U.S. patent application number 17/408060 was filed with the patent office on 2022-04-21 for compositions, systems, kits, and methods for treating an infection.
The applicant listed for this patent is Novan, Inc.. Invention is credited to Ryan Doxey, Megan Martin, Nathan Stasko.
Application Number | 20220118005 17/408060 |
Document ID | / |
Family ID | 1000005787183 |
Filed Date | 2022-04-21 |
United States Patent
Application |
20220118005 |
Kind Code |
A1 |
Doxey; Ryan ; et
al. |
April 21, 2022 |
COMPOSITIONS, SYSTEMS, KITS, AND METHODS FOR TREATING AN
INFECTION
Abstract
Provided herein are compositions, systems, kits, and methods for
treating a viral, bacterial, protozoan, and/or fungal (e.g.,
onychomycosis and/or tinea pedis) infection.
Inventors: |
Doxey; Ryan; (Raleigh,
NC) ; Stasko; Nathan; (Chapel Hill, NC) ;
Martin; Megan; (Cary, NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Novan, Inc. |
Morrisville |
NC |
US |
|
|
Family ID: |
1000005787183 |
Appl. No.: |
17/408060 |
Filed: |
August 20, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16091167 |
Oct 4, 2018 |
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PCT/US2017/027333 |
Apr 13, 2017 |
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17408060 |
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62484252 |
Apr 11, 2017 |
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62356891 |
Jun 30, 2016 |
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62322064 |
Apr 13, 2016 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 47/10 20130101;
A61K 33/00 20130101; A61K 9/06 20130101; A61K 47/34 20130101; A61K
47/6923 20170801; A61K 47/6903 20170801; A61K 31/80 20130101; A61K
9/0014 20130101 |
International
Class: |
A61K 33/00 20060101
A61K033/00; A61K 47/69 20060101 A61K047/69; A61K 9/00 20060101
A61K009/00; A61K 9/06 20060101 A61K009/06; A61K 47/10 20060101
A61K047/10; A61K 47/34 20060101 A61K047/34; A61K 31/80 20060101
A61K031/80 |
Claims
1. A composition comprising: a nitric oxide-releasing active
pharmaceutical ingredient (API) comprising a diazeniumdiolate
functional group; a viscosity increasing agent present in an amount
of about 0.1% to about 10% by weight of the composition, a silicone
emollient present in an amount of about 10% to about 30% by weight
of the composition, a humectant present in an amount of about 10%
to about 30% by weight of the composition, a C1-C4 alcohol present
in an amount of about 1% to about 20% by weight of the composition,
and a glycol ether present in an amount of about 20% to about 40%
by weight of the composition.
2. The composition of claim 1, wherein the nitric oxide-releasing
API is a diazeniumdiolate functional polysiloxane
macromolecule.
3. The composition of claim 1, wherein the composition comprises at
least two different viscosity increasing agents.
4. The composition of claim 1, wherein the emollient is present in
an amount of greater than 15% and up to about 30% by weight of the
composition.
5. The composition of claim 1, wherein the C1-C4 alcohol and glycol
ether are, in total, present in the composition in an amount that
is less than about 50% by weight of the composition.
6. The composition of claim 1, wherein the nitric oxide-releasing
API is present in the composition in an amount of about 0.1% to
about 50% by weight of the composition.
7. The composition of claim 1, wherein the nitric oxide-releasing
API comprises a NO-releasing co-condensed silica particle.
8. The composition of claim 1, wherein the viscosity increasing
agent is selected from cellulose, derivatized cellulose,
hydroxypropylcellulose, alginate, metallic stearates, hydrophobic
and/or hydrophilic fumed silica, silicone elastomers, silicone
elastomer blends, and any combination thereof.
9. The composition of claim 1, wherein the emollient is selected
from cyclomethicone, dimethicone, simethicone, C26-28 alkyl
dimethicone, C26-28 alkyl methicone, polyphenylsisquioxane,
trimethylsiloxysilicate and crosspolymers of cyclopentasiloxane and
dimethicone/vinyltrimethylsiloxysilicate, and any combination
thereof.
10. The composition of claim 1, wherein the humectant is a C1-C10
monoalkylene glycol.
11. The composition of claim 1, wherein the composition is
anhydrous.
12. The composition of claim 1, wherein the composition is in the
form of a gel.
13. An admixture comprising a hydrogel; and the composition of
claim 1.
14. The admixture of claim 13, wherein the hydrogel comprises a
thickening agent present in an amount of about 5% to about 20% by
weight of the hydrogel; water present in an amount of about 50% to
about 99% by weight of the hydrogel; and a buffering agent present
in an amount of about 5% to about 15% by weight of the
hydrogel.
15. A kit comprising: a hydrogel; and the composition of claim
1.
16. The kit of claim 15, wherein the hydrogel comprises a
thickening agent present in an amount of about 5% to about 20% by
weight of the composition; water present in an amount of about 50%
to about 99% by weight of the composition; and a buffering agent
present in an amount of about 0.01% to about 20% by weight of the
composition.
17. A method of treating and/or preventing a viral, bacterial,
protozoan, and/or fungal infection in and/or on a subject, the
method comprising: administering the admixture of claim 13 to the
subject, thereby treating and/or preventing the viral, bacterial,
protozoan, and/or fungal infection in and/or on the subject.
18. A method of treating and/or preventing a viral, bacterial,
protozoan, and/or fungal infection in and/or on a subject, the
method comprising: administering the admixture of claim 14 to the
subject, thereby treating and/or preventing the viral, bacterial,
protozoan, and/or fungal infection in and/or on the subject.
19. A method of increasing the release of nitric oxide from an
anhydrous topical gel comprising a diazeniumdiolate modified
macromolecule, the method comprising: contacting the composition of
claim 1 with a hydrogel to form an admixture; and applying the
admixture to the skin of a subject.
20. A method of treating and/or preventing a viral, bacterial,
protozoan, and/or fungal infection in and/or on a subject, the
method comprising: administering the admixture of claim 13 to the
subject, wherein the composition delivers a total amount of NO of
at least about 50 or 100 nmol of NO/mg of the composition at about
1, 3, 5, 10, 20, 30, 40, 50, or 60 minute(s) after an initial time
point as measured by in vitro release, thereby treating and/or
preventing the viral, bacterial, protozoan, and/or fungal infection
in and/or on the subject.
Description
RELATED APPLICATION INFORMATION
[0001] This application is a continuation of U.S. Ser. No.
16/091,167, filed on Oct. 4, 2018, which is a 35 U.S.C. .sctn. 371
national stage application of International Application No.
PCT/US2017/027333, filed Apr. 13, 2017, which claims the benefit of
U.S. Provisional Patent Application Serial Nos. 62/322,064, filed
Apr. 13, 2016, 62/356,891, filed Jun. 30, 2016, and 62/484,252,
filed Apr. 11, 2017, the disclosure of each of which is
incorporated herein by reference in its entirety.
FIELD
[0002] The present invention relates generally to compositions,
systems, kits, and methods for treating an infection, such as, for
example, a viral, bacterial, protozoan, and/or fungal (e.g.,
onychomycosis and/or tinea pedis) infection.
BACKGROUND
[0003] Fungi can be difficult to kill. Accordingly, fungal
infections of the skin and/or nail can be difficult to treat and
reoccurrence can be a common problem. In addition, fungal
infections can often infect both the skin and the nail, which may
result in the need for two different medications and/or treatment
regimens. This can reduce patient compliance and can thereby reduce
the likelihood of a positive clinical outcome.
SUMMARY
[0004] A first aspect of the present invention is directed to a
method of treating and/or preventing a viral, bacterial, protozoan,
and/or fungal infection in and/or on a subject, the method
comprising administering a composition comprising a nitric oxide
(NO)-releasing macromolecule to the subject, wherein the
composition delivers a total amount of NO of at least about 50 or
100 nmol of NO/mg of the composition at about 1, 2, 3, 4, 5, 6, 7,
8, 9, or 10 minutes after an initial time point as measured by in
vitro release, thereby treating and/or preventing the viral,
bacterial, protozoan, and/or fungal infection in and/or on the
subject. In some embodiments, the composition delivers a total
amount of NO of about 50 or 100 to about 1000 nmol of NO/mg of the
composition at about 1, 3, 5, 10, 20, 30, 40, or 50 minute(s) or 1,
2, 3, 4, 5, 6, 7, or 8 hour(s) as measured by in vitro release. In
some embodiments, the composition has a half life of nitric oxide
release of about 2 minutes to about 10 minutes or about 30 minutes
to about 1 hour.
[0005] A further aspect of the present invention is directed to a
composition including a viscosity increasing agent present in an
amount of about 0.1% to about 10% by weight of the composition, an
emollient present in an amount of about 1% to about 30% by weight
of the composition, a humectant present in an amount of about 1% to
about 30% by weight of the composition, a solvent present in an
amount of about 1% to about 20% by weight of the composition, and a
co-solvent present in an amount of about 1% to about 50% by weight
of the composition. In some embodiments, the composition may have a
shelf life of at least 3 months or more (e.g., 6, 9, 12, 18, or 24
months or more).
[0006] A further aspect of the present invention is directed to a
composition including a thickening agent present in an amount of
about 0.1% to about 25% by weight of the composition, water present
in an amount of about 50% to about 99% by weight of the
composition, and a cosolvent present in an amount of about 0.1% to
about 15% by weight of the composition.
[0007] Another aspect of the present invention is directed to an
admixture including a first composition of the present invention
(e.g., a hydrogel); and a second composition of the present
invention (e.g., an anhydrous gel). In some embodiments, the
admixture may be film-forming. The admixture may be applied to the
nail and/or skin of a subject and/or may be suitable and/or
configured for application to the nail and/or skin of a subject. In
some embodiments, the admixture may have a shelf life of at least 3
months or more (e.g., 6, 9, 12, 18, or 24 months or more).
[0008] A further aspect of the present invention is directed to a
kit including a first composition of the present invention (e.g., a
hydrogel); and a second composition of the present invention (e.g.,
an anhydrous gel). In some embodiments, the kit may form an
admixture upon dispensing the first composition and second
composition. In some embodiments, the kit may have a shelf life of
at least 3 months or more (e.g., 6, 9, 12, 18, or 24 months or
more).
[0009] Another aspect of the present invention is directed to a
packaged composition including a first composition of the present
invention (e.g., a hydrogel); and a second composition of the
present invention (e.g., an anhydrous gel). In some embodiments,
the packaged composition may have a shelf life of at least 3 months
or more (e.g., 6, 9, 12, 18, or 24 months or more).
[0010] A further aspect of the present invention is directed to a
method of treating and/or preventing a viral, bacterial, protozoan,
and/or fungal (e.g., onychomycosis and/or tinea pedis) infection in
a subject, the method including administering a composition of the
present invention to the subject, thereby treating and/or
preventing the viral, bacterial, protozoan, and/or fungal (e.g.,
onychomycosis and/or tinea pedis) infection in the subject. In some
embodiments, the composition may be administered to the nail and/or
skin of a subject and/or may be suitable and/or configured for
application to the nail and/or skin of a subject. In some
embodiments, the composition may be suitable to treat and/or
prevent a fungal infection of the nail and skin of the subject,
such as, for example, the composition may treat and/or prevent
onychomycosis and tinea pedis.
[0011] Another aspect of the present invention is directed to a
method of increasing the release of nitric oxide from an anhydrous
topical gel comprising a diazeniumdiolate modified macromolecule,
the method including contacting the anhydrous topical gel with a
hydrogel of the present invention to provide an admixture; and
applying the admixture to the skin of a subject. In some
embodiments, the admixture may be administered to the nail and/or
skin of a subject and/or may be suitable and/or configured for
application to the nail and/or skin of a subject. In some
embodiments, the admixture may be suitable to treat and/or prevent
a fungal infection of the nail and skin of the subject, such as,
for example, the admixture may treat and/or prevent onychomycosis
and tinea pedis.
[0012] 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
[0013] FIG. 1 is a diagram of a standard vertical diffusion
cell.
[0014] FIG. 2 is a graph showing the mean nitric oxide (NO)
permeation (as detected by nitrite in the receptor medium) through
human cadaver nails for NO-releasing formulations.
[0015] FIG. 3 is an illustration of a ChubTur.RTM. cell.
[0016] FIG. 4 is a graph showing the percent reduction in T. rubrum
for NO-releasing formulations.
[0017] FIG. 5 illustrates the chemical structure of Nitricil.TM.
NVN1 a polysiloxane nitric oxide-releasing macromolecule.
[0018] FIG. 6 shows time-kill curves for representative fungal
isolates following exposures to Nitricil.TM. NVN1 from 4 to 24 hrs.
Reported values are the mean of two independent assays and are
reported as the mean log CFU/mL at the designated timepoint.
Untreated Control; open circles and varying concentrations of
Nitricil.TM. NVN1; closed symbols.
[0019] FIG. 7 shows graphs of the mean percent fungal reduction
following repeated topical application of Nitricil.TM. NVN1 Gel in
the ChubTur infected nail assay.
[0020] FIG. 8 is a graph of the NO release rate over time for the
4%, 8%, and 16% Nitricil.TM. NVN1 formulations.
[0021] FIG. 9 is a graph of the total NO released over time for the
4%, 8%, and 16% Nitricil.TM. NVN1 formulations.
DETAILED DESCRIPTION
[0022] 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.
[0023] 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.
[0024] 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.
[0025] 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").
[0026] 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.
[0027] 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."
[0028] The term "about," as used herein when referring to a
measurable value, such as an amount or concentration and the like,
is meant to refer to 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 value, 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.
[0029] Provided herein are compositions, systems, kits, and/or
methods for treating and/or preventing a viral, bacterial,
protozoan, and/or fungal infection in and/or on a subject. In some
embodiments, a composition, system, kit, and/or method of the
present invention may treat and/or prevent a topical viral,
bacterial, protozoan, and/or fungal infection in and/or on a
subject. In some embodiments, a composition, system, kit, and/or
method of the present invention may treat and/or prevent
onychomycosis and/or tinea pedis. In some embodiments, a
composition of the present invention may be antimicrobial (e.g.,
antiviral, antibacterial, and/or antifungal). In some embodiments,
a composition, system, kit, and/or method of the present invention
may treat and/or prevent a microbial infection in and/or on the
skin and/or nail of a subject.
[0030] In some embodiments, a method of the present invention
comprises administering a composition comprising a NO-releasing
compound (e.g., a NO-releasing macromolecule, such as, e.g., a
co-condensed silica particle prepared from diazeniumdiolated
methylaminopropyl trimethoxysilane (MAP3) and tetra methyl
orthosilicate (TMOS)). The composition may provide a particular
release pattern for nitric oxide. All releases of nitric oxide
described herein, including those described with regard to a time
period after administration to a subject, are referenced with
respect to real time in vitro release testing. The in vivo release
of nitric oxide (e.g., the nitric oxide release when the
composition is applied to a subject) may vary with the subject to
which the composition is applied. In some embodiments, the in vivo
release of nitric oxide may vary depending on the particular
composition. However, it is believed that differences in the in
vitro release will be similarly reflected in the in vivo release of
nitric oxide. Accordingly, for clarity, unless specifically stated
that the nitric oxide release is when applied to a subject,
references to nitric oxide release with regard to embodiments of
the compositions of the present invention will be with reference to
the in vitro release of nitric oxide. Time point zero or the
initial time point of the in vitro release testing may be
correlated to the time of administration to a subject with all
subsequent real-time points corresponding to a certain time after
administration. In some embodiments, when a composition is measured
in vitro, formation of the composition (e.g., combination of two or
more compositions to form an admixture) may be used as equivalent
or comparative in time to administration of the composition to a
subject. In some embodiments, nitric oxide release may be
determined using a chemiluminescent nitric oxide analyzer.
[0031] In some embodiments, the composition may release a total
amount of NO of at least about 50 or 100 nmol of NO/mg of the
composition at about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes after
an initial time point (e.g., after formation of the composition
and/or administration to a subject) as measured by in vitro
release. In some embodiments, the composition may release a total
amount of NO of at least about 300, 400, or 500 nmol of NO/mg of
the composition at about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes
after an initial time point as measured by in vitro release. In
some embodiments, the composition may release a total amount of NO
of about 50 or 100 to about 1000 nmol of NO/mg of the composition
at about 1, 3, 5, 10, 20, 30, 40, or 50 minute(s) or 1, 2, 3, 4, 5,
6, 7, or 8 hour(s) after an initial time point as measured by in
vitro release. In some embodiments, the composition may release, on
average, a total amount of NO of about 50, 100, 150, 200, 250, 300,
350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950,
1000, or more nmol of NO/mg of the composition at about 1, 3, 5,
10, 20, 30, 40, or 50 minute(s) or 1, 2, 3, 4, 5, 6, 7, or 8
hour(s) after an initial time point as measured by in vitro
release.
[0032] In some embodiments, the composition may release a total
amount of NO of at least about 100, 150, or 200 nmol of NO/mg of
the composition at about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15
minutes after an initial time point as measured by in vitro
release. In some embodiments, the composition may release a total
amount of NO of about 100 to about 500 nmol of NO/mg of the
composition at about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15
minutes after an initial time point as measured by in vitro
release. In some embodiments, the composition may release a total
amount of NO of about 150 to about 400 nmol of NO/mg of the
composition at about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15
minutes after an initial time point as measured by in vitro
release.
[0033] In some embodiments, the composition may release, on
average, a total amount of NO of about 50 to about 300 or about 300
to about 500 nmol of NO/mg of the composition at about 30 minutes
as measured by in vitro release. In some embodiments, the
composition may release, on average, a total amount of NO of about
200 to about 600 nmol of NO/mg of the composition at about 1 hour
as measured by in vitro release. In some embodiments, the
composition may release, on average, a total amount of NO of about
200 to about 800 nmol of NO/mg of the composition at about 4 hours
as measured by in vitro release. In some embodiments, the
composition may release, on average, a total amount of NO of about
200 to about 1000 nmol of NO/mg of the composition at about 8 hours
as measured by in vitro release.
[0034] In some embodiments, a composition of the present invention
maintains a real time concentration of NO of at least about 0.2,
0.3, 0.4, 0.5, 0.6, 0.7, 0.8, or 1 pmol of NO/mg of the composition
for at least about 4, 5, 6, 7, 8, 9, or 10 hours as measured by in
vitro release. In some embodiments, the composition maintains a
real time concentration of NO of at least about 50 pmol of NO/mg of
the composition at about 1 to about 5 minutes after the initial
time point (e.g., after formation of the composition and/or
administration to a subject) as measured by in vitro release. In
some embodiments, the composition maintains a real time
concentration of NO in a range of about 50 to about 1500 pmol of
NO/mg of the composition at about 1 to about 5 minutes after the
initial time point as measured by in vitro release.
