present invention may also
comprise an additional antibacterial agent, which are know by those
of skill in the art, such as a halogenated diphenyl ether
(triclosan), herbal extracts or essential oils, biguanide
antiseptics, phenolic antiseptics, hexetidine, povidone iodine,
delmopinol, salifluor, metal ions (e.g., zinc salts, for example,
zinc citrate), sanguinarine, and propolis.
[0075] The oral compositions of the present invention may also
comprise a tooth desensitizing agent, which are known by those of
skill in the art, and include a potassium salt, capsaicin, eugenol,
a strontium salt, a zinc salt, a chloride salt, or combinations
thereof.
[0076] The oral compositions of the present invention may comprise
abrasives and/or polishing agents, such as calcium and silica
abrasives, which are known by those of skill in the art. Preferred
calcium abrasives may include a calcium phosphate abrasive, e.g.,
tricalcium phosphate (Ca.sub.3(PO.sub.4).sub.2), hydroxyapatite
(Ca.sub.10(PO.sub.4).sub.6(OH).sub.2), or dicalcium phosphate
dihydrate (CaHPO.sub.4.2H.sub.2O). Useful silica abrasives may
include precipitated silicas having a mean particle size of up to
about 20 microns, such as Zeodent 115.RTM., marketed by J. M.
Huber. Other useful abrasives also include sodium metaphosphate,
potassium metaphosphate, aluminum silicate, calcined alumina,
bentonite or other siliceous materials, or combinations
thereof.
[0077] The silica abrasive polishing materials useful herein, as
well as the other abrasives, generally have an average particle
size of about 0.1 and about 30 microns, about 5 and about 15
microns. The silica abrasives can be from precipitated silica or
silica gels, such as the silica xerogels, which may be are marketed
under the trade name Syloid.RTM. by the W. R. Grace & Co.,
Davison Chemical Division. The precipitated silica materials
include those marketed by the J. M. Huber Corp. under the trade
name Zeodent.RTM., including the silica carrying the designation
Zeodent 115 and 119.
[0078] In certain embodiments, abrasive materials useful in the
practice of the oral care compositions in accordance with the
invention include silica gels and precipitated amorphous silica
having an oil absorption value of about less than 100 cc/100 g
silica and in the range of about 45 cc/100 g to about 70 cc/100 g
silica. Oil absorption values are measured using the ASTA Rub-Out
Method D281. In certain embodiments, the silicas are colloidal
particles having an average particle size of about 3 microns to
about 12 microns, and about 5 to about 10 microns.
[0079] In particular embodiments, the abrasive materials comprise
very small particles, e.g., having a d50 less than about 5 microns.
For example small particle silica (SPS) having a d50 of about 3 to
about 4 microns, for example Sorbosil AC43.RTM. (Ineos). Such small
particles are particularly useful in formulations targeted at
reducing hypersensitivity. The small particle component may be
present in combination with a second larger particle abrasive. In
certain embodiments, for example, the formulation comprises about
3--about 8% SPS and about 25--about 45% of a conventional
abrasive.
[0080] It has been found that oral compositions containing silica
and the compounds of Formula (I) change color, from white to
yellow, which is undesirable. Such a color change is observable
even if the composition contains antioxidants (previously
discussed). The present invention is also based on the surprising
discovery that the addition of a chelating agent to the oral
composition can inhibit such color change, indeed, reverse such
color change. Chelating agents useful to prevent such color change
have been previously discussed.
[0081] Low oil absorption silica abrasives particularly useful in
the practice of the invention are marketed under the trade
designation Sylodent XWA.RTM. by Davison Chemical Division of W.R.
Grace & Co., Baltimore, Md. 21203. Sylodent 650 XWA.RTM., a
silica hydrogel composed of particles of colloidal silica having a
water content of about 29% by weight averaging about 7 to about 10
microns in diameter, and an oil absorption of less than about 70
cc/100 g of silica is an example of a low oil absorption silica
abrasive useful in the practice of the present invention. The
abrasive is present in the oral care composition of the present
invention at a concentration of about 10 to about 60% by weight, in
other embodiment about 20 to about 45% by weight, and in another
embodiment about 30 to about 50% by weight.
[0082] The oral care compositions of the invention also may include
an agent to increase the amount of foam that is produced when the
oral cavity is brushed, and such agents are known by those of skill
in the art. Illustrative examples of agents that increase the
amount of foam include, but are not limited to polyoxyethylene and
certain polymers including, but not limited to, alginate
polymers.
[0083] The polyoxyethylene may increase the amount of foam and the
thickness of the foam generated by the oral care carrier component
of the present invention. Polyoxyethylene is also commonly known as
polyethylene glycol ("PEG") or polyethylene oxide. The
polyoxyethylenes suitable for this invention will have a molecular
weight of about 200,000 to about 7,000,000. In one embodiment the
molecular weight will be about 600,000 to about 2,000,000 and in
another embodiment about 800,000 to about 1,000,000. The
polyoxyethylene may be present in an amount of about 1% to about
90%, in one embodiment about 5% to about 50% and in another
embodiment about 10% to about 20% by weight of the oral care
carrier component of the oral care compositions of the present
invention. The dosage of foaming agent in the oral care composition
(i.e., a single dose) is about 0.01 to about 0.9% by weight, about
0.05 to about 0.5% by weight, and in another embodiment about 0.1
to about 0.2% by weight.
[0084] The oral compositions of the present invention may also a
surfactant or a mixture of compatible surfactants, which are known
by those of skill in the art. Suitable surfactants are those which
are reasonably stable throughout a wide pH range, for example,
anionic, cationic, nonionic or zwitterionic surfactants, including
mixtures thereof.
[0085] Anionic surfactants useful herein include the water-soluble
salts of alkyl sulfates having about 10 to about 18 carbon atoms in
the alkyl radical and the water-soluble salts of sulfonated
monoglycerides of fatty acids having about 10 to about 18 carbon
atoms, e.g., sodium lauryl sulfate, sodium lauroyl sarcosinate and
sodium coconut monoglyceride sulfonates. Mixtures of anionic
surfactants may also be utilized.
[0086] Cationic surfactants useful herein may include derivatives
of aliphatic quaternary ammonium compounds having one long alkyl
chain containing about 8 to about 18 carbon atoms, e.g., lauryl
trimethylammonium chloride, cetyl pyridinium chloride, cetyl
trimethylammonium bromide,
di-isobutylphenoxyethyldimethylbenzylammonium chloride, coconut
alkyltrimethylammonium nitrite, and cetyl pyridinium fluoride.
[0087] Nonionic surfactants that can be used in the compositions of
the invention can be defined as compounds produced by the
condensation of alkylene oxide groups (hydrophilic in nature) with
an organic hydrophobic compound which may be aliphatic or
alkylaromatic in nature. Examples of nonionic surfactants useful in
the present invention include the Pluronics, 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 of such materials.
[0088] Polaxamers are a particular type of nonionic surfactant that
can be used in the invention. Poloxamers are nonionic triblock
copolymers composed of a central hydrophobic chain of
polyoxypropylene (poly(propylene oxide)) flanked by two hydrophilic
chains of polyoxyethylene (poly(ethylene oxide)). Poloxamers are
also known by the trade name Pluronics. Because the lengths of the
polymer blocks can be customized, many different poloxamers exist
that have slightly different properties. For the generic term
"poloxamer", these copolymers are commonly named with the letter
"P" (for poloxamer) followed by three digits, the first two
digits.times.100 give the approximate molecular mass of the
polyoxypropylene core, and the last digit.times.10 gives the
percentage polyoxyethylene content (e.g., P407=Poloxamer with a
polyoxypropylene molecular mass of 4,000 g/mol and a 70%
polyoxyethylene content). For the Pluronic tradename, coding of
these copolymers starts with a letter to define its physical form
at room temperature (L=liquid, P=paste, F=flake (solid)) followed
by two or three digits, The first digit (two digits in a
three-digit number) in the numerical designation, multiplied by
300, indicates the approximate molecular weight of the hydrophobe;
and the last digit x 10 gives the percentage polyoxyethylene
content (e.g., L61=Pluronic with a polyoxypropylene molecular mass
of 1,800 g/mol and a 10% polyoxyethylene content). In the example
given, poloxamer 181 (P181)=Pluronic L61.
