U.S. patent application number 15/743960 was filed with the patent office on 2018-07-19 for nitric oxide releasing nail coating compositions, nitric oxide releasing nail coatings, and methods of using the same.
The applicant listed for this patent is Novan, Inc.. Invention is credited to Ryan Doxey, Yong Zhang.
Application Number | 20180200541 15/743960 |
Document ID | / |
Family ID | 55078972 |
Filed Date | 2018-07-19 |
United States Patent
Application |
20180200541 |
Kind Code |
A1 |
Doxey; Ryan ; et
al. |
July 19, 2018 |
NITRIC OXIDE RELEASING NAIL COATING COMPOSITIONS, NITRIC OXIDE
RELEASING NAIL COATINGS, AND METHODS OF USING THE SAME
Abstract
The present invention relates to nitric oxide (NO)-releasing
nail coating compositions, NO-releasing coatings, and methods of
using the same, for example, to treat fungal infections of a nail.
Provided according to embodiments of the invention are nitric oxide
(NO)-releasing nail coating compositions and/or coatings. In some
embodiments, a NO-releasing nail coating composition and/or coating
may be in the form of a film. In some embodiments, a NO-releasing
nail coating may be formed from a NO-releasing nail coating
composition. In some embodiments, a NO-releasing nail coating
composition may be in the form of a nail lacquer, a paste, a cream,
a gel, and/or an ointment.
Inventors: |
Doxey; Ryan; (Raleigh,
NC) ; Zhang; Yong; (Cary, NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Novan, Inc. |
Morrisville |
NC |
US |
|
|
Family ID: |
55078972 |
Appl. No.: |
15/743960 |
Filed: |
January 13, 2016 |
PCT Filed: |
January 13, 2016 |
PCT NO: |
PCT/US16/13246 |
371 Date: |
January 11, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
PCT/US2015/040319 |
Jul 14, 2015 |
|
|
|
15743960 |
|
|
|
|
62024200 |
Jul 14, 2014 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 47/38 20130101;
A61P 31/10 20180101; A61K 9/7015 20130101; A61K 8/731 20130101;
A61K 47/10 20130101; A61Q 3/02 20130101; A61K 33/00 20130101; A61K
47/32 20130101; A61K 8/8182 20130101; A61K 9/06 20130101; A61K
2800/884 20130101; A61K 8/25 20130101; A61K 2800/88 20130101; A61K
8/19 20130101; A61K 9/0014 20130101; A61K 31/695 20130101; A61K
2800/22 20130101 |
International
Class: |
A61Q 3/02 20060101
A61Q003/02; A61K 31/695 20060101 A61K031/695; A61K 47/38 20060101
A61K047/38; A61K 47/32 20060101 A61K047/32; A61K 47/10 20060101
A61K047/10; A61P 31/10 20060101 A61P031/10; A61K 9/70 20060101
A61K009/70; A61K 8/25 20060101 A61K008/25; A61K 8/73 20060101
A61K008/73; A61K 8/81 20060101 A61K008/81 |
Claims
1.-37. (canceled)
38. A method of treating and/or preventing a nail disease and/or
disorder in a subject, the method comprising: topically applying a
nail coating composition to a nail of the subject, wherein the nail
coating composition comprises a first component comprising a
NO-releasing co-condensed silica and a second component that is a
hydrogel, thereby treating and/or preventing the nail disease or
disorder in the subject.
39. The method of claim 38, wherein the first component further
comprises at least one viscosity increasing agent, at least one
organic solvent, and at least one humectant.
40. The method of claim 39, wherein the at least one viscosity
increasing agent is present at a concentration in a range of 0.5%
to 30% by weight of the first component, the at least one organic
solvent is present at a concentration in a range of 50% to 90% by
weight of the first component, the at least one humectant is
present at a concentration in a range of 2% to 20% by weight of the
first component, and the NO-releasing co-condensed silica is
present at a concentration in a range of about 0.1% to about 70% by
weight percent of the first component.
41. The method of claim 38, wherein the first component further
comprises: hydroxypropyl cellulose at a concentration in a range of
0.1% to 15% by weight of the first component; ethyl alcohol or
isopropyl alcohol at a concentration in a range of 45% to 95% by
weight of the first component; hexylene glycol at a concentration
in a range of 1% to 20% by weight of the first component;
cyclomethicone at a concentration in a range of 0.5% to 15% by
weight of the first component; and diazeniumdiolated co-condensed
silica particles at a concentration in a range of 0.1% to 40% by
weight of the first component.
42. The method of claim 38, wherein the first component further
comprises a hydrophobic base and an amphiphilic compound.
43. The method of claim 42, wherein the hydrophobic base is present
at a concentration from about 35% to about 90% by weight of the
first component and the amphiphilic compound is present at a
concentration from about 1% to about 30% by weight of the first
component.
44. The method of claim 43, wherein the amphiphilic compound is a
polyethylene glycol (PEG) caprylic/capric glyceride.
45. The method of claim 38, wherein the hydrogel comprises a first
viscosity increasing agent, at least one polyhydric alcohol, at
least one buffering agent, and water.
46. The method of claim 45, wherein the hydrogel comprises the
first viscosity increasing agent in an amount of 0.6% to 5% by
weight of the second component and the at least one polyhydric
alcohol in an amount of 1% to 30% by weight of the second
component.
47. The method of claim 46, wherein the first viscosity increasing
agent is a cellulose ether or a carboxypolymethylene.
48. The method of claim 38, wherein topically applying the nail
coating composition to the nail of the subject comprises separately
topically applying the first component and the second
component.
49. The method of claim 38, wherein topically applying the nail
coating composition to the nail of the subject comprises combining
the first component and the second component to form a combined
composition and topically applying the combined composition to the
nail of the subject.
50. The method of claim 38, wherein topically applying the nail
coating composition to the nail of the subject comprises topically
applying the first component and second component in a ratio in a
range of about 1:1 to about 1:10.
51. The method of claim 38, wherein the nail coating composition is
devoid of acidified nitrite.
52. The method of claim 38, wherein the first component and the
second component are separately stored.
53. The method of claim 38, wherein the method has increased
efficacy in treating and/or preventing the nail disease and/or
disorder in the subject by at least about 5% compared to a
treatment that does not apply a composition comprising a
NO-releasing compound.
54. The method of claim 38, wherein the method decreases the rate
of reinfection of the nail disease and/or disorder in the subject
by at least about 5% compared to a treatment that does not apply a
composition comprising a NO-releasing compound.
55. The method of claim 38, wherein the method reduces treatment
duration in the subject compared to a treatment that does not apply
a composition comprising a NO-releasing compound.
56. The method of claim 38, wherein the method comprises topically
applying the nail coating composition to the nail of the subject at
least 1, 2, or 3 times per day.
57. The method of claim 38, wherein the hydrogel has a pH of about
3.5 to about 6.5.
Description
RELATED APPLICATION INFORMATION
[0001] This application is a continuation-in-part of International
Application No. PCT/US2015/040319, filed Jul. 14, 2015, which
claims the benefit of U.S. Provisional Patent Application Ser. No.
62/024,200, filed Jul. 14, 2014, the disclosure of each of which is
incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to nail coating compositions
and/or coatings that may release nitric oxide. The present
invention also relates to methods of using nail coating
compositions and/or coatings, including methods of using nitric
oxide-releasing nail coating compositions and/or coatings to treat
fungal infections of the nail and/or nail conditions.
BACKGROUND
[0003] The current treatment modes for fungal infections of the
nail typically include oral therapy, topical therapy, or a
combination of the two. Oral therapies often involve a long
treatment period due to low bioavailability of the drug at the
sight of action, as well as a high potential for systemic adverse
effects.
[0004] Topical therapies tend to be advantageous over oral
treatment due to application of the drug directly to the infected
site and minimal systemic adverse effects associated with the
treatment. However, some drawbacks of many antifungal topical
formulations include that drug penetration to the nail bed may be
inhibited due to significant lag times in nail penetration, the
inherent complex structure of the nail and the short time period in
which the formulation remains on the nail.
[0005] The present invention may address previous shortcomings in
the art by providing compositions and/or methods of treating and/or
preventing nail disorders and/or diseases (e.g., fungal infections)
and/or by providing compositions and/or methods of improving the
appearance of a nail.
SUMMARY OF THE INVENTION
[0006] It is noted that aspects described with respect to one
embodiment may be incorporated in different embodiments although
not specifically described relative thereto.
[0007] Provided according to embodiments of the invention are
nitric oxide (NO)-releasing nail coating compositions and/or
coatings. In some embodiments, a NO-releasing nail coating
composition and/or coating may be in the form of a film. In some
embodiments, a NO-releasing nail coating may be formed from a
NO-releasing nail coating composition. In some embodiments, a
NO-releasing nail coating composition may be in the form of a nail
lacquer, a paste, a cream, a gel, and/or an ointment.
[0008] In some embodiments, the NO-releasing nail coating and/or
coating composition may include at least one NO-releasing compound.
In some embodiments, the at least one NO-releasing compound
releases NO upon reaction with a proton source. In some
embodiments, the proton source is a proton donor (e.g., water). In
some embodiments, the at least one NO-releasing compound includes
NO-releasing co-condensed silica.
[0009] Provided according to some embodiments are NO-releasing nail
lacquers. The NO-releasing nail lacquers may include at least one
NO-releasing compound, such as, for example, at least one
NO-releasing compound that releases NO upon reaction with a proton
source (e.g., a proton donor, such as, water). In some embodiments,
the at least one NO-releasing compound includes NO-releasing
co-condensed silica. In some embodiments, the NO-releasing nail
lacquers further include at least one hydrophilic polymer, at least
one film forming polymer, and/or a solvent (e.g., an organic
solvent).
[0010] Further provided according to some embodiments is a one
component NO-releasing nail coating composition. The one component
NO-releasing nail coating composition may be in the form of a
NO-releasing nail lacquer, paste, film, gel, cream, and/or
ointment.
[0011] In some embodiments, a two component NO-releasing nail
coating system is provided. In some embodiments, one component of
the two component NO-releasing nail coating system may include a
NO-releasing coating composition (e.g., a NO-releasing nail
lacquer, paste, and/or ointment) and the other component of the two
component NO-releasing nail coating system may include a
composition including a proton source (e.g., a proton donor, such
as, water). In some embodiments, the composition including a proton
source is a hydrogel.
[0012] In addition, provided according to some embodiments of the
invention are methods of treating a fungal infection of the nail
and/or a nail condition comprising contacting a nail and/or skin
surrounding the nail with a NO-releasing nail coating composition
(e.g., a NO-releasing nail lacquer, paste, and/or ointment)
according to an embodiment of the invention. The NO-releasing nail
coating composition may not stain and/or discolor the nail and/or
skin surrounding the nail.
[0013] In some embodiments, a method of treating a fungal infection
of the nail and/or a nail condition may comprise providing on a
nail and/or skin surrounding the nail a NO-releasing nail coating
according to an embodiment of the invention. The NO-releasing nail
coating may not stain and/or discolor the nail and/or skin
surrounding the nail.
[0014] The foregoing and other aspects of the present invention
will now be described in more detail with respect to other
embodiments described herein. It should be appreciated that the
invention can be embodied in different forms and should not be
construed as limited to the embodiments set forth herein. Rather,
these embodiments are provided so that this disclosure will be
thorough and complete, and will fully convey the scope of the
invention to those skilled in the art.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] FIG. 1 shows an illustration of ChubTur.RTM. cells.
[0016] FIG. 2 shows a graph of the percent of ATP recovery for the
formulations tested compared to the infected control.
DETAILED DESCRIPTION
[0017] The present invention will now be described more fully
hereinafter. This invention may, however, be embodied in different
forms and should not be construed as limited to the embodiments set
forth herein. Rather, these embodiments are provided so that this
disclosure will be thorough and complete, and will fully convey the
scope of the invention to those skilled in the art.
[0018] The terminology used in the description of the invention
herein is for the purpose of describing particular embodiments only
and is not intended to be limiting of the invention. As used in the
description of the invention and the appended claims, the singular
forms "a", "an" and "the" are intended to include the plural forms
as well, unless the context clearly indicates otherwise.
[0019] Unless otherwise defined, all terms (including technical and
scientific terms) used herein have the same meaning as commonly
understood by one of ordinary skill in the art to which this
invention belongs. It will be further understood that terms, such
as those defined in commonly used dictionaries, should be
interpreted as having a meaning that is consistent with their
meaning in the context of the present application and relevant art
and should not be interpreted in an idealized or overly formal
sense unless expressly so defined herein. The terminology used in
the description of the invention herein is for the purpose of
describing particular embodiments only and is not intended to be
limiting of the invention. All publications, patent applications,
patents and other references mentioned herein are incorporated by
reference in their entirety. In case of a conflict in terminology,
the present specification is controlling.
[0020] Also as used herein, "and/or" refers to and encompasses any
and all possible combinations of one or more of the associated
listed items, as well as the lack of combinations when interpreted
in the alternative ("or").
[0021] Unless the context indicates otherwise, it is specifically
intended that the various features of the invention described
herein can be used in any combination. Moreover, the present
invention also contemplates that in some embodiments of the
invention, any feature or combination of features set forth herein
can be excluded or omitted. To illustrate, if the specification
states that a complex comprises components A, B and C, it is
specifically intended that any of A, B or C, or a combination
thereof, can be omitted and disclaimed.
[0022] As used herein, the transitional phrase "consisting
essentially of" (and grammatical variants) is to be interpreted as
encompassing the recited materials or steps "and those that do not
materially affect the basic and novel characteristic(s)" of the
claimed invention. See, In re Herz, 537 F.2d 549, 551-52, 190
U.S.P.Q. 461, 463 (CCPA 1976) (emphasis in the original); see also
MPEP .sctn. 2111.03. Thus, the term "consisting essentially of" as
used herein should not be interpreted as equivalent to
"comprising."
