U.S. patent application number 15/585617 was filed with the patent office on 2017-08-31 for nitric oxide releasing bath compositions and methods of using the same.
The applicant listed for this patent is Novan, Inc.. Invention is credited to Ryan Doxey, Nathan Stasko.
Application Number | 20170246205 15/585617 |
Document ID | / |
Family ID | 48168529 |
Filed Date | 2017-08-31 |
United States Patent
Application |
20170246205 |
Kind Code |
A1 |
Stasko; Nathan ; et
al. |
August 31, 2017 |
NITRIC OXIDE RELEASING BATH COMPOSITIONS AND METHODS OF USING THE
SAME
Abstract
The present invention relates to bath compositions that may
release nitric oxide when combined with an aqueous solution,
thereby producing a nitric oxide releasing soak and/or bath. The
present invention also relates to methods of using nitric oxide
releasing bath compositions.
Inventors: |
Stasko; Nathan; (Chapel
Hill, NC) ; Doxey; Ryan; (Raleigh, NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Novan, Inc. |
Morrisville |
NC |
US |
|
|
Family ID: |
48168529 |
Appl. No.: |
15/585617 |
Filed: |
May 3, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14353599 |
Apr 23, 2014 |
9669041 |
|
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PCT/US2012/062051 |
Oct 26, 2012 |
|
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15585617 |
|
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61552395 |
Oct 27, 2011 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 33/00 20130101;
A61K 31/045 20130101; A61Q 19/10 20130101; A01N 59/00 20130101;
A61K 9/0014 20130101; A61K 31/125 20130101; A61K 47/56 20170801;
A61L 2/18 20130101; A61K 31/695 20130101; A61K 47/38 20130101; A61L
2202/11 20130101; A61K 9/0007 20130101; A61K 47/26 20130101; A61K
9/08 20130101; A61K 8/19 20130101; A61K 47/12 20130101; A61K 8/40
20130101 |
International
Class: |
A61K 33/00 20060101
A61K033/00; A61K 31/125 20060101 A61K031/125; A61K 47/38 20060101
A61K047/38; A61K 47/26 20060101 A61K047/26; A61L 2/18 20060101
A61L002/18; A61K 9/00 20060101 A61K009/00; A61K 9/08 20060101
A61K009/08; A61K 47/12 20060101 A61K047/12; A01N 59/00 20060101
A01N059/00; A61K 31/045 20060101 A61K031/045; A61K 9/46 20060101
A61K009/46 |
Claims
1-46. (canceled)
47. A composition comprising an acid at a concentration in a range
from about 0.1% to about 5% by weight of the composition, and a
nitrite, wherein the composition provides a total NO release of
about 1 .mu.mol NO/L to about 100 mmol NO/L.
48. The composition of claim 47, further comprising an effervescent
agent, wherein the concentration of the effervescent agent is in a
range from about 25% to about 65% by weight.
49. The composition of claim 47, further comprising a pH-modifying
agent, wherein the concentration of the pH modifying agent is in a
range from about 0.1% to about 5% by weight.
50. The composition of claim 47, further comprising an aromatherapy
agent, wherein the concentration of the aromatherapy agent is in a
range from about 0.1% to about 10% by weight.
51. The composition of claim 50, wherein the aromatherapy agent is
selected from menthol and/or camphor.
52. The composition of claim 47, further comprising a glidant,
wherein the concentration of the glidant is in a range from about
0.1% to about 10% by weight.
53. The composition of claim 52, wherein the glidant is selected
from colloidal silicon dioxide and/or talc.
54. The composition of claim 47, further comprising an inert
filler, wherein the concentration of the inert filler is in a range
from about 0.1% to about 60% by weight.
55. The composition of claim 54, wherein the inert filler is
selected from microcrystalline cellulose and/or lactose.
56. The composition of claim 47, wherein the composition is in the
form of a powder, a bead, a granule, a tablet, a film, a coating, a
film-coated tablet, a polymer sheet, and any combination
thereof.
57. The composition of claim 47, wherein the composition is present
as a coating on a surface of a container.
58. The composition of claim 47, wherein the composition further
comprises at least one compound that provides a visual indicator of
when NO, nitrous acid and/or salts thereof are present.
59. The composition of claim 47, wherein the composition provides a
total NO release of about 1 mmol NO/L to about 100 mmol NO/L.
60. A method of treating a subject comprising: a) contacting the
composition of claim 47 with an aqueous solution to form NO,
thereby producing a nitric oxide releasing bath, and b) exposing at
least a portion of the subject to the bath.
61. The method of claim 60, further comprising adjusting the
release rate of the NO by changing the temperature of the bath
and/or modifying the pH of the bath.
62. The method of claim 60, wherein the composition is in the form
of a powder, a bead, a granule, a tablet, a film, a coating, a
film-coated tablet, a polymer sheet, and any combination
thereof.
63. The method of claim 60, wherein the composition is coated on
one or more interior surfaces of a container and the contacting
step comprises contacting the aqueous solution with the one or more
surfaces of the container.
64. The method of claim 60, further comprising providing a visual
indicator to the aqueous solution that signals the presence or
absence of NO, nitrous acid and/or salts thereof in the aqueous
solution.
Description
RELATED APPLICATION DATA
[0001] This application is a continuation application of U.S.
patent application Ser. No. 14/353,599, filed Apr. 23, 2014, which
is a 35 U.S.C. .sctn.371 national stage application of PCT
International Application No. PCT/US2012/062051, filed on Oct. 26,
2012, which claims the benefit of priority to U.S. Provisional
Patent Application Ser. No. 61/552,395, filed on Oct. 27, 2011, the
disclosures of which are incorporated herein by reference in their
entireties.