[0089] Zwitterionic synthetic surfactants useful in the present
invention can be broadly described as 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 about 8 to about
18 carbon atoms and one contains an anionic water-solubilizing
group, e.g., carboxy, sulfonate, sulfate, phosphate or phosphonate.
Illustrative examples of the surfactants suited for inclusion into
the composition include, but are not limited to, sodium alkyl
sulfate, sodium lauroyl sarcosinate, cocoamidopropyl betaine and
polysorbate 20, and combinations thereof.
[0090] The surfactant or mixtures of compatible surfactants can be
present in the compositions of the present invention in about 0.1%
to about 5.0%, in another embodiment about 0.3% to about 3.0% and
in another embodiment about 0.5% to about 2.0% by weight of the
total composition.
[0091] The oral care compositions of the invention may also include
one or more flavoring agents, which are known by those of skill in
the art. Flavoring agents which are used in the practice of the
present invention include, but are not limited to, essential oils
as well as various flavoring aldehydes, esters, alcohols, and
similar materials. Examples of the essential oils include oils of
spearmint, peppermint, wintergreen, sassafras, clove, sage,
rosemary, eucalyptus, marjoram, cinnamon, lemon, lime, grapefruit,
and orange. Also useful are such chemicals as menthol, carvone, and
anethole, and other extracts, such as green tea extract.
[0092] The flavoring agent is incorporated in the oral composition
at a concentration of about 0.1 to about 5% by weight and about 0.5
to about 1.5% by weight. The dosage of flavoring agent in the
individual oral care composition dosage (i.e., a single dose) is
about 0.001 to about 0.05% by weight and in another embodiment
about 0.005 to about 0.015% by weight.
[0093] The oral care compositions of the invention also optionally
include one or more polymers, which are known by those of skill in
the art, such as polyethylene glycols, polyvinylethyl ether maleic
acid copolymers, polysaccharides (e.g., cellulose derivatives, for
example carboxymethyl cellulose, or polysaccharide gums, for
example xanthan gum or carrageenan gum). Acidic polymers, for
example polyacrylate gels, may be provided in the form of their
free acids or partially or fully neutralized water soluble alkali
metal (e.g., potassium and sodium) or ammonium salts. Certain
embodiments include about 1:4 to about 4:1 copolymers of maleic
anhydride or acid with another polymerizable ethylenically
unsaturated monomer, for example, 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 AN 139(M.W. 500,000), AN 119 (M.W. 250,000) and S-97
Pharmaceutical Grade (M.W. 70,000), of GAF Chemicals Corporation.
Such copolymers may improve the antibacterial activity of the
compounds of Formula (I) (IR8387).
[0094] Other operative polymers include those such as the 1:1
copolymers of maleic anhydride with ethyl acrylate, hydroxyethyl
methacrylate, N-vinyl-2-pyrollidone, or ethylene, the latter being
available for example as Monsanto EMA No. 1103, M.W. 10,000 and EMA
Grade 61, and 1:1 copolymers of acrylic acid with methyl or
hydroxyethyl methacrylate, methyl or ethyl acrylate, isobutyl vinyl
ether or N-vinyl-2-pyrrolidone.
[0095] A further class of polymeric agents includes a composition
containing homopolymers of substituted acrylamides and/or
homopolymers of unsaturated sulfonic acids and salts thereof, in
particular where polymers are based on unsaturated sulfonic acids
selected from acrylamidoalykane sulfonic acids such as 2-acrylamide
2 methylpropane sulfonic acid having a molecular weight of about
1,000 to about 2,000,000, described in U.S. Pat. No. 4,842,847,
Jun. 27, 1989 to Zahid, incorporated herein by reference.
[0096] Another useful class of polymeric agents includes polyamino
acids, particularly those containing proportions of anionic
surface-active amino acids such as aspartic acid, glutamic acid and
phosphoserine, as disclosed in U.S. Pat. No. 4,866,161 Sikes et
al., incorporated herein by reference.
[0097] In preparing oral care compositions, it is sometimes
necessary to add some thickening material to provide a desirable
consistency or to stabilize or enhance the performance of the
formulation. Such thickening materials are known by those of skill
in the art, and may include carboxyvinyl polymers, carrageenan,
hydroxyethyl cellulose and water soluble salts of cellulose ethers
such as sodium carboxymethyl cellulose and sodium carboxymethyl
hydroxyethyl cellulose. Natural gums such as karaya, gum arabic,
and gum tragacanth can also be incorporated. Colloidal magnesium
aluminum silicate or finely divided silica can be used as component
of the thickening composition to further improve the composition's
texture. In certain embodiments, thickening agents in an amount of
about 0.5% to about 5.0% by weight of the total composition are
used.
[0098] The oral care compositions of the invention may also
optionally include one or more enzymes known by those of skill in
the art. Useful enzymes include proteases, glucanohydrolases,
endoglycosidases, amylases, mutanases, lipases and mucinases or
compatible mixtures thereof. In certain embodiments, the enzyme is
a protease, dextranase, endoglycosidase and mutanase. In another
embodiment, the enzyme is papain, endoglycosidase or a mixture of
dextranase and mutanase. An enzyme of a mixture of several
compatible enzymes in the current invention constitutes about
0.002% to about 2% in one embodiment or about 0.05% to about 1.5%
in another embodiment or in yet another embodiment about 0.1% to
about 0.5%.
[0099] In addition to the above described components, the
embodiments of this invention can contain a variety of optional
dentifrice ingredients some of which are described below. Optional
ingredients include, for example, but are not limited to,
adhesives, sudsing agents, flavoring agents, sweetening agents,
additional antiplaque agents, abrasives, and coloring agents, which
are known by those of skill in the art.
[0100] The compositions of the present invention can be made using
methods which are common in the oral product area.
[0101] The present invention in one method aspect involves applying
to the oral cavity a safe and effective amount of the oral care
compositions described herein, e.g. with brushing, to (i) reduce or
inhibit formation of dental caries, (ii) reduce, repair or inhibit
pre-carious lesions of the enamel, e.g., as detected by
quantitative light-induced fluorescence (QLF) or electrical caries
measurement (ECM), (iii) reduce or inhibit demineralization and
promote remineralization of the teeth, (iv) reduce hypersensitivity
of the teeth, (v) reduce or inhibit gingivitis, (vi) promote
healing of sores or cuts in the mouth, (vii) reduce levels of acid
producing bacteria, (viii) to increase relative levels of
arginolytic bacteria, (ix) inhibit microbial biofilm formation in
the oral cavity, (x) raise and/or maintain plaque pH at levels of
at least pH 5.5 following sugar challenge, (xi) reduce plaque
accumulation, (xii) reduce dry mouth, (xiii) clean the teeth and
oral cavity (xiv) reduce erosion, (xv) whiten teeth, and/or (xvi)
kill or inhibit cariogenic bacteria.
[0102] The oral compositions may also comprise one or more suitable
solvents. The ability of any solid substance (solute) to dissolve
in any liquid substance (solvent) is dependent upon the physical
properties of the solute and the solvent. When solutes and solvents
have similar physical properties the solubility of the solute in
the solvent will be the greatest. This gives rise to the
traditional understanding that "like dissolves like." Solvents can
be characterized in one extreme as non-polar, lipophilic oils,
while in the other extreme as polar hydrophilic solvents. Oily
solvents dissolve other non-polar substances by Van der WaI
interactions while water and other hydrophilic solvents dissolve
polar substances by ionic, dipole, or hydrogen bonding
interactions. All solvents can be listed along a continuum from the
least polar, i.e. hydrocarbons such as decane, to the most polar
solvent being water. A solute will have its greatest solubility in
solvents having equivalent polarity. Thus, for drugs having minimal
solubility in water, less polar solvents will provide improved
solubility with the solvent having polarity nearly equivalent to
the solute providing maximum solubility. Most drugs have
intermediate polarity, and thus experience maximum solubility in
solvents such as propylene glycol or ethanol, which are
significantly less polar than water. If the drug has greater
solubility in propylene glycol (for example 8% (w/w)) than in water
(for example 0.1% (w/w)).sub.5 then addition of water to propylene
glycol should decrease the maximum amount of drug solubility for
the solvent mixture compared with pure propylene glycol. Addition
of a poor solvent to an excellent solvent will decrease the maximum
solubility for the blend compared with the maximum solubility in
the excellent solvent.