[0035] In some embodiments, a composition of the present invention
provides a maximum concentration (Cmax) of NO released of greater
than 400, 800, 1000, or 1500 pmol of NO/mg of the composition based
on a total NO release determined at 8, 10, 12, or 24 hours measured
by in vitro release. In some embodiments, the composition may
provide a Cmax of NO released of about 400, 500, 600, 700, 800,
900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900,
2000, 2100, 2200, 2300, 2400, 2500, 3000, 3500 pmol of NO/mg or
more based on a total NO release determined at 8, 10, 12, or 24
hours measured by in vitro release. In some embodiments, the Cmax
occurs within about 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 minute(s) or
45 or 30 seconds of the initial time point. In some embodiments,
the Cmax occurs at about 30 seconds to about 2, 3, 4, or 5 minutes
after an initial time point and the Cmax may be at least about 400,
800, 1000, or 1500 pmol of NO/mg of the composition based on a
total NO release determined at 8, 10, 12, or 24 hours and measured
by in vitro release.
[0036] In some embodiments, a composition of the present invention
has a half life of nitric oxide release of at least about 1 or 2
minutes based on a total NO release determined at 8, 10, 12, or 24
hours and measured by in vitro release. A half life of nitric oxide
release is achieved by determining the time at which half the
amount of the total NO released from the composition after a period
of time is released. In some embodiments, a composition of the
present invention has a half life of nitric oxide release of about
1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 2, 30, 35, 40, 45, 50, 55,
or 60 minutes based on a total NO release determined at 8, 10, 12,
or 24 hours and measured by in vitro release. In some embodiments,
a composition of the present invention has a half life of nitric
oxide release of about 2 minutes to about 10 minutes or about 30
minutes to about 1 hour based on a total NO release determined at
8, 10, 12, or 24 hours and measured by in vitro release.
[0037] A composition of the present invention may be a topical
composition (e.g., a topical antimicrobial composition). In some
embodiments, a composition of the present invention may be a
film-forming composition, such as, for example, a film-forming gel.
In some embodiments, a composition of the present invention may be
a gel prior to administration to the skin and/or nail of a subject
(e.g., during storage) and/or during administration to the skin
and/or nail of a subject, and the composition may convert and/or
transform to a film during administration to the skin and/or nail
of a subject and/or after being applied to the skin and/or nail of
a subject. In some embodiments, the primary formulation of a
composition of the present invention is a gel and the secondary
formulation is a film, which may provide longer contact time with
the nail and/or skin of a subject and/or may provide for a longer
therapeutic delivery of the composition and/or API. In some
embodiments, a film formed by a composition of the present
invention may create a barrier that may cause API release into the
skin and/or nail of a subject, which may provide for greater or
improved penetration of the composition and/or API into the skin
and/or nail of the subject. The film may be an occlusive layer that
may direct API release into the skin and/or nail of the subject. In
some embodiments, a composition of the present invention may be
applied to the nail and/or skin of a subject and/or may be suitable
and/or configured for application to the nail and/or skin of a
subject. In some embodiments, the composition may be suitable
and/or configured to treat and/or prevent a viral, bacterial,
protozoan, and/or fungal infection of the nail and skin of the
subject, such as, for example, the composition may treat and/or
prevent onychomycosis and tinea pedis. A system and/or kit of the
present invention may comprise a composition of the present
invention.
[0038] In some embodiments, a composition of the present invention
may comprise a first part and/or phase comprising a first
composition and a second part and/or phase comprising a second
composition. In some embodiments, a composition of the present
invention may be an admixture. "Admixture" as used herein refers to
a composition of the present invention that is a combination of at
least two different compositions. An admixture of the present
invention may comprise at least two parts and/or phases that may
correspond to the at least two different compositions. In some
embodiments, the at least two different compositions may be
miscible upon combination. In some embodiments, the term admixture
refers to the at least two different compositions being maintained
substantially isolated and/or separated from one another until the
proximate time of use or application. In some embodiments, the term
admixture refers to the at least two different compositions being
maintained substantially isolated and/or separated from one another
until dispensing, such as with pharmacist dispensed products. In
some embodiments, one or more compositions that may be present in
an admixture of the present invention may be maintained
substantially isolated and/or separated from one or more other
compositions that may be present in an admixture. The term
admixture is not intended to refer to a composition that is created
at the time of manufacture of the composition or product, such as
by the combining of ingredients to create the composition.
[0039] The combining of two or more different compositions, such
as, e.g., 2, 3, 4, 5, 6, 7, or more compositions, to form an
admixture may be achieved by mixing, blending, contacting, applying
to a same area or region, emulsifying, and/or the like the two or
more different compositions. The combining of two or more different
compositions may be carried out to induce a chemical reaction. A
composition present in and/or used to form an admixture of the
present invention may be different than another composition present
in and/or used to form the admixture in the amount or concentration
of one or more components, the type (e.g., chemical composition) of
one or more components, and/or the presence and/or absence of one
or more components.
[0040] An admixture of the present invention may comprise at least
one composition that modulates a property of another composition
and/or a component present in the admixture. The property modulated
may be compared to the property of the composition and/or component
in the absence of the admixture. For example, the admixture may
comprise at least one composition (e.g., a first composition) that
modulates the pH of another composition (e.g., a second
composition) and/or the release of an active pharmaceutical
ingredient (API) in another composition (e.g., a second
composition). As used herein, release of the API refers to release
of the API itself and/or release of one or more active agents from
the API. For example, in embodiments where the API is a nitric
oxide-releasing API, references to API release may refer to release
of nitric oxide from the API. The pH of the admixture may be
compared to the pH of the second composition when it is not in
admixture with the first composition or vice versa. The release of
the API from the admixture may be compared to the release of the
API in the absence of the admixture (e.g., the release of the
individual API component and/or the release of the API from the
second composition when the second composition is not in admixture
with the first composition).
[0041] "Modulate," "modulating," "modulation," and grammatical
variations thereof as used herein refer to an increase or reduction
in a value or parameter. Modulate and grammatical variations
thereof in reference to the pH of a second composition of the
present invention and/or the release of an API in a second
composition of the present invention refer to an increase or
reduction compared to the pH of the second composition and/or the
release of the API in the second composition in the absence of a
first composition of the present invention. As used herein, the
terms "increase," "increases," "increased," "increasing" and
similar terms indicate an elevation in a value or parameter of at
least about 5%, 10%, 25%, 50%, 75%, 100%, 150%, 200%, 300%, 400%,
500% or more, and, when used in reference to the pH and/or release
of an API, refer to an elevation when compared to the pH and/or
release in the absence of a first composition of the present
invention. As used herein, the terms "reduce," "reduces,"
"reduced," "reduction" and similar terms refer to a decrease in a
value or parameter of at least about 5%, 10%, 25%, 35%, 50%, 75%,
80%, 85%, 90%, 95%, 97% or more, and, when used in reference to the
pH and/or release of an API, refer to a decrease when compared to
the pH and/or release in the absence of a first composition of the
present invention.
[0042] In some embodiments, an admixture may comprise at least two
compositions (i.e., a first composition and a second composition).
The first composition may modulate the pH of the second composition
and/or the release of an API present in the second composition or
vice versa. Admixtures comprising two compositions are described
herein for purposes of illustration, but it is understood that the
admixture may comprise more than two different compositions, such
as, but not limited to, 2, 3, 4, 5, 6, 7, or more compositions. One
or more of the compositions present in the admixture may modulate a
property of another composition in the admixture. The property
modulated may be the same property or a different property. In some
embodiments, two or more different compositions in an admixture may
together modulate a property of another composition in the
admixture.
[0043] An admixture of the present invention may be formed by
direct and/or indirect exposure of at least one component in a
first composition to at least one component in a second
composition. For example, an admixture may be formed by mixing
and/or combining the first composition and second composition prior
to, during, and/or after topical application to a subject. The
admixture may comprise a single phase even though it may be
prepared from at least two different compositions. A further
example of direct exposure of a first composition and second
composition to form an admixture may occur by applying one or more
layers of the second composition onto a subject and then applying
one or more layers of the first composition onto a subject or vice
versa. Indirect exposure may occur by applying a second composition
onto a subject and then applying a first composition onto a subject
through a substrate, such as, but not limited to, a cloth, bandage,
gauze, and the like, or vice versa, to form an admixture.
[0044] An admixture of the present invention may provide a
particular release pattern for an API present in the admixture. The
API release pattern may be determined by comparing the amount or
concentration of API released over a period of time and/or the rate
of release of an API from the admixture over a period of time. In
some embodiments, the at least two different compositions present
in the admixture are selected to provide a particular API release
pattern. The API release pattern may be desirable for a particular
infection, injury, disease, disorder, or treatment indication. In
some embodiments, an admixture and/or two compositions of the
present invention may provide and/or may be configured to provide a
particular release pattern of an API present in the admixture. In
some embodiments, an admixture and/or two compositions of the
present invention may provide and/or may be configured to treat
and/or prevent a viral, bacterial, protozoan, and/or fungal (e.g.,
onychomycosis and/or tinea pedis) infection.
[0045] In some embodiments, the at least two different compositions
present in the admixture may be selected to provide the admixture
with a pH of less than about pH 11, such as, but not limited to,
about 11, 10, 9, 8, 7, 6, 5, 4, 3, or less. In some embodiments,
the at least two different compositions present in the admixture
may be selected to provide the admixture with a pH of greater than
about pH 3, such as, but not limited to, about 3, 4, 5, 6, 7, 8, 9,
10, 11, or more. In certain embodiments, the admixture pH may be
between about pH 3 to about pH 11, such as, but not limited to,
about pH 4 to about pH 9, about pH 7 to about pH 9, about pH 4 to
about pH 8, pH 7 to about pH 10, about pH 4 to about pH 10, or
about pH 5 to about pH 7. In some embodiments, at least one of the
compositions present in the admixture may maintain the pH of the
admixture in a particular pH range. The pH of the admixture may
vary over time and this may cause the release rate of the API from
the admixture to vary over time. For admixtures where the pH
changes over time, the pH of the admixture may be measured within
about 30 minutes after combination, in some embodiments, within
about 10 minutes after combination, and in some embodiments, 2
minutes after combination. In some embodiments, the pH of the
admixture may be measured at about 5 minutes, 30 minutes, 1 hour,
and/or 24 hours after combination.
[0046] A composition of the present invention (e.g., an admixture)
may provide for immediate release of the API from the composition
and/or sustained release of the API from the composition. As used
herein, immediate release refers to the release of 50% or more of
the API within 4 hours of mixing and sustained release refers to
the release of less than 50% of the API within 4 hours of mixing.
In some embodiments, an admixture of the present invention may
increase the amount of API released and/or the potency of an API
present in at least one composition in the admixture by maintaining
the pH of the admixture in a particular pH range compared to the
release and/or potency of the API in the composition in the absence
of the admixture. In some embodiments, the pH of the composition
(e.g., admixture) is maintained below pH 9.
[0047] The API present in the composition may be released
substantially continuously from the composition over a period of
time. "Substantially continuously," and grammatical variants
thereof as used herein refer to a release of an API from the
composition for all or part of the time such that on average the
release of the API confers an overall beneficial effect on the
subject. Thus, there may be one or more short, intermittent and/or
regular time periods in which the API is not being released, but
the overall beneficial effect of the API on the subject remains. In
some embodiments, the composition may provide an API release
pattern that is substantially continuous over a period of time and
may provide a therapeutically effective amount of the API over the
period of time. In some embodiments, the amount of API released
and/or the API release rate may vary over a period of time. In
certain embodiments, the composition may comprise two or more
(e.g., 2, 3, 4, 5 or more) release rates for the API.
[0048] The composition may provide an API release pattern that is
substantially constant over a period of time. "Substantially
constant" as used herein refers to a measureable value, such as the
amount of API or the API release rate, on average, varying less
than about 20%, 15%, 10%, 5%, 1% or less over a period of time. In
some embodiments, the API release rate may be substantially
constant for a period of time and vary over another consecutive or
nonconsecutive period of time and vice versa.
[0049] In some embodiments, the composition may provide an API
release pattern having a rapid release portion and a substantially
constant release portion. The rapid release portion may comprise
the amount of API released from administration (i.e., t=0) to 2
hours after administration or any range therein, such as, but not
limited to, about 0 to about 1 hour or about 0 to about 30 minutes
after administration. The substantially constant release portion
may comprise the amount of API released from immediately after the
rapid release portion to the final amount of API is released. An
API may be released from a composition of the present invention for
any period of time. In some embodiments, an API may be released
from the composition for at least about 4 hours, 6 hours, 12 hours,
24 hours, 2 days, 3, days, 4 days, 5, days, 6 days, 7 days, or
more, or any range and/or individual value therein. The API
released from the composition may be released in an amount that
overall provides a beneficial effect on the subject and/or provides
a therapeutically effective amount of the API over a given period
of time.
[0050] In some embodiments, a greater amount or concentration of
the API may be released during the rapid release portion compared
to the substantially constant release portion or vice versa. In
some embodiments, the amount of API released from the composition
during the rapid release portion may be about 10%, 20%, 30%, 40%,
50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 300%, 400%, 500%, or
more, or any range and/or individual value therein, of the amount
of API released during the substantially constant release portion.
In other embodiments, the amount of API released from the
composition during the substantially constant release portion may
be about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%,
200%, 300%, 400%, 500%, or more, or any range and/or individual
value therein, of the amount of API released during the rapid
release portion.
[0051] In some embodiments, at least 50% or more (e.g., 60%, 70%,
80%, 90%, 95%, or more) of an API may be released from a
composition of the present invention in less than about 2 hours,
1.75 hours, 1.5 hours, 1.25 hours, 1 hour, 45 minutes, or 30
minutes or any range and/or individual value therein. In some
embodiments, the Cmax of an API released from a composition of the
present invention may be achieved in less than about 2 hours, 1.75
hours, 1.5 hours, 1.25 hours, 1 hour, 45 minutes, 30 minutes, 25
minutes, 20 minutes, 15 minutes, 10 minutes, 5 minutes, or 2
minutes or any range and/or individual value therein. In some
embodiments, a composition of the present invention may administer
and/or deliver the API in a concentration or amount sufficient to
penetrate a given skin and/or nail thickness, (e.g., a thickness of
about 4 mm or less) to which the composition is applied. In some
embodiments, a composition of the present invention may administer
and/or deliver an API through a nail of a subject to the respective
nail bed. In some embodiments, a composition of the present
invention may release and/or deliver an API in an amount that
achieves a minimum inhibitory concentration for a respective fungus
to treat and/or prevent a fungal infection. In some embodiments, a
composition of the present invention may release and/or deliver an
API at concentration that provides a 3 log microbial kill in a
given period of time for a respective fungus, such as, for example,
T. rubrum. In some embodiments, the 3 log microbial kill may be in
120 minutes (i.e., MBC120), 3 hours or more, such as, for example,
4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,
22, 23, 24 hours or more.
[0052] In some embodiments, a first composition in an admixture may
modulate the pH of a second composition in the admixture such that
when the admixture is formed and/or applied to the skin of a
subject, the pH of the admixture is less than about 11, in further
embodiments, less than about 10, in still further embodiments, less
than about 9, and in yet further embodiments, between about 5 and
about 8. In some embodiments, a first composition in an admixture
may be configured to maintain and/or stabilize the pH of the
admixture in a desired pH range, such as, but not limited to, a pH
range of about 3 to about 11, about 3 to about 9, about 4 to about
7, or about 5 to about 8.
[0053] An admixture of the present invention may be suitable for
topical administration. The admixture may comprise a single phase
even though it may be prepared or formed from two or more different
compositions. The admixture may be buffered. In some embodiments,
the admixture may comprise a first composition and a second
composition. In some embodiments, the first composition may be a
hydrogel. "Hydrogel," as used herein, refers to a hydrophilic gel
comprising a gel matrix and water. In some embodiments, the second
composition may be an anhydrous gel. The hydrogel and anhydrous gel
when combined may form an admixture having a single phase that is
optionally buffered. The second composition may comprise a nitric
oxide-releasing active pharmaceutical ingredient (NO-releasing
API). In some embodiments, the hydrogel and anhydrous gel when
combined may be a film-forming composition (e.g., a film-forming
gel).
[0054] In some embodiments, a composition, system, kit, and/or
admixture of the present invention comprises, consists essentially
of, or consists of a first composition of the present invention and
a second composition of the present invention. The first
composition and the second composition may be compatible with each
other such that they may be mixed and/or combined together to
provide an admixture of the present invention.
[0055] In some embodiments, a hydrogel and/or admixture of the
present invention may comprise a thickening agent, water, a
co-solvent, and/or buffering agent. The hydrogel and/or admixture
may further comprise a preservative. In some embodiments, the
hydrogel and/or admixture may further comprise other excipients,
such as, e.g., humectants, anti-tacking agents, opacifiers, and/or
acidifying agents. In some embodiments, a composition of the
present invention (e.g., a hydrogel and/or admixture) does not
include a chelating agent.
[0056] One or more (e.g., 1, 2, 3, 4, or more) thickening agent(s)
may be present in a hydrogel and/or admixture of the present
invention. In some embodiments, a hydrogel and/or admixture may
comprise at least two different thickening agents. Example
thickening agents include, but are not limited to, a
carboxypolymethylene; a polyacrylic polymer and/or copolymer such
as polyacrylic acid, a polyacrylate polymer, a cross-linked
polyacrylate polymer, a cross-linked polyacrylic acid polymer
and/or copolymer, and mixtures thereof a cellulose ether such as
hydroxyalkyl cellulose polymers such as hydroxypropyl methyl
cellulose (HPMC), hydroxypropyl cellulose, hyrdoxyethyl cellulose,
methyl cellulose, carboxymethyl cellulose and its salts (e.g.,
sodium carboxymethyl cellulose), and mixtures thereof a
methacrylate; a polyvinylpyrollidone; a cross-linked polyvinyl
pyrrolidone; a copolymer of methyl vinyl ether and maleic
anhydride; a polyvinylpyrrolidone-vinyl acetate copolymer;
polyvinylalcohol; polyethylene oxide; polyethylene glycol;
polyvinylalkyl ether-maleic acid copolymer; 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; and any combination
thereof. In some embodiments, the thickening agent may be a film
forming agent (e.g., a film forming polymer), such as, but not
limited to, ammonium alginate, chitosan, chlorpheniramine maleate,
copovidone, dibutyl phthalate, dibutyl sebacate, diethyl phthalate,
dimethyl phthalate, ethyl lactate, ethylcellulose, gelatin,
hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose,
hypromellose acetate succinate, maleic acid, maltodextrin,
polyethylene glycol, polyethylene oxide, polymethacrylates,
poly(methylvinyl ether/maleic anhydride), copolymers of methyl
vinyl ether and maleic acid, and/or polyvinyl acetate
phthalate.