FIELD OF THE INVENTION
[0002] The present invention relates to bath compositions that may
release nitric oxide when combined with an aqueous solution,
thereby producing a nitric oxide releasing soak and/or bath. The
present invention also relates to methods of using nitric
oxide-releasing bath compositions.
BACKGROUND OF THE INVENTION
[0003] Bath therapies can be used to relieve various aches, pains,
and topical ailments by immersing a portion of a subject's body
into the bath or soak. The skin may benefit from a soak as the soak
can stimulate the skin, provide relief from skin irritations, such
as itching, and/or provide moisture to the skin. In some instances,
therapeutic agents may also be added to a bath or soak to provide a
subject with further therapeutic benefits.
[0004] It is known that nitric oxide possesses a broad-spectrum of
antimicrobial activity and may be used as an alternative to
conventional antibiotics for drug resistant bacteria. Furthermore,
some recent studies have demonstrated that nitric oxide may also
play an important role in the wound healing process by promoting
angiogenesis through stimulation of vascular endothelial growth
factor (VEGF) and increase fibroblast collagen synthesis. See
Schaffer M R, et al., Diabetes-impaired healing and reduced wound
nitric oxide synthesis: A possible pathophysiologic correlation.
Surgery 1997;121(5):513-9; and Shi H P, et al., The role of iNOS in
wound healing. Surgery 2001;130 (2):225-9. Furthermore, nitric
oxide has been shown to have other beneficial properties, including
reducing inflammation and participation in wound healing
biochemical cascades.
SUMMARY OF THE INVENTION
[0005] Provided according to some embodiments of the invention are
compositions that include at least one nitric oxide (NO)-releasing
compound. In some embodiments, the at least one NO-releasing
compound releases NO upon reaction with water. Further, in some
embodiments, the at least one NO-releasing compound includes at
least one NO-releasing macromolecule, such as, for example,
NO-releasing co-condensed silica.
[0006] Also provided are methods of treating a subject that include
contacting a bath composition according to an embodiment of the
invention with an aqueous solution to form NO, thereby producing a
nitric oxide releasing bath; and exposing at least a portion of the
subject to the bath.
[0007] Further provided are methods of cleaning and/or disinfecting
an article, device and/or instrument that include contacting a bath
composition according to an embodiment of the invention, with an
aqueous solution to form NO, thereby producing a NO-releasing bath;
and exposing at least a portion of the article, device and/or
instrument to the bath.
[0008] In addition, provided are methods of providing NO to a plant
that include contacting a bath composition according to an
embodiment of the invention with an aqueous solution to form NO,
thereby producing a NO-releasing bath, and contacting at least a
portion of the plant to the NO-releasing bath.
[0009] Also provide according to embodiments of the invention are
methods of treating a subject that include contacting a bath
composition according to an embodiment of the invention with an
aqueous solution to form a bath solution; optionally heating the
bath solution, and exposing at least a portion of the subject to
the bath. Further provided according to embodiments of the
invention are methods of cleaning an article, device and/or
instrument that include contacting a bath composition according to
an embodiment of the invention with an aqueous solution to form a
bath solution; optionally heating the bath solution, and exposing
at least a portion of the article, device and/or instrument to the
bath.
BRIEF DESCRIPTION OF THE FIGURES
[0010] The foregoing and other objects, features and advantages of
the invention will become more apparent from the following more
particular description of exemplary embodiments of the invention
and the accompanying drawings. The drawings are not necessarily to
scale, emphasis instead being placed upon illustrating the
principles of the invention.
[0011] FIG. 1 is a diagram of a bath/soak according to some
embodiments of the present invention.
[0012] FIG. 2 is a diagram of a bath/soak according to further
embodiments of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0013] 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.
[0014] 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.
[0015] 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.
[0016] 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.
[0017] 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").
[0018] 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.
[0019] 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."
[0020] The term "about," as used herein when referring to a
measurable value, such as, for example, an amount or concentration,
is meant to encompass variations of .+-.20%, .+-.10%, .+-.5%,
.+-.1%, .+-.0.5%, or even .+-.0.1% of the specified amount. A range
provided herein for a measureable value may include any other range
and/or individual value therein.
[0021] 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.
[0022] 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.
[0023] 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.
[0024] 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.
[0025] 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.
[0026] 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.
[0027] "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.
[0028] "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.
[0029] "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.
[0030] "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.
[0031] "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.
[0032] "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-).
[0033] 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.+).
[0034] 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 quartemary amines carry a positive charge.
[0035] The term "alkylamine" refers to the -alkyl-NH.sub.2
group.
[0036] The term "carbonyl" refers to the --(C.dbd.O)-- group.
[0037] The term "carboxyl" refers to the --COOH group and the term
"carboxylate" refers to an anion formed from a carboxyl group,
i.e., --COO.sup.-.
[0038] The terms "halo", "halide", or "halogen" as used herein
refer to fluoro, chloro, bromo, and iodo groups.
[0039] The term "hydroxyl" and "hydroxy" refer to the --OH
group.
[0040] The term "hydroxyalkyl" refers to an alkyl group substituted
with an --OH group.
[0041] The term "mercapto" or "thio" refers to the --SH group. The
term "silyl" refers to groups comprising silicon atoms (Si).
[0042] 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).
[0043] The term "silanol" refers to a Si--OH group.