[0103] When compounds are incorporated into oral care formulations
the concentration of active ingredient in the formulation may be
limited by the solubility of the active ingredient in the chosen
solvent and/or carrier. Non-lipophilic drugs typically display very
low solubility in pharmaceutically acceptable solvents and/or
carriers. For example, the solubility of some borinic acid
complexes in water is less than 0.00025% wt/wt. The solubility of
the same borinic acid complexes can be less than about 2% wt/wt in
either propylene glycol or isopropyl myristate. In one embodiment
of the present invention, diethylene glycol monoethyl ether (DGME)
is the solvent used to dissolve the compounds of Formula I. The
borinic acid complexes useful in the present formulation are
believed to have a solubility of from about 10% wt/wt to about 25%
wt/wt in DGME. In another embodiment a DGME water cosolvent system
is used to dissolve the compounds of Formula I. The solvent
capacity of DGME drops when water is added; however, the DGME/water
cosolvent system can be designed to maintain the desired
concentration of from about 0.1% to about 5% wt/wt active
ingredient. Preferably the active ingredient is present from about
0.5% to about 3% wt/wt, and more preferably at about 1% wt/wt. This
increased solubility reduces the likelihood of reduced
bioavailability caused by precipitation.
[0104] Liquid forms may include a suitable aqueous or nonaqueous
vehicle with buffers, suspending and dispensing agents, thickeners,
and the like. Solid forms such as creams or pastes or the like may
include, for example, any of the following ingredients, water, oil,
alcohol or grease as a substrate with surfactant, polymers such as
polyethylene glycol, thickeners, solids and the like. Liquid or
solid formulations may include enhanced delivery technologies such
as liposomes, microsomes, microsponges and the like. Additionally,
the compounds can be delivered using a sustained-release system,
such as semipermeable matrices of solid hydrophobic polymers
containing the therapeutic agent. Various sustained-release
materials have been established and are well known by those skilled
in the art.
[0105] The invention comprises topical pharmaceutical compositions
comprising an effective amount of a compound of formula A. By
"effective" amount of a drug, formulation, or permeant is meant a
sufficient amount of an active agent to provide the desired local
or systemic effect. "Topically effective," "cosmetically
effective," "pharmaceutically effective," or "therapeutically
effective" amount refers to the amount of drug needed to effect the
desired therapeutic result. "Topically effective" refers to a
material that, when applied to the skin, produces a desired
pharmacological result either locally at the place of application
or systemically as a result of transdermal passage of an active
ingredient in the material. "Cosmetically effective" refers to a
material that, when applied to the skin, produces a desired
cosmetic result locally at the place of application of an active
ingredient in the material.
[0106] Compounds of formula A may be provided in free or
pharmaceutically acceptable salt for. "Pharmaceutically acceptable
salts" refers to pharmaceutically acceptable salts of a compound,
which salts are derived from a variety of organic and inorganic
counter ions well known in the art and are not toxic at the levels
of exposure provided by normal use of the products of the
invention. Such salts may include, by way of example only,
hydrochloric, phosphoric, hydrobromic, sulfuric, sulfuric, formic,
toluenesulfonic, methanesulfonic, hydroxy-ethanesulfonic, nitric,
benzoic, citric, tartaric, maleic, fumaric hydroiodic, lactic,
succinic, alkanoic such as acetic, HOOC--(CH.sub.2).sub.p--CH.sub.3
where p is 0-4, and the like. In addition, pharmaceutically
compatible salts can be formed with many acids, including but not
limited to non-toxic pharmaceutical base addition salts including
salts of bases such as sodium, potassium, calcium, ammonium, and
the like. Those skilled in the art will recognize a wide variety of
nontoxic pharmaceutically acceptable addition salts.
[0107] The term "pharmaceutically acceptable carrier" or
"pharmaceutically acceptable vehicle" refers to any formulation or
carrier medium that provides the appropriate delivery of an
effective amount of a active agent as defined herein, does not
interfere with the effectiveness of the biological activity of the
active agent, and that is sufficiently non-toxic to the host or
patient. Representative carriers include water, oils, both
vegetable and mineral, cream bases, lotion bases, ointment bases
and the like. These bases include suspending agents, thickeners,
penetration enhancers, and the like. Their formulation is well
known to those in the art of cosmetics and topical pharmaceuticals.
Additional information concerning carriers can be found in Part 8
of Remington's Pharmaceutical Sciences, 17.sup.th edition, 1985,
Mack Publishing Company, Easton, Pa., which is incorporated herein
by reference.
[0108] "Pharmaceutically acceptable topical carrier" and equivalent
terms refer to pharmaceutically acceptable carriers, as described
herein above, suitable for topical application; An inactive liquid
or cream vehicle capable of suspending or dissolving the active
agent(s), and having the properties of being nontoxic and
non-inflammatory when applied to the skin is an example of a
pharmaceutically-acceptable topical carrier. This term is
specifically intended to encompass carrier materials approved for
use in topical cosmetics as well. The term "pharmaceutically
acceptable additive" refers to preservatives, antioxidants,
fragrances, emulsifiers, dyes and excipients known or used in the
field of drug formulation and that do not unduly interfere with the
effectiveness of the biological activity of the active agent, and
that is sufficiently non-toxic to the host or patient. Additives
for topical formulations are well-known in the art, and may be
added to the topical composition, as long as they are
pharmaceutically acceptable and not deleterious to the epithelial
cells or their function. Further, they should not cause
deterioration in the stability of the composition. For example,
inert fillers, anti-irritants, tackifiers, excipients, fragrances,
opacifiers, antioxidants, gelling agents, stabilizers, surfactant,
emollients, coloring agents, preservatives, buffering agents, other
permeation enhancers, and other conventional components of topical
or transdermal delivery formulations as are known in the art. The
terms "enhancement," "penetration enhancement" or "permeation
enhancement" relate to an increase in the permeability of the skin
to a drug, so as to increase the rate at which the drug permeates
through the skin. The enhanced permeation effected through the use
of such enhancers can be observed, for example, by measuring the
rate of diffusion of the drug through animal or human skin using a
diffusion cell apparatus. A diffusion cell is described by Merritt
et al. Diffusion Apparatus for Skin Penetration, J of Controlled
Release, 1 (1984) pp. 161-162. The term "permeation enhancer" or
"penetration enhancer" intends an agent or a mixture of agents,
which, alone or in combination, act to increase the permeability of
the skin to a drug. The term "excipients" is conventionally known
to mean carriers, diluents and/or vehicles used in formulating drug
compositions effective for the desired use. The term "topical
administration" refers to the application of a pharmaceutical agent
to the external surface of the skin, such that the agent is locally
active and/or crosses the external surface of the skin and enters
the underlying tissues. Topical administration includes application
of the composition to intact skin, to broken, raw or open wound of
skin. Topical administration of a pharmaceutical agent can result
in a limited distribution of the agent to the skin and surrounding
tissues or, when the agent is removed from the treatment area by
the bloodstream, can result in systemic distribution of the agent.
The term "transdermal delivery" refers to the diffusion of an agent
across the barrier of the skin resulting from topical
administration or other application of a composition. The stratum
corneum acts as a barrier and few pharmaceutical agents are able to
penetrate intact skin. In contrast, the epidermis and dermis are
permeable to many solutes and absorption of drugs therefore occurs
more readily through skin that is abraded or otherwise stripped of
the stratum corneum to expose the epidermis. Transdermal delivery
includes injection or other delivery through any portion of the
skin or mucous membrane and absorption or permeation through the
remaining portion. Absorption through intact skin can be enhanced
by placing the active agent in an appropriate pharmaceutically
acceptable vehicle before application to the skin. Passive topical
administration may consist of applying the active agent directly to
the treatment site in combination with emollients or penetration
enhancers. As used herein, transdermal delivery is intended to
include delivery by permeation through or past the integument, i.e.
skin, hair, or nails.
[0109] Active agents useful in the presently claimed topical
formulations are compounds that are active against acne vulgaris
and/or secondarily infected skin conditions. Examples of active
agents useful in the presently claimed topical formulations are
disclosed in U.S. patent application Ser. No. 10/867,465 filed on
Jun. 16, 2004, which application is incorporated herein in its
entirety. Preferably the active agents are the borinic acid
complexes of Formula A described herein above.