[0023] The term "about," as used herein when referring to a
measurable value, such as, for example, an amount or concentration
and the like, is meant to encompass variations of up to .+-.20% of
the specified value, such as, but not limited to, +10%, +5%, 1%,
+0.5%, or even .+-.0.1% of the specified amount, as well as the
specified value. For example, "about X" where X is the measurable
value, is meant to include X as well as variations of .+-.20%,
.+-.10%, .+-.5%, .+-.1%, 0.5%, or even .+-.0.1% of X. A range
provided herein for a measureable value may include any other range
and/or individual value therein.
[0024] As used herein the term "alkyl" refers to C.sub.1-20
inclusive, linear (i.e., "straight-chain"), branched, or cyclic,
saturated or at least partially and in some cases fully unsaturated
(i.e., alkenyl and alkynyl) hydrocarbon chains, including for
example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
tert-butyl, pentyl, hexyl, octyl, ethenyl, propenyl, butenyl,
pentenyl, hexenyl, octenyl, butadienyl, propynyl, butynyl,
pentynyl, hexynyl, heptynyl, and allenyl groups. "Branched" refers
to an alkyl group in which a lower alkyl group, such as methyl,
ethyl or propyl, is attached to a linear alkyl chain. Exemplary
branched alkyl groups include, but are not limited to, isopropyl,
isobutyl, tert-butyl. "Lower alkyl" refers to an alkyl group having
1 to about 8 carbon atoms (i.e., a C.sub.1-8 alkyl), e.g., 1, 2, 3,
4, 5, 6, 7, or 8 carbon atoms. "Higher alkyl" refers to an alkyl
group having about 10 to about 20 carbon atoms, e.g., 10, 11, 12,
13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. In certain
embodiments, "alkyl" refers, in particular, to C.sub.1-5
straight-chain alkyls. In other embodiments, "alkyl" refers, in
particular, to C.sub.1-5 branched-chain alkyls.
[0025] Alkyl groups may optionally be substituted (a "substituted
alkyl") with one or more alkyl group substituents, which may be the
same or different. The term "alkyl group substituent" includes but
is not limited to alkyl, substituted alkyl, halo, arylamino, acyl,
hydroxyl, aryloxyl, alkoxyl, alkylthio, arylthio, aralkyloxyl,
aralkylthio, carboxyl, alkoxycarbonyl, oxo, and cycloalkyl. There
may be optionally inserted along the alkyl chain one or more
oxygen, sulfur or substituted or unsubstituted nitrogen atoms,
wherein the nitrogen substituent is hydrogen, lower alkyl (also
referred to herein as "alkylaminoalkyl"), or aryl.
[0026] Thus, as used herein, the term "substituted alkyl" includes
alkyl groups, as defined herein, in which one or more atoms or
functional groups of the alkyl group are replaced with another atom
or functional group, including for example, alkyl, substituted
alkyl, halogen, aryl, substituted aryl, alkoxyl, hydroxyl, nitro,
amino, alkylamino, dialkylamino, sulfate, and mercapto.
[0027] The term "aryl" is used herein to refer to an aromatic
substituent that may be a single aromatic ring, or multiple
aromatic rings that are fused together, linked covalently, or
linked to a common group, such as, but not limited to, a methylene
or ethylene moiety. The common linking group also may be a
carbonyl, as in benzophenone, or oxygen, as in diphenylether, or
nitrogen, as in diphenylamine. The term "aryl" specifically
encompasses heterocyclic aromatic compounds. The aromatic ring(s)
may comprise phenyl, naphthyl, biphenyl, diphenylether,
diphenylamine and benzophenone, among others. In particular
embodiments, the term "aryl" means a cyclic aromatic comprising
about 5 to about 10 carbon atoms, e.g., 5, 6, 7, 8, 9, or 10 carbon
atoms, and including 5- and 6-membered hydrocarbon and heterocyclic
aromatic rings.
[0028] The aryl group may be optionally substituted (a "substituted
aryl") with one or more aryl group substituents, which may be the
same or different, wherein "aryl group substituent" includes alkyl,
substituted alkyl, aryl, substituted aryl, aralkyl, hydroxyl,
alkoxyl, aryloxyl, aralkyloxyl, carboxyl, acyl, halo, nitro,
alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acyloxyl,
acylamino, aroylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
arylthio, alkylthio, alkylene, and --NR.sup.1R'', wherein R.sup.1
and R'' may each be independently hydrogen, alkyl, substituted
alkyl, aryl, substituted aryl, and aralkyl.
[0029] Thus, as used herein, the term "substituted aryl" includes
aryl groups, as defined herein, in which one or more atoms or
functional groups of the aryl group are replaced with another atom
or functional group, including for example, alkyl, substituted
alkyl, halogen, aryl, substituted aryl, alkoxyl, hydroxyl, nitro,
amino, alkylamino, dialkylamino, sulfate, and mercapto. Specific
examples of aryl groups include, but are not limited to,
cyclopentadienyl, phenyl, furan, thiophene, pyrrole, pyran,
pyridine, imidazole, benzimidazole, isothiazole, isoxazole,
pyrazole, pyrazine, triazine, pyrimidine, quinoline, isoquinoline,
indole, carbazole, and the like.
[0030] "Cyclic" and "cycloalkyl" refer to a non-aromatic mono- or
multicyclic ring system of about 3 to about 10 carbon atoms, e.g.,
3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The cycloalkyl group may
be optionally partially unsaturated. The cycloalkyl group also may
be optionally substituted with an alkyl group substituent as
defined herein, oxo, and/or alkylene. There may be optionally
inserted along the cyclic alkyl chain one or more oxygen, sulfur or
substituted or unsubstituted nitrogen atoms, wherein the nitrogen
substituent is hydrogen, alkyl, substituted alkyl, aryl, or
substituted aryl, thus providing a heterocyclic group.
Representative monocyclic cycloalkyl rings include cyclopentyl,
cyclohexyl, and cycloheptyl. Multicyclic cycloalkyl rings include
adamantyl, octahydronaphthyl, decalin, camphor, camphane, and
noradamantyl.
[0031] "Alkoxyl" refers to an alkyl-O-- group wherein alkyl is as
previously described. The term "alkoxyl" as used herein may refer
to, for example, methoxyl, ethoxyl, propoxyl, isopropoxyl, butoxyl,
f-butoxyl, and pentoxyl. The term "oxyalkyl" may be used
interchangeably with "alkoxyl". In some embodiments, the alkoxyl
has 1, 2, 3, 4, or 5 carbons.
[0032] "Aralkyl" refers to an aryl-alkyl group wherein aryl and
alkyl are as previously described, and included substituted aryl
and substituted alkyl. Exemplary aralkyl groups include, but are
not limited to, benzyl, phenylethyl, and naphthylmethyl.
[0033] "Alkylene" refers to a straight or branched bivalent
aliphatic hydrocarbon group having from 1 to about 20 carbon atoms,
e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,
18, 19, or 20 carbon atoms. The alkylene group may be straight,
branched or cyclic. The alkylene group also may be optionally
unsaturated and/or substituted with one or more "alkyl group
substituents." There may be optionally inserted along the alkylene
group one or more oxygen, sulfur or substituted or unsubstituted
nitrogen atoms (also referred to herein as "alkylaminoalkyl"),
wherein the nitrogen substituent is alkyl as previously described.
Exemplary alkylene groups include, but are not limited to,
methylene (--CH.sub.2--); ethylene (--CH.sub.2--CH.sub.2--);
propylene (--(CH.sub.2).sub.3--); cyclohexylene
(--C.sub.6H.sub.10--); --CH.dbd.CH--CH.dbd.CH--;
--CH.dbd.CH--CH.sub.2--; wherein each of q and r is independently
an integer from 0 to about 20, e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, and R is hydrogen or
lower alkyl; methylenedioxyl (--O--CH.sub.2--O--); and
ethylenedioxyl (--O--(CH.sub.2).sub.2--O--). An alkylene group may
have about 2 to about 3 carbon atoms and may further have 6-20
carbons.
[0034] "Arylene" refers to a bivalent aryl group. An exemplary
arylene is phenylene, which may have ring carbon atoms available
for bonding in ortho, meta, or para positions with regard to each
other, i.e., respectively. The arylene group may also be
napthylene. The arylene group may be optionally substituted (a
"substituted arylene") with one or more "aryl group substituents"
as defined herein, which may be the same or different.
[0035] "Aralkylene" refers to a bivalent group that contains both
alkyl and aryl groups. For example, aralkylene groups may have two
alkyl groups and an aryl group (i.e., -alkyl-aryl-alkyl-), one
alkyl group and one aryl group (i.e., -alkyl-aryl-) or two aryl
groups and one alkyl group (i.e., -aryl-alkyl-aryl-).
[0036] The term "amino" and "amine" refer to nitrogen-containing
groups such as NR.sub.3, NH.sub.3, NHR.sub.2, and NH.sub.2R,
wherein R may be alkyl, branched alkyl, cycloalkyl, aryl, alkylene,
arylene, aralkylene. Thus, "amino" as used herein may refer to a
primary amine, a secondary amine, or a tertiary amine. In some
embodiments, one R of an amino group may be a cation stabilized
diazeniumdiolate (i.e., NONO.sup.-X.sup.+).
[0037] The terms "cationic amine" and "quaternary amine" refer to
an amino group having an additional (i.e., a fourth) group, for
example a hydrogen or an alkyl group bonded to the nitrogen. Thus,
cationic and quaternary amines carry a positive charge.
[0038] The term "alkylamine" refers to the -alkyl-NH.sub.2
group.
[0039] The term "carbonyl" refers to the --(C.dbd.O)-- group.
[0040] The term "carboxyl" refers to the --COOH group and the term
"carboxylate" refers to an anion formed from a carboxyl group,
i.e., --COO--.
[0041] The terms "halo", "halide", or "halogen" as used herein
refer to fluoro, chloro, bromo, and iodo groups.
[0042] The term "hydroxyl" and "hydroxy" refer to the --OH
group.
[0043] The term "hydroxyalkyl" refers to an alkyl group substituted
with an --OH group.
[0044] The term "mercapto" or "thio" refers to the --SH group. The
term "silyl" refers to groups comprising silicon atoms (Si).
[0045] As used herein the term "alkoxysilane" refers to a compound
comprising one, two, three, or four alkoxy groups bonded to a
silicon atom. For example, tetraalkoxysilane refers to
Si(OR).sub.4, wherein R is alkyl. Each alkyl group may be the same
or different. An "alkylsilane" refers to an alkoxysilane wherein
one or more of the alkoxy groups has been replaced with an alkyl
group. Thus, an alkylsilane comprises at least one alkyl-Si bond.
The term "fluorinated silane" refers to an alkylsilane wherein one
of the alkyl groups is substituted with one or more fluorine atoms.
The term "cationic or anionic silane" refers to an alkylsilane
wherein one of the alkyl groups is further substituted with an
alkyl substituent that has a positive (i.e., cationic) or a
negative (i.e. anionic) charge, or may become charged (i.e., is
ionizable) in a particular environment (i.e., in vivo).
[0046] The term "silanol" refers to a Si--OH group.
[0047] Provided according to some embodiments of the invention are
nail coating compositions and/or coatings that include at least one
nitric oxide (NO)-releasing compound (i.e., NO-releasing nail
coating compositions and/or coatings). A nail coating composition
as described herein may provide and/or form a nail coating, as
described herein, on a nail and/or skin of a subject after topical
application. A nail coating composition of the present invention
may or may not change in form (e.g., from a liquid to another form,
such as a solid or semi-solid film) upon and/or after application
to a subject to provide a nail coating of the present invention. A
nail coating composition and/or nail coating of the present
invention may release NO onto and/or into a nail of a subject to
which the composition and/or coating is in contact with and/or onto
and/or into skin under and/or around the nail. In some embodiments
of the invention, the at least one NO-releasing compound included
in the composition and/or coating may release NO upon reaction with
a proton source, such as, but not limited to, water. In some
embodiments, the at least one NO-releasing compound includes a
diazeniumdiolate functional group.
[0048] Any suitable NO-releasing compound may be used in a nail
coating composition and/or coating according to embodiments of the
invention. Nitric oxide may be released from the NO-releasing
compound by any suitable mechanism, including via reaction with a
proton source (e.g., a proton donor, such as, water) and/or thermal
degradation. Examples of NO-releasing functional groups that may be
included in the NO-releasing compound include, but are not limited
to, diazeniumdiolate, nitrosamine, hydroxyl nitrosamine,
nitrosothiol, hydroxyl amine, hydroxyurea, metal nitrosyl
complexes, and any combination thereof. Other NO-releasing
functional groups that are capable of releasing nitric oxide in a
therapeutic manner in a one component and/or two component nail
coating composition and/or coating may also be utilized.
[0049] The NO-releasing compound may be a small molecule, oligomer,
macromolecule and/or polymer and may be in any suitable physical
form, including, but not limited to, particles, gels, hydrogels,
films, liquids, and the like. In some embodiments, the nitric
oxide-releasing compound includes diazeniumdiolate-functionalized
polysiloxane macromolecules as described below. Other examples of
NO-releasing compounds include NO-releasing zeolites as described
in United States Patent Application Publication Nos. 2006/0269620
or 2010/0331968; NO-releasing metal organic frameworks (MOFs) as
described in United States Patent Application Publication Nos.
2010/0239512 or 2011/0052650; NO-releasing multi-donor compounds as
described in U.S. Patent Application Publication No. 2014/0171395;
NO-releasing dendrimers or metal structures as described in U.S.
Patent Application Publication No. 2009/0214618; nitric oxide
releasing coatings as described in U.S. Patent Application
Publication No. 2011/0086234; and compounds as described in U.S.
Patent Application Publication No. 2010/0098733. The disclosures of
each of the references in this paragraph are incorporated herein by
reference in their entirety. Additionally, NO-releasing
macromolecules may be fabricated as described in International
Publication No. WO 2012/100174, the disclosure of which is
incorporated herein by reference in its entirety.