[0044] Provided according to some embodiments of the present
invention are bath compositions that include at least one nitric
oxide (NO)-releasing compound. In some embodiments of the
invention, the at least one NO-releasing compound included in the
bath composition may release NO upon reaction with water. In other
embodiments, the NO-releasing compound may release NO via thermal
degradation as a function of temperature of the bath composition.
In some embodiments, the at least one NO-releasing compound
includes a NO-releasing macromolecule. Furthermore, in some
embodiments, the at least one NO-releasing macromolecule includes a
diazeniumdiolate functional group. In particular embodiments, the
NO-releasing macromolecule includes a
diazeniumdiolate-functionalized co-condensed silica.
[0045] In some embodiments of the invention, the components of the
bath composition are selected based on the properties of the
NO-releasing compound and the indication for which the resulting
bath is to be used, such that the interaction of the properties of
the bath composition, NO-releasing compound, and aqueous
environment act to provide the desired NO release profile.
[0046] Any suitable NO-releasing compound may be used in bath
compositions according to embodiments of the invention. The NO may
be released from the NO-releasing compound by any suitable
mechanism, including via reaction with 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, such as acidified nitrite, may also be
utilized.
[0047] The NO-releasing compound may be a small molecule, oligomer
and/or polymer and may be in any suitable physical form, including,
but not limited to, particles, coatings, films, liquids, solutions
and the like. In some embodiments, the nitric oxide-releasing
compound comprises diazeniumdiolate-functionalized polysiloxane
macromolecules as described below. Other non-limiting examples of
NO-releasing compounds include NO-releasing zeolites as described
in United States Patent 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. Provisional Patent Application Ser. No.
61/526,918 entitled "TUNABLE NITRIC OXIDE-RELEASING MACROMOLECULES
HAVING MULTIPLE NITRIC OXIDE DONOR S I RUCTURES"; NO-releasing
dendrimers or metal structures as described in U.S. Publication No.
2009/0214618; nitric oxide releasing coatings as described in U.S.
Publication No. 2011/0086234; and compounds as described in U.S.
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 Application No.
PCT/US2012/022048 entitled "Temperature Controlled Sol-Gel
Co-Condensation" filed Jan. 20, 2012, the disclosure of which is
incorporated herein by reference in its entirety.
[0048] 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. 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.
[0049] 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.
[0050] 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, a 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.
[0051] 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.
[0052] 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).
[0053] 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.
[0054] 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.
[0055] 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.
[0056] 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 temperature and pH (37.degree. C.
and pH=7.4).
[0057] 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 the
suspension/diffusion of the diazeniumdiolate-modified polysiloxane
macromolecules throughout 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.
[0058] 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 coating. 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-polyethyleneoxide 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.
[0059] 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, but are not limited to,
heptadecafluoro-1,1,2-2-tetrahydrodecyl)triethoxysilane,
(3,3,3-trifluoropropyl)trimethoxysilane,
(perfluoroalkyl)ethyltriethoxysilane,
nonafluorohexyltrimethoxysilane, nonafluorohexyltriethoxysilane,
(tridecafluoro-1,1,2,2-tetrahydrooctyl)triethoxysilane, and
(tridecafluoro-1,1,2,2-tetrahydrooctyl)trimethoxysilane.
[0060] 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.
[0061] In some embodiments of the invention, the hydrodynamic
radius of the diazeniumdiolate-functionalized co-condensed silica
particles is within a range from about 1 nm to about 1,000 .mu.m or
any other range and/or individual value therein, such as, but not
limited to, from about 1000 nm to about 10 microns, about 100 nm to
about 1,000 .mu.m, or about 1 nm to about 100 nm. In some
embodiments, to maximize trans-epidermal skin penetration and
enhance nitric oxide delivery to deeper skin structures, the size
of the macromolecular scaffold may be selected to be in a range
from about 5 nm to about 50 nm. In other embodiments, the
macromolecular scaffold may be selected to be in a range from about
101 nm to about 10 .mu.m to selectively accumulate
diazeniumdiolate-modified polysiloxane macromolecules in the
stratum corneum and limit skin penetration, systemic absorption,
and any resulting toxicity of the macromolecular scaffold. In some
embodiments, the size of the macromolecule scaffold may be selected
to be in a range from about 1 .mu.m to about 100 .mu.m to target
skin penetration via the trans-follicular route. Selective delivery
to the stratum corneum, epidermis or dermis may be achieved by
varying the particle size. Skin naturally has a low permeability to
particulate materials and the stratum corneum provides an effective
barrier to most inorganic nanosized particles with gold
nanoparticles, silver nanoparticles, quantum dots, titanium
dioxodie, and zinc oxide being the most extensively studied. See,
e.g., Baroli, B., Penetration of Nanoparticles and Nanomaterials in
the Skin: Fiction or Reality? Journal of Pharmaceutical Sciences,
2009 December; 99:21-50.
[0062] The size of the NO-releasing compound may affect the release
rate of nitric oxide from in the aqueous bath. Properties of the
NO-releasing compound may be controlled to affect the release rate
of nitric oxide include altering the surface area and porosity of
particulate NO donors and controlling particle size to govern the
rate of moisture diffusion throughout the particulate matrix to
affect the rate at which the particle itself hydrates.