[0110] The present invention includes topical pharmaceutical
compositions. These topical pharmaceutical compositions can be
manufactured in a manner that is itself known, e.g., by means of a
conventional mixing, dissolving, granulating, dragee-making,
levigating, emulsifying, encapsulating, entrapping or lyophilizing
processes. Pharmaceutical compositions for use in accordance with
the present invention thus can be formulated in conventional manner
using one or more physiologically acceptable carriers comprising
excipients and auxiliaries that facilitate processing of the active
compounds into preparations that can be used pharmaceutically.
Proper formulation is dependent upon the desired product
chosen.
[0111] The compositions of the present invention comprises fluid or
semi-solid vehicles that may include but are not limited to
polymers, thickeners, buffers, neutralizers, chelating agents,
preservatives, surfactants or emulsifiers, antioxidants, waxes or
oils, emollients, sunscreens, and a solvent or mixed solvent
system. The solvent or mixed solvent system is important to the
formation because it is primarily responsible for dissolving the
drug. The best solvent or mixed solvent systems are also capable of
maintaining clinically relevant levels of the drug in solution
despite the addition of a poor solvent to the formulation. The
topical compositions useful in the subject invention can be made
into a wide variety of product types. These include, but are not
limited to, lotions, creams, gels, sticks, sprays, ointments,
pastes, foams, mousses, and cleansers. These product types can
comprise several types of carrier systems including, but not
limited to particles, nano-particles, and liposomes. If desired,
disintegrating agents can be added, such as the cross-linked
polyvinyl pyrrolidone, agar or alginic acid or a salt thereof such
as sodium alginate Techniques for formulation and administration
can be found in "Remington's Pharmaceutical Sciences." Mack
Publishing Co, Easton, Pa. The formulation can be selected to
maximize delivery to a desired target site in the body.
[0112] Lotions, which are preparations that are to be applied to
the skin surface without friction, are typically liquid or
semi-liquid preparations in which finely divided solid, waxy, or
liquid are dispersed. Lotions will typically contain suspending
agents to produce better dispersions as well as compounds useful
for localizing and holding the active agent in contact with the
skin, e.g., methylcellulose, sodium carboxymethyl-cellulose, or the
like.
[0113] Creams containing the active agent for delivery according to
the present invention are viscous liquid or semisolid emulsions,
either oil-in-water or water-in-oil. Cream bases are
water-washable, and contain an oil phase, an emulsifier and an
aqueous phase. The oil phase is generally comprised of petrolatum
or a fatty alcohol, such as cetyl- or stearyl alcohol; the aqueous
phase usually, although not necessarily, exceeds the oil phase in
volume, and generally contains a humectant. The emulsifier in a
cream formulation, as explained in Remington: The Science and
Practice of Pharmacy, supra, is generally a nonionic, anionic,
cationic or amphoteric surfactant.
[0114] Gel formulations can also be used in connection with the
present invention. As will be appreciated by those working in the
field of topical drug formulation, gels are semisolid. Single-phase
gels contain organic macromolecules distributed substantially
uniformly throughout the carrier liquid, which is typically
aqueous, but also may be a solvent or solvent blend.
[0115] Ointments, which are semisolid preparations, are typically
based on petrolatum or other petroleum derivatives. As will be
appreciated by the ordinarily skilled artisan, the specific
ointment base to be used is one that provides for optimum delivery
for the active agent chosen for a given formulation, and,
preferably, provides for other desired characteristics as well,
e.g., emolliency or the like. As with other carriers or vehicles,
an ointment base should be inert, stable, nonirritating and
non-sensitizing. As explained in Remington: The Science and
Practice of Pharmacy, 19th Ed. (Easton, Pa.: Mack Publishing Co.,
1995), at pages 1399-1404, ointment bases may be grouped in four
classes: oleaginous bases; emulsifiable bases; emulsion bases; and
water-soluble bases. Oleaginous ointment bases include, for
example, vegetable oils, fats obtained from animals, and semisolid
hydrocarbons obtained from petroleum. Emulsifiable ointment bases,
also known as absorbent ointment bases, contain little or no water
and include, for example, hydroxystearin sulfate, anhydrous lanolin
and hydrophilic petrolatum. Emulsion ointment bases are either
water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions, and
include, for example, cetyl alcohol, glyceryl monostearate, lanolin
and stearic acid. Preferred water-soluble ointment bases are
prepared from polyethylene glycols of varying molecular weight;
again, reference may be had to Remington: The Science and Practice
of Pharmacy, supra, for further information.
[0116] Useful formulations of the invention also encompass sprays.
Sprays generally provide the active agent in an aqueous and/or
alcoholic solution which can be misted onto the skin for delivery.
Such sprays include those formulated to provide for concentration
of the active agent solution at the site of administration
following delivery, e.g., the spray solution can be primarily
composed of alcohol or other like volatile liquid in which the drug
or active agent can be dissolved. Upon delivery to the skin, the
carrier evaporates, leaving concentrated active agent at the site
of administration.
[0117] The topical pharmaceutical compositions may also comprise
suitable solid or gel phase carriers. Examples of such carriers
include but are not limited to calcium carbonate, calcium
phosphate, various sugars, starches, cellulose derivatives,
gelatin, and polymers such as polyethylene glycols.
[0118] The topical pharmaceutical compositions may also comprise a
suitable emulsifier which refers to an agent that enhances or
facilitates mixing and suspending oil-in-water or water-in-oil. The
emulsifying agent used herein may consist of a single emulsifying
agent or may be a nonionic, anionic, cationic or amphoteric
surfactant or blend of two or more such surfactants; preferred for
use herein are nonionic or anionic emulsifiers. Such surface-active
agents are described in "McCutcheon's Detergent and Emulsifiers,"
North American Edition, 1980 Annual published by the McCutcheon
Division, MC Publishing Company, 175 Rock Road, Glen Rock, N.J.
07452, USA. Preferred for use herein are high molecular weight
alcohols such as cetearyl alcohol, cetyl alcohol, stearyl alcohol,
emulsifying wax, glyceryl monostearate. Other examples are ethylene
glycol distearate, sorbitan tristearate, propylene glycol
monostearate, sorbitan monooleate, sorbitan monostearate (SPAN 60),
diethylene glycol monolaurate, sorbitan monopalmitate, sucrose
dioleate, sucrose stearate (CRODESTA F-160), polyoxyethylene lauryl
ether (BRIJ 30), polyoxyethylene (2) stearyl ether (BRIJ 72),
polyoxyethylene (21) stearyl ether (BRIJ 721), polyoxyethylene
monostearate (Myrj 45), polyoxyethylene sorbitan monostearate
(TWEEN 60), polyoxyethylene sorbitan monooleate (TWEEN 80),
polyoxyethylene sorbitan monolaurate (TWEEN 20) and sodium oleate.
Cholesterol and cholesterol derivatives may also be employed in
externally used emulsions and promote w/o emulsions. Especially
suitable nonionic emulsifying agents are those with
hydrophile-lipophile balances (HLB) of about 3 to 6 for w/o system
and 8 to 18 for o/w system as determined by the method described by
Paul L. Lindner in "Emulsions and Emulsion", edited by Kenneth
Lissant, published by Dekker, New York, N.Y., 1974, pages 188-190.
More preferred for use herein are one or more nonionic surfactants
that produce a system having HLB of about 8 to about 18. Examples
of such nonionic emulsifiers include but are not limited to "BRIJ
72", the trade name for a polyoxyethylene (2) stearyl ether having
an HLB of 4.9; "BRIJ 721", the trade name for a polyoxyethylene
(21) stearyl ether having an HLB of 15.5, "Brij 30", the trade name
for polyoxyethylene lauryl ether having an HLB of 9.7; "Polawax",
the trade name for emulsifying wax having an HLB of 8.0; "Span 60",
the trade name for sorbitan monostearate having an HLB of 4.7;
"Crodesta F-160", the trade name for sucrose stearate" having an
HLB of 14.5. All of these materials are available from Ruger
Chemicals Inc.; Croda; ICI Americas, Inc.; Spectrum Chemicals; and
BASF. When the topical formulations of the present invention
contain at least one emulsifying agent, each emulsifying agent is
present in amount from about 0.5 to about 2.5 wt %, preferably 0.5
to 2.0%, more preferably 1.0% or 1.8%. Preferably the emulsifying
agent comprises a mixture of steareth 21 (at about 1.8%) and
steareth 2 (at about 1.0%).