[0057] In some embodiments, a hydrogel and/or admixture of the
present invention may comprise a copolymer of methyl vinyl ether
and maleic acid, such as, but not limited to, those commercially
available from Ashland, Inc. of Covington, Ky. under the trade name
Gantrez.TM.. Example Gantrez.TM. polymers that may be present in a
hydrogel and/or admixture of the present invention include, but are
not limited to, Gantrez.TM. S polymers such as, for example,
Gantrez.TM. S-97, Gantrez.TM. S-95, and/or Gantrez.TM. S-97 BF.
[0058] In some embodiments, a hydrogel and/or admixture of the
present invention may comprise a carboxypolymethylene, a
crosslinked polyacrylate polymer, and/or a cross-linked polyacrylic
acid copolymer, such as, but not limited to, those commercially
available from Lubrizol Corporation of Wickliffe, Ohio under the
trade name Carbopol.RTM.. Example Carbopol.RTM. polymers that may
be present in a hydrogel and/or admixture of the present invention
include, but are not limited to, Carbopol.RTM. 974P NF polymer,
such as Type A, Type B and/or Type C Homopolymers; Carbopol.RTM.
2020 ETD, Carbopol.RTM. Ultrez 10, 20, 21 NF polymer; Carbopol.RTM.
971P NF polymer; Carbopol.RTM. 980 Homopolymer Type C polymer,
Carbopol.RTM. 980 NF polymer, Carpobol.RTM. 980P polymer,
Carbopol.RTM. ETD 2020 NF polymer, Carbopol.RTM. 71 G NF polymer,
Carbopol.RTM. 981P NF polymer, Carbopol.RTM. 970P NF polymer,
Carbopol.RTM. 981P NF polymer, Carbopol.RTM. 5984P NF polymer,
Carbopol.RTM. 934P NF polymer, Carbopol.RTM. 940P NF polymer,
Carbopol.RTM. 941P NF polymer, Carbopol.RTM. 13242 NF polymer,
Carbopol.RTM. AA-1 USP NF polymer, Carbopol.RTM. TR1 NF polymer,
Carbopol.RTM. TR2 NF polymer, Lubrizol Aqua CC polymer and SF-2
polymer, and any combination thereof.
[0059] In some embodiments, a thickening agent present in a
hydrogel and/or admixture of the present invention may be a polymer
comprising acidic groups, such as, but not limited to, carboxylic
acid groups. The acidic groups of the polymer may be partially
neutralized in a hydrogel and/or admixture of the present
invention. In some embodiments, a thickening agent present in a
hydrogel and/or admixture of the present invention may be a
carboxypolymethylene, a crosslinked polyacrylate polymer, and/or a
cross-linked polyacrylic acid copolymer. In some embodiments, a
carboxypolymethylene, a crosslinked polyacrylate polymer, and/or a
cross-linked polyacrylic acid copolymer present in a hydrogel
and/or admixture of the present invention may be partially
neutralized. A hydrogel of the present invention may comprise a
carboxypolymethylene, a crosslinked polyacrylate polymer, and/or a
cross-linked polyacrylic acid copolymer and have a pH of about 3 to
about 7, about 3.5 to about 6.5, about 3.5 to about 6, about 3 to
about 4, or about 4 to about 6. In certain embodiments, a hydrogel
of the present invention may comprise a carboxypolymethylene, a
crosslinked polyacrylate polymer, and/or a cross-linked polyacrylic
acid copolymer and have a pH of about 3, 3.5, 4, 4.5, 5, 5.5, 6,
6.5, or 7.
[0060] One or more thickening agent(s) (e.g., 1, 2, 3, 4, 5 or
more), alone or together, may be present in a hydrogel of the
present invention at a concentration from about 0.1% to about 30%
by weight of the hydrogel or any range and/or individual value
therein, such as, but not limited to, about 0.2% to about 20%,
about 0.1% to about 25%, about 5% to about 20%, about 0.5% to about
2%, about 0.5% to about 5%, or about 10% to about 20% by weight of
the hydrogel. In some embodiments, one or more thickening agent(s)
may be present in the hydrogel in an amount of 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%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%,
10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14%, 14.5%, 15%,
15.5%, 16%, 16.5%, 17%, 17.5%, 18%, 18.5%, 19%, 19.5%, 20%, 20.5%,
21%, 21.5%, 22%, 22.5%, 23%, 23.5%, 24%, 24.5%, or 25% by weight of
the hydrogel or any range and/or individual value therein. In some
embodiments, one or more thickening agent(s) may be present in a
hydrogel in an amount greater than 5% by weight of the hydrogel. In
some embodiments, the total amount of thickening agent(s) present
in a hydrogel of the present invention (i.e., the sum of the amount
of all thickening agents present in the hydrogel) may be greater
than 5% and up to 30% by weight of the hydrogel. In some
embodiments, a hydrogel and/or admixture of the present invention
comprises a copolymer of methyl vinyl ether and maleic acid,
carboxymethylcellulose or a salt thereof, and/or a crosslinked
polyacrylic acid polymer.
[0061] Water may be present in a hydrogel and/or admixture of the
present invention. Water may be a solvent in a hydrogel of the
present invention. In some embodiments, water may be present in a
hydrogel of the present invention in an amount of about 50% or more
by weight of the hydrogel, such as, for example, about 50% to about
75%, about 50% to about 70%, about 50% to about 60%, or about 70%
to about 80% by weight of the hydrogel. In some embodiments, water
may be present in a hydrogel of the present invention in an amount
of about 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 hydrogel or any range and/or individual value
therein. In some embodiments, water may be present in amount less
than 70% by weight of the hydrogel.
[0062] One or more (e.g., 1, 2, 3, 4, or more) co-solvent(s) may be
present in a hydrogel and/or admixture of the present invention. In
some embodiments, a hydrogel and/or admixture may comprise at least
two different co-solvents. Example co-solvents include, but are not
limited to, acetone, an alcohol (e.g., methyl alcohol, benzyl
alcohol, ethanol, isopropyl alcohol, butyl alcohol, and/or
phenoxyethanol), dimethyl isosorbide, cyclomethicone, propylene
glycol, hexylene glycol, glycerol, isopropanol, ethylene glycol,
polyethylene glycol, ethoxydiglycol, isopropyl palmitate, butylene
glycol, pyrrolidone, dimethyl sulfoxide (DMSO), ethyl acetate, an
ether (e.g., diethylene glycol monoethyl ether), and any
combination thereof. In some embodiments, the co-solvent may be an
alcohol. As one of skill in the art will understand, the
co-solvent(s) in the hydrogel and/or admixture may be miscible with
the solvent(s) in the hydrogel and/or admixture.
[0063] One or more co-solvent(s) (e.g., 1, 2, 3, 4, 5 or more),
alone or together, may be present in a hydrogel of the present
invention at a concentration from about 0.1% to about 20% by weight
of the hydrogel or any range and/or individual value therein, such
as, but not limited to, about 0.1% to about 15%, about 0.1% to
about 10%, about 1% to about 10%, about 5% to about 10%, about 0.5%
to about 3.5%, or about 2.5% to about 10% by weight of the
hydrogel. In some embodiments, one or more co-solvent(s) may be
present in the hydrogel in an amount of 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%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%,
10.5%, 11%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14%, 14.5%, or 15% by
weight of the hydrogel or any range and/or individual value
therein. In some embodiments, the total amount of co-solvent(s)
(e.g., alcohol(s)) present in a hydrogel of the present invention
(i.e., the sum of the amount of all co-solvents present in the
hydrogel) may be 20% or less by weight of the hydrogel, and in some
embodiments, may be less than 15% or 10% by weight of the hydrogel.
In some embodiments, the admixture and/or hydrogel comprises an
alcohol.
[0064] A hydrogel of the present invention may be unbuffered or
buffered. In some embodiments, a hydrogel of the present invention
may be unbuffered. In other embodiments, a hydrogel of the present
invention may be buffered. Example buffering agents that may be
present in hydrogel and/or admixture of the present invention
include, but are not limited to, acetic acid, an acetate (e.g.,
sodium acetate, etc.), hydrochloric acid, a citrate (e.g., sodium
citrate, calcium citrate, etc.), a citro-phosphate, citric acid,
lactic acid, tartaric acid, malic acid, glycine/HCl, saline (e.g.,
phosphate buffered saline (PBS), Tris-buffered saline (TBS),
Tris-HCl, NaCl, Tween buffered saline (TNT), Triton X-100 (PBT) and
mixtures thereof), cacodylate, barbital, tris, boric acid, a borate
(e.g, sodium boradate), succinic acid, a succinate (e.g., sodium
succinate), a phosphate (e.g., potassium phosphate monobasic,
monobasic sodium phosphate, etc.), a carbonate (e.g., calcium
carbonate, etc.), a bicarbonate (e.g., sodium bicarbonate), and any
combination thereof.
[0065] One or more buffering agent(s) (e.g., 1, 2, 3, 4, 5 or
more), alone or together, may be present in a hydrogel of the
present invention in an amount of about 0.01% to about 20% by
weight of the hydrogel or any range and/or individual value
therein, such as, but not limited to, about 0.1% to about 15%,
about 10% to about 20%, about 5% to about 15%, or about 1% to about
15% by weight of the hydrogel. In some embodiments, a buffering
agent is present in a hydrogel of the present invention 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%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%,
7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13%,
13.5%, 14%, 14.5%, 15%, 15.5%, 16%, 16.5%, 17%, 17.5%, 18%, 18.5%,
19%, 19.5%, or 20% by weight of the hydrogel or any range and/or
individual value therein. In some embodiments, one or more
buffering agent(s) may be present in a hydrogel in an amount
greater than 2% by weight of the hydrogel. In some embodiments, the
total amount of buffering agent(s) present in a hydrogel of the
present invention (i.e., the sum of the amount of all buffering
agents present in the hydrogel) may be greater than 2% and up to
20% by weight of the hydrogel.
[0066] In some embodiments, a buffering agent may present in a
hydrogel of the present invention in an amount sufficient for the
first composition to have a pH of about 3 to about 8 or any range
and/or individual value therein, such as, but not limited to, about
3 to about 6, about 3 to about 5, about 3 to about 4, about 4 to
about 7, about 5 to about 7, or about 6 to about 7. In some
embodiments, a buffering agent may be present in a hydrogel of the
present invention in an amount sufficient for the hydrogel to have
a pH of about 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, or 8, or any
range and/or individual value therein. In some embodiments, the pH
of the hydrogel is about 3.5 to about 4.5.
[0067] In some embodiments, a buffering agent may be present in a
hydrogel and/or admixture of the present invention in an amount
sufficient to provide a desired pH for the admixture comprising the
hydrogel and a second composition of the present invention (e.g.,
an anhydrous gel). For example, an admixture of the present
invention may comprise the second composition and a hydrogel
comprising a buffering agent, wherein the buffering agent is
present in an amount sufficient to provide the admixture with a pH
of about 3 to about 11, such as, but not limited to, about 3 to
about 8, about 7 to about 11, about 8 to about 10, about 3 to about
5, about 4 to about 7, about 5 to about 7, or about 6 to about 7.
In some embodiments, a buffering agent may be present in a hydrogel
of the present invention in an amount sufficient for the admixture
to have a pH of about 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8,
8.5, 9, 9.5, 10, 10.5, or 11, or any range and/or individual value
therein. In some embodiments, the buffering agent may be present in
a hydrogel of the present invention in an amount sufficient to
provide a desired pH upon administration of an admixture of the
present invention comprising the hydrogel and a second composition
of the present invention to the skin of a subject.
[0068] A hydrogel and/or admixture of the present invention may
comprise one or more (e.g., 2, 3, 4, or more) preservative(s).
Example preservatives that may be present in a hydrogel and/or
admixture of the present invention include, but are not limited to,
sorbic acid, benzoic acid, methyl-paraben, propyl-paraben,
methylchloroisothiazolinone, metholisothiazolinone, diazolidinyl
urea, chlorobutanol, triclosan, benzethonium chloride,
p-hydroxybenzoate, chlorhexidine, digluconate, hexadecyltrimethyl
ammonium bromide, alcohols, benzalkonium chloride, boric acid,
bronopol, butylparaben, butylene calcium acetate, calcium chloride,
calcium lactate, carbon dioxide, cationic, and bentonite,
cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol,
chlorocresol, chloroxylenol, citric acid monohydrate, cresol,
dimethyl ether, ethylparaben, glycerin, hexetidine, imidurea,
isopropyl alcohol, lactic acid, monothioglycerol, pentetic acid,
phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric
acetate, phenylmercuric borate, phenylmercuric nitrate, potassium
benzoate, potassium metabisulfite, potassium sorbate, propionic
acid, propyl gallate, propylene glycol, sodium acetate, sodium
benzoate, sodium borate, sodium lactate, sodium sulfite, sodium
propionate, sodium metabisulfite, xylitol, sulphur dioxide, carbon
dioxide, and any combination thereof.
[0069] A preservative may be present in a hydrogel of the present
invention in an amount of about 0.01% to about 1% by weight of the
hydrogel or any range and/or individual value therein, such as, but
not limited to, about 0.01% to about 0.1%, about 0.05% to about 1%,
or about 0.1% to about 1% by weight of the hydrogel. In some
embodiments, a preservative may be present in a hydrogel of the
present invention 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%, or 1% by weight of the hydrogel or any
range and/or individual value therein.
[0070] A hydrogel and/or admixture of the present invention may
comprise one or more (e.g., 2, 3, 4, or more) moisturizer(s).
Example moisturizers that may be present in a hydrogel and/or
admixture of the present invention include, but are not limited to,
almond oil, aluminum stearate, canola oil, castor oil, ceratonia
extract, cetostearyl alcohol, cetyl alcohol, cetyl esters wax,
cholesterol, coconut oil, cottonseed oil, cyclomethicone, dibutyl
sebacate, dimethicone, ethylene glycol palmitostearate, glycerin,
glycerin monostearate, glyceryl monooleate, glyceryl monostearate,
isopropyl myristate, isopropyl palmitate, lanolin, lecithin, light
mineral oil, medium-chain triglycerides, mineral oil, mineral oil
and lanolin alcohols, myristyl alcohol, octyldodecanol, oleyl
alcohol, petrolatum, petrolatum and lanolin alcohols, safflower
glycerides, safflower oil, soybean oil, stearyl alcohol, sunflower
oil, tricaprylin, triolein, xylitol, zinc acetate, cyclomethicone,
and any combination thereof.
[0071] A moisturizer may be present in a hydrogel of the present
invention in an amount of about 0.01% to about 10% by weight of the
hydrogel or any range and/or individual value therein, such as, but
not limited to, about 0.01% to about 0.1%, about 0.05% to about 1%,
about 1% to about 10%, about 2% to about 8%, about 5% to about 8%,
or about 0.1% to about 1% by weight of the hydrogel. In some
embodiments, a moisturizer may be present in a hydrogel of the
present invention 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%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%,
5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10% by weight of
the hydrogel or any range and/or individual value therein.
[0072] A composition (e.g., hydrogel, second composition, and/or
admixture) of the present invention may further comprise one or
more excipients. Excipients for use in pharmaceutical compositions
are well-known in the art and examples may be found in the Handbook
of Pharmaceutical Excipients (Rowe, R. C. et al., APhA
Publications; 5th ed., 2005). Classes of excipients may include,
but are not limited to, a humectant, a pH modifier, a water
repelling agent, an anti-foaming agent, a surfactant, a
solubilizer, an emulsifying agent, a wetting agent, a penetration
enhancer, opacifier (e.g., titanium dioxide) and/or an
antioxidant.
[0073] An excipient may be present in a composition of the present
invention at any suitable concentration. In some embodiments, an
excipient may be present in a composition of the present invention
at a concentration from about 0.1% to about 20% by weight of the
composition or any range and/or individual value therein, such as,
but not limited to, from about 1% to about 15%, about 0.1% to about
10%, or about 5% to about 10% by weight of the composition. In some
embodiments, a excipient may be present in a composition of the
present invention in an amount of 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%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 10.5%,
11%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14%, 14.5%, 15%, 15.5%, 16%,
16.5%, 17%, 17.5%, 18%, 18.5%, 19%, 19.5%, or 20% by weight of the
composition or any range and/or individual value therein.
[0074] In some embodiments, a hydrogel of the present invention
comprises, consists essentially of, or consists of a thickening
agent present in an amount of about 0.1% to about 25% or 30% by
weight of the hydrogel, water present in an amount of about 50% to
about 99% by weight of the hydrogel, and a co-solvent present in an
amount of about 0.1% to about 15% by weight of the hydrogel. The
hydrogel may be buffered to have a pH in a range of about 3 to
about 8, about 3 to about 6, or about 3 to about 5. In some
embodiments, a hydrogel of the present invention comprises,
consists essentially of, or consists of a thickening agent present
in an amount of greater than 5% and up to about 25% or 30% by
weight of the hydrogel, a co-solvent present in an amount of about
0.1% to about 5% or 10% by weight of the hydrogel, and water
present in an amount of about 50% to less than 70% by weight of the
hydrogel. The hydrogel may comprise at least two different
thickening agents and/or at least two different co-solvents. In
some embodiments, the hydrogel may comprise a buffering agent
present in an amount of about 0.01% to about 20% by weight of the
hydrogel. The hydrogel may further comprise a buffering agent
present in an amount of about 0.1% to about 20% by weight of the
hydrogel, and, in some embodiments, in an amount of greater than 2%
and up to about 20% by weight of the hydrogel. The hydrogel may
further comprise a preservative in an amount of about 0.1% to about
1% by weight of the hydrogel and/or a moisturizer present in an
amount of about 0.1% to about 10% by weight of the hydrogel.
[0075] In some embodiments, a hydrogel of the present invention
comprises, consists essentially of, or consists of a thickening
agent present in an amount of about 0.1% to about 25% or 30% by
weight of the hydrogel, water present in an amount of about 50% to
about 70% by weight of the hydrogel, a buffering agent present in
an amount of about 1% to about 20% by weight of the hydrogel, and a
co-solvent present in an amount of about 1% to about 15% by weight
of the hydrogel. The hydrogel may be buffered to have a pH in a
range of, or about 3 to about 5 or may have a pH of about 4. The
hydrogel may comprise at least two different thickening agents and
the total amount of the thickening agent agents present in the
hydrogel may be less than 25% or 30% by weight of the hydrogel.