[0050] In some embodiments, the NO-releasing compound includes a
macromolecule that includes an NO donor group. A "macromolecule" is
defined herein as any compound that has a molecular weight of 500
daltons or greater. Any suitable macromolecule may be used,
including crosslinked or non-crosslinked polymers, dendrimers,
metallic compounds, organometallic compounds, inorganic-based
compounds, and other macromolecular scaffolds. In some embodiments,
the macromolecule has a nominal diameter ranging from about 0.1 nm
to about 100 .mu.m and may comprise the aggregation of two or more
macromolecules, whereby the macromolecular structure is further
modified with an NO donor group.
[0051] In some embodiments, the NO-releasing macromolecule includes
diazeniumdiolate-functionalized co-condensed silica. The term
"diazeniumdiolate-functionalized co-condensed silica" refers to
co-condensed polysiloxane macromolecules functionalized with
diazeniumdiolate, such as the NO-releasing particles described in
U.S. Patent Application Publication No. 2009/0214618, the
disclosure of which is incorporated by reference herein in its
entirety. Such particles may be prepared by methods described
therein.
[0052] In some embodiments, the diazeniumdiolate-functionalized
co-condensed silica may be formed from an aminoalkoxysilane by a
pre-charging method, and the co-condensed siloxane network may be
synthesized from the condensation of a silane mixture that includes
an alkoxysilane and the aminoalkoxysilane to form a nitric oxide
donor modified co-condensed siloxane network. As used herein, the
"pre-charging method" means that aminoalkoxysilane is "pretreated"
or "precharged" with nitric oxide prior to the co-condensation with
alkoxysilane. In some embodiments, the precharging nitric oxide may
be accomplished by chemical methods. In another embodiment, the
"pre-charging" method may be used to create co-condensed siloxane
networks and materials more densely functionalized with
NO-donors.
[0053] The co-condensed siloxane network may be silica particles
with a uniform size, a collection of silica particles with a
variety of size, amorphous silica, fumed silica, a nanocrystalline
silica, ceramic silica, colloidal silica, a silica coating, a
silica film, organically modified silica, mesoporous silica, silica
gel, bioactive glass, or any suitable form or state of silica.
[0054] In some embodiments, the alkoxysilane is a tetraalkoxysilane
having the formula Si(OR).sub.4, wherein R is an alkyl group. The R
groups may be the same or different. In some embodiments the
tetraalkoxysilane is selected as tetramethyl orthosilicate (TMOS)
or tetraethyl orthosilicate (TEOS). In some embodiments, the
aminoalkoxysilane has the formula:
R''--(NH--R').sub.n--Si(OR).sub.3, wherein R is alkyl, R' is
alkylene, branched alkylene, or aralkylene, n is 1 or 2, and R'' is
selected from the group consisting of alkyl, cycloalkyl, aryl, and
alkylamine.
[0055] In some embodiments, the aminoalkoxysilane may be selected
from N-(6-aminohexyl)aminopropyltrimethoxysilane (AHAP3);
N-(2-aminoethyl)-3-aminopropyltrimethoxysilane (AEAP3);
(3-trimethoxysilylpropyl)di-ethylenetriamine (DET3);
(aminoethylaminomethyl)phenethyltrimethoxysilane (AEMP3);
[3-(methylamino)propyl]trimethoxysilane (MAP3);
N-butylamino-propyltrimethoxysilane(n-BAP3);
t-butylamino-propyltrimethoxysilane(t-BAP3);
N-ethylaminoisobutyltrimethoxysilane(EAiB3);
N-phenylamino-propyltrimethoxysilane (PAP3); and
N-cyclohexylaminopropyltrimethoxysilane (cHAP3).
[0056] In some embodiments, the aminoalkoxysilane has the formula:
NH[R'--Si(OR).sub.3].sub.2, wherein R is alkyl and R' is alkylene.
In some embodiments, the aminoalkoxysilane may be selected from
bis(3-triethoxysilylpropyl)amine,
bis-[3-(trimethoxysilyl)propyl]amine and
bis-[(3-trimethoxysilyl)propyl]ethylenediamine.
[0057] In some embodiments, as described herein above, the
aminoalkoxysilane is precharged for NO-release and the amino group
is substituted by a diazeniumdiolate. Therefore, in some
embodiments, the aminoalkoxysilane has the formula:
R''--N(NONO.sup.-X.sup.+)--R'--Si(OR).sub.3, wherein R is alkyl or
silyl, R' is alkylene or aralkylene, R'' is alkyl or alkylamine,
and X.sup.+ is a cation selected from the group consisting of
Na.sup.+, K.sup.+, Cs.sup.+, Li.sup.+, NH.sub.4.sup.+, or other
quaternary ammonium cation.
[0058] In some embodiments of the invention, the
diazeniumdiolate-functional aminoalkoxysilane may be
O.sup.2-protected prior to the preparation of the nitric oxide
releasing macromolecules. Such O.sup.2-protected diazeniumdiolate
functional aminoalkoxysilanes may have the formula:
R''--N(NONO--R''')--R'--Si(OR).sub.3, wherein each R is
independently H, alkyl or substituted alkyl, R' is substituted or
unsubstituted alkylene, substituted or unsubstituted arylene,
substituted or unsubstituted alkylarylene or substituted or
unsubstituted arylalkylene, R'' is H, alkyl or substituted alkyl
and R''' is a protecting group that imparts enzymatic, photolytic,
or thiolation triggering mechanisms. Such protecting groups are
known to those skilled in the art of forming O.sup.2-protected
diazeniumdiolates.
[0059] The chemical composition of the siloxane network, (e.g.,
amount or the chemical composition of the aminoalkoxysilane), the
porosity of the silica network within the macromolecular structure,
the size of the co-condensed silica particles, and the nitric oxide
charging conditions (e.g., the solvent and base) may be varied to
optimize the amount and duration of nitric oxide release. Thus, in
some embodiments, the composition of the silica particles may be
modified to regulate the half-life of NO release from silica
particles with half-lives of nitric oxide release ranging from
slow, defined by t.sub.1/2 values greater than about 60 minutes to
fast, defined by t.sub.1/2 values ranging from about 30 seconds to
about 10 minutes (at physiological conditions--37.degree. C. and
pH=7.4).
[0060] In some embodiments of the invention, the co-condensed
siloxane network of nitric oxide releasing silica particles is
formed from at least one additional silane that modifies surface
charge and/or hydrophilicity/hydrophobicity of the co-condensed
silica product which affect the octanol/water partition coefficient
of the macromolecular delivery vehicle. These parameters control
the route of skin penetration, depth of penetration, and diffusion
of the diazeniumdiolate-modified polysiloxane macromolecules into
the aqueous solution. Any suitable alkoxysilane that may impart
surface charge to the diazeniumdiolate-modified polysiloxane
macromolecule may be used. Thus, in some embodiments, the
additional alkoxysilane may include a cationic alkoxysilane such as
(2-N-benyzlaminoethyl)-3-aminopropyl-trimethoxysilane,
hydrocholoride; bis(methoxyethyl)-3-trimethoxysilylpropyl-ammonium
chloride; N--N-didecyl-N-methyl-N-(3-trimethoxysilyl)ammonium
chloride; N-trimethyoxysilylpropyl-N,N,N-trimethyl ammonium
chloride; octadecylbis(triethoxysilylpropyl)-ammonium chloride; and
octadecyldimethyl(3-trimethoxysilylpropyl)ammonium chloride. In
some embodiments, the additional alkoxysilane may include an
anionic alkoxysilanes such as 3-trihydroxysilylpropylmethyl
phosphonate, sodium salt and carboxyethylsilanetriol, sodium
salt.
[0061] Any suitable alkoxysilane that may impart hydrophilic
properties to the diazeniumdiolate-modified polysiloxane
macromolecule may be used. Alkoxysilanes containing repeat
poly(ethylene)oxy groups may be used to increase the wetability of
the NO-releasing particles thereby helping to improve
biocompatibility upon topical application and also enhance the rate
of water uptake into the co-condensed siloxane network. Surface
hydrophilicity may thus be utilized to enhance the NO-release
kinetics of the diazeniumdiolated aminoalkoxysilane derivatives.
Therefore, in some embodiments, the multifunctional alkoxysilane
may include a hydrophilic silane such as
N-triethoxysilylpropyl)-O-poly ethyleneoxide urethane;
N-3-[amino(polypropylenoxy)]aminopropyltrimethoxysilane;
bis-[3-(triethoxysilylpropoxy)-2-hydroxypropoxy]polyethylene oxide;
bis(3-triethoxysilylpropyl)polyethylene oxide (25-30);
[hydroxy(polyethyleneoxy)propyl]-triethoxysilane; and
2-[methoxy(polyethyleneoxy)propyl]-trimethoxysilane.
[0062] Any suitable alkoxysilane that may impart hydrophobic
properties to the diazeniumdiolate-modified polysiloxane
macromolecule may be used. Hydrophobic silanes are known to those
skilled in the art to increase lipophilicity of particle surfaces.
In some embodiments, the additional alkoxysilane may include linear
alkyl, branched and cyclic alkylalkoxysilanes having at least three
carbon atoms, substituted and unsubstituted phenyl alkoxysilanes,
and fluorinated alkoxysilanes. Exemplary fluoroalkoxysilanes may
include heptadecafluoro-1,1,2-2-tetrahydrodecyl)triethoxysilane,
(3,3,3-trifluoropropyetrimethoxysilane,
(perfluoroalkyl)ethyltriethoxysilane,
nonafluorohexyltrimethoxysilane, nonafluorohexyltriethoxysilane,
(tridecafluoro-1,1,2,2-tetrahydrooctyl)triethoxysilane, and
(tridecafluoro-1,1,2,2-tetrahydrooctyl)trimethoxysilane.
[0063] The hydrophilicity of the diazeniumdiolate-functionalized
polysiloxane macromolecules may be assessed by the use of a
water/octanol partition coefficient. See Octanol-Water Partition
Coefficients: Fundamentals and Physical Chemistry, Vol. 2 of Wiley
Series in Solution Chemistry. Chichester: John Wiley & Sons
Ltd. (1997), which is herein incorporated by reference in its
entirety. For example, hydrophobic diazeniumdiolate-functionalized
polysiloxane macromolecules may have a water/octanol partition
coefficient in a range from about 0.1 to about 7, and hydrophilic
diazeniumdiolate-functionalized polysiloxane macromolecules may
have a water/octanol partition coefficient in a range from about -2
to about 0.
[0064] In some embodiments of the invention, the hydrodynamic
radius of the diazeniumdiolate-functionalized co-condensed silica
particles is in a range of about 10 nm to about 100 .mu.m. The
particular size, sizes or range of sizes may be selected to
maximize nail penetration and/or enhance nitric oxide delivery to
skin structures beneath the nail. The size(s) of the particle may
also be selected based on the ability of the particle to provide
substantially uniform coverage when suspended in the nail coating
and/or nail coating composition. Additionally, the size(s) of the
particles may also vary when other nitric oxide releasing materials
are utilized. For example, a nitric oxide releasing dendrimer may
be sized to penetrate the nail.
[0065] In some embodiments, a nail coating composition and/or nail
coating does not comprise acidified nitrite. "Acidified nitrite",
as used herein, refers to a nitric oxide releasing composition
where the primary mechanism of nitric oxide release is when a
nitrite is reduced, in the presence of an acid, to dinitrogen
trioxide, which can dissociate into nitric oxide and nitrous
oxide.
[0066] A NO-releasing compound may be present in a nail coating
composition and/or nail coating according to embodiments of the
invention at any suitable concentration. In some embodiments, a
NO-releasing compound may be present in a nail coating composition
and/or nail coating at a concentration sufficient to exert a
therapeutic effect, including in some cases, an antimicrobial
effect and/or an antimycotic effect. In some embodiments, a
NO-releasing compound may be present in a nail coating composition
and/or nail coating in a treatment effective and/or prevention
effective amount.
[0067] In some embodiments, a nail coating composition and/or nail
coating may comprise a NO-releasing compound and may store and/or
release nitric oxide in an amount of about 0.05% to about 20% by
weight of the nail coating composition and/or nail coating, such
as, but not limited to, about 0.15% to about 2%, about 0.15% to
about 1%, about 0.3% to about 1.2%, about 0.15% to about 6%, about
1% to about 10%, about 3% to about 6%, about 2% to about 20%, about
5% to about 15%, about 10% to about 20%, or about 1% to about 5% by
weight of the nail coating composition and/or nail coating. In
certain embodiments, a nail coating composition and/or nail coating
of the present invention may comprise a NO-releasing compound and
may store and/or release NO in an amount of about 0.15%, 0.3%,
0.6%, 0.9%, 1%, 1.25%, 1.5%, 1.75%, 2%, 2.25%, 2.5%, 2.75%, 3%,
3.25%, 3.5%, 3.75%, 4%, 4.25%, 4.5%, 4.75%, 5%, 5.25%, 5.5%, 5.75%,
6%, 6.25%, 6.5%, 6.75%, 7%, 7.25%, 7.5%, 7.75%, 8%, 8.25%, 8.5%,
8.75%, 9%, 9.25%, 9.5%, 9.75%, 10%, 10.25%, 10.5%, 10.75%, 11%,
11.25%, 11.5%, 11.75%, 12%, 12.25%, 12.5%, 12.75%, 13%, 13.25%,
13.5%, 13.75%, 14%, 14.25%, 14.5%, 14.75%, 15%, 15.25%, 15.5%,
15.75%, 16%, 16.25%, 16.5%, 16.75%, 17%, 17.25%, 17.5%, 17.75%,
18%, 18.25%, 18.5%, 18.75%, 19%, 19.25%, 19.5%, 19.75%, or 20% by
weight of the nail coating composition and/or nail coating. The
amount of nitric oxide released may be determined using real time
in vitro release testing. In some embodiments, nitric oxide release
may be determined using a chemiluminescent nitric oxide
analyzer.
[0068] In some embodiments, a NO-releasing compound (e.g., a
NO-releasing macromolecule) present in a nail coating composition
and/or nail coating may be in the form of a nanoparticle. In some
embodiments, the NO-releasing compound may be dissolved in (e.g.,
completely or partially) and/or suspended in the vehicle for the
nail coating composition and/or nail coating, which may be in the
form of a liquid, gel, cream, ointment, etc.