[0119] The topical pharmaceutical compositions may also comprise
suitable emollients. Emollients are materials used for the
prevention or relief of dryness, as well as for the protection of
the skin. Useful emollients include, but are not limited to, cetyl
alcohol, isopropyl myristate, stearyl alcohol, and the like. A wide
variety of suitable emollients are known and can be used herein.
See e.g., Sagarin, Cosmetics, Science and Technology, 2nd Edition,
Vol. 1, pp. 32-43 (1972), and U.S. Pat. No. 4,919,934, to Deckner
et al., issued Apr. 24, 1990, both of which are incorporated herein
by reference in their entirety. These materials are available from
Ruger Chemical Co, (Irvington, N.J.). When the topical formulations
of the present invention contain at least one emollient, each
emollient is present in an amount from about 0.1 to 15%, preferably
0.1 to about 3.0, more preferably 0.5, 1.0, or 2.5 wt %. Preferably
the emollient is a mixture of cetyl alcohol, isopropyl myristate
and stearyl alcohol in a 1/5/2 ratio. The emollient may also be a
mixture of cetyl alcohol and stearyl alcohol in a 1/2 ratio.
[0120] The topical pharmaceutical compositions may also comprise
suitable antioxidants, substances known to inhibit oxidation.
Antioxidants suitable for use in accordance with the present
invention include, but are not limited to, butylated
hydroxytoluene, ascorbic acid, sodium ascorbate, calcium ascorbate,
ascorbic palmitate, butylated hydroxyanisole,
2,4,5-trihydroxybutyrophenone,
4-hydroxymethyl-2,6-di-tert-butylphenol, erythorbic acid, gum
guaiac, propyl gallate, thiodipropionic acid, dilauryl
thiodipropionate, tert-butylhydroquinone and tocopherols such as
vitamin E, and the like, including pharmaceutically acceptable
salts and esters of these compounds. Preferably, the antioxidant is
butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate,
ascorbic acid, pharmaceutically acceptable salts or esters thereof,
or mixtures thereof. Most preferably, the antioxidant is butylated
hydroxytoluene. These materials are available from Ruger Chemical
Co, (Irvington, N.J.). When the topical formulations of the present
invention contain at least one antioxidant, the total amount of
antioxidant present is from about 0.001 to 0.5 wt %, preferably
0.05 to about 0.5 wt %, more preferably 0.1%.
[0121] The topical pharmaceutical compositions may also comprise
suitable preservatives. Preservatives are compounds added to a
pharmaceutical formulation to act as an antimicrobial agent. Among
preservatives known in the art as being effective and acceptable in
parenteral formulations are benzalkonium chloride, benzethonium,
chlorohexidine, phenol, m-cresol, benzyl alcohol, methylparaben,
propylparaben, chlorobutanol, o-cresol, p-cresol, chlorocresol,
phenylmercuric nitrate, thimerosal, benzoic acid, and various
mixtures thereof. See, e.g., Wallhausser, K.-H., Develop. Biol.
Standard, 24:9-28 (1974) (S. Krager, Basel). Preferably, the
preservative is selected from methylparaben, propylparaben and
mixtures thereof. These materials are available from Inolex
Chemical Co (Philadelphia, Pa.) or Spectrum Chemicals. When the
topical formulations of the present invention contain at least one
preservative, the total amount of preservative present is from
about 0.01 to about 0.5 wt %, preferably from about 0.1 to 0.5%,
more preferably from about 0.03 to about 0.15. Preferably the
preservative is a mixture of methylparaben and proplybarben in a
5/1 ratio. When alcohol is used as a preservative, the amount is
usually 15 to 20%.
[0122] The topical pharmaceutical compositions may also comprise
suitable chelating agents to form complexes with metal cations that
do not cross a lipid bilayer. Examples of suitable chelating agents
include ethylene diamine tetraacetic acid (EDTA), ethylene
glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA)
and
8-Amino-2-[(2-amino-5-methylphenoxy)methyl]-6-methoxyquinoline-N.sub.5N,N-
',N'-tetraacetic acid, tetrapotassium salt (QUIN-2). Preferably the
chelating agents are EDTA and citric acid. These materials are
available from Spectrum Chemicals. When the topical formulations of
the present invention contain at least one chelating agent, the
total amount of chelating agent present is from about 0.005% to
2.0% by weight, preferably from about 0.05% to about 0.5 wt %, more
preferably about 0.1% by weight.
[0123] The topical pharmaceutical compositions may also comprise
suitable basifying agents and buffers to adjust and maintain the pH
of the formulation to a range of at least pH 8. When the topical
formulations of the present invention contain at least one
basifying or buffering agent, the total amount of agent present is
from about 0.1 wt % to about 10 wt %, preferably 0.1 wt % to about
5.0 wt %, and more preferably about 1.0 wt %. The agent is
generally added in whatever amount is required to bring the
formulation to the desired pH.
[0124] The topical pharmaceutical compositions may also comprise
suitable viscosity increasing agents. These components are
diffusible compounds capable of increasing the viscosity of a
polymer-containing solution through the interaction of the agent
with the polymer. CARBOPOL ULTREZ 10 may be used as a
viscosity-increasing agent. These materials are available from
Noveon Chemicals, Cleveland, Ohio. When the topical formulations of
the present invention contain at least one viscosity increasing
agent, the total amount of viscosity increasing agent present is
from about 0.25% to about 5.0% by weight, preferably from about
0.25% to about 1.0 wt %, and more preferably from about 0.4% to
about 0.6% by weight.
[0125] The topical pharmaceutical compositions may also comprise
one or more suitable solvents. The ability of any solid substance
(solute) to dissolve in any liquid substance (solvent) is dependent
upon the physical properties of the solute and the solvent. When
solutes and solvents have similar physical properties the
solubility of the solute in the solvent will be the greatest. This
gives rise to the traditional understanding that "like dissolves
like." Solvents can be characterized in one extreme as non-polar,
lipophilic oils, while in the other extreme as polar hydrophilic
solvents. Oily solvents dissolve other non-polar substances by Van
der WaI interactions while water and other hydrophilic solvents
dissolve polar substances by ionic, dipole, or hydrogen bonding
interactions. All solvents can be listed along a continuum from the
least polar, i.e. hydrocarbons such as decane, to the most polar
solvent being water. A solute will have its greatest solubility in
solvents having equivalent polarity. Thus, for drugs having minimal
solubility in water, less polar solvents will provide improved
solubility with the solvent having polarity nearly equivalent to
the solute providing maximum solubility. Most drugs have
intermediate polarity, and thus experience maximum solubility in
solvents such as propylene glycol or ethanol, which are
significantly less polar than water. If the drug has greater
solubility in propylene glycol (for example 8% (w/w)) than in water
(for example 0.1% (w/w)).sub.5 then addition of water to propylene
glycol should decrease the maximum amount of drug solubility for
the solvent mixture compared with pure propylene glycol. Addition
of a poor solvent to an excellent solvent will decrease the maximum
solubility for the blend compared with the maximum solubility in
the excellent solvent.
[0126] When compounds are incorporated into topical formulations
the concentration of active ingredient in the formulation may be
limited by the solubility of the active ingredient in the chosen
solvent and/or carrier. Non-lipophilic drugs typically display very
low solubility in pharmaceutically acceptable solvents and/or
carriers. For example, the solubility of some borinic acid
complexes in water is less than 0.00025% wt/wt. The solubility of
the same borinic acid complexes can be less than about 2% wt/wt in
either propylene glycol or isopropyl myristate. In one embodiment
of the present invention, diethylene glycol monoethyl ether (DGME)
is the solvent used to dissolve the compounds of Formula I. The
borinic acid complexes useful in the present formulation are
believed to have a solubility of from about 10% wt/wt to about 25%
wt/wt in DGME. In another embodiment a DGME water cosolvent system
is used to dissolve the compounds of Formula I. The solvent
capacity of DGME drops when water is added; however, the DGME/water
cosolvent system can be designed to maintain the desired
concentration of from about 0.1% to about 5% wt/wt active
ingredient. Preferably the active ingredient is present from about
0.5% to about 3% wt/wt, and more preferably at about 1% wt/wt, in
the as-applied topical formulations. Because DGME is less volatile
than water, as the topical formulation evaporates upon application,
the active agent becomes more soluble in the cream formulation.