[0076] As those skilled in the art will recognize in light of the
present disclosure, the properties of a hydrogel of the present
invention may confer and/or provide the same and/or similar
properties to a composition of the present invention. For example,
in some embodiments, a hydrogel of the present invention may
comprise a preservative that is present in an amount sufficient to
provide antimicrobial activity to an admixture in which the
hydrogel is present. Thus, in some embodiments, a hydrogel,
composition, and/or admixture of the present invention may be
antimicrobial.
[0077] A composition and/or hydrogel of the present invention may
have a viscosity in a range of about 5,000 cP to about 25,000 cP or
any range and/or individual value therein, such as, but not limited
to, about 5,000 cP to about 20,000 cP or about 7,000 cP to about
15,000 cP. In certain embodiments, a composition and/or hydrogel of
the present invention may have a viscosity of about 5,000, 5,500,
6,000, 6,500, 7,000, 7,500, 8,000, 8,500, 9,000, 9,500, 10,000,
10,500, 11,000, 11,500, 12,000, 12,500, 13,000, 13,500, 14,000,
14,500, 15,000, 15,500, 16,000, 16,500, 17,000, 17,500, 18,000,
18,500, 19,000, 19,500, 20,000, 20,500, 21,000, 21,500, 22,000,
22,500, 23,000, 23,500, 24,000, 24,500, or 25,000 cP or any range
and/or individual value therein.
[0078] In some embodiments, a composition of the present invention
may comprise a hydrogel of the present invention that has a
viscosity that allows for mixing and/or combination with a second
composition. For example, a hydrogel of the present invention may
have a viscosity suitable and/or sufficient for mixing and/or
combination with a second composition of the present invention in a
person's hand and/or on a subject's skin. A hydrogel with too low
of a viscosity may run off the skin of a subject prior to mixing
and/or combination. A hydrogel with too high a viscosity may be
difficult to mix with a second composition of the present invention
and/or difficult to spread and/or apply the admixture on the skin
of a subject. In some embodiments, a second composition of the
present invention may have a viscosity in a range of about 30,000
cP to about 100,000 cP or any range and/or individual value
therein, such as, but not limited to, about 30,000 cP to about
75,000 cP or about 75,000 cP to about 100,000 cP. In some
embodiments, a second composition of the present invention may have
a viscosity of about 50,000, 55,000, 60,000, 65,000, 70,000,
75,000, 80,000, 85,000, 90,000, 95,000, or 100,000 cP or any range
and/or individual value therein.
[0079] A composition of the present invention may comprise an
active pharmaceutical ingredient (API). Any suitable API or
combinations of APIs may be included in a composition of the
present invention. Examples of APIs include, but are not limited
to, antimicrobial agents, anti-acne agents, anti-inflammatory
agents, analgesic agents, anesthetic agents, antihistamine agents,
antiseptic agents, immunosuppressants, antihemorrhagic agents,
vasodilators, wound healing agents, anti-biofilm agents, and any
combination thereof. Example APIs include, but are not limited to,
those described in International Application Publication No. WO
2013/006608, which is incorporated herein by reference in its
entirety.
[0080] In some embodiments, a hydrogel of the present invention may
not comprise an API. In certain embodiments, a hydrogel of the
present invention does not contain a nitric oxide (NO) releasing
API. In some embodiments, a hydrogel of the present invention may
comprise at least one API, but the hydrogel may not comprise an
NO-releasing API.
[0081] In some embodiments, a hydrogel of the present invention may
comprise an API. In some embodiments, a hydrogel of the present
invention comprises an API and a second composition of the present
invention comprises a second API (e.g., a moisture sensitive API).
In some embodiments, the API in the hydrogel and the second API in
the second composition may not be chemically compatible and/or
stable in the composition of the present invention. For example,
the API in the hydrogel and the second API in the second
composition may not be chemically compatible and/or stable when
stored together in a composition of the present invention.
[0082] A hydrogel of the present invention may be suitable for use
and/or combination with one or more, such as, but not limited to,
2, 3, 4, or more, compositions that may be the same and/or
different. In some embodiments, a hydrogel of the present invention
may be suitable for use and/or combination with one or more
pharmaceutical compositions. A hydrogel of the present invention
may be used as a drug delivery system and/or a drug release system.
For example, a hydrogel of the present invention may be configured
to modulate the release of an API in a second composition upon
contact of the hydrogel and the second composition. Alternatively
or in addition, a hydrogel of the present invention may be
configured to modulate the pH of a second composition upon contact
of the hydrogel of the present invention and the second
composition. In some embodiments, a hydrogel of the present
invention may be configured to modulate the pH of a second
composition comprising a nitric oxide (NO) releasing API and/or the
release of nitric oxide from an NO releasing API in a second
composition.
[0083] "Contact," as used herein in reference to a first
composition of the present invention (e.g., a hydrogel of the
present invention) and a second composition of the present
invention (e.g., an anhydrous composition of the present
invention), refers to direct and/or indirect exposure of at least
one component in the first composition to the second composition.
Contact of the first composition and second composition may be
accomplished by any means, such as, but not limited to, by mixing,
stirring, blending, dispersing, milling, homogenizing, combining,
applying to same area or region, and the like, and in some
embodiments may optionally form an admixture of the present
invention. For example, a hydrogel may come into direct contact
with a second composition, such as, but not limited to, by mixing
and/or combining the hydrogel and second composition to form an
admixture of the present invention prior to, during, and/or after
topical application to a subject. Direct contact of a hydrogel and
second composition may occur by applying one or more layers of the
second composition onto a subject and then applying one or more
layers of the hydrogel onto a subject or vice versa to form an
admixture of the present invention. Indirect contact may occur by
applying a second composition onto a subject and then applying a
hydrogel onto a subject through a substrate, such as, but not
limited to, a cloth, bandage, gauze, and the like, or vice versa to
optionally form an admixture of the present invention.
[0084] According to some embodiments of the present invention, upon
contact of a hydrogel of the present invention and a second
composition of the present invention, the hydrogel may be
configured to modulate the release of an API present in the second
composition, such as, but not limited to, an NO releasing API. In
some embodiments, water and/or proton(s) present in a hydrogel of
the present invention may contact a second composition to modulate
the release of an API present in the second composition, such as,
but not limited to, an NO releasing API. Alternatively or in
addition, in some embodiments, contact of a hydrogel of the present
invention with a second composition may modulate the pH of the
second composition, thereby modulating the release of an API
present in the second composition, such as, but not limited to, an
NO releasing API. In some embodiments, a hydrogel of the present
invention is configured to supply water and/or a proton(s) to a
second composition of the present invention and/or configured to
modulate the pH of a second composition of the present
invention.
[0085] While not wishing to be bound to any particular theory, it
is believed that a composition of the present invention comprising
a hydrogel of the present invention and a NO-releasing API may
provide a proton donating system that may provide for a high
release of nitric oxide from the composition and/or a continuous
release of nitric oxide from the composition. The proton donating
system, while not wishing to be bound to any particular theory, may
be an acid that may be formed by an admixture of the present
invention (e.g., a composition comprising a hydrogel of the present
invention and a second composition of the present invention) and/or
a hydrogel of the present invention. A composition of the present
invention may provide and/or allow for a proton to be in close
proximity to an NO-donor in an NO-releasing API to thereby allow
for the release of nitric oxide. A composition of the present
invention may provide and/or allow for a proton to be in proximity
of an NO-donor for an extended period of time to provide a
continuous release of NO for about 1 or more hours, such as, but
not limited to, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more hours.
In some embodiments, a composition of the present invention
provides a release of NO of at least about 0.3, 0.5, or 1 pmol of
NO per mg of the composition for at least about 4, 6, or 8 hours as
measured in vitro.
[0086] The proton donating system may be provided by a hydrogel of
the present invention. For example, a proton donating system may be
provided by a hydrogel of the present invention comprising a
thickening agent, water, a co-solvent, a buffering agent, a
preservative, and/or a moisturizer.
[0087] In some embodiments, a hydrogel of the present invention
modulates the pH of a second composition such that when the
hydrogel and second composition are contacted and/or applied to the
skin of a subject, the pH of the second composition and/or
admixture may be less that about 11, in some embodiments, less than
about 10, in certain embodiments, less than about 8.5, in further
embodiments, less than about 7, and in still further embodiments,
between about 6 and about 8.
[0088] In some embodiments, the pH of an admixture of the present
invention changes upon application of the admixture to the skin of
a subject. In some embodiments, the pH of an admixture of the
present invention is decreased by the buffering capacity of the
skin upon application of the admixture to the skin of a subject. In
some embodiments, the pH of an admixture of the present invention
after application of the admixture to the skin of a subject is less
than the pH of the second composition applied to the skin without
the hydrogel. In embodiments where the release kinetics of the API
in a second composition varies with pH, the buffering capacity of
the skin may be utilized to modulate release while improving
stability of the admixture after combination and before
application. Thus, for example, the pH of a second composition that
includes a nitric oxide-releasing macromolecule may be greater than
10 before mixing, 9 after mixing and 8 after application to the
skin. With each decrease in pH, the release of nitric oxide from
the macromolecule may be increased. Accordingly, taking advantage
of the changing pH and buffering capacity of the skin may allow for
increased working time (e.g., mixing and application time) for a
combined composition of the present invention.
[0089] In some embodiments, a composition of the present invention
may comprise a second composition and the second composition may be
an anhydrous composition. "Anhydrous," as used herein, means that
there is no direct addition of water to the second composition when
it is being prepared. However, those skilled in the art will
recognize that water may be physically and/or chemically absorbed
by the second composition and/or by one or more ingredients in the
second composition at any time during the preparation, storage,
and/or use of the second composition (i.e., indirect addition of
water to the second composition). In some embodiments, the term
"anhydrous" means that the second composition has a water content
of less than 5% by weight of the second composition or any range
and/or individual value therein. A second composition may have a
water content of less than 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%,
1%, or 0.5%, or any range therein, by weight of the second
composition. Water content may be measured by methods known to
those of skill in the art, such as, but not limited to, Karl
Fischer titration. In some embodiments, upon contact with a second
composition of the present invention, a hydrogel of the present
invention adds water to the second composition and/or the second
composition absorbs water from the hydrogel of the present
invention.
[0090] A second composition of the present invention may comprise,
consist essentially of, or consist of a viscosity increasing agent,
an emollient, a humectant, a solvent, a co-solvent, and/or an API.
In some embodiments, the second composition is an anhydrous
composition.
[0091] One or more viscosity agents (e.g., 1, 2, 3, 4, or more) may
be present in a second composition and/or admixture of the present
invention. In some embodiments, the second composition and/or
admixture may comprise at least two different viscosity agents.
Example viscosity increasing agents that may be present in a second
composition and/or admixture of the present invention include, but
are not limited to, co-polymers of carboxymethylcellulose and
acrylic acid, N-vinylpyrrolidone, polyalkylene glycols (e.g.,
poly(ethylene glycol)), polyalkylene oxides (e.g., polyethylene
oxide), polyvinyl alcohols, polyvinylpyrrolidone, polysiloxanes,
poly(vinyl acetates), cellulose, derivatized celluloses,
hydroxypropylcellulose, alginates, copolymers thereof, 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,
emulsifying waxes, and any combination thereof. In some
embodiments, a second composition of the present invention may
comprise a hydroxypropylcellulose, such as, but not limited to,
hydroxypropylcellulose under the tradename Klucel.RTM. (e.g.,
Klucel.RTM. MF Pharm grade). In some embodiments, a second of the
composition of the present invention may comprise a silicone
elastomer blend, such as, for example, a silicone elastomer blend
under the tradename Dow Corning.RTM. ST-Elastomer 10.
[0092] A viscosity increasing agent may be present in a second
composition of the present invention in an amount of about 0.1% to
about 10% by weight of the second composition or any range and/or
individual value therein, such as, but not limited to, about 0.5%
to about 10%, about 0.1% to about 2%, about 0.1% to about 5%, about
1% to about 10%, or about 1% to about 5% by weight of the second
composition. In some embodiments, a viscosity increasing agent may
be present in the second composition in an amount of about 0.1%,
0.25%, 0.5%, 0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% by
weight of the second composition or any range and/or individual
value therein. In some embodiments, one or more viscosity
increasing agent(s) may be present in a second composition of the
present invention in an amount of about 0.5% to about 5% by weight
of the second composition. In some embodiments, the total amount of
viscosity increasing agent(s) present in a second composition of
the present invention (i.e., the sum of the amount of all viscosity
increasing agents present in the second composition) may be less
than 10% by weight of the second composition. In some embodiments,
the second composition may comprise at least two different
viscosity increasing agents.
[0093] One or more emollients (e.g., 1, 2, 3, 4, or more) may
present in a second composition and/or admixture of the present
invention. Example emollients that may be provided in a second
composition and/or admixture, include, but not limited to,
silicones, such as, for example, cyclomethicone, dimethicone,
simethicone, C26-28 alkyl dimethicone, C26-28 alkyl methicone,
polyphenylsisquioxane, trimethylsiloxysilicate and crosspolymers of
cyclopentasiloxane and dimethicone/vinyltrimethylsiloxysilicate,
almond oil, aluminum stearate, canola oil, castor oil, ceratonia
extract, cetostearyl alcohol, cetyl alcohol, cetyl esters wax,
cholesterol, coconut oil, cottonseed oil, cyclomethicone, dibutyl
sebacate, dimethicone, ethylene glycol palmitostearate, glycerin,
glycerin monostearate, glyceryl monooleate, glyceryl monostearate,
isopropyl myristate, isopropyl palmitate, lanolin, lecithin, light
mineral oil, medium-chain triglycerides, mineral oil, mineral oil
and lanolin alcohols, myristyl alcohol, octyldodecanol, oleyl
alcohol, petrolatum, petrolatum and lanolin alcohols, safflower
glycerides, safflower oil, soybean oil, stearyl alcohol, sunflower
oil, tricaprylin, triolein, xylitol, zinc acetate, and any
combination thereof. In some embodiments, an emollient present in a
second composition and/or admixture of the present invention may be
cyclomethicone.
[0094] An emollient may be present in a second composition of the
present invention in an amount of about 1% to about 30% by weight
of the second composition or any range and/or individual value
therein, such as, but not limited to, about 1% to about 5%, about
5% to about 10%, about 16% to about 30%, or about 20% to about 30%
by weight of the second composition. In some embodiments, an
emollient may be present in the second composition in an amount of
about 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%,
7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 10.5%, 11%, 11.5%, 12%, 12.5%,
13%, 13.5%, 14%, 14.5%, 15%, 15.5%, 16%, 16.5%, 17%, 17.5%, 18%,
18.5%, 19%, 19.5%, or 20% by weight of the second composition or
any range and/or individual value therein. In some embodiments, one
or more emollient(s) may be present in a second composition of the
present invention in an amount greater than 15% by weight of the
second composition. In some embodiments, the total amount of
emollient(s) present in a second composition of the present
invention (i.e., the sum of the amount of all emollients present in
the second composition) may be greater than 15% and up to 30% by
weight of the second composition.
[0095] One or more humectants (e.g., 1, 2, 3, 4, or more) may be
present in a second composition and/or admixture of the present
invention. Example humectants that may be present in a second
composition and/or admixture of the present invention include, but
are not limited to, glycols, such as, e.g., diethylene glycol
monoethyl ether; glycerols; sugar polyols, such as, e.g., sorbitol,
xylitol and maltitol; polyols such as, e.g., polydextroses;
quillaia, urea, and blends thereof. In some embodiments, a
humectant in a second composition and/or admixture may comprise a
C1-C10 monoalkylene glycol, such as, for example, hexylene
glycol.
[0096] A humectant may be present in the second composition in an
amount of about 1% to about 30% by weight of the second composition
or any range and/or individual value therein, such as, but not
limited to, about 2% to about 15%, about 5% to about 15%, about 10%
to about 25%, or about 10% to about 30% by weight of the second
composition. In some embodiments, a humectant may be present in the
second composition 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%, or 30% by weight of
the second composition or any range and/or individual value
therein. In some embodiments, one or more humectant(s) may be
present in a second composition of the present invention in an
amount of about 5% to about 30% by weight of the second
composition. In some embodiments, the total amount of humectant(s)
present in a second composition of the present invention (i.e., the
sum of the amount of all humectants present in the second
composition) may be about 5% to about 30% by weight of the second
composition.
[0097] A second composition and/or admixture of the present
invention may comprise a solvent. Example solvents that may be
present in a second composition and/or admixture of the present
invention include, but are not limited to, acetone, an alcohol,
such as, e.g., methyl alcohol, benzyl alcohol, ethanol, isopropyl
alcohol, butyl alcohol, and/or phenoxyethanol; dimethyl isosorbide,
propylene glycol, hexylene glycol, glycerol, isopropanol, ethylene
glycol, polyethylene glycol, ethoxydiglycol, isopropyl palmitate,
butylene glycol, pyrrolidone, dimethyl sulfoxide (DMSO), ethyl
acetate, an ether (e.g., diethylene glycol monoethyl ether), and
any combination thereof. In some embodiments, the solvent in a
second composition and/or admixture may be a C1-C4 alcohol, such
as, for example, ethanol and/or isopropyl alcohol.
[0098] A solvent may be present in a second composition of the
present invention in an amount of about 1% to about 20% by weight
of the second composition or any range and/or individual value
therein, such as, but not limited to, about 2% to about 15%, about
5% to about 20%, about 10% to about 15%, or about 10% to about 20%
by weight of the second composition. In some embodiments, a solvent
may be present in the second composition 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 second composition or any
range and/or individual value therein. In some embodiments, a
solvent (e.g., an alcohol) may be present in a second composition
of the present invention in an amount of about 1% to about 20% by
weight of the second composition. In some embodiments, the solvent
(e.g., an alcohol) may be present in a second composition of the
present invention in an amount less than 20% by weight of the
second composition. In some embodiments, the solvent may be a C1-C4
alcohol (e.g., ethanol and/or isopropyl alcohol), and the total
amount of the C1-C4 alcohol (e.g., ethanol and/or isopropyl
alcohol) present in a second composition of the present invention
(i.e., the sum of the amount of C1-C4 alcohols present in the
second composition) may be less than 20% by weight of the second
composition.