[0063] In some embodiments, the size of the NO-releasing compound
may also be adjusted to affect the physical properties of the soak
solution. Physical properties that are governed by particle size
include segregation of the powdered formulation during packaging or
manufacturing, the dispersion quality and rate at which the powder
disperses into the aqueous media, fluid dynamics of the
NO-releasing macromolecule in a bath solution and settling time of
the particulate matter to the bottom of the soak/bath solution (in
other words, how long it stays suspended). In specific embodiments,
this property may be adjusted to optimize delivery of NO to a body
surface, e.g., the bottom of a foot such that the release all comes
from the bottom of the soak vessel or container (See, FIG. 1). In
other embodiments, the particle size may be small enough to allow
for rapid, uniform dispersion for delivery to a total body surface
area through the media. In some embodiments, the particle size of
the bath composition may be adjusted to match the instructions for
adding the powder under turbulent flow conditions capable of
dispersing larger macromolecular powders (jets, whirpool, or under
a running faucet) or sprinkled on top of the water which may
require relatively small (e.g., <10 .mu.m) particle sizes.
[0064] The at least one NO-releasing compound may be present in
bath compositions according to embodiments of the invention at any
suitable concentration, but in some embodiments, the NO-releasing
compounds are present in the bath compositions at a concentration
sufficient to increase the rate of wound healing, decrease
inflammation and/or exert an antimicrobial effect. For example, in
particular embodiments, the concentration of
diazeniumdiolate-functionalized co-condensed silica in the bath
composition is in a range from about 0.01 percent to about 80
percent w/w. In some embodiments, the concentration of the at least
one NO-releasing compound in the composition may be adjusted to
modulate the amplitude of nitric oxide release (mol NO/g
composition) either by changing the weight percentage in the bath
composition or by varying the loading of nitric oxide on a
macromolecular scaffold to create a desirable therapeutic
outcome.
[0065] In some embodiments, the fmal NO storage per gram of the
powdered bath composition may be in a range from about 0.1 pmol
NO/g to about 10 mmol NO/g composition or any range and/or
therapeutic value therein, such as, but not limited to, from about
0.1 pmol NO/g to about 100 nmol NO/g composition, about 1 nmol NO/g
to about 10 mmol NO/g composition, about 1 nmol NO/g composition to
about 10 .mu.mol NO/g composition, or about 10 .mu.mol NO/g
composition to about 1 mmol NO/g composition. In some embodiments,
to reduce inflammation and associated inflammatory response
factors, the final NO storage per gram of the bath composition may
be in a range from about 1 nmol NO/g composition to about 1 mmol
NO/g composition. In some embodiments, to promote wound healing,
the fmal NO storage per gram of the bath composition may be in a
range from about 10 nmol NO/g composition to about 5 mmol NO/g
composition. In some embodiments, to exert antimicrobial activity,
the final NO storage per gram of the bath composition may be in a
range from about 10 .mu.mol NO/g composition to about 5 mmol NO/g
composition. In some embodiments, to treat biofilms by dispersal,
the final NO storage per gram of the bath composition may be in a
range from about 1 nmol NO/g composition to about 1 mmol NO/g
composition, and in some embodiments, to treat biofilms by direct
microbicidal activity, the final NO storage per gram of the bath
composition may be in a range from about 100 .mu.mol NO/g
composition to about 10 mmol NO/g composition.
[0066] In some embodiments, the concentration of NO delivered in
the bath/soak solution following mixture depends on the volume of
the aqueous medium. The volume of the bath/soak solution changes
depending on its application and may range from as small as about
0.05 L to soak medical articles or fingers to as large as an entire
Olympic sized swimming pools of about 2,500,000 L capable of
treating more than one subject at once. In some embodiments, the
overall concentration of NO delivered may be in the range from
about 1 .mu.mol NO/L up to about 2.5 mol NO/L. In some embodiments,
the total NO delivered in the bath/soak solution is calculated as
instantaneous rate or the level of release at a particular time. In
other embodiments, the total NO delivered in the bath/soak solution
is integrated over time, such as a total release or total release
over a time interval. In some embodiments, the total NO delivered
is in the range from about 1 mmol NO/L to about 100 mmol NO/L. In
some embodiments, the total NO delivered is greater than about 16
mmol NO/L.
[0067] As discussed above, the present invention relates to bath
compositions that comprise, consist essentially of, or consist of
at least one NO-releasing compound, such as, for example,
NO-releasing macromolecules including
diazeniumdiolate-functionalized co-condensed silica. In certain
embodiments of the present invention,
diazeniumdiolate-functionalized co-condensed silica are present in
the bath composition in a concentration in a range from about 20%
to about 70% by weight of the composition or any range and/or
individual value therein. In particular embodiments of the present
invention, diazeniumdiolate-functionalized polysiloxane
macromolecules are present in the bath composition in a
concentration of about 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%, or any range therein.
[0068] The bath compositions of the present invention when
contacted with an aqueous solution may produce a nitric oxide
releasing bath or soak. The term "contact" and grammatical
variations thereof, as used herein in reference to the contacting
of the bath composition and aqueous solution, is intended to
include mixing, adding, dissolving, combining, soaking, suspending,
immersing, saturating, dipping, incorporating, wetting, submerging,
and/or any variation and/or combination thereof. The bath
compositions of the present invention may be contacted with an
aqueous solution in any suitable manner. For example, a bath
composition may be contacted with an aqueous solution before,
during, and/or after the aqueous solution is placed in a vessel or
container. The term "aqueous solution," as used herein, refers to
any liquid solution comprising water. Exemplary aqueous solutions
include, but are not limited to, water, deoxygenated water, saline
solutions, acidic or alkaline buffer solutions, and/or any
combination thereof.