This increased solubility reduces the likelihood of reduced
bioavailability caused by the drug precipitating on the surface of
the skin.
[0127] Liquid forms, such as lotions suitable for topical
administration or suitable for cosmetic application, may include a
suitable aqueous or nonaqueous vehicle with buffers, suspending and
dispensing agents, thickeners, penetration enhancers, and the like.
Solid forms such as creams or pastes or the like may include, for
example, any of the following ingredients, water, oil, alcohol or
grease as a substrate with surfactant, polymers such as
polyethylene glycol, thickeners, solids and the like. Liquid or
solid formulations may include enhanced delivery technologies such
as liposomes, microsomes, microsponges and the like. Additionally,
the compounds can be delivered using a sustained-release system,
such as semipermeable matrices of solid hydrophobic polymers
containing the therapeutic agent. Various sustained-release
materials have been established and are well known by those skilled
in the art.
[0128] Topical treatment regimens according to the practice of this
invention comprise applying the composition directly to the skin at
the application site, from one to several times daily.
[0129] Formulations of the present invention can be used to treat,
ameliorate or prevent conditions or symptoms associated with
bacterial infections, acne, inflammation and the like.
[0130] The following are examples of the cosmetic and
pharmaceutical agents that can be added to the topical
pharmaceutical formulations of the present invention. The following
agents are known compounds and are readily available commercially.
Anti-inflammatory agents include, but are not limited to, bisaboloL
mentholatum, dapsone, aloe, hydrocortisone, and the like. Vitamins
include, but are not limited to, Vitamin B, Vitamin E, Vitamin A,
Vitamin D, and the like and vitamin derivatives such as tazarotene,
calcipotriene, tretinoin, adapalene and the like. Anti-aging agents
include, but are not limited to, niacinamide, retinol and retinoid
derivatives, AHA, Ascorbic acid, lipoic acid, coenzyme Q1O, beta
hydroxy acids, salicylic acid, copper binding peptides,
dimethylaminoethyl (DAEA), and the like. Sunscreens and or sunburn
relief agents include, but are not limited to, PABA, jojoba, aloe,
padimate-O, methoxycinnamates, proxamine HCl, lidocaine and the
like. Sunless tanning agents include, but are not limited to,
dihydroxyacetone (DHA). Anti-microbial agents include, but are not
limited to, clotrimazole, miconazole nitrate, terbinafine HCL,
triclosan, and the like. Psoriasis-treating agents and/or
acne-treating agents include, but are not limited to, salicylic
acid, benzoyl peroxide, coal tar, selenium sulfide, zinc oxide,
pyrithione (zinc and/or sodium), tazarotene, calcipotriene,
tretinoin, adapalene and the like. Agents that are effective to
control or modify keratinization, including without limitation:
tretinoin, tazarotene, and adapalene.
[0131] The compositions comprising an active agent of Formula I,
and optionally at least one of these additional agents, are to be
administered topically. In a primary application, this leads to the
boronic acid and any other active agent working upon and treating
the skin. Alternatively, any one of the topically applied active
agents may also be delivered systemically by transdermal routes. In
such compositions an additional cosmetically or pharmaceutically
effective agent, such as an anti-inflammatory agent, vitamin,
anti-aging agent, sunscreen, anti-microbial agent, and/or
acne-treating agent, for example, is usually a minor component
(from about 0.001% to about 20% by weight or preferably from about
0.01% to about 10% by weight) with the remainder being various
vehicles or carriers and processing aids helpful for forming the
desired dosing form.
[0132] The invention is further described in the following
examples. The examples are merely illustrative and do not in any
way limit the scope of the invention as described and claimed.
Example 1
Stability in Low Water Dentifrice
[0133] The stability of a dentifrice formulation containing the
active ingredient,
3-hydroxypyridine-2-carbonyloxy-bis(3-chloro-4-methylphenyl)-borane
(COMPOUND 1), in a silica base is evaluated at different water
levels. The formulations are as follows:
TABLE-US-00001 TABLE 1 0% added 6% added Component (% w/w) water
water G series Demineralized water 6.0 31.367 99.0-101.0% vegetable
69.507 53.407 30.84 glycerin Dental type Silica - Zeodent 12 10 105
- high cleaning silica Dental type silica abrasive 8.5 (Zeodent
115) Dental type silica - Zeodent 8 12 114-synth. amorphous ppt
silica Dental type silica - Zeodent 9 2.5 165-synth. amorphous ppt
silica Tetrasodium pyrophosphate - 0.5 0.5 0.5 fine Sodium
saccharin 0.3 0.3 COP Sodium saccharin 0.3 Sodium fluoride 0.243
0.243 0.243 Sucralose 0.15 0.15 0.15 Titanium dioxide 1 0.75 0.75
Carrageenan concentrate PS-223 0.4 Sodium CMC-12 1 Sodium CMC food
grade 7MF 0.4 Poly(vinylpyrrolidone) 1 (Polyclar .RTM. 10) Xanthan
gum 0.3 0.5 Gantrez S-97 1.95 1.95 Sodium hydroxide 50% 1.2 1.2
solution Flavor K91-6507 1.3 1 1 Polyethylene glycol 300 6.25 6.72
6.72 Compound 1 0.75 0.75 0.75 Sodium Lauryl Sulfate powder 1.7 1.5
1.5 Sodium ascorbyl phosphate 0.2 0.2 Butylated hydroxytoluene 0.03
0.03 Vitamin E 0.5
[0134] Incorporating Compound 1 into low-water dentifrice enhances
the stability of the active ingredient in comparison to dentifrice
formulas with higher water content. These low water formula options
exhibit antibacterial and anti-inflammatory efficacy in-vitro
equivalent to a positive control, Colgate Total.RTM. with triclosan
as antibacterial agent.
[0135] The difference in water levels among these formulations is
significant. The G series has a water activity level (expressed as
vapor pressure of water in sample over vapor pressure of free water
at the same temperature) of 0.75, compared to 0.25 for the 6% water
formulation, and 0.09 for the formulation with no added water. The
stability of Compound 1 over time in the different formulations is
shown in the following table:
TABLE-US-00002 TABLE 2 Initial 1 month CRT 1 month 40.degree. C. 2
month CRT 2 month 40.degree. C. Cp 1 F.sup.- Cp 1 F.sup.- Cp 1
F.sup.- Cp 1 F.sup.- Cp 1 F.sup.- 6% added 0.72 1153 0.71 1077 0.70
1160 0.74 1215 0.68 1041 water (96%) ppm (94%) ppm (93%) ppm (99%)
ppm (91%) ppm 0% added 0.67 1042 0.72 1131 0.68 1130 0.72 1160 0.61
1135 water (90%) ppm (96%) ppm (91%) ppm (96%) ppm (81%) ppm
G-series 0.72 1144 0.74 1026 0.66 1076 0.71 880 0.51 990 (96%) ppm
(99%) ppm (93%) ppm (99%) ppm (91%) ppm
[0136] The reduction in the water level in the dentifrice appears
to have a positive impact on the stability of Compound 1 in the
formulation. After two months aging at controlled room temperature
and 40.degree. C., there is less drop in the % recovery of Compound
1 in the 0% and 6% added water formulations than in the more
conventional G-series formulation.
[0137] The stability of these formulations is also challenged by
the addition of a 1:1 molar ratio of hydrogen peroxide to Compound
1. Formulations which are susceptible to degradation by hydrogen
peroxide are less stable upon aging. For example, the G-series
formula had a 59% Compound 1 recovery after three months at
40.degree. C. and 35% recovery of Compound 1 after peroxide
challenge while a more stable formula, used as a positive control
in this experiment, exhibited 87% recovery after three months
40.degree. C. and 85% recovery after challenge with peroxide.
(Note: The positive control for this experiment was chemically
stable but ineffective in in-vitro test). There is only a 1% drop
in Compound 1 recovery in the 0% added water
[0138] formulation and a 10% drop in % recovery in the 6% added
water formulation. Both formulations demonstrate significantly less
degradation than the 44% drop in Compound 1 recovery observed in
the G-series formula.
[0139] Based on the peroxide challenge experiment and the two
months aging results, it can be concluded that reducing the level
of water in the dentifrice enhances the stability of the active.