[0099] One or more co-solvents (e.g., 1, 2, 3, 4, or more) may be
present in the second composition and/or admixture of the present
invention. Example co-solvents that may be present in a second
composition and/or admixture of the present invention include, but
are not limited to, acetone, an alcohol, such as, e.g., methyl
alcohol, benzyl alcohol, ethanol, isopropyl alcohol, butyl alcohol,
and/or phenoxyethanol; dimethyl isosorbide, propylene glycol,
hexylene glycol, glycerol, isopropanol, ethylene glycol,
polyethylene glycol, ethoxydiglycol, isopropyl palmitate, butylene
glycol, pyrrolidone, dimethyl sulfoxide (DMSO), ethyl acetate, an
ether (e.g., diethylene glycol monoethyl ether), and any
combination thereof. In some embodiments, the co-solvent in a
second composition may be an ether, such as, for example,
diethylene glycol monoethyl ether. In some embodiments, the
co-solvent present in the second composition and/or admixture may
comprise diethylene glycol monoethyl ether, such as, e.g., those
commercially available from Gattefossee of Saint-Priest (Lyon,
France) under the trade name Transcutol.RTM..
[0100] A co-solvent may be present in a second composition of the
present invention in an amount of about 1% to about 50% by weight
of the second composition or any range and/or individual value
therein, such as, but not limited to, about 2% to about 15%, about
25% to about 35%, about 10% to about 40%, or about 20% to about 40%
by weight of the second composition. In some embodiments, a
co-solvent may be present in the second composition 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%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, or 50%
by weight of the second composition or any range and/or individual
value therein. In some embodiments, a co-solvent (e.g., an ether)
may be present in a second composition of the present invention in
an amount of about 1% to about 50% by weight of the second
composition. In some embodiments, a co-solvent (e.g., an ether) may
be present in a second composition of the present invention in an
amount of less than 50% by weight of the second composition. In
some embodiments, the total amount of co-solvent(s) present in a
second composition of the present invention (i.e., the sum of the
amount of co-solvents present in the second composition) may be
less than 50% by weight of the second composition.
[0101] In some embodiments, a second composition of the present
invention may comprise a C1-C4 alcohol (e.g., methanol, ethanol,
isopropyl alcohol, and/or butyl alcohol) as the solvent and an
ether (e.g., diethylene glycol monoethyl ether) as the co-solvent,
and the C1-C4 alcohol may be present in the second composition in
an amount less than 20% by weight of the second composition and the
ether may be present in the second composition in an amount less
than 50% by weight of the second composition. In some embodiments,
the solvent is ethanol and/or isopropyl alcohol, and the total
amount of ethanol and/or isopropyl alcohol present in a second
composition of the present invention (i.e., the sum of the amount
of ethanol and/or isopropyl alcohol present in the second
composition) may be less than 20% by weight of the second
composition.
[0102] In some embodiments, the total amount of solvent(s) and
co-solvent(s) present in a second composition of the present
invention (i.e., the sum of the amount of solvents and co-solvents
present in the second composition) may be less than 50% by weight
of the second composition, such as, for example, less than about
49%, 48%, 47%, 46%, 45%, 44%, 43%, 42%, 41%, 40%, 39%, 38%, 37%,
36%, 35%, 34%, 33%, 32%, 31%, 30%, 29%, 28%, 27%, 26%, 25%, 24%,
23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, or
10% by weight of the second composition or any range and/or
individual value therein. In some embodiments, the total amount of
solvent(s) and co-solvent(s) present in a second composition of the
present invention may be about 10% to about 50% by weight of the
second composition or any range and/or individual value therein,
such as, but not limited to, about 30% to about 49%, about 10% to
about 20%, about 10% to about 30%, or about 30% to about 40% by
weight of the second composition.
[0103] In some embodiments, a second composition of the present
invention comprises an API, such as, e.g., a moisture sensitive
API. The second composition may stably store a moisture sensitive
API. In some embodiments, the moisture sensitive API may comprise
an NO-releasing API, such as, but not limited to a diazeniumdiolate
modified macromolecule. In some embodiments, the NO-releasing API
may be Nitricil.TM. NVN1 and/or Nitricil.TM. NVN4, which are
NO-releasing diazeniumdiolate-functionalized co-condensed silica
from Novan, Inc. of Durham, N.C.
[0104] "Nitric oxide releasing active pharmaceutical ingredient"
and "NO releasing API," as used herein, refer to a compound or
other composition that provides nitric oxide to the skin of a
subject, but is not gaseous nitric oxide. In some embodiments, the
NO releasing API includes a nitric oxide-releasing compound,
hereinafter referred to as a "NO-releasing compound." An
NO-releasing compound includes at least one NO donor, which is a
functional group that may release nitric oxide under certain
conditions. In some embodiments, the at least one NO donor of an
NO-releasing compound releases NO when in contact with a
composition of the present invention. In certain embodiments, a
composition of the present invention modulates the amount of NO
released from an NO-releasing compound and/or the rate of NO
released from an NO-releasing compound. In some embodiments, a
composition of the present invention increases the amount of NO
released from an NO-releasing compound and/or the rate of NO
released from an NO-releasing compound.
[0105] Any suitable NO-releasing compound may be used. In some
embodiments, the NO-releasing compound includes a small molecule
compound that includes an NO donor group. "Small molecule compound"
as used herein is defined as a compound having a molecular weight
of less than 500 daltons, and includes organic and/or inorganic
small molecule compounds. 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.
[0106] In some embodiments, the NO-releasing compound includes a
diazeniumdiolate functional group as an NO donor. The
diazeniumdiolate functional group may produce nitric oxide under
certain conditions, such as upon exposure to water. As another
example, in some embodiments, the NO-releasing compound includes a
nitrosothiol functional group as the NO donor. The NO donor may
produce nitric oxide under certain conditions, such as upon
exposure to light. Examples of other NO donor groups include
nitrosamine, hydroxyl nitrosamine, hydroxyl amine and hydroxyurea.
Any suitable combination of NO donors and/or NO-releasing compounds
may also be used in a second composition as described herein.
Additionally, the NO donor may be incorporated into or onto the
small molecule or macromolecule through covalent and/or
non-covalent interactions.
[0107] An NO-releasing macromolecule may be in the form of an
NO-releasing particle, such as those described in U.S. Application
Publication No. 2009/0214618, the disclosure of which is
incorporated by reference herein in its entirety. 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 International
Application No. PCT/US2012/052350 entitled "Tunable Nitric
Oxide-Releasing Macromolecules Having Multiple Nitric Oxide Donor
Structures"; 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.
[0108] As an example, in some embodiments of the present invention,
a nitric oxide-releasing active pharmaceutical ingredient may
include NO-loaded precipitated silica. The NO-loaded precipitated
silica may be formed from nitric oxide donor modified silane
monomers into a co-condensed siloxane network. In some embodiments,
the nitric oxide donor may be an N-diazeniumdiolate. In some
embodiments, the nitric oxide-releasing active pharmaceutical
ingredient may comprise, consist essentially of, or consist of a
co-condensed siloxane network comprising a diazeniumdiolate (e.g.,
a N-diazeniumdiolate).
[0109] In some embodiments, the nitric oxide donor 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.
In some embodiments of the present invention, the nitric
oxide-releasing active pharmaceutical ingredient may comprise,
consist essentially of, or consist of a co-condensed silica network
synthesized from the condensation of a silane mixture comprising an
alkoxysilane and at least one aminoalkoxysilane having an amine
substituted by a diazeniumdiolate (e.g., a N-diazeniumdiolate).
[0110] 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.
[0111] In some embodiments, the alkoxysilane is a tetraalkoxysilane
having the formula Si(OR)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')n-Si(OR)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.
[0112] 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).
[0113] In some embodiments, the aminoalkoxysilane has the formula:
NH [R'--Si(OR)3]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.
[0114] 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--X+)--R'--Si(OR)3, wherein R is alkyl, R' is alkylene
or aralkylene, R'' is alkyl or alkylamine, and X+ is a cation
selected from the group consisting of Na+, K+ and Li+.
[0115] The composition of the siloxane network, (e.g., amount or
the chemical composition of the aminoalkoxysilane) 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.
[0116] In another embodiment, the amino group of aminoalkoxysilane
is substituted with a diazeniumdiolate, and the aminoalkoxysilane
having a formula of R''--N(NONO--X+)--R'--Si(OR)3, wherein: R is
alkyl, R' is alkylene or aralkylene, R'' is alkyl or alkylamine,
and X+ is a cation selected from the group consisting of Na+ and
K+.
[0117] In certain embodiments, the NO-releasing API may comprise a
co-condensed silica network comprising diazeniumdiolated
aminoethylaminopropyl trimethoxy silane (AEAP3) and tetra methyl
orthosilicate (TMOS) and/or a co-condensed silica network
comprising diazeniumdiolated aminoethylaminopropyl trimethoxy
silane (AEAP3) and tetraethyl orthosilicate (TEOS). In some
embodiments, the NO-releasing API may comprise a co-condensed
silica network comprising diazeniumdiolated methylaminopropyl
trimethoxysilane (MAP3) and tetra methyl orthosilicate (TMOS)
and/or a co-condensed silica network comprising diazeniumdiolated
methylaminopropyl trimethoxysilane (MAP3) and tetraethyl
orthosilicate (TEOS).
[0118] In some embodiments, the particle size of a NO-releasing API
may be in a range of about 20 nm to about 20 .mu.m or any range
therein, such as, but not limited to, about 100 nm to about 20
.mu.m or about 1 .mu.m to about 20 .mu.m. The particle size may be
tailored to minimize or prevent toxicity and/or penetration through
the epidermis (or compromised dermis) and into the blood vessels.
In particular embodiments, the particle size is distributed around
a mean particle size of less than 20 .mu.m, or any range therein,
and the size may allow the particle to enter a follicle. In some
embodiments, a NO-releasing API may have a particle size that is
distributed around a mean particle size of about 20, 19, 18, 17,
16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 .mu.m. In
further embodiments, a NO-releasing API may have a particle size
that is distributed around a mean particle size of less than 10
.mu.m, or any range therein, such as, but not limited to about 2
.mu.m to about 10 .mu.m or about 4 .mu.m to about 8 .mu.m. In other
embodiments, the particle size may be distributed around a mean
particle size of greater than 20 .mu.m, or any range therein, and
the size may prevent the particle from entering the follicle. In
still further embodiments, a mixture of particles with mean
particle sizes distributed around two or more mean particle sizes
may be provided. A NO-releasing API may be micronized (e.g., ball
and/or jet milled). Methods for providing a desired particle size
and/or micronization include, but are not limited to, those
described in U.S. Patent Application Publication No. 2013/0310533,
which is incorporated herein by reference in its entirety.
[0119] A nitric oxide-releasing active pharmaceutical ingredient
(e.g., diazeniumdiolate-functionalized co-condensed silica) may be
present in a composition of the present invention in an amount of
about 0.1% to about 50% by weight of the composition, and/or any
range and/or individual value therein, such as, for example, about
0.1% to about 35%, about 20% to about 30%, about 2% to about 15%,
about 10% to about 40%, about 5% to about 35%, or about 1% to about
10% by weight of the composition. In some embodiments, a nitric
oxide-releasing active pharmaceutical ingredient may be present in
a composition of the present invention 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%, or 50%
by weight of the composition. In some embodiments, a nitric
oxide-releasing active pharmaceutical ingredient (e.g.,
diazeniumdiolate-functionalized co-condensed silica) may be present
in a second composition of the present invention in an amount of
about 0.1% to about 50% by weight of the second composition and/or
any range and/or individual value therein.
[0120] A composition of the present invention (e.g., a second
composition of the present invention) may comprise a nitric
oxide-releasing active pharmaceutical ingredient and may store
and/or release nitric oxide in an amount of about 0.05% to about
20% by weight of the composition, 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
composition. In some embodiments, a composition 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
composition. 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.
[0121] In some embodiments, a composition of the present invention
may comprise a NO-releasing compound that may store and/or release
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, 5, 5.5, 6, 6.5, or 7 .mu.mol of NO per mg of the
NO-releasing compound. The amount of nitric oxide released may be
determined using real time in vitro release testing.
[0122] In some embodiments, a hydrogel of the present invention may
increase the amount of NO released from a composition (e.g., a
second composition comprising a NO-releasing API) compared to the
amount of NO released from the composition in the absence of the
hydrogel over the same period of time. In certain embodiments, a
hydrogel of the present invention may increase the amount of NO
released from a composition of the present invention comprising the
hydrogel and a NO-releasing API by at least about 10%, 20%, 30%,
40%, 50%, 60%, 70%, 80%, 90, 100%, 150%, 200%, or more, or any
range and/or individual value therein compared to the amount of NO
released in the absence of a hydrogel of the present invention over
the same period of time. Therefore, a composition of the present
invention (e.g., a composition comprising a hydrogel of the present
invention and a second composition comprising a NO-releasing API)
may release about 1.5 to about 100 times more NO than the amount of
NO released in the absence of a hydrogel of the present invention
(e.g., the second composition alone) over the same period of time
or any range and/or individual value therein, such as, but not
limited to between about 2 and 10 times more NO or between about 5
and about 50 times more NO.
[0123] A second composition of the present invention may comprise,
consist essentially of, or consist of a viscosity increasing agent
present in an amount of about 0.1% to about 10% by weight of the
second composition, an emollient present in an amount of about 1%
to about 30% by weight of the second composition, a humectant
present in an amount of about 1% to about 30% by weight of the
second composition, a solvent present in an amount of about 1% to
about 20% by weight of the second composition, a co-solvent present
in an amount of about 1% to about 50% by weight of the second
composition, and/or a moisture sensitive API (e.g., a NO-releasing
API) in an amount of about 0.1% to about 50% by weight of the
second composition. In some embodiments, the second composition may
comprise at least two different viscosity increasing agents and the
total amount of the viscosity increasing agents present in the
second composition may be less than 10% by weight of the second
composition. In some embodiments, the second composition may
comprise, consist essentially of, or consist of a viscosity
increasing agent present in an amount of less than about 10% by
weight of the second composition, the emollient present in an
amount of greater than 15% and up to about 30% by weight of the
second composition, the humectant present in an amount of about 1%
to about 30% by weight of the second composition, the solvent
(e.g., a C1-C4 alcohol) present in an amount of less than 20% by
weight of the second composition, the co-solvent present in an
amount of less than 50% by weight of the second composition, and/or
a moisture sensitive API (e.g., a NO-releasing API) in an amount of
about 0.1% to about 50% by weight of the second composition. In
some embodiments, the total amount of the solvent(s) and
co-solvent(s) present in the second composition is less than 50% by
weight of the second composition.
[0124] A second composition of the present invention may comprise,
consist essentially of, or consist of a viscosity increasing agent
present in an amount of about 0.1% to about 5% by weight of the
second composition, an emollient present in an amount of about 5%
to about 30% by weight of the second composition, a humectant
present in an amount of about 5% to about 30% by weight of the
second composition, a solvent (e.g., an alcohol) present in an
amount of about 1% to about 20% by weight of the second
composition, a co-solvent present in an amount of about 15% to
about 50% by weight of the second composition, and/or a moisture
sensitive API (e.g., a NO-releasing API) in an amount of about 0.1%
to about 40% by weight of the second composition. In some
embodiments, the second composition may comprise at least two
different viscosity increasing agents and the total amount of the
viscosity increasing agents present in the second composition may
be less than 5% by weight of the second composition.
[0125] A composition of the present invention may comprise a first
composition (e.g., a hydrogel) of the present invention and a
second composition of the present invention. As those of skill in
the art will recognize, the amount or concentration of individual
components in a composition of the present invention may vary
depending on the amount of the first composition and second
composition present in the composition (e.g., the ratio of the
first composition and second composition present in the
composition). In some embodiments, the ratio of a first composition
of the present invention to a second composition of the present
invention in a composition of the present invention may be about
10:1 or less, such as, e.g., about 9:1 or less, about 8:1 or less,
about 7:1 or less, about 6:1 or less, about 5:1 or less, about 4:1
or less, about 3:1 or less, about 2:1 or less, about 1:1 or less,
about 0.5:1 or less, or about 0.2:1 or less. In some embodiments,
the ratio may be about 3:1. In further embodiments, the ratio may
be about 1:1.
[0126] A composition of the present invention (e.g., a first
composition of the present invention and a second composition of
the present invention) may be buffered to a pH of about 3 to about
11, such as, but not limited to, about 3 to about 9.5 or about 3 to
about 8. In some embodiments, an admixture of the present invention
may have a pH of 9.5 or greater. In some embodiments, the
composition may comprise at least one API, such as, but not limited
to, a nitric oxide-releasing active pharmaceutical ingredient. In
some embodiments, a composition of the present invention may
comprise a second composition comprising a nitric oxide-releasing
active pharmaceutical ingredient. In some embodiments, the second
composition may be anhydrous.
[0127] In some embodiments, an admixture of the present invention
may comprise, consist essentially of, or consist of a first
composition and a second composition, the first composition
comprising a thickening agent present in an amount of about 0.1% to
about 25% by weight of the first composition, water present in an
amount of about 50% to about 99% by weight of the first
composition, a cosolvent present in an amount of about 0.1% to
about 15% by weight of the first composition, a buffering agent
present in an amount of about 0.01% to about 20% by weight of the
first composition, a preservative in an amount of about 0.1% to
about 1% by weight of the first composition, and/or a moisturizer
present in an amount of about 0.1% to about 10% by weight of the
first composition; and the second composition comprising a
viscosity increasing agent present in an amount of about 0.1% to
about 10% by weight of the second composition, an emollient present
in an amount of about 1% to about 30% by weight of the second
composition, a humectant present in an amount of about 1% to about
30% by weight of the second composition, a solvent present in an
amount of about 1% to about 20% by weight of the second
composition, a co-solvent present in an amount of about 1% to about
50% by weight of the second composition, and/or a moisture
sensitive API (e.g., a NO-releasing API) in an amount of about 0.1%
to about 50% by weight of the second composition. The first
composition may be a hydrogel and/or the second composition may be
an anhydrous composition. In some embodiments, the admixture may be
a film-forming composition (e.g., a film-forming gel). In some
embodiments, the total amount of the thickening agent present in
the first composition may be greater than 5% and up to about 25% by
weight of the first composition, the total amount of the co-solvent
may be about 0.1% to about 5% by weight of the first composition,
water may be present in an amount of about 50% to less than 70% by
weight of the first composition, and/or the buffering agent may be
present in an amount of greater than 2% and up to about 20% by
weight of the hydrogel. In some embodiments, the total amount of
the viscosity increasing agent present in the second composition
may be less than about 10% by weight of the second composition, the
emollient may be present in an amount of greater than 15% and up to
about 30% by weight of the second composition, the solvent (e.g., a
C1-C4 alcohol) may be present in an amount of less than 20% by
weight of the second composition, and/or the co-solvent may be
present in an amount of less than 50% by weight of the second
composition, optionally with the total amount of the solvent(s) and
co-solvent(s) present in the second composition is less than 50% by
weight of the second composition. The admixture may have a pH of
less than about 11, such as, but not limited to, less than about
9.5, less than about 7, or less than about 6. In some embodiments,
the admixture may be cosmetically elegant.