[0069] According to some embodiments of the present invention, the
nitric oxide releasing bath may effervesce. Effervescence is the
release of a gas, such as carbon dioxide, in an aqueous solution
and produces bubbles, fizz, and/or foaming in an aqueous solution.
Effervescence may be beneficial in stimulating the skin and may
provide relief from fatigue. In some embodiments of the present
invention, effervescence may enhance the delivery and/or activity
of the nitric oxide. In certain embodiments of the present
invention, effervescence provides a delivery mechanism for the
nitric oxide to the subject in the bath. In some embodiments of the
present invention, effervescence increases the half-life of the
nitric oxide in the aqueous solution.
[0070] Chemical compounds and/or compositions that may be used to
produce effervescence are known in the art and include, but are not
limited to, those described in U.S. Pat. Nos. 4,650,667; 4,666,707;
5,110,603; and 6,121,215, which are each incorporated herein by
reference in their entirety. For example, effervescence may be
produced by combining a carbonate and an acid with an aqueous
solution. Exemplary carbonates include, but are not limited to,
sodium hydrogen carbonate, sodium carbonate, sodium
sesquicarbonate, potassium hydrogen carbonate, potassium carbonate,
potassium sesquicarbonate, ammonium hydrogen carbonate, ammonium
carbonate, ammonium sesquicarbonate, and any combination thereof.
Exemplary acids include, but are not limited to, organic acids such
as citric acid, tartaric acid, malic acid, fumaric acid, and
phosphoric acid; acidic salts of organic acids; straight-chain
aliphatic acids such as acetic acid, propanoic acid, butyric acid
and valeric acid; dicarboxylic acids such as oxalic acid, malonic
acid, and succinic acid; acidic amino acids such as glutamic acid
and aspartic acid; hydroxy acids such as glycolic acid, lactic
acid, and a-hydroxy butyric acid; and inorganic acids such as
phosphoric acid, potassium dihydrogen phosphate, sodium dihydrogen
phosphate, sodium sulfite, potassium sulfite, and sulfamic acid;
and any combination thereof.
[0071] In certain embodiments of the present invention, a carbonate
may be present in the bath composition at a concentration in a
range from about 25% to about 65% by weight of the composition or
any range and/or individual value therein. For example a carbonate
may be present in the bath composition at a concentration of about
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% by weight or any range therein. In some embodiments, an
acid is present in the bath composition at a concentration from
about 0.1% to about 15% by weight of the composition or any range
therein and/or individual value therein. For example, in some
embodiments, an acid is present in the bath composition at a
concentration of about 0.1%, 0.25%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%
by weight, or any range therein. In particular embodiments of the
present invention, the bath composition includes sodium bicarbonate
and citric acid and/or tartaric acid.
[0072] In some embodiments of the present invention, the bath
composition includes diazeniumdiolate-functionalized polysiloxane
macromolecules at a concentration in a range from about 45% to
about 55% by weight; sodium bicarbonate at a concentration in a
range from about 40% to about 50% by weight; and citric acid and/or
tartaric acid at a concentration in a range fin about 0.2% to about
2% by weight.
[0073] In some embodiments of the invention, an aromatherapy agent
is present in the bath compositions. Any suitable concentration may
be used, but in some embodiments, the aromatherapy agent is present
in the bath composition at a concentration in a range from about
0.1% to about 10% by weight of the composition or any range and/or
individual value therein. In certain embodiments of the present
invention, an aromatherapy agent is present in an amount of about
0.1%, 0.25%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%
by weight, or any range therein. Exemplary aromatherapy agents
include, but are not limited to, menthol, camphor, jasmine,
rosewood oil, eucalyptus oil, sandalwood oil, ylang ylang oil,
lavender oil, patchouli oil, wintergreen oil, clove oil, nutmeg
oil, aniseed oil, vanilla bean oil, thyme oil, mint oil, sassafras
oil, rose oil, orange oil, lavandin oil, chamomile oil, rosemary
oil, and any combination thereof. In particular embodiments of the
present invention, the bath composition comprises menthol and/or
camphor, optionally at a concentration in a range from about 0.1%
to about 1% by weight.
[0074] In some embodiments of the invention, a glidant is present
in the bath compositions. Any suitable concentration of glidant may
be used, but in some embodiments, the glidant is present in the
bath compositions at a concentration in a range from about 0.1% to
about 10% by weight of the composition or any range and/or
individual value therein. In certain embodiments of the present
invention, a glidant is present in an amount of about 0.1%, 0.25%,
0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10% by weight, or
any range therein. Exemplary glidants include, but are not limited
to, colloidal silicon dioxide, talc, calcium silicate, fumed
silica, precipitated silica, hydrated silica, aluminum starch
octenylsuccinate, stearic acid, magnesium stearate, calcium
stearate, and any combination therof. In particular embodiments of
the present invention, the bath composition comprises colloidal
silicon dioxide and/or talc, optionally at a concentration in a
range from about 0.1% to about 5% by weight.