The 0% and 6% added water formulations are tested in an assay
measuring inhibition of growth of A. viscosus and shown to retain
their antibacterial efficacy. The 0% added water formulation is
also tested in an anti-inflammatory assay measuring induction of
PGE2 and shown to be as effective as the positive control,
Total.RTM. toothpaste with triclosan, with a value of <200 pg/ml
PGE2 vs >1200 pg/ml for placebo control, and about 400 pg/ml for
the G formulation.
Example 2
High pH Formulations
[0140] The stability of a dentifrice formulation containing the
active ingredient,
3-hydroxypyridine-2-carbonyloxy-bis(3-chloro-4-methylphenyl)-borane
(COMPOUND 1), in a silica base is evaluated at different water
levels. It is found that the stability of COMPOUND 1 in dentifrice
is dependent on the pH of the formula. Specifically, a significant
increase in stability is observed when the pH of the dentifrice is
increased from 7 to 9, without negative impact on the antibacterial
or anti-inflammatory efficacy of the formulation.
[0141] The first formula base is referred to as the G-series and
the second referred to as the low water formula, corresponding to
the G-series and 6% added water formulations of the preceding
example. The major difference between the two formulas is the level
of added water. The G-series has about 32% added water while the
low water formula has 6% added water. In both formulations the
level of COMPOUND 1 is 0.75%. The pH is varied by adjusting the
ratio of sodium hydroxide to glycerin in the formulations of the
previous example to obtain dentifrices at pH 7, 8.5 and 9.
[0142] The results of COMPOUND 1 stability upon accelerated aging
at 40.degree. C. is shown in Table 2. For the G-series, the
percentage of COMPOUND 1 recovery after three months of accelerated
aging is nearly 30% greater in the pH 8.5 and pH 9 formulas when
compared to the formula at pH 7. The same trend is also observed in
the low water formula. These results demonstrate a marked
improvement in COMPOUND 1 stability as a result of increasing the
dentifrice pH. Although the pH is the major driver, the reduction
in the water level also appears to have a positive impact on the
stability of COMPOUND 1 in the formula.
[0143] After two months aging at controlled room temperature and
40.degree. C. there is less drop in the % recovery of COMPOUND 1 in
the 0% and 6% added water formulas than in the G-series
formula:
TABLE-US-00003 TABLE 3 % COMPOUND 1 recovery after accelerated
aging at 40.degree. C. Initial 1 Month 2 Month 3 Month G - pH 7 90%
88% 68% 61% G - pH 8.5 108% 104% 96% 89% G - pH 9 100% 97% 97% 90%
LW - pH 7 99% 93% 87% 63% LW - pH 8.5 103% 100% 96% 100% LW - pH 9
97% 97% 92% 97%
[0144] To further investigate the effect of pH on COMPOUND 1
stability, a series of pastes are prepared having pH values ranging
from 5.7 to 9. The pastes are aged at 60.degree. C. for two weeks
in order to quickly evaluate trends in formula stability as a
function of pH. In the G-series, the percentage of COMPOUND 1
recovered decreases as the pH decreases from pH 9 to pH 7.5 but
increases from pH 7 to pH 5.7. In the low water base, the
percentage of COMPOUND 1 recovered decreases from pH 9 to pH 5.7.
While the stability at acidic pH is different in the two formula
bases, pH 9 results in the greatest percentage COMPOUND 1 recovery
in both formulas. In addition, it was observed that the ratio of
COMPOUND 1 isomers strongly depends on pH. At pH 9, COMPOUND 1
exists only in its nonpolar form and the amount of the polar
rotamer increases as pH of the dentifrice decreases. A similar
trend is observed in the liquid dentifrice.
[0145] FIG. 1 shows the percentage of COMPOUND 1 recovery after two
weeks at 60.degree. C. as a function of formula pH in the (a)
G-series base and (b) the low water base.
[0146] As dentifrice contains many components, it is important to
understand whether the observed relation between COMPOUND 1
stability and pH is dependent on a dentifrice ingredient or is
simply the response of COMPOUND 1 to pH itself. Therefore, a study
of the effect of pH on COMPOUND 1 is conducted in a simple solution
of 50/50 acetonitrile/water. The result is shown in FIG. 2. In this
study, a series of samples having pH from 9 to 6 were prepared and
aged at 70.degree. C. for one day. The solution at pH 9 had the
highest percentage of COMPOUND 1 recovery. It was also observed
that only the nonpolar isomer is present at pH 9 and the ratio of
the nonpolar to polar rotamer decreases as the pH decreases, the
same trend observed in dentifrice. These results indicate that the
nonpolar rotamer of COMPOUND 1 is fundamentally less susceptible to
degradation and the ratio of nonpolar to polar isomer is directly
affected by pH. These results help to explain the observed increase
in % COMPOUND 1 recovery in formulas at pH 9 and 8.5 compared to pH
7. Differences between the stability of COMPOUND 1 at lower pH in
the two formula bases likely reflect the ability of formula
ingredients to partially stabilize the polar rotamer.
[0147] FIG. 2 shows the percentage of COMPOUND 1 recovery in a
50/50 acetonitrile/water solution as a function of pH after 1 day
at 70.degree. C.
[0148] The anti-inflammatory effect of COMPOUND 1 does not appear
to have been impacted by an increase in dentifrice pH. Both the
G-series and low water formulas at pH 7 and 9 performed well in the
suppression of the anti-inflammatory marker PGE2. The antibacterial
effect of COMPOUND 1, as measured by growth inhibition of A.
viscosus, is comparable to that of the pH 7 paste as well as
commercial high quality toothpaste.
[0149] The uptake of COMPOUND 1 onto the hydroxyapatite (HAP) disk
is significantly increased by the increase in pH. Although the
release of COMPOUND 1 at pH 9 is only 29%, the quantity of COMPOUND
1 released by G-pH 7 and G-pH 9 formulas is equivalent.
Example 3
Efficacy of COMPOUND 1 in Inhibiting Oral Bacteria
[0150] The minimum inhibitory concentration for COMPOUND 1 against
common oral bacteria is found to be as follows. Ethanol is used as
vehicle.
TABLE-US-00004 TABLE 4 Bacterial Species ppm Gram Negative A.
actinomycetemcomitans >15.6 F. nucleatum 1-2 P. gingivalis
.ltoreq.0.12 P. intermedia 3.9-7.8 T. forsythia T. denticola V.
parvula 7.8 Gram Positive A. naeslundii 1-2 A. viscosus 1 E.
nodatum L. casei .sup. 2-3.9 S. gordonii .ltoreq.0.12-0.25.sup. S.
mutans 0.25-0.5 S. oralis .ltoreq.0.12-0.25.sup. S. sanguinis
0.25-0.5 S. sobrinus .ltoreq.0.12-0.5 .sup.
Example 4
Solubilization of Compound 1
[0151] a. Solubilization in Copolymers of Ethylene Glycol and
Propylene Glycol
[0152] The poor solubility of Compound A presents some formulation
challenges. Its solubility in water is less than 100 ppm, and its
solubility in flavor oils (often used to solubilize actives) is
less than 0.5%. We have discovered that co-polymers of polyethylene
glycol and polypropylene glycol are able to solubilize Compound 1.
Fluraflo L4370 (BASF) is able to solubilize 1% Compound 1 (% w/w).
It is necessary to stir the solution over low heat to fully
solubilize the active. The resulting solution is cloudy, reflecting
the nature of the Fluraflo L4370 itself. The solution of 1%
Compound 1 in Fluraflo L4370 is diluted 1:1 with 1.5% SLS in water
to produce a clear solution, composed of 0.5% AN0128, 0.75% SLS,
50% Fluraflo L4370 in water Similar results are achieved using
Fluracare L1220.
[0153] The solution of 0.5% AN0128.0.75% SLS. 50% Fluraflo L4370 in
water is then tested in a biofilm disruption assay. The percent
reduction achieved versus the negative control is 65%, indicating
that Compound 1 retains its antibacterial activity when solubilized
in Fluraflo L4370.
b. Solubilization Using Tri-Block Co-Polymer
[0154] We also discovered that Tri-block Co-polymer Surfactant F127
is able to further enhance solubilization of Compound 1. In
experimental liquid dentifrice formulas (Table 3), Compound 1 is
not completely soluble over time, as evidenced by precipitation and
crystallization over time. After the addition of 5% F127,
experimental liquid dentifrice formulas (Table 4) remain clear.