[0069] In some embodiments, at least one NO-releasing macromolecule
may be present in a nail coating composition and/or nail coating.
The at least one NO-releasing macromolecule may be present in a
nail coating composition and/or nail coating according to
embodiments of the invention at any suitable concentration. In some
embodiments, NO-releasing macromolecules may be present in a nail
coating composition and/or nail coating at a concentration
sufficient to exert a therapeutic effect, including in some cases,
an antimicrobial effect and/or an antimycotic effect. In some
embodiments, a NO-releasing macromolecule may be present in a nail
coating composition and/or nail coating in a treatment effective
and/or prevention effective amount. For example, in some
embodiments, the concentration of diazeniumdiolate-functionalized
co-condensed silica in a nail coating composition (e.g., a nail
lacquer) may be in a range from about 0.1% to about 70% by weight
of the nail coating composition, and/or any range and/or individual
value therein, such as, for example, about 0.1% to about 25%, 1% to
about 40%, or about 0.1% to about 50% by weight of the nail coating
composition. In some embodiments, a diazeniumdiolate-functionalized
co-condensed silica may be present in a nail coating composition in
an amount of about 0.1%, 0.25%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%,
6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%,
20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%,
33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%,
46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%,
59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, or 70% by
weight of the nail coating composition. Thus, upon and/or after
topical application to a nail of a subject, the resulting nail
coating may have a concentration of diazeniumdiolate-functionalized
co-condensed silica in a range from about 0.1% to about 70% or more
by weight of the coating, and/or any range and/or individual value
therein.
[0070] As one of skill will recognize, the weight percentages for
ingredients in a nail coating composition may be different than
those of a coating resulting from the composition, such as, for
example, due to drying and/or curing of the composition and/or
evaporation of one or more solvents in the composition. In some
embodiments, a weight percentage provided herein for an ingredient
in a nail coating composition is based on the weight of the
composition prior to drying and/or curing. In some embodiments, a
weight percentage provided herein for an ingredient in a nail
coating composition and/or coating is based on the weight of the
composition and/or coating without the NO-releasing compound (i.e.,
the weight percentage for an ingredient may be based on the vehicle
coating composition and/coating).
[0071] In some embodiments, the NO release may be tuned by
adjusting the concentration of the NO-releasing macromolecules in
the composition and/or coating and/or adjusting the NO loading (mol
NO/g composition and/or coating) of the macromolecules therein to
create the desired NO release profile.
[0072] In some embodiments, the final NO storage per milligram of
the nail coating composition and/or nail coating may be in a range
from about 1 nmol NO/mg composition and/or coating to about 2.5
.mu.mol NO/mg composition and/or coating, or any range and/or
individual value therein. In some embodiments, the NO storage per
milligram of nail coating composition and/or nail coating is in a
range from about 0.25 .mu.mol NO/mg to about 5 .mu.mol NO/mg, or
any range and/or individual value therein. In some embodiments, the
NO storage is about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1,
1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5 .mu.mol NO/mg, or any range
and/or individual value therein.
[0073] In some embodiments of the invention, a NO-releasing nail
coating composition and/or nail coating may include at least one
film-forming polymer. Any suitable film-forming polymer may be used
in a nail coating composition and/or nail coating of the present
invention, and such polymers include film-forming polymers
previously known and used in nail coating compositions and/or
coatings, and those found to be useful as film-forming polymers in
nail coating compositions and/or coatings. In some embodiments, the
film-forming polymer has suitable adhesion to nail keratin (and/or
skin) and/or forms water-insoluble and/or water-resistant
films.
[0074] Examples of film-forming polymers that may be used in a nail
coating composition and/or nail coating described herein, include,
but are not limited to, cellulose derivatives such as ethyl
cellulose, polyvinyl acetate, mixed polymers (or copolymers) of
vinyl acetate with acrylic or methacrylic acid, copolymers of
(meth)acrylic acid and (meth)acrylate esters, copolymers of
(meth)acrylic acid esters with amino group and/or quaternary
ammonium group-containing comonomers, nitrocellulose, methyl vinyl
ether/maleic acid copolymer (e.g., Gantrez.TM. S-97), vinyl
pyrrolidone/vinyl acetate copolymer (Plasdone.TM. S-630), poly
N-vinylacetamide/sodium acrylate copolymer (PNVA), and the like.
Further examples of film-forming polymers include, but are not
limited to, Ethocel.TM. polymers, such as, for example, Ethocel.TM.
STD-10P, ETHOCEL.TM. STD-7P, and ETHOCEL.TM. STD-20P from
Colorcon/Dow, methacrylate polymers (e.g., EUDRAGIT.RTM. L,
EUDRAGIT.RTM. S) and copolymers (e.g., EUDRAGIT.RTM. E,
EUDRAGIT.RTM. RS, EUDRAGIT.RTM. RL), polyethylene, polyvinyl
acetate and/or cellulose acetate.
[0075] A film-forming polymer may be used alone in a nail coating
composition and/or nail coating or in a mixture with one or more
(e.g., 1, 2, 3, 4, or more) different film-forming polymer(s). A
film-forming polymer may be either water-soluble or
water-insoluble, and, in some embodiments a mixture of both may be
used in a nail coating composition and/or nail coating. A
water-insoluble polymer may protect the nail and/or provide a
stronger coating and/or film. A water-soluble polymer may allow
controlled and/or limited amounts of water to penetrate the coating
and/or film, thus aiding in the release of nitric oxide. The
particular combination of film-forming polymers may depend on the
desired release rate of nitric oxide and the particular nitric
oxide-releasing compound incorporated in the nail coating
composition and/or nail coating.
[0076] According to some embodiments of the invention, the
concentration of a film-forming polymer in a nail coating
composition and/or nail coating may be in a range of about 1% to
about 25% by weight of the nail coating composition and/or nail
coating, or any range and/or individual value therein, such as, for
example, about 1% to about 10%, about 1% to about 15%, about 1% to
about 5%, about 5% to about 25%, or about 10% to about 20% by
weight of the nail coating composition and/or nail coating. In
certain embodiments, a film-forming polymer may be present in a
nail coating composition and/or nail coating in an amount of about
1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%,
16%, 17%, 18%, 19%, or 20% by weight of the nail coating
composition and/or nail coating or any range and/or individual
value therein.
[0077] In some embodiments, a hydrophilic polymer may be present in
a nail coating composition and/or nail coating of the present
invention. Any suitable hydrophilic polymer may be used in
embodiments described herein. As used herein, a hydrophilic polymer
is one that will absorb an amount of water (dependent on structure
and molecular weight) and form a network around the water molecules
creating a hydrogel without dissolving the polymer structure.
Example hydrophilic polymers include, but are not limited to,
hydroxypropyl methyl cellulose (e.g., METHOCEL.RTM.), hydroxypropyl
cellulose (e.g., KLUCEL.RTM.), methylcellulose,
polyvinylpyrrolidone polymer (PVP) and copolymers (e.g.,
KOLLIDON.RTM.), sodium carboxy methylcellulose and/or polyvinyl
alcohol.
[0078] According to some embodiments of the invention, the
concentration of a hydrophilic polymer in a nail coating
composition and/or nail coating may be in a range of about 0.1% to
about 15% by weight of the nail coating composition and/or nail
coating, or any range and/or individual value therein, such as, for
example, about 0.1% to about 10%, about 0.5% to about 10%, about
0.1% to about 1%, about 0.1% to about 5%, about 1% to about 15%,
about 2% to about 8%, about 1% to about 5%, about 5% to about 10%,
or about 5% to about 15% by weight of the nail coating composition
and/or nail coating. In certain embodiments, a hydrophilic polymer
may be present in a nail coating composition and/or nail coating in
an amount of about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%,
0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%,
or 15% by weight of the nail coating composition and/or nail
coating or any range and/or individual value therein.
[0079] In some embodiments, a solvent (e.g., an organic and/or
inorganic solvent) may be present in a nail coating composition
and/or nail coating of the present invention. One or more (e.g., 1,
2, 3, 4, or more) solvent(s) may be present in a nail coating
composition and/or nail coating of the present invention. Any
suitable solvent may be used in embodiments described herein.
Examples of organic solvents include, but are not limited to,
hydrocarbons, halogenated hydrocarbons, alcohols, ethers, ketones
and esters customary in cosmetics. Examples of inorganic solvents
include, but are not limited to, silicones (e.g., cyclomethicone).
In some embodiments, the organic solvent may be an acetic ester of
monohydric alcohols (e.g., ethyl acetate, n-butyl acetate, etc.),
that may be mixed with an aromatic hydrocarbon such as, for
example, toluene and/or alcohols such as ethanol or isopropanol
and/or aliphatic sulfoxides and sulfones such as, for example,
dimethyl sulfoxide or sulfolane. Further examples of organic
solvents include acetone, ethyl acetate, ethyl alcohol, denatured
alcohol, isopropyl alcohol, propylene glycol, and/or hexylene
glycol.
[0080] The type and/or quantity of the solvent(s) may be important
for determining the drying time, ease of spreading and/or other
properties of the composition and/or coating. In some embodiments
of the invention, the solvent(s) (e.g., organic solvent) may be
anhydrous or substantially anhydrous, in order to prevent water
reactive NO-releasing functional groups from releasing NO prior to
application on a nail and/or skin surrounding the nail.
[0081] According to some embodiments of the invention, the
concentration of a solvent in a nail coating composition and/or
nail coating may be in a range of about 1% to about 99% by weight
of the nail coating composition and/or nail coating, or any range
and/or individual value therein, such as, for example, about 1% to
about 5%, about 1% to about 10%, about 1% to about 20%, about 5% to
about 15%, about 30% to about 99%, about 5% to about 30%, about 30%
to about 50%, about 30% to about 80%, about 50% to about 99%, about
75% to about 99%, or about 80% to about 99% by weight of the nail
coating composition and/or nail coating. In certain embodiments, a
solvent may be present in a nail coating composition and/or nail
coating in an amount of about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%,
10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%,
23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%,
36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%,
49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%,
62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%,
75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%,
88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% by
weight of the nail coating composition and/or nail coating or any
range and/or individual value therein.
[0082] A nail coating composition and/or nail coating according to
embodiments of the invention may also contain additives common in
cosmetics. Examples include, but are not limited to, plasticizer(s)
(e.g., trimethyl pentanyl diisobutyrate, triphenyl phosphate,
and/or those based on phthalates or camphor), emollient(s) (e.g.,
isopropyl palmitate, cyclomethicone, etc.), humectant(s) (e.g.,
hexylene glycol), colorant(s), pigment(s), perlescent agent(s),
thickening agent(s) (e.g., stearalkonium hectorite and/or cetyl
alcohol), adhesive agent(s), sedimentation retardant(s),
sulfonamide resin(s), silicate(s), antioxidant(s), perfume(s),
wetting agent(s) (e.g., sodium dioctylsulfosuccinate), lanolin
derivative(s), sunscreen agent(s) (e.g.,
2-hydroxy-4-methoxybenzophenone), substance(s) having antibacterial
activity, and/or substance(s) with a keratolytic and/or
keratoplastic action (e.g., ammonium sulfite, esters and salts of
thioglycolic acid, urea, allantoin, enzymes and/or salicylic
acid).
[0083] One or more additives may be present in a nail coating
composition and/or nail coating in a concentration in a range from
about 0.01% to about 20% by weight of the nail coating composition
and/or nail coating, or any range and/or individual value therein,
such as, for example, about 0.05% to about 1%, about 1% to about
20%, about 1% to about 10%, about 1% to about 5%, or about 5% to
about 15% by weight of the nail coating composition and/or nail
coating. In certain embodiments, one or more additives may be
present in a nail coating composition and/or nail coating in an
amount of about 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%,
0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%,
1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%,
16%, 17%, 18%, 19%, or 20% by weight of the nail coating
composition and/or nail coating or any range and/or individual
value therein.
[0084] In some embodiments, a nail coating composition (e.g., a
nail lacquer) may comprise a NO-releasing compound in an amount of
about 0.1% to about 70% by weight of the nail coating composition
and/or nail coating, a film-forming polymer in an amount of about
1% to about 25% by weight of the nail coating composition and/or
nail coating, an organic solvent in an amount of about 30% to about
99% by weight of the nail coating composition and/or nail coating,
optionally a hydrophilic polymer in an amount of about 1% to about
15% by weight of the nail coating composition and/or nail coating,
and optionally one or more additives (e.g., a plasticizer,
thickening agent, antioxidant, colorant, pigment, etc.) each
optionally present in an amount of about 0.01% to about 20% by
weight of the nail coating composition and/or nail coating. In some
embodiments, the NO-releasing compound may be present in an amount
of about 0.1% to about 50% by weight of the nail coating
composition and/or nail coating.
[0085] In some embodiments, a nail coating composition (e.g., a
nail lacquer) may comprise a NO-releasing compound in an amount of
about 0.1% to about 50% by weight of the nail coating composition
and/or nail coating, a film-forming polymer in an amount of about
1% to about 15% by weight of the nail coating composition and/or
nail coating, an organic solvent in an amount of about 65% to about
99% by weight of the nail coating composition and/or nail coating,
optionally a hydrophilic polymer in an amount of about 1% to about
15% by weight of the nail coating composition and/or nail coating,
and optionally one or more additives (e.g., a plasticizer,
thickening agent, antioxidant, colorant, pigment, etc.) each
optionally present in an amount of about 0.01% to about 10% by
weight of the nail coating composition and/or nail coating. In some
embodiments, the NO-releasing compound may be present in an amount
of about 0.1% to about 25% by weight of the nail coating
composition and/or nail coating.
[0086] In some embodiments, a nail coating composition (e.g., a
nail paste, cream, and/or ointment) may comprise a NO-releasing
compound, one or more hydrophobic base(s), an amphiphilic compound,
optionally a solvent and/or cosolvent, optionally a thickening
agent, and optionally one or more additives (e.g., a plasticizer,
emollient, antioxidant, colorant, pigment, etc.). Example pastes,
creams, and/or ointments include, but are not limited to, those
described in International Application Publication Nos. WO
2013/138075 and WO 2015/021382, and International Application No.