[0075] In some embodiments, inert filler is present in the bath
compositions of the present invention. Any suitable concentration
of inert filler may be present, but in some embodiments, inert
filler is present at a concentration in a range from about 0.1% to
about 75% by weight of the composition or any range and/or any
individual value therein. In certain embodiments of the present
invention, an inert filler is present 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% by weight, or any
range therein. Exemplary inert fillers include, but are not limited
to, microcrystalline cellulose, lactose, dextrin, dextrose
monohydrate, starch, dibasic calcium phosphate dehydrate, sucrose,
saccharides, oatmeal milled ultrafine, crystalline sorbitol,
magnesium oxide, calcium sulfate dehydrate, carboxymethyl starch,
polyacrylate copolymers, and polymethacrylate. In particular
embodiments of the present invention, the bath composition
comprises microcrystalline cellulose and/or lactose, optionally at
a concentration in a range from about 0.5% to about 50% by
weight
[0076] Other components, such as a colorant, an emollient, a
surfactant, a moisturizer, a humectant, a sunscreen, an anti-caking
agent, a skin protectant, a softening agent, and/or a pH modifying
agent, may optionally be added to the bath compositions of the
present invention. Exemplary humectants include, but are not
limited to, polyethylene glycol, glycerin, polyvinyl alcohol,
sorbitol, polyvinylpyrollidone, and any combination thereof.
Exemplary emollients include, but are not limited to, mineral oils,
fatty acid esters, fatty alcohols, dimethicones, isopropyl
palmitate, and any combination thereof. Exemplary surfactants
include, but are not limited to, sodium dodecyl sulfate, sodium
stearoyl lactylate, sodium laureth sulfate, lauramide DEA, sodium
methyl cocoyl taurate, cocamidopropyl betaine, and any combination
thereof. Exemplary moisturizers include, but are not limited to,
aloe vera, polydimethysiloxane, panthenol, collinsonia Canadensis,
wheatgrass extract, oatmeal milled ultrafine, and any combination
thereof.
[0077] In some embodiments of the present invention, a pH modifying
agent may be used to control and/or stabilize the pH of the bath or
soak. A pH modifying agent may be used to increase or decrease the
pH of the bath or soak. Exemplary pH modifying agents include, but
are not limited to, acidic compounds such as p-anisic acid and
citric acid; basic compounds such as calcium hydroxide, sodium
hydroxide, sodium carbonate, and triethanolamine; and organic and
inorganic salts such as sodium bicarbonate, magnesium sulfate, and
pentasodium triphosphate.
[0078] A colorant may be present in the bath compositions of the
present invention to impart a color to the nitric oxide releasing
bath. In some embodiments of the present invention, a colorant may
provide a color to the bath throughout the duration of the bath. In
other embodiments, a colorant may provide a color to the bath
solution that fades and/or changes over time. The color of the bath
may fade and/or change to provide a visual indicator. The visual
indicator may indicate the end of nitric oxide release, the
concentration of nitric oxide and/or nitrous acid, a change in
temperature, a change in pH, and/or any combination thereof. In
certain embodiments of the present invention, the color of the bath
may fade and/or change after a specific duration of time. In
another aspect of the present invention, a colorant may be present
in the bath composition to delineate the order of operation for the
addition of the components of the bath composition and/or to
delineate the order of the steps in the methods of treatment of the
present invention.
[0079] Additional optional components of the bath compositions of
the present invention may include excipients that facilitate the
formation of an emulsion when an aqueous solution is contacted with
a bath composition of the present invention. Thus, a
self-emulsifying delivery system may be provided by the bath
compositions of the present invention. In other embodiments of the
present invention, excipients that enhance and/or accelerate nitric
oxide donor lifetime in solution may be included in the bath
compositions of the present invention. These excipients may provide
enhanced delivery of the nitric oxide to the subject. See, e.g.,
Bach T., et al., "Effect of Hydrophobic Structure on the Catalysis
of Nitric Oxide Release from Zwitterionic Diazeniumdiolates in
Surfactant and Liposome Media" Nitric Oxide: Biology and Chemistry,
13, 204-209 (2005) and Price, Stacy E., et al., "Micellar Catalysis
of Nitric Oxide Dissociation from Diazeniumdiolates" Langmuir, 19,
2096-2102 (2003), which are incorporated herein by reference in
their entirety.
[0080] In particular embodiments of the present invention, the bath
composition may controllably release nitric oxide when contacted
with an aqueous solution and/or when one or more components of the
bath composition are combined and contacted with an aqueous
solution. The release of nitric oxide may be immediate upon contact
with an aqueous solution and/or may begin after a certain duration
of time. Nitric oxide may be released from the bath continuously
and/or intermittently, for example, by exposure to repeated
light/dark cycles. The release kinetics of the nitric oxide may be
varied and/or tuned by changing the temperature and/or pH of the
aqueous solution and/or bath. To decrease the release rate of
nitric oxide, the temperature of the aqueous solution and/or bath
may be decreased and/or the pH of the aqueous solution and/or bath
may be increased. To increase the release rate of nitric oxide, the
temperature of the aqueous solution and/or bath may be increased
and/or the pH of the aqueous solution and/or bath may be decreased.
In some embodiments of the present invention, the amount of nitric
oxide released may be controlled by the concentration of
NO-releasing compounds in the bath composition and/or by the amount
of bath composition contacted with the aqueous solution and/or
bath. For example, a high concentration of NO-releasing compounds
in the bath composition and/or contacting a greater amount of the
bath composition with the aqueous solution, may result in more
nitric oxide released in the bath or soak.
[0081] In certain embodiments of the present invention, the amount
of nitric oxide released increases over time, and after a certain
amount of time, the amount of nitric oxide released may decrease.
In some embodiments, the amount of nitric oxide released is
substantially constant (i.e., on average varying less than about
.+-.20%, .+-.15%, .+-.10%, or .+-.5%) over a period of time. In
other embodiments of the present invention, the amount of nitric
oxide released varies over the duration of the bath. The release of
nitric oxide, in some embodiments, may occur in random and/or
sequential releases of the same or varying concentration.