Therefore, Tri-block Co-polymer Surfactant F127 is able to further
solubilize Compound 1 and is suitable for use in formulations.
TABLE-US-00005 TABLE 5 Experimental formulations without tri-block
co-polymer A2 A3 Compound 1 0.6 0.6 PEG-300 12 12 Propylene glycol
10 10 Fluroflo L4370 10 10 Glycerin 10 SLS 1.5 1.5 H.sub.2O 38 38
Total 72.1 72.1
TABLE-US-00006 TABLE 6 Experimental formulations with tri-block
co-polymer A5 A6 Compound 1 0.6 0.6 PEG-300 11.4 11.4 Propylene
glycol 10 10 Fluroflo L4370 10 10 Glycerin 10 SLS 1.5 1.5 H.sub.2O
34 34 Pluronic F127 5 5 Total 72.5 72.5
c. Solubilization Using PEG
[0155] We further discovered that low molecular weight polyethylene
glycol 300 (PEG 300) (Dow Chemical Company) solubilizes 10%
Compound 1 (% w/w). It is necessary to stir the solution over low
heat to fully solubilize the active. The resulting solution is
clear with a slight yellow tint due to the color of Compound 1. We
also discovered that PEG 600 can solubilize Compound 1. Therefore,
we conclude that solvents containing oligomers and/or polymers of
ethylene glycol are capable of solubilizing Compound 1 and are
suitable for formulation.
[0156] A solution of 2% Compound 1 in PEG 300 is diluted 1:1 with
2% SLS in water to produce a solution composed of 1% Compound 1, 1%
SLS, 50% PEG 300 in water which is then tested in a biofilm
disruption assay. The percent reduction achieved versus the
negative control is 76%, indicating that Compound 1 retains its
antibacterial activity when solubilized in PEG 300.
[0157] The properties of Compound 1 in conjunction with other
excipients are further evaluated by diluting a solution of Compound
1 in PEG 300 into other solvents such as propylene glycol and
glycerin at varying ratios. A solution containing 1% Compound 1 in
19% PEG 300 and 80% propylene glycol is clear. This solution is
then diluted 1:1 with 1% SLS in water to produce a solution
composed of 0.5% Compound 1, 0.5% SLS, 9.5% PEG 300 and 40%
propylene glycol in water which is then tested in the biofilm
disruption assay. The percent reduction achieved versus the
negative control is 80%. These results indicate that Compound 1
retains its antibacterial activity in the mixed solvent solution.
Similar results are achieved with PEG and glycerin.
Example 5
Buffered Formulations
[0158] Two pH 7.2 formulations of Compound 1 are prepared, one with
phosphate buffer, one without, and the decomposition of Compound 1
is measured over 14 days. While measurable decomposition is seen in
both formulations, the slope of the rate of decomposition Compound
1 in the buffered formulation is decreased by 3.3 fold compared to
that of the unbuffered formulation.
Example 6
Effect of Gantrez
[0159] Addition of Gantrez into liquid formulations of Compound 1
is shown to improve the activity of the compound in a biofilm
assay. Compositions are prepared as follows:
TABLE-US-00007 TABLE 7 Liquid dentifrice ID G5 G7 Compound 1 0.5
0.5 BHT -- 0.05 gantrez -- 2 PEG 300 4.5 4.45 glycerin 20 20 flavor
1 1 SLS 1.5 1.5 NaF 0.24 0.24 Saccharin 0.3 0.3 Aq. Buffer, pH 7.0
48.5 46.5 Total 76.54 76.54
[0160] We measure the activity of these dentifrices against biofilm
formation by A. viscosus an organism that we have found to be
relatively resistant to Compound 1 compared to many other
biofilm-forming bacteria. G7 has very good efficacy, inhibiting the
biofilm in this assay to the same extent as commercial Total.RTM.
toothpaste with triclosan, whereas G5 is only slightly better than
the control. Thus the addition of Gantrez (methyl vinyl
ether-maleic acid copolymer or PVM/MA copolymer) significantly
increases the activity of Compound A against biofilm formation by
A. viscosus.
Example 7
Optimization of Dentifrice
[0161] Table 8 shows three silica-based toothpaste formulations
comprising Compound 1, component amounts given as % w/w, water
adjusted to compensate for difference in glycerin level:
TABLE-US-00008 G H I Compound 1 0.75 0.75 0.75 Sodium fluoride
0.243 0.243 0.243 99.0-101.0% 30.84 20.84 40.84 vegetable glycerin
Demineralized water qs qs qs Gantrez S-97 15 15 15 Dental type
Silica - 10 10 10 Zeodent 105 - high cleaning silica Dental type
silica 8.5 8.5 8.5 abrasive (Zeodent 115) Polyethylene glycol 6.72
6.72 6.72 300 Dental type silica - 2.5 2.5 2.5 Zeodent 165-synth.
amorphous ppt silica Sodium Lauryl 1.5 1.5 1.5 Sulfate powder
Sodium hydroxide 1.2 1.2 1.2 50% solution Sodium CMC-12 1.0 1.0 1.0
Flavor K91-6507 1.0 1.0 1.0 Titanium dioxide 0.75 0.75 0.75
Tetrasodium 0.5 0.5 0.5 pyrophosphate - fine Xanthan gum 0.5 0.5
0.5 Sodium saccharin 0.3 0.3 0.3 Sodium ascorbyl 0.2 0.2 0.2
phosphate or dl-.alpha.- tocopherol Sucralose 0.15 0.15 0.15
Butylated 0.03 0.03 0.03 hydroxytoluene
[0162] These formulations are measured for inhibition of grown of
A. viscosus over 24 hours, growth being measured as optical density
at 610 nm. The value after 24 hrs for water or formulation G
without Compound 1 was >1.4, compared to <0.2 for formulation
G with Compound 1. This shows very good efficacy against this
organism, as good or better than the positive control, commercial
Total.RTM. toothpaste with triclosan. Similarly, in a multispecies
biofilm assay, the CFU mean for formulation G and for Total.RTM. 0
was <2 (SD 0) compared to 1.1.times.10.sup.9 (SD
1.5.times.10.sup.8), showing that toothpaste containing Compound 1
is capable of inhibiting biofilm formation.
Example 8
Use of Chelating Agent
[0163] It is observed that a silica-based dentifrice quickly
changes color from white to yellow upon addition of 0.25-1% of
Compound 1 in the final step of the formulation. This color change
is observed with or without presence of an antioxidant, such as
butylated hydroxytoluene (BHT), vitamin E or vitamin C. The
addition of a small amount of a metal chelating agent, however,
returns the dentifrice to its original white color. Chelating
agents effective for this purpose include 0.5% Tetrasodium
pyrophosphate (TSPP), as well as tetrapotassium pyrophosphate,
ethylene diamine tetraacetic acid, ethylene glycol tetraacetic
acid, sodium pyrophosphate, sodium tripolyphosphate, potassium
tripolyphosphate, sodium hexamephosphate, and citric acid.
Example 9
Use of Antioxidants
[0164] Borinic esters can be oxidized by molecular oxygen or
peroxides that can be formed from ethers such as PEG by the action
of oxygen in the air. These highly oxidative species can attack the
carbon-boron bond leading to cleavage and formation of
corresponding boronic acid derivatives and phenol derivatives. The
oxidation products are then inactive. Addition of oxygen scavengers
and/or antioxidants such as vitamins C (ascorbic acid), vitamin E
(.alpha.-tocopherol) or 2,6-di-tert-butyl-4-methyl-phenol
(butylated hydroxytoluene or BHT) eliminates the oxygen and reduces
the peroxides already present in the formulation. The amount of
antioxidant does not need to exceed the amount of borinic ester
used in a given formulation.
[0165] The stability of three formulations of Compound 1 are
compared, the formulations being identical except that one is
without any antioxidants, one contains .alpha.-tocopherol, and the
third contains sodium ascorbylphosphate. Decomposition of formula I
is significantly reduced the formulation containing sodium
ascorbylphosphate, and is even less in the formulation containing
.alpha.-tocopherol. This demonstrates that the use of an
antioxidant enhances the stability of Compound 1 in
formulation.
* * * * *