[0128] An admixture of the present invention may provide a
structure suitable for suspending an API, such as, but not limited
to, a particulate API and/or an insoluble API. In some embodiments,
an admixture of the present invention may encapsulate an API, such
as, but not limited to, a particulate API and/or an insoluble API.
For example, an admixture of the present invention may encapsulate
an API in at least one viscosity increasing agent and/or thickening
agent and/or may provide a structure suitable for encapsulating an
API. An admixture of the present invention may prevent and/or
reduce agglomeration of an API in the admixture. While not wishing
to be bound to any particular theory, a hydrogel of the present
invention may provide means for suspending and/or encapsulating an
API and/or for preventing and/or reducing agglomeration of an API
in the admixture. For example, a hydrogel of the present invention
may provide a structure (e.g., a gel matrix) suitable for
suspending and/or encapsulating an API in an admixture of the
present invention and/or for preventing and/or reducing
agglomeration of an API in an admixture of the present
invention.
[0129] An admixture of the present invention may not be gritty
and/or may have a reduced grittiness compared to the API in the
absence of a composition of the present invention. The admixture
may not be tacky (i.e., sticky) and/or may have a reduced tackiness
(i.e., stickiness) compared to the API in the absence of a
composition of the present invention. The admixture may have a
reduced and/or increased stiffness (i.e., hardness) and/or may have
an increased homogeneity compared to the API in the absence of a
composition of the present invention. In some embodiments, an
admixture of the present invention may comprise an API and may be a
cosmetically elegant, homogeneous composition. While not wishing to
be bound to any particular theory, a hydrogel of the present
invention may provide means for providing a cosmetically elegant,
homogeneous composition. For example, a hydrogel of the present
invention may provide a structure (e.g., a gel matrix) suitable for
providing a cosmetically elegant, homogeneous composition.
[0130] According to embodiments of the present invention, the
preparation of two separate parts for a composition of the present
invention may provide an improved composition. A composition of the
present invention comprising at least two parts may allow for an
API (e.g., an API that is difficult to formulate) to be prepared in
one part and later combined with the second part to prepare a
cosmetically elegant composition and/or a composition comprising a
more stable API compared to the same API prepared in a composition
formed with one part and/or in the absence of a composition of the
present invention. The API may be more stable in that the API could
have a greater activity compared to its activity in the absence of
a composition of the present invention and/or the API may be stored
for a longer period of time compared to its storage in the absence
of a composition of the present invention. In some embodiments, a
composition of the present invention comprising an API (e.g., an
API that is difficult to formulate) may provide a more cosmetically
elegant composition compared to the API in a composition in the
absence of a composition of the present invention. For example, a
composition of the present invention comprising a particulate API
and/or an insoluble API may provide a less gritty composition and
thereby a more cosmetically elegant composition.
[0131] In some embodiments, two or more different compositions of
the present invention (e.g., first and second compositions of the
present invention) may be separately stored. Any suitable packaging
for a composition of the present the invention may be used. In some
embodiments, each composition may be separately stored in a tube,
jar, sachet, dual chamber container (e.g., a dual pump container,
dual dispensing container, a dual pouch sachet, and/or a trilayer
sachet). In some embodiments, a composition of the present
invention may be refrigerated until use to reduce the likelihood of
premature release of the nitric oxide.
[0132] In some embodiments, a composition of the present invention
may be provided in sealed, single dose container (e.g., a vial,
sachet, etc.) that may be oxygen and/or moisture impermeable to
prevent moisture from reaching the composition and/or API. The
single dose container may be opened at the time of application and
the composition(s) may be applied to skin and/or a nail of a
subject. In some embodiments, a hydrogel of the present invention
and a second composition of the present invention may be separately
stored in a container (e.g., a single dose container) and, upon
opening the container (e.g., upon opening a sachet), both
compartments storing the hydrogel and second composition are opened
and can dispense and/or are configured for dispensing of each
composition. The hydrogel and second composition may be dispensed
from the single dose container concurrently and/or may be dispensed
side by side. In some embodiments, a single action on the container
(e.g., sachet) may dispense the compositions. In some embodiments,
the hydrogel and second composition after dispensing may be mixed
(e.g., manually by a subject) to form an admixture and/or some
mixing may occur during dispensing (e.g., some contact and/or
mixing may occur if the compositions are dispensed such that they
contact each other). In some embodiments, a hydrogel of the present
invention and a second composition of the present invention may be
separately stored in two different compartments of a container
(e.g., a sachet or tube) including a barrier between the
compartments storing the hydrogel and second composition and the
barrier is broken to combine the hydrogel and/or second composition
prior to opening the container and/or dispensing the
compositions.
[0133] According to some embodiments of the present invention, a
kit may be provided. In some embodiments, a kit of the present
invention may comprise a first composition of the present invention
(e.g., a hydrogel) and a second composition of the present
invention. The second composition may be an anhydrous composition.
In some embodiments, a kit of the present invention may comprise
means for forming an admixture with the first composition and
second composition, such as, but not limited to, by mixing,
combining, contacting, and the like the compositions prior to
and/or during application to a subject. In some embodiments, the
kit may be configured to admix the two compositions upon dispensing
and/or application to a subject. In some embodiments, a kit may be
configured to provide an admixture with increased performance
and/or activity of the API compared to the performance and/or
activity of the API in the absence of one or more of the
compositions in the admixture.
[0134] A kit of the present invention may separately store a first
composition of the present invention and a second composition of
the present invention. In some embodiments, a kit of the present
invention may contact and/or may allow for contact to occur between
the first composition and second composition, such as, but not
limited to, by mixing the compositions, prior to application to a
subject.
[0135] A kit of the present invention may provide a ratio of the
first composition to the second composition, which may be applied
to a subject, of about 10:1 or less, such as, for example, about
9:1 or less, about 8:1 or less, about 7:1 or less, about 6:1 or
less, about 5:1 or less, about 4:1 or less, about 3:1 or less,
about 2:1 or less or about 1:1. In some embodiments, the ratio may
be about 3:1. In some embodiments, the ratio may be about 1:1. In
certain embodiments, a kit and/or system of the present invention
comprises means for dispensing and/or delivering the first and
second compositions in the appropriate amounts to achieve the
desired ratio (e.g., dual dispensing pump, trilayer sachet, etc.).
In some embodiments, the ratio of the first composition and second
composition in the admixture may be adjusted and/or modified to
achieve a desired API release pattern. In some embodiments, a kit
and/or system of the present invention comprises a dual dispensing
device, such as, for example, a dual dispensing pump, sachet,
and/or the like, that separately stores a first composition of the
present invention and second composition of the present invention
and that in use (e.g., dispensing and/or administration) may
provide a given ratio of the first composition to the second
composition.
[0136] Providing a first composition and a second composition that
are combined upon and/or during application to the skin of a
subject may allow for a longer shelf life of a composition, kit,
and/or system of the present invention than if the compositions
were stored mixed together in the kit and/or system. For example,
the formulation and loading of API in a second composition of the
present invention may provide a stable product with a long shelf
life. Thus, for example, pH and water content of the second
composition may be adjusted to reduce or minimize release of a
water-activated API so as to provide a composition that is stable
at room temperature. A first composition of the present invention
may then be combined with the second composition to adjust the
combined pH and provide a proton and/or water to activate the API.
The second composition may be combined with the first composition
in differing ratios to provide a desired release, pH and/or dose in
the combined composition. Such an approach may allow for a single
manufacturing process to be utilized for production of a more
complex and costly second composition and then particular products
defined by the composition and/or quantity of the first composition
with which the second composition is mixed.
[0137] As used herein, the term "shelf life" refers to the length
of time a product (e.g., a composition and/or kit of the present
invention) maintains the ability to release a therapeutically
effective amount of a therapeutic agent, such as, but not limited
to, nitric oxide, in an unopened package stored under recommended
storage conditions. The shelf life may, for example, be evidenced
by the "use by" or "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 composition under packaged and/or
stored conditions may be different (i.e., faster or slower) than
the rate of release of nitric oxide when the composition is in use
(e.g., when the composition comprising the NO-releasing API is in
admixture with another composition). In certain embodiments, the
rate of release of nitric oxide from a composition of the present
invention may be more rapid when the composition is in use compared
to the rate of release of nitric oxide when a composition
comprising the API was packaged and/or stored.
[0138] In some embodiments, shelf life may be determined by
extrapolation of data at accelerated temperatures, such as, for
example, by using the Arrhenius equation. In some embodiments,
shelf life may be determined using linear regression analysis, such
as, for example, when the kinetics of API degradation is not
temperature dependent. In some embodiments, shelf life may be
evaluated and/or determined by measuring the API (e.g.,
NO-releasing API), such as, for example, using high pressure liquid
chromatography.
[0139] 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 of nitric oxide that the product may release
when packaged. In some embodiments, the shelf life of the product
is the time that the product maintains the ability to release about
60%, at least 70%, at least 80%, at least 90%, at least 95%, or at
least 98% of the initial amount of nitric oxide that the product
may release when packaged. In some embodiments, the shelf life of
the product is the time that the product maintains the ability to
release a therapeutically effective amount of nitric oxide over a
desired period of time. 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
between 1.degree. C.-12.degree. C., or any range and/or individual
value therein. In some embodiments, a packaged product may have a
shelf life of at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,
13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 months or more,
or any range and/or individual value therein.
[0140] Some embodiments may provide packaged compositions of the
present invention that have a useful life of at least about 7 days
after opening the package. In some 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, the packaged compositions have
a useful life of from at least about 60 days to at least about 730
days. 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.
[0141] Accordingly, the term "useful life" as used herein should be
construed as including both an "actual" useful life of the product
or 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 useful 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.
[0142] As will be appreciated by those of skill in the art in light
of the present disclosure, a hydrogel of the present invention may
provide means for adjusting the pH of a pharmaceutical composition
as well as means for activating an API of a pharmaceutical
composition. In some embodiments, a hydrogel of the present
invention may provide means for maintaining and/or stabilizing the
pH of a second composition of the present invention when used to
form an admixture with the hydrogel. Means for maintaining and/or
stabilizing the pH of an admixture may be configured to activate
and/or initiate release of an API. In some embodiments, a hydrogel
of the present invention may provide means for maintaining and/or
stabilizing the pH of an admixture comprising a diazeniumdiolate
modified co-condensed polysiloxane macromolecule. In some
embodiments, the pH may be maintained and/or stabilized within a pH
range of about 5 to about 8. In further embodiments, a hydrogel of
the present invention may provide means for releasing nitric oxide
from a pharmaceutical composition comprising a diazeniumdiolate
modified co-condensed polysiloxane macromolecule. In some
embodiments, a hydrogel of the present invention may provide means
for reducing the pH of a second composition of the present
invention comprising a diazeniumdiolate modified co-condensed
polysiloxane macromolecule. In some embodiments, a first
composition of the present invention may provide means for
releasing nitric oxide from a second composition of present
invention comprising a diazeniumdiolate modified co-condensed
polysiloxane macromolecule.
[0143] According to some embodiments, a method of the present
invention may comprise administering a composition (e.g., hydrogel,
second composition and/or admixture) of the present invention to
the skin and/or nail of a subject. For example, the composition may
be administered to a subject's hand, foot, toe, and/or nail. In
some embodiments, the composition may be topically administered. A
method of the present invention may comprise forming an admixture
prior to and/or during the administering step. An admixture may be
prepared by mixing, blending, contacting, applying to a same area
or region, emulsifying, and the like a hydrogel of the present
invention, and a second composition of the present invention, such
as, but not limited to an anhydrous composition. In some
embodiments, a method of the present invention may administer a
composition of the present invention as a monotherapy to treat at
least two different conditions, infections and/or diseases. In some
embodiments, a method of the present invention may administer a
composition of the present invention as a monotherapy to treat
onychomycosis and tinea pedis. In some embodiments, a method of the
present invention may administer a composition of the present
invention in combination with a different therapy (e.g., in
combination with an oral therapy such as, e.g., orally administered
terbinafine). In some embodiments, a method and/or step of the
present invention includes, but is not limited to, a composition,
method, and/or step described in International Application Nos.
PCT/US2015/040319, PCT/US2016/013246, and/or PCT/US2016/043880, the
contents of each of which are incorporated herein by reference in
their entirety.
[0144] A method of the present invention may comprise topically
applying a first composition of the present invention to the skin
of a subject in combination and/or admixture with a second
composition of the present invention. The second composition may
comprise a nitric oxide-releasing active pharmaceutical ingredient
(e.g., a NO-releasing macromolecule).
[0145] In some embodiments, a composition and/or method of the
present invention provides and/or delivers nitric oxide to the skin
and/or nail of a subject in a concentration effective to inhibit
fungi growth and/or kill fungi, such as, for example, Trichophyton
rubrum. In some embodiments, a composition and/or method of the
present invention provides and/or delivers nitric oxide to a
subject's nail bed. In some embodiments, the nitric oxide may
diffuse and/or penetrate through the subject's nail to the
respective nail bed. In some embodiments, a method of the present
invention comprises delivering a therapeutically effective amount
of a composition of the present invention to the skin and/or nail
of a subject. A composition and/or method of the present invention
may provide and/or deliver nitric oxide to a subject's skin and/or
nail and may be delivered to the nail bed under the subject's
nail.
[0146] As used herein, the term "therapeutically effective amount"
refers to an amount of a composition of the present invention that
elicits a therapeutically useful response in a 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. In some embodiments, a therapeutically
effective amount of a composition of the present invention may
include delivering a therapeutically effective amount of a
component of the composition, such as, but not limited to, an
active pharmaceutical ingredient (e.g., a nitric oxide-releasing
API). Therefore, a therapeutically effective amount of nitric oxide
may be delivered and/or administered by a composition of the
present invention.
[0147] "Treat," "treating" or "treatment of" (and grammatical
variations thereof) as used herein 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 a viral,
bacterial, protozoan, and/or fungal (e.g., onychomycosis and/or
tinea pedis) infection is achieved and/or there is a delay in the
progression of the infection and/or condition. In some embodiments,
the severity of an infection (e.g., a fungal infection caused by T.
rubrum) may be reduced in a subject compared to the severity of the
infection in the absence of a method of the present invention. In
certain embodiments, a method of the present invention treats a
viral, bacterial, protozoan, and/or fungal (e.g., onychomycosis
and/or tinea pedis) infection in a subject, such as, e.g., a fungal
infection that has affected the skin and/or nail of the subject. In
some embodiments, a method of the present invention may treat a
viral, bacterial, protozoan, and/or fungal (e.g., onychomycosis
and/or tinea pedis) infection by eliminating and/or reducing the
size and/or appearance of at least one clinical symptom associated
with the infection (e.g., a disfiguration, discoloration, and/or
benign lesion such as a scaly patch). In some embodiments, a method
of the present invention may treat a viral, bacterial, protozoan,
and/or fungal (e.g., onychomycosis and/or tinea pedis) infection by
eliminating at least one clinical symptom associated with the
infection for a given period of time (e.g., 1, 2, 3, 4, 5, or 6
day(s), or 1, 2, 3, 4, or more weeks, or 1, 2, 3, 4, 5, 6, or more
months, etc.).
[0148] In some embodiments, a composition of the present invention
(e.g., an admixture) may be administered in a treatment effective
amount. A "treatment effective" amount as used herein is an amount
that is sufficient to treat (as defined herein) a 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. In some embodiments, a treatment effective
amount may be achieved by administering a composition of the
present invention. In some embodiments, administration of a
composition of the present invention does not produce systemic
effects from the administration of nitric oxide, such as, for
example, in a treatment effective amount.
[0149] The terms "prevent," "preventing" and "prevention" (and
grammatical variations thereof) refer to avoidance, reduction
and/or delay of the onset of a viral, bacterial, protozoan, and/or
fungal (e.g., onychomycosis and/or tinea pedis) infection and/or a
clinical symptom associated therewith in a subject and/or a
reduction in the severity of the onset of the infection and/or
clinical symptom relative to what would occur in the absence of a
method of the present invention. The prevention can be complete,
e.g., the total absence of the infection and/or clinical symptom.
The prevention can also be partial, such that the occurrence of the
infection and/or clinical symptom 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. In certain embodiments, a method
of the present invention prevents a viral, bacterial, protozoan,
and/or fungal (e.g., onychomycosis and/or tinea pedis) infection in
a subject, such as, e.g., a fungal infection that can affect the
skin and/or nail of the subject.
[0150] In some embodiments, a composition of the present invention
(e.g., an admixture) may be administered in a prevention effective
amount. A "prevention effective" amount as used herein is an amount
that is sufficient to prevent (as defined herein) a viral,
bacterial, protozoan, and/or fungal (e.g., onychomycosis and/or
tinea pedis) infection and/or clinical symptom in the 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. In some embodiments, a prevention
effective amount may be achieved by administering a composition of
the present invention. In some embodiments, administration of a
composition of the present invention does not produce systemic
effects from the administration of nitric oxide, such as, for
example, in a prevention effective amount.
[0151] The present invention finds use in both veterinary and
medical applications. Subjects suitable to be treated with a method
embodiment of the invention include, but are not limited to, avian
and mammalian subjects. Mammals of the present invention include,
but are not limited to, canines, felines, bovines, caprines,
equines, ovines, porcines, rodents (e.g. rats and mice),
lagomorphs, primates (e.g., simians and humans), non-human primates
(e.g., monkeys, baboons, chimpanzees, gorillas), and the like, and
mammals in utero. Any mammalian subject in need of being treated
according to the present invention is suitable. Human subjects of
both genders and at any stage of development (i.e., neonate,
infant, juvenile, adolescent, adult) may be treated according to
the present invention. 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
of all ages including fetal, neonatal, infant, juvenile,
adolescent, adult, and geriatric subjects as well as pregnant
subjects. In particular embodiments of the present invention, the
subject is a human adolescent and/or adult.
[0152] Illustrative avians according to the present invention
include chickens, ducks, turkeys, geese, quail, pheasant, ratites
(e.g., ostrich) and domesticated birds (e.g., parrots and
canaries), and birds in ovo.