PCT/US2015/013043, the contents of each of which are incorporated
herein by referenced in their entirety.
[0087] In some embodiments, a nail coating composition (e.g., a
nail paste, cream, and/or ointment) may comprise a NO-releasing
compound in an amount of about 0.1% to about 70% by weight of the
nail coating composition and/or nail coating, one or more
hydrophobic base(s) (e.g., a hydrocarbon base and/or a hydrophobic
polymer), alone or together, in an amount of about 1% to about 90%
by weight of the nail coating composition and/or nail coating, an
amphiphilic compound in an amount of about 1% to about 30% by
weight of the nail coating composition and/or nail coating,
optionally a solvent and/or cosolvent in an amount of about 1% to
about 30% by weight of the nail coating composition and/or nail
coating, optionally a thickening agent in an amount of about 1% to
about 25% by weight of the nail coating composition and/or nail
coating, optionally one or more additives each optionally present
in an amount of about 0.01% to about 20% by weight of the nail
coating composition and/or nail coating. In some embodiments, a
nail coating composition may comprise two or more (e.g., 2, 3, 4,
or more) hydrophobic bases and/or solvents. In some embodiments,
the thickening agent may have a low water solubility, such as, for
example a water solubility of about 5.times.10.sup.-2 mg/L at
25.degree. C. or less.
[0088] "Hydrophobic base" as used herein refers to a natural and/or
synthetic fat, wax, oil, and/or the like. Any suitable hydrophobic
base may be used in a nail coating composition of the present
invention. In certain embodiments, a nail coating composition
comprises two or more hydrophobic bases, such as, but not limited
to, 2, 3, 4, 5, or more hydrophobic bases. In certain embodiments,
a hydrophobic base in addition to having hydrophobic properties,
may also have hydrophilic properties and thus may be an amphiphilic
base. Example hydrophobic bases include, but are not limited to,
branched and unbranched hydrocarbons, branched and unbranched
hydrocarbon waxes, vaseline, hydrocarbon gel, liquid paraffin,
white petrolatum, petrolatum, microcrystalline wax, andelilla wax,
carnauba wax, lanolin (wool wax), wool wax alcohol, esparto grass
wax, cork wax, guaruma wax, rice bran wax, sugar cane wax, berry
wax, ouricury wax, soy wax, jojoba oil, uropygial grease, ceresine,
paraffin waxes, micro waxes, plant oils, animal oils, carnauba wax,
beeswax, cacao butter, hard fat, mineral oil, vegetable oil,
avocado oil, borage oil, canola oil, castor oil, chamomile oil,
coconut oil, corn oil, cottonseed oil, rapeseed oil, evening
primrose oil, safflower oil, sunflower oil, soybean oil, sweet
almond, palm oil, palm kernel oil, arctium lappa seed oil, sesame
oil, borgo officialis seed oil, brassica campestris oleifera oil,
brevoortia oil, bubulum oil, cistus ladaniferus oil, elaeis
guineensis oil, almond oil, pine oil, olive oil, peanut oil, wheat
germ oil, grape seed oil, thistle oil, lard, tallow, palm olein,
illipe butter, shea butter, cocoa butter, kokum butter, sal butter,
lecithin, japan wax lanolin, partially hydrogenated vegetable oils,
hydrophobic polymers, and any combination thereof.
[0089] In some embodiments, a hydrophobic base may comprise a
hydrophobic polymer. Any suitable hydrophobic polymer may be used
in a nail coating composition of the present invention. Example
hydrophobic polymers include, but are not limited to hydrocarbon
polymers and/or co-polymers, aromatic polyurethanes, silicone
rubber, polysiloxanes, polycaprolactone, polycarbonate,
polyvinylchloride, polyethylene, polyethylene glycols (6-4000),
poly-L-lactide, poly-DL-glycolide, polyetheretherketone (PEEK),
polyamide, polyimide and polyvinyl acetate. In certain embodiments,
a hydrophobic base may be an amphiphilic base, such as, but not
limited to, a polyethylene glycol (6-4000). In particular
embodiments of the present invention, a nail coating composition of
the present invention comprises one or more hydrocarbon polymers
and/or co-polymers. In certain embodiments, a nail coating
composition and/or nail coating of the present invention may
comprise one or more hydrocarbon polymers and/or co-polymers, such
as, but not limited to, those commercially available from Calumet
Specialty Products Partners of Indianapolis, Ind. under the
trademark Versagel.RTM. and/or those commercially available from
Croda International Plc of East Yorkshire, United Kingdom under the
trade name Crodabase SQ.
[0090] In some embodiments, a nail coating composition may comprise
at least one hydrophobic base comprising one or more plant and/or
mineral oils. Any suitable oil may be used in a nail coating
composition and/or nail coating of the present invention. Example
mineral oils include, but are not limited to, light mineral oil,
white mineral oil, paraffinic oils, naphtenic oils, aromatic oils,
and any combination thereof.
[0091] One or more hydrophobic bases (e.g., 1, 2, 3, 4, 5 or more
hydrophobic bases), alone or together, may be present in the nail
coating composition at a concentration from about 1% to about 99%
by weight of the nail coating composition and/or nail coating or
any range and/or individual value therein, such as, but not limited
to, from about 2% to about 20% by weight, about 1% to about 10% by
weight, about 1% to about 15% by weight, about 15% to about 65% by
weight, about 25% to about 98% by weight, about 30% to about 98% by
weight, about 35% to about 99% by weight, about 35% to about 90% by
weight, about 25% to about 50% by weight, about 25% to about 55% by
weight, about 30% to about 50% by weight, about 35% to about 55% by
weight, about 40% to about 80% by weight, about 50% to about 90% by
weight, about 65% to about 95% by weight, about 70% to about 80% by
weight, about 75% to about 95% by weight, about 80% to about 99% by
weight, about 90% to about 99% by weight, or about 50% to about 70%
by weight of the nail coating composition and/or nail coating. In
certain embodiments, one or more hydrophobic bases, alone or
together, may be present in a nail coating composition and/or nail
coating at a concentration from about 50% to about 90% by weight of
the nail coating composition and/or nail coating. In some
embodiments, one or more hydrophobic bases, alone or together, may
be present in a nail coating composition and/or nail coating at a
concentration from about 70% to about 99% by weight of the nail
coating composition and/or nail coating.
[0092] "Amphiphilic compound" as used herein refers to a compound
comprising hydrophilic and hydrophobic properties. An amphiphilic
compound may comprise two or more compounds, each of which may
provide the hydrophilic property and/or the hydrophobic property.
In some embodiments, the amphiphilic compound may comprise one
compound having hydrophilic and hydrophobic properties. In
particular embodiments of the present invention, an amphiphilic
compound may absorb moisture without substantially absorbing
vaporous moisture. An amphiphilic compound may have a
hydrophilic-lipophilic balance (HLB) value of 12 to 20 or any range
and/or individual value therein, such as, but not limited to, 15 to
20 or 18 to 20. In certain embodiments of the present invention, an
amphiphilic compound may have a HLB value of 19.
[0093] Example amphiphilic compounds include, but are not limited
to, fatty acid esters. One or more fatty acid ester(s) may be
present in a nail coating composition and/or nail coating of the
present invention, such as 2, 3, 4, or more fatty acid esters.
Example fatty acid esters include, but are not limited to,
C.sub.6-C.sub.22 alkyl and/or alkenyl fatty acid esters such as
methyl laurate, ethyl laurate, ethyl myristate, ethyl palmitate,
ethyl linoleate, propyl isobutylate, isopropyl laurate, isopropyl
myristate, isopropyl palmitate, oleyl myristate, oleyl stearate,
and oleyl oleate; ether-esters such as fatty acid esters of
ethoxylated fatty alcohols; polyhydric alcohol esters such as
ethylene glycol mono- and di-fatty acid esters, diethylene glycol
mono- and di-fatty acid esters; polyethylene glycol (6-2000) fatty
acid mono- and/or diesters such as PEG-6-laurate, PEG-6-stearate,
PEG-8-dilaurate, PEG-8-distearate, etc.; polyethylene glycol
glycerol fatty acid esters such as PEG-20-glyceryl laurate,
PEG-20-glyceryl stearate, and PEG-20-glyceryl oleate; propylene
glycol mono- and di-fatty acid esters; polypropylene glycol 2000
monooleate; polypropylene glycol 2000 monostearate; ethoxylated
propylene glycol monostearate; glyceryl mono- and di-fatty acid
esters; polyglycerol fatty acid esters such as polyglyceryl-10
laurate, etc.; ethoxylated glyceryl monostearate; 1,3-butylene
glycol monostearate; 1,3-butylene glycol distearate;
polyoxyethylene polyol fatty acid ester; sorbitan fatty acid esters
including sorbitan trioleate and sorbitan monolaurate; polyethylene
glycol sorbitan fatty acid esters such as PEG-6 sorbitan
monooleate; polyoxyethylene sorbitan fatty acid esters including
polyoxyethylene (20) sorbitan monolaurate; sucrose fatty acid
esters such as saccharose monopalmitate and saccharose
monostearate; wax esters such as beeswax, spermaceti, myristyl
myristate, stearyl stearate and arachidyl behenate; polyethylene
glycol alkyl ethers such as PEG-10 oleyl ether or PEG-9 cetyl
ether; polyethylene glycol alkyl phenols such as PEG-10-100 nonyl
phenol; polyoxyethylene-polyoxypropylene block copolymers such as
poloxamer 188; sterol esters such as cholesterol fatty acid esters,
and any combination thereof.
[0094] In certain embodiments, a fatty acid ester may comprise a
polyethylene glycol (PEG) glyceride. The polyethylene glycol
portion of a PEG glyceride may provide the hydrophilic property of
an amphiphilic compound and may include, but is not limited to, PEG
5-1000 or any range and/or individual value therein, and any
combination thereof. The glyceride portion of a PEG glyceride may
provide the hydrophobic property of an amphiphilic compound and may
include, but is not limited to, a natural and/or hydrogenated oil,
such as but not limited to, castor oil, hydrogenated castor oil,
vitamin A, vitamin D, vitamin E, vitamin K, a plant oil (e.g., corn
oil, olive oil, peanut oil, palm kernel oil, apricot kernel oil,
almond oil, etc.), and any combination thereof. Example
polyethylene glycol (PEG) glycerides include, but are not limited
to, PEG-20 castor oil, PEG-20 hydrogenated castor oil, PEG-20 corn
glycerides, PEG-20 almond glycerides; PEG-23 trioleate, PEG-40 palm
kernel oil, PEG-8 caprylic/capric glycerides, PEG-6 caprylic/capric
glycerides, lauroyl macrogol-32 glyceride, stearoyl macrogol
glyceride, tocopheryl PEG-1000 succinate, and any combination
thereof. In some embodiments, a fatty acid ester may comprise a PEG
5-30 (i.e., PEG 5, 6, 7, 8, 9, 10, etc.) and a caprylic/capric
glyceride. In particular embodiments, a nail coating composition
and/or nail coating may comprise a PEG-5-caprylic/capric glyceride,
a PEG-6-caprylic/capric glyceride, a PEG-7-caprylic/capric
glyceride, and/or a PEG-8-caprylic/capric glyceride. In certain
embodiments, a nail coating composition and/or nail coating may
comprise one or more fatty acid esters such as, but not limited to,
those commercially available from Sasol of Hamburg, Germany under
the trademark SOFTIGEN.RTM..
[0095] An amphiphilic compound may be present in a nail coating
composition and/or nail coating at a concentration from about 0.5%
to about 30% by weight of the nail coating composition and/or nail
coating or any range and/or individual value therein, such as, but
not limited to, from about 0.5% to about 10% by weight, about 2% to
about 20% by weight, about 1% to about 10% by weight, about 1% to
about 5% by weight, or about 5% to about 15% by weight of the nail
coating composition and/or nail coating. In certain embodiments, an
amphiphilic compound may be present in a nail coating composition
and/or nail coating of the present invention at a concentration of
about 10% by weight of the nail coating composition and/or nail
coating. In some embodiments, an amphiphilic compound may be
present in a nail coating composition and/or nail coating of the
present invention at a concentration of from about 0.5% to about
10% by weight of the nail coating composition and/or nail
coating.
[0096] A solvent and/or cosolvent may be present in a nail coating
composition and/or nail coating at a concentration from about 1% to
about 30% by weight of the nail coating composition and/or nail
coating or any range and/or individual value therein, such as, but
not limited to, from about 1% to about 15% by weight, about 1% to
about 20% by weight, about 2% to about 20% by weight, about 5% to
about 25% by weight, or about 5% to about 15% by weight of the nail
coating composition and/or nail coating. In certain embodiments of
the present invention, a solvent and/or cosolvent may be present in
a nail coating composition and/or nail coating of the present
invention at a concentration from about 10% to about 15% by weight
of the nail coating composition and/or nail coating. In some
embodiments, a solvent and/or cosolvent may be present in a nail
coating composition and/or nail coating of the present invention at
a concentration of from about 1% to about 15% by weight of the nail
coating composition and/or nail coating.
[0097] Example solvents and/or cosolvents include, but are not
limited to, a fatty acid ester, propylene glycol, glycerol,
polyethylene glycol, a silicone such as cyclomethicone, and any
combination thereof. In some embodiments, a solvent and/or
cosolvent may comprise a neutral oil. In certain embodiments, a
solvent and/or cosolvent comprises a caprylic and/or capric fatty
acid ester, such as a caprylic and/or capric triglyceride. Example
solvents and/or cosolvents include, but are not limited to, those
commercially available from Sasol of Hamburg, Germany under the
trademark MIGLYOL.RTM..