[0082] A bath composition of the present invention may be in any
suitable form, including a powder, a bead, a granule, a tablet, a
film, a coating, a film-coated tablet, and/or a polymer sheet. The
polymers and/or solid compositions may or may not dissolve or break
down in water. In some embodiments, polymeric compositions that may
be used include those described in U.S. patent application Ser. No.
13/256,925, filed on Sep. 15, 2011, the contents of which are
herein incorporated by reference in their entirety.
[0083] For example, as illustrated in FIG. 1, a bath/soak is
provided as tablets that release nitric oxide in a concentrated
area. An item, such as a foot, is placed in the bath with water and
the tablets and the item is placed in proximity to the tablets to
receive the nitric oxide released from the tablets. FIG. 2
illustrates an alternative embodiment where the nitric oxide
releasing material is distributed throughout the bath/soak. As seen
in FIG. 2, the item, such as a foot, is placed in the bath/soak
with a composition, such as a powder, and water and the powder
mixed throughout the water to release the nitric oxide throughout
the bath.
[0084] The bath compositions of the present invention may be
packaged and/or stored in a single dose unit and/or a multi-dose
unit. One or more components of the bath composition may be
packaged and/or stored separately from the other components of the
bath composition in a single dose unit and/or a multi-dose unit.
For example, in some embodiments of the present invention, the
NO-releasing compounds may be packaged and/or stored separately
from the other components of the bath composition, such as but not
limited to an acid, until contacted with the aqueous solution. In
other embodiments of the present invention, a pH modifying agent is
packaged and/or stored separately from the other components of the
bath composition. When separate, the one or more components of the
bath composition may be contacted with an aqueous solution in any
order. In another aspect of the present invention, the bath
composition may be coated onto one or more interior surfaces of a
vessel, such as, but not limited to, a disposable tub and/or a foot
basin, and/or on one or more surfaces of an inert object, such as,
but not limited to, a sponge, loofah, cloth, toy, and/or
massager.
[0085] The bath composition may be packaged and/or stored in any
manner. In certain embodiments of the present invention, the bath
composition is packaged and/or stored such that the packaging
minimizes contact with air, water, and/or light. Exemplary packages
for the bath composition include, but are not limited to, a bottle,
a plastic wrap or container, a foil sachet, a polyethylene sachet,
and any combination thereof. In certain embodiments of the present
invention, the packaging may be used as a vesicle or container in
which to add the aqueous solution and/or the packaging may be used
in the methods of treatment of the present invention.
[0086] In some embodiments, packaged bath compositions of the
present invention may be provided with a shelf life of at least
about one week. In further embodiments, the packaged bath
compositions 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, the packaged bath compositions
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 bath composition of the present invention)
maintains the ability to release a therapeutically 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 bath 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
bath composition is in use. In certain embodiments, the rate of
release of nitric oxide may be faster when a bath composition is in
use compared to the rate of release of nitric oxide when the bath
composition was packaged and/or stored.
[0087] 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 to about 12.degree. C.
[0088] Further embodiments may provide packaged bath compositions
that have a useful life of at least about 7 days after opening the
package. In further embodiments, the useful life may be at least
about 30 days, at least about 60 days or at least about 90 days. In
still further embodiments, the packaged bath compositions 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.
[0089] A further aspect of the present invention provides methods
of treating a subject by contacting a bath composition of the
present invention with an aqueous solution, thereby producing a
nitric oxide releasing bath, and exposing a portion of the subject
to the bath. Thus, by exposing the subject to the nitric oxide
bath, the subject may be treated with nitric oxide. The terms
"treat", "treating", and grammatical variants thereof, as used
herein in reference to treating a subject, refers to treating
and/or inhibiting and/or protecting against a disease, disorder,
infection, wound, and/or clinical symptom in a subject. The methods
of the present invention may provide for the total absence of the
disease, disorder, infection, wound, and/or clinical symptom in the
subject. The methods 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.
[0090] The term "exposing" and grammatical variants thereof, as
used herein in reference to the subject and the bath, refer to
submerging, contacting, immersing, dipping, wetting, dousing,
washing, rinsing, soaking, plunging, dunking, dampening, and/or
placing any portion of the subject (e.g., one or more extremities,
the whole body, etc.) into contact with the bath for any duration
of time. In certain embodiments of the present invention, the
subject is exposed to the bath for a time sufficient to obtain a
treatment effective amount of nitric oxide. 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.
[0091] The methods of the present invention may include modifying
the release kinetics of the nitric oxide in the bath. As described
above, the release kinetics of the nitric oxide may be varied
and/or tuned by changing the temperature and/or pH of the aqueous
solution and/or bath. To decrease the release rate of nitric oxide,
the temperature of the aqueous solution and/or bath may be
decreased and/or the pH of the aqueous solution and/or bath may be
increased. To increase the release rate of nitric oxide, the
temperature of the aqueous solution and/or bath may be increased
and/or the pH of the aqueous solution and/or bath may be decreased.
In some embodiments of the present invention, the amount of nitric
oxide released may be controlled and/or changed by adding the same
or varying amounts of the bath composition to the bath at various
times throughout the duration of the bath. For embodiments wherein
the temperature and/or bath is increased, any temperature that may
suitably allow for the release of NO may be used, including, for
example, temperatures in a range from about 25 or 30 to 40.degree.