[0153] A method of the present invention may also be carried out on
animal subjects, particularly mammalian subjects such as mice,
rats, dogs, cats, livestock and horses for veterinary purposes,
and/or for drug screening and drug development purposes.
[0154] In some embodiments, the subject is "in need of" or "in need
thereof" a method of the present invention, for example, the
subject is in an at-risk population (e.g. the subject may be
at-risk for or more susceptible to a fungal infection), the subject
has findings typically associated with a viral, bacterial,
protozoan, and/or fungal infection, is suspected to have a viral,
bacterial, protozoan, and/or fungal infection, and/or the subject
has a viral, bacterial, protozoan, and/or fungal infection. In some
embodiments, a subject in need thereof has a viral, bacterial,
protozoan, and/or fungal infection and/or a clinical sign or
symptom associated therewith that may be treated with a method of
the present invention. The present invention may be particularly
suitable for children, adolescents, adults, and/or geriatric
subjects.
[0155] In some embodiments, a composition of the present invention
may be topically administered to a subject. A composition of the
present invention may be administered and/or applied topically to
any portion of a subject's skin and/or a nail of a subject. For
example, a composition may be topically administered to a subject's
hand, finger, foot, toe, nail (including the skin surrounding
and/or under the nail), etc. In some embodiments, a composition of
the present invention may be topically administered to at least a
portion of a subject's hand, finger, foot, toe, and/or nail (e.g.,
fingernail and/or toenail). "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. In some embodiments, a method
of the present invention may comprise applying a composition of the
present invention 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), and/or the skin of a hand and/or foot of a
subject. In some embodiments, a composition of the present
invention may be applied to a subject's nail, interdigital skin,
and/or to the skin of a subject's hand and/or foot, and may treat
and/or prevent a viral, bacterial, protozoan, and/or fungal
infection in and/or on the skin and/or nail, such as, e.g.,
onychomycosis and/or tinea pedis. In some embodiments, a
composition of the present invention 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.
[0156] In some embodiments, a method and/or composition of the
present invention may kill and/or inhibit the growth of one or more
pathogens, such as, for example, one or more pathogens that may
cause and/or be associated with a viral, bacterial, protozoan,
and/or fungal infection.
[0157] Example fungal infections include, but are not limited to,
onychomycosis, tinea pedis, tinea capitis, cutaneous candidiasis,
tinea corporis, and/or tinea cruris. In some embodiments, a fungal
infection may be caused by a dermatophyte, such as, for example, T.
rubrum and/or Trichophyton mentagrophytes. In some embodiments, a
composition of the present invention may be a topical monotherapy
to treat and/or prevent a fungal infection, such as, for example,
onychomycosis and/or tinea pedis. In some embodiments, a method
and/or composition of the present invention treats and/or prevents
a fungal infection caused by a fungus and/or non-dermatophyte that
is resistant to an azole and/or allylamine. In some embodiments, a
method and/or composition of the present invention treats and/or
prevents a fungal infection that is KOH positive as determined in
accordance with a KOH test at baseline (i.e., at the start of
treatment) and/or the subject has a negative fungal culture from a
target lesion at baseline. In some embodiments, a method and/or
composition of the present invention treats and/or prevents a
fungal infection that is KOH positive as determined in accordance
with a KOH test at baseline (i.e., at the start of treatment)
and/or the subject has a positive fungal culture from a target
lesion at baseline.
[0158] In some embodiments, a method and/or composition of the
present invention may be used to treat and/or prevent onychomycosis
in a subject and/or may inhibit and/or kill one or more
dermatophyte(s), non-dermatophyte mold(s), and/or yeast(s) in
and/or on the subject. Onychomycosis in the subject may be caused
by and/or associated with one or more of the following
dermatophytes, such as, but not limited to, Arthroderma benhamiae,
Epidermophyton jloccosum, Microsporum species (e.g., Microsporum
canis, cookei, and gypseum), and Trichophyton species (e.g.,
Trichophyton ajelloi, interdigitale, mentagrophytes, rubrum,
schoenleinii, tonsurans, verrucosum, and violaceum). In some
embodiments, the dermatophyte is a Trichophyton species or
Epidermophyton species. Alternatively or in addition, onychomycosis
in the subject may be caused by and/or associated with one or more
of the following non-dermatophyte molds, such as, but not limited
to, Acremonium species (e.g., Acremonium potronii and
sclerotigenum), Alternaria species (e.g., Alternaria alternata),
Arthrographis kalrae, Aspergillus species (e.g., Aspergillus
versicolor, flavus, fumigatus, nidulans, niger, nomius, sydowii,
and terreus), Auxarthron species (e.g., Auxarthron ostraviense and
umbrinum), Botryodiplodia theobromae, Chaetomium species (e.g.,
Chaetomium globosum), Cladosporium carrionii, Fusarium species
(e.g., Fusarium oxysporum and solani), Geotrichum candidum,
Hendersonula toruloidea, Lasiodiplodia theobromae, Nattrassia
mangiferae, Neoscytalidium species, Nigrospora sphaerica,
Onychocola species (e.g., Onychocola canadensis, pyrenochaeta, and
unguis-hominis), Paecilomyces species (e.g., Paecilomyces variotii
and lilacinus), Penicillium species, Phaeoacremonium parasiticum,
Phialophora species, Pseudallescheria boydii, Pyrenochaeta
unguis-hominis, Rhizopus species, Scopulariopsis species (e.g.,
Scopulariopsis brevicaulis and brumptii), Scytalidium species
(e.g., Scytalidium dimidiatum and hyalimum), Talaromyces
indigoticus, Tritirachium species (e.g., Tritirachium oryzae), and
Tintelnotia. Alternatively or in addition, onychomycosis in the
subject may be caused by and/or associated with one or more of the
following yeast, such as, but not limited to, Aureobasidium
pullulans (black yeast-like), Candida species (e.g., Candida
albicans, glabrate, guilliermondii, kefyr, krusei, lusitaniae,
parapsilosis, stellatoidea, and tropicalis), Cladophialophora
boppii (black yeast-like), Cryptococcus neoformans, Exophiala
oligosperma, Kodamaea ohmeri, Malassezia species (e.g., Malassezia
globose, slooffiae, and pachydermatis), Rhodotorula species (e.g.,
Rhodotorula rula and minuta), and Trichosporon species (e.g.,
Trichosporon asahii, beigeleii, and mucoides). In some embodiments,
the yeast is a Candida species or Malassezia species.
[0159] In some embodiments, a method and/or composition of the
present invention may be used to treat and/or prevent tinea pedis
in a subject and/or may inhibit and/or kill one or more
dermatophyte(s), non-dermatophyte mold(s), and/or yeast(s) in
and/or on the subject. Tinea pedis in the subject may be caused by
and/or associated with one or more of the following dermatophytes,
such as, but not limited to, Arthroderma benhamiae, Epidermophyton
floccosum, Microsporum canis, Microsporum gypseum, Trichophyton
interdigitale, Trichophyton mentagrophytes, Trichophyton rubrum,
and Trichophyton tonsurans. Alternatively or in addition, tinea
pedis in the subject may be caused by and/or associated with one or
more of the following non-dermatophyte molds, such as, but not
limited to, Aureobasidium pullulans, Aspergillus species, Fusarium
species, and Hendersonula toruloidea. Alternatively or in addition,
tinea pedis in the subject may be caused by and/or associated with
one or more of the following yeast, such as, but not limited to,
Candida parapsilosis, Rhodotorula mucilaginosa, Phoma species,
Debaryomyces hansenii, and Acremonium species.
[0160] Provided according to some embodiments of the present
invention is a method of treating and/or preventing a viral,
bacterial, protozoan, and/or fungal infection in a subject. In some
embodiments, a method of treating and/or preventing a viral,
bacterial, protozoan, and/or fungal (e.g., onychomycosis and/or
tinea pedis) infection in a subject may comprise administering a
composition of the present invention to the subject. In some
embodiments, the method may comprise forming an admixture before
and/or during the step of administering the composition. In some
embodiments, a composition of the present invention may be
administered onto skin and/or a nail of a subject 1 or more times
(e.g., 1, 2, 3, 4, or more times) a day; every day; every other
day; every 3, 4, 5, or 6 days; or once a week. In some embodiments,
the composition may be administered onto skin and/or nail of a
subject 1, 2 or 3 times a day for 1, 2, 3, or 4 weeks. In some
embodiments, a composition of the present invention may be
administered onto skin and/or a nail of a subject at least once
daily for a period of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25,
30, 35, 40, 45, 50, or more weeks, or any range and/or individual
value therein, to treat and/or prevent a viral, bacterial,
protozoan, and/or fungal infection in the subject. In some
embodiments, a composition of the present invention may be
administered onto skin and/or a nail of a subject at least once
daily for a period of less than 50 weeks, e.g., less than 48, 45,
40, 35, 30, 25, 20, 15, 12, 10, 6, 4, 3, or 2 weeks or less, or any
range and/or individual value therein, to treat and/or prevent a
viral, bacterial, protozoan, and/or fungal infection in the
subject.
[0161] In some embodiments, a composition and/or method of the
present invention may not stain and/or discolor the nail and/or
skin of a subject to which it is in contact with and/or applied. In
some embodiments, a composition 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 composition 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 composition 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.
[0162] A method of the present invention may have increased or
improved efficacy in treating and/or preventing a viral, bacterial,
protozoan, and/or fungal (e.g., onychomycosis and/or tinea pedis)
infection in and/or on the skin and/or nail of 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 composition
of the present invention and/or a conventional treatment). In some
embodiments, a method of applying a composition 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 viral, bacterial,
protozoan, and/or fungal (e.g., onychomycosis and/or tinea pedis)
infection in and/or on the skin and/or nail of 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.
[0163] In some embodiments, a method of the present invention may
decrease the rate of reinfection of a viral, bacterial, protozoan,
and/or fungal (e.g., onychomycosis and/or tinea pedis) infection in
and/or on the skin and/or nail of 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.
[0164] 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 composition of the present
invention). 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.
[0165] In some embodiments, a method of the present invention may
provide a decrease or reduction in at least one clinical symptom
associated with a viral, bacterial, protozoan, and/or fungal (e.g.,
onychomycosis and/or tinea pedis) infection (e.g., a reduction in
the size and/or appearance of a benign lesion) in less time than
compared to a treatment in the absence of a method of the present
invention. In some embodiments, a subject may see a decrease or
reduction in at least one clinical symptom associated with a viral,
bacterial, protozoan, and/or fungal (e.g., onychomycosis and/or
tinea pedis) infection within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,
12, 13, or more day(s) and/or week(s).
[0166] In some embodiments, a method of the present invention may
prevent and/or reduce the appearance and/or size of a benign
lesion. Example benign lesions include, but are not limited to,
lesions caused by T. rubrum, such as, for example, scaly patches
and red and/or brown lesions (e.g., those associated with jock
itch). A method of the present invention may reduce the appearance
and/or size of a benign lesion by at least about 5%, 10%, 15%, 20%,
25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,
90%, 95%, 97% or 100% compared to the appearance and/or size of a
benign lesion prior to administering of a composition of the
present invention. The appearance of the benign lesion may be
evaluated visually, such as, but not limited to, by the subject
and/or a physician. The size of the benign lesion may be determined
using methods known to those of skill in the art.
[0167] A method of the present invention may reduce the number of
benign lesions by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%,
40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97% or
100% compared to the number of benign lesions prior to
administering of a composition of the present invention. The number
of benign lesions may be evaluated visually, such as, but not
limited to, by the subject and/or a physician. The number of benign
lesions may be determined using methods known to those of skill in
the art.
[0168] A method of the present invention may decrease the rate of
recurrence of a viral, bacterial, protozoan, and/or fungal (e.g.,
onychomycosis and/or tinea pedis) infection 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%, 97% or 100% compared to the
rate of recurrence of the viral, bacterial, protozoan, and/or
fungal (e.g., onychomycosis and/or tinea pedis) infection in the
absence of administering of a composition of the present invention.
The rate of recurrence may be determined using methods known to
those of skill in the art. For example, after a treatment of a
viral, bacterial, protozoan, and/or fungal (e.g., onychomycosis
and/or tinea pedis) infection, reinfection may be determined after
a given period of time to determine the rate of recurrence.
[0169] The present invention is explained in greater detail in the
following non-limiting Examples.
EXAMPLES
Example 1
[0170] Example hydrogels and gels, Tables 1 and 2, respectively,
were prepared. Each hydrogel was evaluated individually for
cosmetic asthetics and in combination with a gel to form an
admixture.
TABLE-US-00001 TABLE 1 Example hydrogel formulations. PHO-030
PHO-031 PHO-032 PHO-033 PHO-034 Ingredient 3.5 4.0 4.5 3.5 4.0
Gantrez S-97 18.00% 18.00% -- 18.00% 18.00% (Thickener) Sodium
1.00% 2.30% 1.00% 1.50% 2.30% Carboxymethylcellulose (Thickener)
Carbopol 980 0.25% -- -- -- -- (Thickener) Carbopol 2020 ETD -- --
-- 0.50% -- (Thickener) Avicel RC-591 -- 5.00% 5.00% -- 5.00%
(Thickener) Benzyl Alcohol -- -- -- 2.50% 2.50% (Co-Solvent)
Potassium Phosphate 11.50% 11.50% 11.50% 11.50% 11.50% Monobasic
(Buffering Agent) EDTA 0.50% -- -- 0.10% -- (Chelating Agent)
Ethanol 5.00% 5.00% 5.00% 5.00% 5.00% (Co-Solvent) Cyclomethicone
5.00% -- 5.00% 5.00% -- (Moisturizer) Phenoxyethanol -- -- -- 1.00%
1.00% (Co-Solvent) Benzoic Acid 0.10% 0.10% 0.10% 0.10% 0.10%
(Preservative) Purified Water (Solvent) 58.65% 58.10% 72.40% 54.80%
54.60% Total 100.00% 100.00% 100.00% 100.00% 100.00%
TABLE-US-00002 TABLE 2 Example gel formulations. Ingredient 32% 25%
20% 16% 10% 5% 3.2% Placebo Elastomer 10 2.00% 2.00% 2.00% 2.00%
2.00% 2.00% 2.00% 2.00% (Thickener) Cyclomethicone 17.00% 20.00%
21.00% 22.00% 23.00% 23.50% 24.00% 24.50% (Emollient) Hexylene
Glycol 14.00% 16.00% 18.00% 19.00% 21.00% 22.00% 23.00% 23.00%
(Humectant) Nitricil .TM. NVN1 32.00% 25.00% 20.00% 16.00% 10.00%
5.00% 3.20% 0.00% (Active Ingredient) Klucel MF 1.00% 1.00% 1.00%
1.00% 1.00% 1.50% 1.50% 1.50% (Thickener) Ethanol, Anhy. 8.00%
9.00% 10.00% 11.00% 13.00% 14.00% 15.00% 16.00% (Solvent)
Transcutol 26.00% 27.00% 28.00% 29.00% 30.00% 32.00% 31.30% 33.00%
(Co-Solvent)
Example 2
[0171] The penetration of nitric oxide through ex vivo human
cadaver finger nails from NO-releasing formulations was evaluated
using vertical diffusion cells. The in vitro vertical diffusion
cell model is a valuable tool for the study of percutaneous
penetration and determination of the pharmacokinetics of topically
applied drugs. The model has also been adapted to be used for the
ex vivo human cadaver fingernails mounted in specially designed
vertical diffusion cells allowing the nail to be maintained at a
temperature and hydration that are intended to represent in vivo
conditions. The nail adapters were Neoflon, 28 mm wide by 34 mm
long, and included o-rings and clamps to prevent leakage. A finite
dose of each formulation was applied to the outer surface of the
nail and absorption was measured by monitoring the rate of drug
appearance in the receiving medium bathing the basal surface of the
nail. Four human nail donors were selected in order to ensure donor
specific permeation patterns would be identified and
normalized.
[0172] Study Design
[0173] Apparatus: Vertical diffusion cells with nail adapters
[0174] Test Formulation 1: Nitricil.TM. NVN1 Cream, 32% (Table
3)+pH 4.5 hydrogel (Table 4)
[0175] Test Formulation 2: Nitricil.TM. NVN1 Gel, 32% (Table
2)+PHO-031 hydrogel (Table 1)
[0176] Test Formulation 3: Nitricil.TM. NVN1 Gel, 32% (Table
2)+PHO-033 hydrogel (Table 1)
[0177] Test Formulation 4: Nitricil.TM. NVN1 Gel, 32% (Table
2)+PHO-034 hydrogel (Table 1)
[0178] No. Fingernail Donors: 4
[0179] No. Fingernail Replicates: 6 nails per formulation,
randomized for donor, gender, and finger
[0180] Fingernail Type: Ex vivo human fingernails
[0181] Nail Adapter Dose Area: 0.2 cm.sup.2
[0182] Diffusion Cell Volume: Approximately 8 mL
[0183] Temperature: 37.degree. C..+-.1.0.degree. C.
[0184] Application Amount: 8 .mu.L (adjusted to nominal dosing
area), the hydrogel (4 .mu.L) and respective formulation (4 .mu.L)
were dosed separately onto the nail and mixed directly on the nail
using the tip of the pipet.
[0185] Dosing intervals: Nails were dosed daily for 7 days within
one hour of original dosing time. The original and subsequent
dosing times were recorded in the study records.
[0186] Fingernail Cleansing Regimen: Daily
[0187] Sampling Intervals: On day 1: 500 .mu.L receiving media was
collected at 0 h, 1 h, 4 h, 8 h, 24 h. Each day following the start
of the study, 500 .mu.L of receiving media was collected once per
day approximately one hour prior to the next dose application.
[0188] Sample Aliquot: Collect sample and replace with pre-warmed
fresh medium
[0189] Receiving Medium: Phosphate buffered saline pH 7.4.+-.0.1
(PBS) with 0.01% w/v sodium azide
TABLE-US-00003 TABLE 3 Nitricil .TM. NVN1 Cream, 32% Component %
w/w Nitricil .TM.NVN1 Drug Substance 32.00 Petrolatum and
polyethylene 26.50 Crodabase SQ White Petrolatum 26.50 Super White
Petrolatum USP Medium chain triglycerides 8.00 Miglyol 812
Caprylocaproyl polyoxylglycerides 4.00 Softigen 767 Mineral oil
Drakeol 34 USP 3.00 To Make Total 100.0
TABLE-US-00004 TABLE 4 pH 4.5 hydrogel Component % w/w Purified
water 75.30 Potassium phosphate monobasic 11.80 Glycerin 10.00
Sodium carboxymethylcellulose 2.80 Benzoic acid 0.10 To Make Total
100.0
[0190] Test Procedure
[0191] The following test procedure was followed:
[0192] 1.1 Set the Heater/Circulator to a temperature such that the
media within the cells are maintained at 32.degree. C.