[0098] In some embodiments, a nail coating composition and/or nail
coating may comprise an emulsifier. Example emulsifiers include,
but are not limited to, metallic stearates (e.g., aluminum
stearate, magnesium stearate, zinc stearate, etc), hydrophobic
and/or hydrophilic fumed silica, silicone elastomers, silicone
elastomer blends, and/or synthetic and/or emulsifying waxes. One or
more emulsifiers may be present in a nail coating composition
and/or nail coating in an amount of about 0.1% to about 30% by
weight of the nail coating composition and/or nail coating, or any
range and/or individual value therein, such as, for example, about
0.5% to about 1%, about 1% to about 20%, about 1% to about 10%,
about 1% to about 5%, or about 5% to about 15% by weight of the
nail coating composition and/or nail coating. In certain
embodiments, one or more emulsifiers may be present in a nail
coating composition and/or nail coating in an amount of about 0.1%,
0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%,
6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%,
20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30% by weight
of the nail coating composition and/or nail coating or any range
and/or individual value therein.
[0099] In some embodiments, a nail coating composition may be in
the form of a nail lacquer. In some embodiments, a nail coating
composition may be in the form of a nail paste, cream, and/or
ointment. In some embodiments, a nail coating composition may be in
the form of liquid or in the form of a gel and/or film.
[0100] In some embodiments, a nail coating composition may be
applied to a nail of a subject and/or to skin surrounding the nail.
The nail coating composition may provide and/or form a nail coating
of the present invention on the nail and/or skin surrounding the
nail. In some embodiments, a nail coating composition of the
present invention may dry and/or cure to form a nail coating of the
present invention. In some embodiments, a nail coating composition
(e.g., a nail lacquer) may include one or more organic solvent(s)
that may evaporate, optionally as the nail coating composition
dries and/or cures, after topical application to a nail of a
subject and/or to skin surrounding the nail to form a nail coating.
A nail coating of the present invention may be in the form of a
film. In some embodiments, the nail coating may be a semi-solid or
hardened film.
[0101] A nail coating of the present invention may adhere to a nail
of a subject and/or to skin surrounding the nail. In some
embodiments, a nail coating described herein may adhere to keratin
in a nail of a subject. In some embodiments, the nail coating may
adhere to a nail (e.g., a natural and/or coated nail) for at least
1, 2, 3, 4, 5, 6, 7, 8, 9, 10 day(s), or more and may optionally
adhere to the nail for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10
day(s), or more without adhesion loss and/or breakdown of the
coating (e.g., chipping, cracking, peeling, etc.).
[0102] A NO-releasing nail coating composition and/or nail coating
described herein may be formed by any suitable method. In some
embodiments, a NO-releasing nail coating composition may be formed
by mixing the individual components of the composition and carrying
out, when necessary, further processing appropriate for the
particular formulation.
[0103] In some embodiments of the invention, a nail coating
composition and/or nail coating is prepared by dissolving and/or
dispersing a polymer (e.g., a film-forming and/or hydrophilic
polymer) and/or a hydrophobic base, along with any other additives,
into a solvent (e.g., an organic solvent); homogenizing the
mixture; and then adding a NO-releasing compound (e.g.,
NO-releasing macromolecules) to the mixture to disperse the
NO-releasing compound into the mixture. The NO-releasing compound
may be added to the mixture under continuous agitation.
[0104] Any suitable packaging of a nail coating composition
according to embodiments of the invention may be used. In some
embodiments, a NO-releasing nail coating composition may be
provided in sealed single dose container (e.g., a vial, such as a
10 mL vial) that is oxygen and moisture impermeable to prevent
moisture from reaching the topical therapeutic and causing release
of the nitric oxide. The container may be opened at the time of
application and the product (i.e., the nail coating composition)
may be applied to the surface of a nail of a subject and/or to skin
surrounding the nail. The product may be refrigerated until use to
reduce the likelihood of premature release of the nitric oxide.
[0105] The NO-releasing nail coating compositions described herein
may be a one-component formulation, such that it is not necessary
to combine two or more compositions immediately prior to
application. The nail coating composition may be applied as
packaged, or in some cases, after agitation of the composition. In
some embodiments, the one component NO-releasing nail coating
composition may be in the form of a NO-releasing nail lacquer,
paste, cream, gel, film, and/or ointment. Upon topical application
to a nail of a subject and/or to skin surrounding the nail, the
one-component formulation may release NO onto and/or into the nail
and/or onto and/or into skin under and/or around the nail.
[0106] In some embodiments, a two component NO-releasing nail
coating system is provided. One component of the two component
NO-releasing nail coating system may include a nail coating
composition as described herein (e.g., a NO-releasing nail lacquer,
gel, film, paste, cream, and/or ointment) and the other component
of the two component NO-releasing nail coating system may include a
composition comprising a proton source (e.g., water). Each
component may be separately stored. In some embodiments, each
component may be separately stored in a dual chamber container
(e.g., a dual pump container or dual dispensing container). The
composition comprising a proton source may initiate and/or increase
the release NO from the nail coating composition and/or coating. In
some embodiments, the composition comprising the proton source may
increase the release of NO from the nail coating composition and/or
coating by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%,
45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 125%,
150%, 175%, 200%, or more compared to the release of NO from the
nail coating composition and/or coating in the absence of the
composition comprising the proton source.
[0107] The composition comprising the proton source may be
topically applied to a nail of a subject and/or to the skin
surrounding the nail at the same time that the nail coating
composition is applied and/or at a given time before and/or after
the nail coating composition is applied. For example, the
composition comprising the proton source may be applied at about 1,
2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,
21, 22, 23, 24 hour(s) or about 1, 2, 3, 4, 5, 6, 7, or more day(s)
before and/or after the nail coating composition is applied to a
nail of a subject and/or to the skin surrounding the nail. In some
embodiments, the composition comprising the proton source is
applied after the nail coating composition is applied.
[0108] A composition comprising a proton source may be applied onto
a nail containing a nail coating composition and/or nail coating of
the present invention. In some embodiments, the composition
comprising a proton source is applied on top of or over the nail
coating composition and/or nail coating of the present invention.
In some embodiments, a composition comprising a proton source may
be applied immediately after a nail coating composition of the
present invention has been applied to a nail and/or after it has
solidified and/or dried to form a nail coating of the present
invention. In some embodiments, a composition comprising a proton
source may be applied onto a nail containing a nail coating
composition and/or nail coating 2 or more times, such as, for
example, 2, 3, 4, or more times during a day; every day; every
other day; every 3, 4, 5, or 6 days; once a week; etc. The
composition comprising the proton source may modify the release of
NO from the nail coating composition and/or coating. In some
embodiments, a composition, system, and/or method of the present
invention may provide a continuous release or pulsatile release of
NO from the NO nail coating composition and/or coating.
[0109] In some embodiments, the composition comprising the proton
source may be provided in and/or on a substrate (e.g., a bandage,
patch, dressing, tape, etc.). The substrate may be applied onto a
nail of a subject such that the composition comprising the proton
source may contact the nail coating composition and/or coating
and/or provide a proton to the nail coating composition and/or
coating. In some embodiments, the substrate comprises a gaseous
and/or moisture impermeable backing layer. The proton source may be
applied onto a nail of a subject such that the composition
comprising the proton source may be present on the nail in any
suitable ratio with the nail coating composition and/or coating
(e.g. a ratio of about 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9,
1:10, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1) (proton
source:nail coating composition and/or coating). In some
embodiments, the composition comprising the proton source is
combined and/or mixed with the nail coating composition and/or
coating prior to application onto the nail of a subject. In some
embodiments, a composition comprising a proton source may be
applied to cover all or a portion (e.g., at least about 10%, 20%,
30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, 99%, or 100%) of the
nail of a subject and/or all or a portion (e.g., at least about
10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, 99%, or
100%) of the nail coating composition and/or coating on the nail of
a subject.
[0110] In some embodiments, the composition comprising a proton
source may be in the form of a hydrogel. A hydrogel for use with a
nail coating composition and/or nail coating of the present
invention may comprise a gelling agent and water. Water may be
present in a hydrogel in an amount of about 55% to about 99% by
weight of the hydrogel, such as, for example, about 60% to about
99%, about 65% to about 99%, or about 70% to about 99% by weight of
the hydrogel. A gelling agent may be present in a hydrogel an
amount of about 0.01% to about 10% by weight of the hydrogel, such
as, for example, about 0.01% to about 5% by weight of the hydrogel.
In some embodiments, the hydrogel may have a pH of about 3 to about
7, such as, for example, about 3.5 to about 6.5, about 3.5 to about
6, about 4 to about 5, or about 4 to about 4.5.
[0111] Example gelling agents include, but are not limited to,
carboxypolymethylene; a polyacrylic polymer such as polyacrylic
acid, a polyacrylate polymer, a cross-linked polyacrylate polymer,
a cross-linked polyacrylic acid, and mixtures thereof; a cellulose
ether such as hydroxyalkyl cellulose polymers such as hydroxypropyl
methyl cellulose (HPMC), hydroxypropyl cellulose, hydroxyethyl
cellulose, methyl cellulose, carboxymethyl cellulose, and salts and
mixtures thereof; a methacrylate; a polyvinylpyrrolidone;
cross-linked polyvinyl pyrrolidone; polyvinylpyrrolidone-vinyl
acetate copolymer; polyvinylalcohol; polyethylene oxide;
polyethylene glycol; polyvinylalkyl ether-maleic acid copolymer; a
poloxamer; a carboxy vinyl polymer; a polysaccharide; a gum such as
sodium alginate, carrageenan, xantham gum, gum acacia, arabic gum,
guar gum, pullulan, agar, chitin, chitosan, pectin, karaya gum,
zein, hordein, gliadin, locust bean gum, tragacantha, and mixtures
thereof; a protein such as collagen, whey protein isolate, casein,
milk protein, soy protein, gelatin, and mixtures thereof; a starch
such as maltodextrin, amylose, high amylose starch, corn starch,
potato starch, rice starch, tapioca starch, pea starch, sweet
potato starch, barley starch, wheat starch, waxy corn starch,
modified starch (e.g. hydroxypropylated high amylose starch),
dextrin, levan, elsinan, gluten, and mixtures thereof; bentonite;
calcium stearate; ceratonia; colloidal silicon dioxide; dextrin;
hypromellose; polycarbophil; kaolin; saponite; sorbitan esters;
sucrose; sesame oil; tragacanth; potassium alginate; povidone;
sodium starch glycolate; phospholipids; alginate; and any
combination thereof. In some embodiments, a gelling agent may be a
cellulose, such as, but not limited to, a carboxymethyl cellulose
or a salt thereof. In some embodiments, a gelling agent may be a
commercially available gelling agent, such as, but not limited to,
those commercially available from Lubrizol Corporation of
Wickliffe, Ohio under the trade name Carbopol.RTM. (e.g.,
Carbopol.RTM. 980 Homopolymer Type C polymer, Carbopol.RTM. 980 NF
polymer, Carpobol.RTM. 980P polymer, etc.).
[0112] Example hydrogels include, but are not limited to, those
described in International Application Publication No. WO
2014/134502 and International Application No. PCT/US15/39908, the
portions of which that are relevant to hydrogels are incorporated
herein by reference in their entirety.
[0113] In some embodiments, the hydrogel may be provided in the
form of a film. In some embodiments, the hydrogel may be in a form
that can be peeled off of a backing layer and applied to a nail of
a subject and/or to a nail coating composition and/or nail coating
of the present invention. In some embodiments, the hydrogel may be
a commercially available hydrogel, such as, but not limited to,
those commercially available from Covidien or Axelgaard
Manufacturing Co., Ltd.
[0114] Provided according to some embodiments is a kit. The kit may
comprise a first composition comprising at least one NO-releasing
compound and a second composition comprising a proton source (e.g.,
water). In some embodiments, the first composition may be a nail
coating composition as described herein and the second composition
may be a hydrogel as described herein. In some embodiments, the
second composition may be provided on and/or in a substrate and/or
in the form of a bandage, dressing, patch, or tape. In some
embodiments, the first composition and the second composition may
be separately stored.
[0115] In some embodiments, a packaged NO-releasing nail coating
composition may be provided with a shelf life of at least about one
week. In some embodiments, a packaged NO-releasing nail coating
composition may have a shelf life of at least about four weeks, at
least about 12 weeks, at least about 26 weeks, or at least about 52
weeks. In still further embodiments, a packaged NO-releasing nail
coating composition may have a shelf life of from at least about 12
to at least about 104 weeks, or any range and/or individual value
therein. As used herein, the term "shelf life" refers to the length
of time that the product (i. e., a NO-releasing nail coating
composition described herein) maintains the ability to release a
therapeutically effective amount (e.g., a treatment and/or
prevention effective amount) of nitric oxide in an unopened package
stored under recommended storage conditions. The shelf life may,
for example, be evidenced by the "use by" of "best if used by" date
for the product, the manufacturer's expiration date of the product
and/or the actual product characteristics after the specified
period of time. Accordingly, the term "shelf life" as used herein
should be construed as including both an "actual" shelf life of the
product and a "predicted" shelf life of the product unless stated
otherwise. As one skilled in the art will recognize, the rate of
release of nitric oxide in a NO-releasing nail coating composition
described herein under packaged and/or stored conditions may be
different (i.e., faster or slower) than the rate of release of
nitric oxide when the nail coating composition and/or nail coating
is in use. In certain embodiments, the rate of release of nitric
oxide may be faster when a nail coating composition and/or nail
coating is in use compared to the rate of release of nitric oxide
when the nail coating composition was packaged and/or stored.
[0116] In some embodiments, the shelf life of the product is the
time that the product maintains the ability to release at least 50%
of the initial amount nitric oxide that the product may release
when packaged. In further embodiments, the shelf life of the
product is the time that the product maintains the ability to
release at least 70%, at least 80%, at least 90%, at least 95%, or
at least 98% of the initial amount nitric oxide that the product
may release when packaged. In some embodiments, the recommended
storage conditions are room temperature. In some embodiments, the
recommended storage conditions are refrigerated storage conditions.
In particular embodiments, the refrigerated storage conditions are
in a range from about 1.degree. C. to about 12.degree. C.
[0117] Further embodiments may provide packaged NO-releasing nail
coating compositions that have a useful life of at least about 7
days after opening the package. In further embodiments, the useful
life is at least about 30 days, at least about 60 days or at least
about 90 days. In still further embodiments, a packaged
NO-releasing nail coating composition may have a useful life of
from at least about 60 days to at least about 730 days, or any
range and/or individual value therein. As used herein, the term
"useful life" refers to the length of time that the product
maintains the ability to release a therapeutically effective amount
of nitric oxide from an opened packaged when applied as recommended
and when stored under recommended storage conditions. The useful
life may, for example, be evidenced by the manufacturer's
recommended time to dispose of the product after opening or
measurements of the products characteristics after opening.