C., or greater. In embodiments wherein the bath compositions are
used for articles, devices and/or instruments, the temperature
range may be much higher, such as, for example, in a range from
about 30 to 40, 50, 60, 70 80, 90, 100.degree. C., or greater.
[0092] The present invention fmds use in both veterinary and
medical applications, including drug evaluation 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.
[0093] In particular embodiments of the present invention, the
methods of the present invention are used to treat a dermatological
condition, wound, burn, and any combination thereof. Exemplary
dermatological conditions include, but are not limited to, atopic
dermatitis, contact dermatitis, chicken pox, psoriasis, impetigo,
secondary skin infections, bed sores, diabetic foot ulcers, venous
leg ulcers, burns, surgical incisions, acne vulgaris, truncal acne
and/or cystic nodular acne, onychomycosis, tinea pedis, tinea
cruris, tinea capitis, molluscum contagiosum, common and genital
warts, and any combination thereof. Bath compositions according to
embodiments of the invention may be used to treat other skin
ailments, either via anti-microbial action, anti-inflammatory
action, or by any other mechanism.
[0094] In addition to dermatological conditions, the present
invention could also be utilized to treat pain, inflammation or
other conditions affected by nitric oxide delivery. For example, a
nitric oxide-releasing bath or soak could be used to treat
arthritis, tendonitis, plantar facitis, sprains, sports injuries,
repetitive motion injuries, such as carpal tunnel syndrome or
muscle overuse.
[0095] Such methods may be used in combination with any other known
methods of wound 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 or after contact with the bath compositions
of the present invention.
[0096] In some embodiments of the present invention, bath
compositions may be used to deliver NO to articles, devices and/or
instruments, for example, to clean, disinfect, decrease the
microbial burden and/or decrease or remove biofilms. For example,
in some embodiments, a bath composition described herein may be
used to clean or disinfect medical or surgical instruments. The
term "instrument" is intended to be defined broadly, to include any
items, objects, implements or devices. Simply by way of example and
without limitation, instruments may be implements employed in
patient or client contact (human or veterinary) during the practice
of surgery, medicine, dentistry, podiatry, pathology for e.g.,
therapeutic, diagnostic and/or research purposes. Examples include,
but are not limited to, surgical instruments, e.g., scalpels,
probes, clamps, etc., endoscopes, operating room or dental hand
pieces, ventilation tubes, and the like. Surgical instruments and
equipment inevitably pick up amounts of bio-burden on them after
being employed in operations on humans or animals. Surgical
instruments include, for example, rigid and flexible scopes,
laparoscopic instruments, frays and anything that may have contact,
directly or indirectly, with a patient or subject.
[0097] As another example, bath compositions described herein may
be used to clean/disinfect articles implanted or otherwise
associated with a subject, including contact lenses, implantable
medical devices, dental implants and appliances, dentures, and the
like.
[0098] Other devices that may be subjected to the bath compositions
also include, but are not limited to, miscellaneous other
instruments and/or implements employed in cosmetic and beauty
applications. These applications include hair cutting, nail care,
body art, skin piercing, collection of body fluids, and the like.
The bath compositions according to embodiments of the invention are
also contemplated to be useful for cleaning implements and items
employed in the food processing and pharmaceutical industries.
[0099] The articles, devices and/or instruments may be combined
with an NO-releasing bath solution by any suitable method,
including using the NO-releasing bath solutions alone, or with
other washes and agents. Other cleaning solutions may be used in
combination or they may be used in sequential rinse/cleaning
cycles. Water rinsing or soaking may also be performed before
and/or after contact with the NO-releasing bath solutions.
[0100] In some embodiments, bath compositions according to an
embodiment of the invention may also be used in aqueous solutions
that are applied or in contact with plants, including trees,
flowers, herbs, bushes, grasses, vines, ferns, mosses, green algae
and the like. The term "plant" includes any living organism in the
kingdom Plantae, including common and exotic plant varieties. In
particular embodiments, the NO-releasing bath solutions may be used
with cut plants to prolong life in vases, potters, and the
like.
[0101] 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
[0102] Tables 1 through 3 illustrate particular exemplary bath/soak
formulations according to some embodiments of the present
invention. Table 1 illustrates three possible effervescent
formulations. Table 2 illustrates three possible non-effervescent
formulations. Table 3 illustrates three possible bath salt
formulations. 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.
TABLE-US-00001 TABLE 1 Proposed Effervescent Formulations
Ingredient % w/w Nitricil .TM. 50.0 50.0 50.0 Sodium bicarbonate
40.0 -- 40.0 Potassium carbonate -- 40.0 -- Citric acid, anhydrous
10.0 10.0 5.0 Tartaric acid -- -- 5.0 % Total 100.0 100.0 100.0
TABLE-US-00002 TABLE 2 Proposed Non-Effervescent Formulations
Ingredient % w/w Nitricil .TM. 50.0 50.0 50.0 Colloidal oatmeal
42.9 44.9 42.7 Citric acid, anhydrous 5.0 -- 5.0 Sodium dodecyl
sulfate 2.0 5.0 2.0 Menthol 0.1 0.1 -- Camphor -- -- 0.3 % Total
100.0 100.0 100.0
TABLE-US-00003 TABLE 3 Proposed Bath Salt Formulations Ingredient %
w/w Nitricil .TM. 50.0 50.0 50.0 Magnesium sulfate 49.9 49.5 42.5
Citric acid, anhydrous -- -- 7.0 Menthol 0.1 -- 0.5 Camphor -- 0.5
-- % Total 100.0 100.0 100.0
[0103] 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.
* * * * *