Accordingly, the term "useful life" as used herein should be
construed as including both an "actual" useful life of the product
and a "predicted" useful life of the product unless stated
otherwise. In some embodiments, the useful life of the product is
the time that the product maintains the ability to release at least
50% of the initial amount nitric oxide that the product may release
when the package is opened. In further embodiments, the shelf life
of the product is the time that the product maintains the ability
to release at least 70%, at least 80%, at least 90%, at least 95%,
or at least 98% of the initial amount nitric oxide that the product
may release when the package is opened. In some embodiments, the
recommended storage conditions after opening are room temperature.
In particular embodiments, the recommended storage conditions after
opening are refrigerated conditions.
[0118] According to some embodiments of the invention, provided are
methods of treating a subject by contacting a subject with a nail
coating composition and/or nail coating according to embodiments of
the invention. Thus, by contacting the subject with the
NO-releasing nail coating composition and/or nail coating, the
subject may be treated with nitric oxide.
[0119] In some embodiments, a method of treating and/or preventing
a nail disease and/or disorder in a subject may comprise topically
applying a nail coating composition described herein to a nail of
the subject, thereby treating and/or preventing the nail disease or
disorder. In some embodiments, a method of the present invention
may comprise topically applying a NO-releasing nail coating
composition described herein to a nail to form a NO-releasing
coating. The NO-releasing coating composition and/or coating may
adhere to and/or cover the area of the nail to which it is applied.
In some embodiments, the method may comprise topically applying to
the nail a two-component NO-releasing nail coating system as
described herein.
[0120] "Nail" as used herein may refer to any part of a fingernail
and/or a toenail of a subject. A nail may be a full or partially
intact nail. A nail may be a healthy nail, a diseased nail, and/or
a damaged nail. A method disclosed herein may treat and/or prevent
a nail disease and/or disorder in a nail of a subject. A
NO-releasing coating composition described herein may be applied to
all or any portion of a subject's nail. In some embodiments, a
method may comprise applying a NO-releasing coating composition
described herein to a nail and/or to the skin surrounding the nail
such as, but not limited to, the cuticle, interdigital skin (i.e.,
interdigital webbing), the skin of a hand and/or foot of a subject.
In some embodiments, a NO-releasing coating composition may be
applied to a subject's nail, interdigital skin, and/or to the skin
of a subject's hand and/or foot. In some embodiments, a
NO-releasing coating composition may be applied to a subject's nail
and/or skin surrounding the nail where a pathogen (e.g., fungus
and/or mold) may live.
[0121] A nail coating composition, nail coating, and/or method of
the present invention may not stain and/or discolor the nail and/or
skin of the subject to which it is in contact with and/or applied.
In some embodiments, a nail coating composition, nail coating,
and/or method of the present invention may deliver and/or
administer nitric oxide to the nail and/or skin of a subject
without staining and/or discoloring the nail and/or skin of the
subject. For example, a nail coating composition, nail coating,
and/or method of the present invention may not stain and/or
discolor the subject's nail and/or skin yellow, brown, and/or
black. In some embodiments, a nail coating composition, nail
coating, and/or method of the present invention may stain and/or
discolor less than about 10% (e.g., less than about 9%, 8%, 7%, 6%,
5%, 4%, 3%, 2%, 1%, or 0.5%) of the nail and/or skin in contact
with the nail coating composition and/or nail coating. Staining
and/or discoloration of the nail and/or skin may be determined by
visual comparison of the nail and/or skin prior to and after
contact with the nail coating composition and/or nail coating.
[0122] A method of the present invention may have increased or
improved efficacy in treating and/or preventing a nail disease
and/or disorder in a subject by at least about 5%, 10%, 15%, 20%,
25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,
90%, 95%, 100%, 125%, 150%, 175%, 200%, or more compared to a
treatment in the absence of a method of the present invention
(e.g., one that does not apply a NO-releasing coating composition
and/or one that is applied only or primarily to the nail of the
subject). In some embodiments, a method of applying a NO-releasing
coating composition and/or nail coating of the present invention to
a subject's nail, interdigital skin, and/or to the skin of a
subject's hand and/or foot may increase and/or improve efficacy in
treating and/or preventing a nail disease and/or disorder in a
subject by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%,
45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 125%,
150%, 175%, 200%, or more compared to a treatment in the absence of
a method of the present invention.
[0123] In some embodiments, a method of applying a NO-releasing
coating composition and/or nail coating of the present invention to
a subject's nail, interdigital skin, and/or to the skin of a
subject's hand and/or foot may decrease the rate of reinfection of
a nail disease and/or disorder in a subject by at least about 5%,
10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%,
75%, 80%, 85%, 90%, 95%, 100%, 125%, 150%, 175%, 200%, or more
compared to a treatment in the absence of a method of the present
invention.
[0124] In some embodiments, a method of the present invention may
reduce or decrease the treatment duration in a subject compared to
a treatment in the absence of a method of the present invention
(e.g., one that does not apply a NO-releasing coating composition
and/or nail coating and/or one that is applied only or primarily to
the nail of the subject). For example, a method of the present
invention may reduce or decrease the treatment duration in a
subject by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%,
45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 125%,
150%, 175%, 200%, or more compared to a treatment in the absence of
a method of the present invention.
[0125] The terms "treat", "treating", and grammatical variants
thereof, as used herein in reference to treating a subject, refer
to any type of treatment that imparts a benefit to a subject and
may mean that the severity of the subject's condition is reduced,
at least partially improved or ameliorated and/or that some
alleviation, mitigation or decrease in at least one clinical
symptom associated with the condition is achieved and/or there is a
delay in the progression of the nail disease or disorder. In some
embodiments, the severity of a subject's condition may be reduced
compared to the severity of the condition in the absence of a
method of the present invention. A method of the present invention
may provide the total absence of the disease, disorder, infection,
wound, and/or clinical symptom in the subject. A method of the
present invention may also provide partial treatment, such as
relieving and/or reducing the effects and/or severity of the
disease, disorder, infection, wound, and/or clinical symptom in the
subject and/or delaying the progression and/or onset of the
disease, disorder, infection, wound, and/or clinical symptom
compared to what would occur in the absence of the methods of the
present invention.
[0126] The terms "prevent," "preventing", "prevention", and
grammatical variations thereof refer to avoidance, reduction and/or
delay of the onset of a nail disease, disorder and/or a clinical
symptom(s) in a subject and/or a reduction in the severity of the
onset of the nail disease, disorder and/or clinical symptom(s)
relative to what would occur in the absence of a method of the
present invention. The prevention may be complete, e.g., the total
absence of the nail disease, disorder and/or clinical symptom(s).
The prevention may be partial, such that the occurrence of the nail
disease, disorder and/or clinical symptom(s) in the subject and/or
the severity of onset is less than what would occur in the absence
of a method of the present invention.
[0127] The term "contacting" and grammatical variants thereof,
refers to coating, submerging, painting, exposing, immersing,
dipping, wetting, pasting, sticking, dousing, washing, rinsing,
soaking, plunging, dunking, dampening, and/or placing any portion
of the subject (e.g., a nail) into contact with a nail coating
composition, nail coating, and/or composition comprising a proton
source (e.g., a hydrogel) for any duration of time. In certain
embodiments of the present invention, the subject is exposed to
and/or in contact with a NO-releasing nail coating composition
and/or nail coating for a time sufficient to obtain a treatment
effective and/or a prevention effective amount of nitric oxide.
[0128] A "treatment effective" amount as used herein is an amount
that is sufficient to treat (as defined herein) the subject. Those
skilled in the art will appreciate that the therapeutic effects
need not be complete or curative, as long as some benefit is
provided to the subject.
[0129] A "prevention effective" amount as used herein is an amount
that is sufficient to prevent (as defined herein) a nail disease,
disorder and/or clinical symptom in a subject. Those skilled in the
art will appreciate that the level of prevention need not be
complete, as long as some benefit is provided to the subject.
[0130] A nail coating composition and/or nail coating of the
present invention may be applied to a subject using any method
known to those of skill in the art. In some embodiments, the
composition and/or coating may be applied (e.g., topically applied)
to the subject at least 1, 2, 3, or more times per day. In some
embodiments, the composition and/or coating may be topically
applied to the subject at least 1, 2, 3, 4, 5, 6, 7, 8, or more
times per week and/or month. In certain embodiments, the
composition and/or coating may be topically applied to the subject
once daily, twice daily, every other day, every third day, once per
week, or twice per week. In some embodiments, the composition
and/or coating may be applied at least once daily for an extended
period of time (e.g., 1, 2, or 3 week(s), or 1, 2, or 3 month(s),
etc.) and/or until the nail disease and/or disorder and/or clinical
symptom associated therewith has been treated and/or prevented. In
some embodiments, the composition and/or coating may be applied on
an as needed basis.
[0131] The present invention finds use in both veterinary and
medical applications, including drug screening and drug development
purposes. Suitable subjects of the present invention include, but
are not limited to avians and mammals. The term "avian" as used
herein includes, but is not limited to, chickens, ducks, geese,
quail, turkeys, pheasants, ratites (e.g., ostrich), parrots,
parakeets, macaws, cockatiels, canaries, finches, and birds in ovo.
The term "mammal" as used herein includes, but is not limited to,
primates (e.g., simians and humans), non-human primates (e.g.,
monkeys, baboons, chimpanzees, gorillas), bovines, ovines,
caprines, ungulates, porcines, equines, felines, canines,
lagomorphs, pinnipeds, rodents (e.g., rats, hamsters, and mice),
and mammals in utero. In some embodiments of the present invention,
the subject is a mammal and in certain embodiments the subject is a
human. Human subjects include both males and females and subjects
of all ages including fetal, neonatal, infant, juvenile,
adolescent, adult, and geriatric subjects. Subjects may be treated
for any purpose, such as, but not limited to, treatment and/or
prevention of infection.
[0132] In particular embodiments of the present invention, a nail
coating composition and/or nail coating may be used to treat
onychomycosis or any other infection of the nail and/or skin
beneath and/or around the nail caused by a fungus, bacteria, virus,
yeast, and/or mold. In some embodiments, a nail coating composition
and/or nail coating according to embodiments of the invention may
be used to treat other ailments and/or conditions of the nail
and/or skin surrounding and/or beneath the nail, either via
anti-microbial action, anti-inflammatory action, and/or by any
other mechanism. Example nail ailments and/or conditions include,
but are not limited to, nail psoriasis, paronychia infection, nail
dystrophy, nail brittleness, nail pitting, nail peeling, nail
clubbing, nail separation, dermatophytosis, psoriatic nail
dystrophy, onychia, onychiagryposis, onychia trophia,
onychocryptosis, onychodystrophy, onychomycosis, onychogryposis,
onycholysis, onychomadesis, onychauxis, onychorrhexis,
onychoschizia, tinea unguium, onychophosis, onychoptosis,
paronychia, pseudomonas, pterygium and pterygium inversum unguis,
koilonychia, subungual hematoma or other trauma to the nail, folic
acid deficiency, subungual hyperkeratosis, leukonychia, nail
patella syndrome, melanonychia, protein deficiency, methyl
methacrylate damaged nails, vitamin C deficiency, vitamin
deficiency, tinea unguis, thinning nails associated with lichen
planus, Raynaud's disease, nail dystrophy associated with
rheumatoid arthritis, beau's lines, Mee's lines associated with
certain kinds of poisoning, discoloration, lamellar splitting,
longitudinal grooves and/or ridges, transverse grooves, pitting,
soft nails, brittle nail syndrome, and any combination thereof.
[0133] In some embodiments, a method of improving the appearance of
a nail may be provided. The method may comprise topically applying
a nail coating composition (e.g., a one component coating
composition) and/or nail coating described herein to the nail of a
subject, thereby improving the appearance of the nail. In some
embodiments, the method may comprise applying a two component
NO-releasing nail coating system as described herein. In some
embodiments, the appearance of the nail may be improved compared to
the appearance of a nail in the absence of a method of the present
invention.
[0134] In some embodiments, a method of the present invention may
improve the appearance of a nail by increasing or improving nail
health compared to nail health in the absence of a method of the
present invention. Nail health may be evaluated by how the nail
grows, the nail color, the smoothness of the nail, the shape of the
nail, and/or the thickness of the nail. For example, the method may
increase and/or improve nail health by decreasing yellowing and/or
discoloration of a nail (e.g., due to onychomycosis); decreasing
nail dullness; decreasing nail ridges (e.g., longitudinal and/or
horizontal ridges), pits, and/or the like; decreasing nail peeling,
splitting, cracking, and/or the like; increasing proper nail
growth; decreasing nail thickness; decreasing onycholysis;
decreasing subungual hyperkeratosis; increasing nail strength; and
any combination thereof.
[0135] Improvement in the appearance of a nail may be determined by
a visual assessment of the nail, such as by visually assessing the
color, surface smoothness, shape, and/or thickness. In some
embodiments, a method of the present invention may improve nail
strength compared to the strength of a nail in the absence of a
method of the present invention.
[0136] Such methods may be used in combination with any other known
methods of treatment, including the application of other
therapeutic agents, such as those that have anti-inflammatory,
pain-relieving, immunosuppressant, vasodilating, wound healing
and/or anti-biofilm-forming properties. For the methods used
herein, additional therapeutic agents and methods may be used prior
to, concurrently with and/or after contact with a nail coating
composition and/or nail coating of the present invention.
[0137] The invention will now be described further with respect to
the foregoing examples. It should be appreciated that these
examples are for the purpose of illustrating the invention, and do
not limit the scope of the invention as defined by the claims
EXAMPLES
Example 1: Vehicle Nail Lacquer
[0138] Vehicle nail lacquer solutions were initially prepared to
evaluate the film-forming potential, upon solvent evaporation, of
formulations comprised of a single polymer. Additional nail lacquer
vehicles were prepared to evaluate formulations containing
combinations of a strong film-forming polymer and a hydrophilic
polymer. While not wishing to be bound to any particular theory,
the intention of the binary polymer formulations is that the
hydrophilic polymer will form channels within a robust, protective
film allowing moisture penetration without disrupting or dissolving
the film.
[0139] The vehicle nail lacquers were prepared by first mixing
weighed amounts of the solvents and emollient in a 250-mL glass
beaker. The weighed amount of polymer was then dissolved in the
mixture using an IKA T-18 Homogenizer at a low-to-medium speed
setting. The resulting solution was transferred to a 20-mL glass
vial, and the visual appearance of the solution was recorded as
provided in Table 2. The prototype vehicle formulations that were
evaluated are summarized in Table 1.
TABLE-US-00001 TABLE 1 Vehicle Nail Lacquer Formulations VNL-01
VNL-02 VNL-03 VNL-04 VNL-05 VNL-06 VNL-07 VNL-08 VNL-09 VNL-10
Ingredient % w/w % w/w % w/w % w/w % w/w % w/w % w/w % w/w % w/w %
w/w Denatured 78.0 75.0 70.0 70.0 70.0 70.0 70.0 72.0 72.0 72.0
alcohol, anhy. Acetone, 15.0 15.0 15.0 15.0 15.0 15.0 15.0 15.0
15.0 15.0 anhy. Isopropyl 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0
palmitate ETHOCEL 2.0 5.0 10.0 -- -- -- -- 5.0 5.0 -- STD-10P
EUDRAGIT -- -- -- -- -- -- 10.0 -- -- -- E 100 EUDRAGIT -- -- -- --
-- 10.0 -- -- 5.0 RL 100 KOLLIDON -- -- -- -- 10.0 -- -- 3.0 -- --
VA64 PVP -- -- -- 10.0 -- -- -- -- 3.0 3.0 % Total 100.0 100.0
100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0
[0140] Each lacquer vehicle was evenly spread across glass
microscope slides using a small paintbrush to measure the solvent
evaporation time and apparent film quality upon solvent
evaporation. The resulting polymer film was also assigned a "Film
Grade" ranging from 1 to 5, with 5 being the highest grade. The
results of the formulation assessments are summarized in Table
2.
TABLE-US-00002 TABLE 2 Vehicle Nail Lacquer Results Summary
Formulation Polymer Solution Evaporation Apparent Film Reference (%
w/w) Appearance Time (sec.) Film Quality Grade VNL-01 2% ETHOCEL
Clear, faint-to- 32 Colorless, continuous film. 3 STD-10P light
yellow Film appears to be fragile but solution have good adhesion.
VNL-02 5% ETHOCEL Clear, light 28 Colorless, continuous film. 5
STD-10P yellow solution Film appears to be robust and have good
adhesion. VNL-03 10% ETHOCEL Clear, light 29 Colorless, continuous
film. 4 STD-10P yellow solution Film appears to be rigid and have
good adhesion. VNL-04 10% PVP Clear, colorless 58 Hazy, continuous
film. 2 (MW 40,000) solution Film appears to be fragile and have
poor adhesion. VNL-05 10% KOLLODON Clear, colorless 62 Slightly
hazy, continuous film. 3 VA64 solution Film appears to be robust
but have poor adhesion. VNL-06 10% EUDRAGIT Clear, light 51
Colorless, continuous film. 4 RL 100 yellow solution Film appears
to be robust and have good adhesion. VNL-07 10% EUDRAGIT Clear,
light 49 Colorless, continuous firm. 4 E 100 yellow solution Film
appears to be robust and have good adhesion. VNL-08 5% ETHOCEL
STD-10P Clear, light 68 Colorless, continuous film. 5 3% KOLLIDON
VA64 yellow solution Film appears to be robust and have good
adhesion. VNL-09 5% ETHOCEL STD-10P Clear, light 57 Slightly hazy,
continuous film. 4 3% PVP yellow solution Film appears to be robust
and have good adhesion. VNL-10 5% EUDRAGIT RL 100 Clear, light 74
Colorless, continuous film. 4 3% KOLLIDON VA64 yellow solution Film
appears to be robust and have good adhesion.
Example 2: Nitric-Oxide Releasing Nail Lacquer
[0141] A diazeniumdiolate-functionalized co-condensed silica
(Nitricil.TM.) was prepared according to known methods and milled
Nitricil.TM. is a NO-releasing co-condensed silica, from Novan,
Inc. and may be provided with one or more different release
profiles and/or functional groups, such as, but not limited to,
diazeniumdiolate-functionalized co-condensed silica. Nitricil.TM.
was analyzed for nitric oxide (NO) content, moisture content, and
the particle size distribution of pre-milled and milled
Nitricil.TM. was determined prior to initiation of the formulation
development. The results from the analyses are summarized in Table
3.
TABLE-US-00003 TABLE 3 Diazeniumdiolate-functionalized Co-Condensed
Silica Properties Particle Size Particle Size Moisture Distribution
- Distribution - NO Content Content Pre-Milled Milled Result 4.57
.mu.mol/mg 6.1% w/w D.sub.10: 18.90 .mu.m D.sub.10: 1.25 .mu.m
(13.71% w/w) D.sub.50: 442.38 .mu.m D.sub.50: 4.34 .mu.m D.sub.90:
843.41 .mu.m D.sub.90: 10.59 .mu.m
[0142] The initial development of the Nitricil.TM. Nail Lacquer was
based on vehicle formulation reference VNL-8 to contain 2%
Nitricil.TM. and to deliver 0.3% NO. The lacquer was prepared in a
250-mL glass beaker by dissolving the polymers in the solvent and
emollient mixture using an IKA T-18 Homogenizer at a low-to-medium
speed setting. While under continuous agitation, the weighed amount
of Nitricil.TM. was added and dispersed into the mixture. The
resulting lacquer suspension was transferred to 5 separate 20-mL
glass vials, and the visual appearance of the suspension was
recorded as provided in Table 5. The formulation prepared is
summarized in Table 4.
TABLE-US-00004 TABLE 4 NVN1000 Nail Lacquer, 2% (0.3% NO) ANL-01
Ingredient % w/w Denatured alcohol, anhydrous 70.0 Acetone,
anhydrous 15.0 Isopropyl palmitate 5.0 ETHOCEL STD-10P 5.0 KOLLIDON
VA64 3.0 Nitricil .TM. 2.0 % Total 100.0
[0143] A sample of the Nitricil.TM. Nail Lacquer was submitted to
test the NO content and moisture content of the formulation. The
lacquer was also spread evenly across glass microscope slides using
a small paintbrush to measure the solvent evaporation time and
apparent film quality upon solvent evaporation. The resulting film
was also assigned a "Film Grade" ranging from 1 to 5, with 5 being
the highest grade. The results of the formulation assessments are
summarized in Table 5.
TABLE-US-00005 TABLE 5 Nitricil .TM. Nail Lacquer Results Summary
Formulation NO Moisture Solution Evaporation Apparent Film
Reference Content Content Appearance Time Film Quality Grade ANL-01
0.3% 0.7% Opaque, faintly 64 sec Hazy, continuous 5 w/w w/w yellow
film. suspension Film appears to be robust with good adhesion.
Example 3: Additional Vehicle Nail Lacquers
[0144] Additional example vehicle nail lacquers are provided in
Formulas 1-5 below. A NO-releasing compound (e.g., a
diazeniumdiolate-functionalized co-condensed silica) may be added
to an example vehicle nail lacquer in an amount of about 0.1% to
about 70% by weight of the lacquer composition.
Formula 1
TABLE-US-00006 [0145] Ingredient %/Weight Function Isopropyl
Alcohol 65-85 Solvent Nitrocellulose 1-12 Film Former Adipic
Acid/Neopentyl 1-12 Film Former Glycol/Trimellitic Anhydride
Copolymer Trimethyl Pentanyl 1-6 Plasticizer Diisobutyrate
Triphenyl Phosphate 1-6 Plasticizer Stearalkonium Hectorite 1-2
Thickening Agent Benzophenone-1 0.1 Antioxidant Titanium Dioxide
Quantity sufficient Colorant
Formula 2
TABLE-US-00007 [0146] Ingredient %/Weight Function PNVA 1-3 Film
Former Isopropyl Alcohol 30-80 Solvent Propylene Glycol 1-10
Solvent Glycerine 1-10 Solvent
Formula 3
TABLE-US-00008 [0147] Ingredient %/Weight Function Gantrez S-97
1-10 Film Former Isopropyl Alcohol 30-80 Solvent Propylene Glycol
1-10 Solvent Glycerin 1-10 Solvent
Formula 4
TABLE-US-00009 [0148] Ingredient %/Weight Function Plasdone S-630
1-20 Film Former Isopropyl Alcohol 30-80 Solvent Propylene Glycol
1-10 Solvent Glycerin 1-10 Solvent
Formula 5
TABLE-US-00010 [0149] Ingredient %/Weight Function Plasdone S-630
1-20 Film Former Isopropyl Alcohol 30-80 Solvent Propylene Glycol
1-10 Solvent Glycerin 1-10 Solvent
Example 4: Nail Paste or Ointment Formulations
[0150] Ranges for ingredients in example nail paste or ointment
formulations are provided in Formula 6 below.
[0151] Formula 6
TABLE-US-00011 Ingredient %/Weight Function Nitricil .TM. 0.01-50
Active Pharmaceutical Ingredient (API) Crodabase SQ 0-40
Hydrocarbon Base Petrolatum, White, USP 0-40 Hydrocarbon Base
Miglyol 812 0-10 Solvent Cetyl Alcohol, NF 1-7 Thickening Agent
Mineral Oil, USP 1-6 Solvent Softigen 767 1-2 Amphiphilic
agent/Solvent
Example 5
[0152] Different nail compositions in combination with a hydrogel
in a 1:1 ratio were tested for effectiveness against T. rubrum. The
underside of nails were infected with T. rubrum and each nail was
subsequently mounted in ChubTur.RTM. cells as shown in FIG. 1. A
receiver chamber under the nail was filled with sterile Ringer's
solution. T. rubrum was grown at 25.degree. C. for 14 days. After
the 14 day incubation, a 50 .mu.L dose (i.e., 25 .mu.L of the nail
composition combined with 25 .mu.L of the hydrogel) of each
formulation was applied to the surface of a nail opposite of fungal
inoculation (FIG. 1). Each formulation included a pH 4.5 hydrogel
that, prior to application, was premixed in a 1:1 ratio with one of
the following nail compositions: 8% SB208, 16% SB208, 32% SB208,
32% Ointment, 32% LQ208, or 38.8% SB218 to provide the 4% SB208, 8%
SB208, 16% SB208, 16% Ointment, 16% LQ208, and 19.4% SB218
formulations, respectively (Table 6). The formulations remained on
the nail for 24 hrs. After 24 hrs, excess formulation was removed
and the nails were washed with deionized water. The nails were then
dried with a cotton swab and air exposure (30 mins). Nails were
subsequently removed from the ChubTur.RTM. cells and fungal
viability was assessed using an ATP bioluminescence assay
(surrogate for fungal viability).
[0153] The percent of ATP recovery for the formulations tested was
compared to the infected control and is shown in FIG. 2 with
100%=untreated infected nail controls. The greatest anti-fungal
efficacy was observed with 16% LQ208 which resulted in 1% ATP
recovery when compared to the infected nail control. The 4%, 8%,
and 16% SB208 formulations resulted in a greater than 80% reduction
in ATP recovery when compared to the untreated infected nail
control correlating to a significant reduction in T. rubrum
viability. There was no statistical difference in the percentage
ATP recovery between any of the tested formulations following a
single topical application. While not wishing to be bound by any
particular theory, the results suggest that the rapid penetration
of nitric oxide gas is sufficient to inhibit fungal growth.
TABLE-US-00012 TABLE 6 4% SB208, 8% SB208, 16% SB208, 16% Ointment,
16% LQ208, and 19.4% SB218 formulations. 4% 8% 16% 16% 16% 19.4%
Ingredient SB208 SB208 SB208 Ointment LQ208 SB218 Isopropyl
Alcohol, 39.25 35.25 27.25 -- -- 24.10 Anhydrous Water, Purified*
32.45 32.45 32.45 32.45 32.45 32.45 Ethanol, Anhydrous -- -- -- --
32.25 -- Crodabase SQ -- -- -- 14.30 -- -- White Petrolatum -- --
-- 14.30 -- -- Potassium Phosphate 5.75 5.75 5.75 5.75 5.75 5.75
Monobasic* Ethanol* 5.00 5.00 5.00 5.00 5.00 5.00 Hexylene Glycol*
6.50 6.50 6.50 1.50 1.50 6.50 Glycerin* 4.00 4.00 4.00 4.00 4.00
4.00 Medium Chain -- -- -- 2.70 -- -- Triglycerides Ethylcellulose
-- -- -- -- 1.75 -- Cyclomethicone* 1.25 1.25 1.25 -- -- 1.25
Carboxymethylcellulose 1.25 1.25 1.25 1.25 1.25 1.25 Sodium*
Mineral Oil -- -- -- 1.35 -- -- PEG-6 Caprylic/Capric -- -- -- 1.35
-- -- Glycerides Hydroxypropylcellulose 0.50 0.50 0.50 -- -- 0.25
Benzoic Acid* 0.05 0.05 0.05 0.05 0.05 0.05 Nitricil .TM. NVN1 4.00
8.00 16.00 16.00 16.00 -- Nitricil .TM. NVN4 -- -- -- -- -- 19.40
To Make Total 100.00 100.00 100.00 100.00 100.00 100.00 *Denotes an
ingredient from the hydrogel
[0154] The foregoing is illustrative of the present invention, and
is not to be construed as limiting thereof. The invention is
defined by the following claims, with equivalents of the claims to
be included therein. All publications, patent applications,
patents, patent publications, and other references cited herein are
incorporated by reference in their entireties for the teachings
relevant to the sentence and/or paragraph in which the reference is
presented.
* * * * *