[0193] 1.2 Human, ex vivo, cadaver fingernails without obvious
signs of nail disease that have been stored at -20.degree. C. or
lower will be used. Prior to dosing, thaw the nails at room
temperature, clear of any underlying tissue, and rinse with water
to remove any additional materials from the surface.
[0194] 1.3 Apply nails to each nail adapter and secure in place. A
small amount of silicone glue may be used to secure the nails in
place. Allow the silicone glue to appropriately solidify prior to
filling the cells with receiving medium.
[0195] 1.4 Verify that the temperature of the media of a few cells
is within 37.+-.1.degree. C. prior to filling the cells. Add
receiving medium and a stir bar, to each cell such that the cell is
full, and allow the cells and receiving medium to equilibrate at
37.degree. C. The cell volumes are determined as described in the
Cumulative Penetration Calculation section prior to initiating the
study. Assemble the cells using nail adapters and clamps to secure
nail adapters in place. Remove any air bubbles that were introduced
during assembly of the cells.
[0196] 1.5 Prior to dosing, each cell will be evaluated for leaks.
If any leaks are identified, apply additional silicone glue to seal
the leaks. A pre-dose sample will be collected for analysis, and an
equal volume will be replaced with pre-warmed fresh media. Dose
approximately 8 .mu.L of formulation by pipette to each cell,
covering the entire surface area of the nail. Occlude the sampling
port to prevent evaporation during the study. The day of
administration will be considered day one of the study. The actual
dosing time will be recorded in the study records.
[0197] 1.6 Each day for 7 days after the initial dosing, within one
hour of the original dosing time, apply an additional equivalent
dose to each cell as described previously. Prior to applying the
additional dose, each cell is sampled as described in section 1.7
and cleansed according the following procedures:
[0198] For all groups, following receiving medium collection,
cleanse the surface of the nails with a cotton tipped swab that has
been moistened with water (not dripping wet), then cleanse with a
dry cotton tipped swab. Discard the swabs after use.
[0199] 1.7 At each of the sampling intervals, remove 500 .mu.L
receiving media before application of the next dose. After removing
the media, add fresh receiving medium into the cell to replace the
volume removed during sampling, and ensure the nail adapters and
clamps are secure. Remove any air bubbles that were introduced
during assembly of the cells.
[0200] An aliquot of the receptor fluid will be submitted for HPLC
analysis. The remainder of the receptor fluid will be stored at
-20.degree. C.
[0201] Cumulative Penetration Calculation
[0202] The cumulative amount (Q) of active penetrating per surface
area of nail is:
Q = { C n .times. V .times. n = 1 n - 1 .times. .times. C i .times.
S } .times. / .times. A ##EQU00001##
Where:
[0203] Q=Cumulative amount of active penetrated per surface area of
nail (.mu.g/cm.sup.2) C.sub.n=Concentration of active (.mu.g/mL) in
the receiving medium determined at nth sampling interval (as
determined by the HPLC analysis) V=Volume of individual vertical
diffusion cell
i = 1 n - 1 .times. .times. C i = Sum .times. .times. of .times.
.times. concentrations .times. .times. of .times. .times. active
.times. .times. ( .mu. .times. .times. g .times. / .times. mL )
.times. .times. determined .times. .times. at .times. .times.
sampling .times. .times. intervals .times. .times. 1 .times.
.times. through .times. .times. n - 1 ##EQU00002##
S=Volume of sampling aliquot (.mu.L) A=Surface area of nail
(cm.sup.2) Penetration may be calculated for each day (C.sub.n)
and/or as a sum of cumulative penetration during the entire study
period.
[0204] Results
[0205] The mean nitric oxide permeation through human cadaver
nails, as detected by nitrite in the receiving medium, is presented
in Tables 5 and 6 and FIG. 2, and a standard vertical diffusion
cell is shown in FIG. 1.
TABLE-US-00005 TABLE 5 Mean nitric oxide permeation through human
cadaver nails on day 1. Average Cumulative Amount (.mu.g/cm.sup.2)
(Average .+-. SD) Formulations 1 hour 4 hour 8 hour Day 1 Test
Formulation 1 0.00 .+-. 0.00 0.00 .+-. 0.00 2.41 .+-. 5.92 2.66
.+-. 5.26 Test Formulation 2 0.00 .+-. 0.00 0.00 .+-. 0.00 0.00
.+-. 0.00 0.43 .+-. 1.05 Test Formulation 3 0.00 .+-. 0.00 0.00
.+-. 0.00 0.00 .+-. 0.00 0.69 .+-. 1.70 Test Formulation 4 0.00
.+-. 0.00 0.00 .+-. 0.00 0.00 .+-. 0.00 0.40 .+-. 0.99
TABLE-US-00006 TABLE 6 Mean nitric oxide permeation through human
cadaver nails on days 2-7. Average Amount (.mu.g/cm.sup.2) (Average
.+-. SD) Formulations Day 2 Day 3 Day 4 Day 6 Day 6 Day 7 Test
17.54 .+-. 205.19 .+-. 159.81 .+-. 48.91 .+-. 337.47 .+-. 803.50
.+-. Formulation 1 15.75 154.18 288.24 51.62 629.34 470.76 Test
14.21 .+-. 54.48 .+-. 7.48 .+-. 80.16 .+-. 63.90 .+-. 168.88 .+-.
Formulation 2 27.41 42.02 4.79 130.28 79.44 138.88 Test 0.46 .+-.
47.68 .+-. 4.12 .+-. 3.19 .+-. 29.67 .+-. 97.40 .+-. Formulation 3
0.99 52.05 3.69 3.34 53.27 50.91 Test 10.96 .+-. 101.25 .+-. 12.65
.+-. 10.00 .+-. 100.84 .+-. 188.93 .+-. Formulation 4 19.52 162.06
18.76 11.15 184.39 172.43
[0206] The mean cumulative penetration after 8 days of dosing of
each of four formulations indicated that nitrite appearance in the
receptor medium was greatest from Nitricil.TM. NVN1 Cream, 32%+pH
4.5 hydrogel. The mean cumulative amount of 803.50.+-.470.76
.mu.g/cm.sup.2 was several fold higher than from the remaining
three formulations. Among the remaining three formulations, there
was no observable difference between their absorption profiles.
[0207] For the lead formulation (Nitricil.TM. NVN1 Cream, 32%+pH
4.5 hydrogel), quantifiable appearance of nitrite was detected
after eight hours. For the remaining three formulations, nitrite
was not detected until the 24 hour sample. Interestingly, the
concentrations of nitrite in all cells peaked at the three day
sampling; the concentrations then decreased until the 5-6 day
samples, after which they began to increase again (FIG. 1).
[0208] During the HPLC analysis, a set of standards was prepared
and added to the autosampler tray along with the samples; however,
because there were more samples and standards than the autosampler
tray could hold, a set of standards and samples were frozen at
-20.degree. C. until additional space became available on the
autosampler tray. Once space became available, the frozen standards
and samples were thawed to room temperature, then added to the
autosampler tray to complete the analysis. During review of the
data, a clear reduction in peak area was observed for the standards
that had been frozen after preparation and before analysis,
indicating a potential freeze/thaw impact on samples containing
nitrite. The overall impact on the study is unknown, as each sample
was frozen immediately after collection during the nail penetration
study, and stored at -20.degree. C. until analysis. This phenomenon
may have contributed to the penetration profile trend (i.e.
increasing and decreasing over the eight days of sampling) observed
in all formulations.
Example 3
[0209] Different strengths of an NO-releasing gel in combination
with a hydrogel in a 1:1 ratio were tested for effectiveness
against T. rubrum. The underside of cadaver donor nails were
infected with T. rubrum and each nail was subsequently mounted in
ChubTur.RTM. cells as shown in FIG. 3. 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 of each admixture formulation was applied to the surface
of a nail opposite of fungal inoculation (FIG. 3). Each formulation
included the pH 4.0 hydrogel (PHO-033; (Table 1) that, prior to
application, was premixed in a 1:1 ratio with either 3.2%
Nitricil.TM. NVN1 Gel (Table 2) or 32% Nitricil.TM. NVN1 Gel (Table
2). 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). Each formulation was then applied for a
subsequent 24 hr exposure such that dosing continued for up to 7
days of topical application. However, on Days 1, 3, and 7 a subset
of nails were subsequently removed from the ChubTur.RTM. cells and
fungal viability was assessed using an ATP bioluminescence assay,
where the results of ATP signal are inversely proportional to the
percent fungal killing of T. rubrum.
[0210] During the infected nail investigation, the antimicrobial
efficacy of the high strength (16%) formulation (containing the 32%
NVN1 gel) was significantly greater (p.ltoreq.0.05) than that of
the low strength (1.6%) formulation (containing the 3.2% NVN1 gel)
after a single 1 day application of the test formulations (FIG. 4);
however, despite the apparent differences between the antimicrobial
efficacies of the low (80.03-98.58% kill of T. rubrum) and high
strength (93.60-99.61% kill of organism) formulations following
daily dosing for 3 and 7 days, there was no statistical difference
in the percentage ATP recovery of these multiple dose regimens when
compared as a whole population (p >0.05) (FIG. 4). The 3-day
dosing regimen was able to completely clear the nail of the
organism for the high strength (16%) formulation (p.ltoreq.0.05),
but not the low strength formulation which was statistically
different to the t=3 days non-infected control (p >0.05). The
7-day dosing regimen was able to achieve complete kill of the
organism with both the high and low strength formulations (p
<0.05) (FIG. 4). Taken together these data indicate that
following repeated application (at least 7 days) the antimicrobial
efficacy observed with topical application of either low or high
strength formulation is indistinguishable from one another.
Therefore, in the clinical setting it is probable that repeated
topical application of the lower strength formulation is likely to
achieve significant antimicrobial efficacy.
Example 4
[0211] Nitricil.TM. NVN1, the lead candidate of the platform, was
assessed for its spectrum of in vitro activity against a broad
range of filamentous fungi and yeast species commonly associated
with cutaneous fungal infections. Time-kill assays demonstrated
that Nitricil.TM. NVN1 produced fungicidal activity in as early as
4 hours. Additionally, the penetration of several unique
NO-releasing drug product formulations (gel, cream, lacquer) was
evaluated following a single topical application to an infected
human nail. Nitricil.TM. NVN1-containing topical formulations
demonstrated effective fungal growth inhibition following a single
treatment in the in vitro infected nail assay. Repeated topical
application in this model demonstrated that lower strength doses of
NO could achieve the same efficacy of higher strengths. Together,
these results demonstrate that NO-releasing treatments, with rapid
penetration of the nail plate and eradication of fungal infection,
represent promising novel topical therapies for the treatment of
onychomycosis and other superficial fungal infections.
[0212] Materials and Methods
[0213] Synthesis of Nitricil.TM. NVN1 Nitric Oxide-Releasing
Macromolecules
[0214] Nitricil.TM. NVN1 is a copolymer derived from
aminoalkoxysilanes and alkylalkoxysilanes terminated with
silanonals (FIG. 5). Nitricil.TM. NVN1 is formed from the
co-condensation of N-methylaminopropyltimethoxysilane (MAP3),
tetraethoyxysilane (TEOS) and
N,N-methylaminopropyldiazeniumdiolate-trimethoxysilane sodium salt
(MAP3-NONOate) via a sol-gel process, as described previously
(Shin, et. al., J. Am. Chem. Soc. 2007, 129:4612-19), to create a
network of siloxane bonds with organic functionality throughout.
This process yields 5 .mu.mol NO/mg of Nitricil.TM. NVN1 drug
substance as determined via assessment of NO content under acidic
conditions (pH 3) with a Sievers nitric oxide analyzer (Boulder,
Colo.). Following jet milling the median particle size distribution
(D50) value was 5.04 .mu.m as determined by the Malvern Mastersizer
2000.
[0215] Niricil.TM. NVN1 Drug Product Formulations
[0216] The nitric oxide-releasing active pharmaceutical ingredient
can be formulated for topical delivery in a variety of drug product
compositions. As the release of nitric oxide from the silica-based
backbone is proton-initiated, exposure to moisture directly affects
drug stability. To ensure stability Nitricil.TM. NVN1 is formulated
in anhydrous compositions. To determine the most efficacious
topical formulation for the delivery of nitric oxide to the nail
bed and cutaneous tissues Nitricil.TM. NVN1 was formulated into a
topical gel, ointment, or lacquer. Prior to topical application the
stable active phase was mixed in a 1:1 ratio with a hydrogel phase
providing the proton source necessary for initiation of nitric
oxide release from the drug product. The Nitricil.TM. NVN1 Gel is a
gel consisting of anhydrous ethanol, hexylene glycol,
cyclomethicone, hydroxypropyl cellulose, Transcutol, Elastomer 10,
and titanium dioxide. The Nitricil.TM. NVN1 Cream admixture results
from the admixture of an Nitricil.TM. NVN1 petrolatum-based
ointment with a benzoic acid-preserved potassium phosphate-based
aqueous hydrogel phase. The Nitricil.TM. NVN1 Lacquer formulation
results from the admixture of the ethylcellulose polymer-based
Nitricil.TM. NVN1 Lacquer and a benzoic acid-preserved potassium
phosphate-based aqueous hydrogel phase.
[0217] Microorganisms--Growth Media and Conditions
[0218] Challenge fungal species included both clinical isolates, as
well as strains obtained from the American Type Culture Collection
and National Collection of Pathogenic Fungi, representing T.
rubrum, T. mentragrophytes, Epidermophyton floccosum, as well as
Fusarium, Candida, and Malassezia species.
[0219] Time-Kill and Minimum Inhibitory Concentration
Determinations
[0220] Time-kill evaluations were determined following ASTM Method
E2783-11. Briefly, a 0.1 mL aliquot of the fungal challenge
prepared in 0.9% Sodium Chloride Irrigation was added to test tubes
containing the appropriate concentration of Nitricil.TM. NVN1 test
article dissolved in 10 mL of Tris pH 7.5-7.7 and vortexed. The
challenge suspension was exposed to each test article concentration
for 4 hours .+-.5 minutes and 24 hours .+-.5 minutes at 25.degree.
C..+-.2.degree. C. After exposure, a 0.1 mL aliquot of the
challenge suspension/test article was transferred to a new test
tube containing 9.9 mL of neutralizing agent, Butterfield's
phosphate buffer solution with product neutralizers (BBP++), and
mixed thoroughly via vortex. Additionally, ten-fold dilutions were
prepared in BBP++ as described. Duplicate aliquots
(10.sup.-1-10.sup.-5) were plated on the appropriate agar and
plates were incubated at 25.degree. C..+-.2.degree. C. until
sufficient growth was observed, at which time viable counts were
determined. The fungicidal effects (99.9% reduction in the original
inoculum) were determined from the control population (CFU/mL) and
the post-exposure population (CFU/mL) at each timed exposure.
[0221] The minimum inhibitory concentration (MIC) of Nitricil.TM.
NVN1 was determined in vitro for 40 strains of fungi to determine
the spectrum of antifungal activity. All MIC testing was conducted
in accordance with the Clinical and Laboratory Standards Institute
(CLSI) guidelines for antimicrobial testing of yeasts (M27-A2) and
filamentous fungi (M38-A2), apart from the lipophilic Malassezia
species, which were incubated in supplemented buffered RPMI-1640
medium. The challenge strains were exposed to a series of doubling
dilutions of Nitricil.TM. NVN1 prepared in RPMI-1640 medium in
triplicate. Fungal species were also challenged with ketoconazole,
prepared in DMSO, as a comparator. Tubes were inoculated with
fungal suspensions to a final concentration of
0.5-2.5.times.10.sup.3 cells/mL for yeasts and
0.4-5.0.times.10.sup.4 colony-forming units (CFU)/mL for
filamentous fungi. The MIC was determined following a 1- to 4-day
incubation period.
[0222] In Vitro Antifungal Activity Under the Human Nail Plate
[0223] The growth inhibition of T. rubrum under the human nail
plate was determined as previously described (Traynor, et. al,
Pharm Pharmacol, 2010, 62:730-37). Distal nail clippings obtained
from healthy human volunteers were individually infected on the
underside of the nail with 5 .mu.L of the T. rubrum suspension. The
suspension was allowed to dry on the underside of the nail for 30
minutes in a laminar flow cabinet and subsequently was mounted onto
the nail gasket within the ChubTur cell. The receiver chamber was
then filled with an inert humidity control fluid (sterile Ringer's
solution) and incubated at 25.degree. C. for 14 days to establish
the fungal nail infection. Following fungal incubation, the cells
were dosed with 50 .mu.L of the test article admixture formulation,
which was applied to the surface of the nail opposite to the T.
rubrum inoculation. After 24 hours of topical treatment, the nails
were cleaned of any residual formulation with a dry cotton swab and
gently rinsed with deionized water. The nails were air-dried for 30
minutes prior to the application of the next topical dose to remove
any moisture from the nail. After the completion of dosing, the
ChubTur cells were removed from incubation and the ChubTur cells
were dismantled. The nails were completely cleaned of all residual
test article as described above and once clean the nails were
subsequently placed in individual wells of a 96-well plate
containing the ATP standard (55.0 ng/mL) and analyzed for the
presence of ATP from the viable fungi via an ATP luminescence assay
(BacTiter-Glo.RTM.) as previously described (Traynor, 2010). ATP
calibration standards of known concentrations were prepared via
sequential dilution of a stock ATP standard (1 mg/mL) in Ringer's
solution. The wells of the 96-well plate were analyzed for the
presence of ATP and the ATP recovery was compared to ATP standards
and untreated infected positive controls. The mean percent ATP
recovery form each test article formulation was compared to the
infected control and statistical analyses performed using a one-way
ANOVA with a post-hoc Tukey's test using a 95% confidence interval.
This model was utilized in a preliminary experiment to assess the
nail penetration and subsequent fungicidal activity of Nitricil.TM.
NVN1 when formulated into a variety of topical drug products (gel,
cream, or lacquer). In the preliminary experiment the fungicidal
efficacy of each Nitricil.TM. NVN1-containing drug product
formulation was assessed following a single topical application as
this was hypothesized to allow the greatest differentiation amongst
the given drug product formulations. 10% efinaconazole solution was
included as the positive control in this single application
experiment. A second experiment was conducted with the infected
nail model to assess the time to complete fungal eradication
following repeat dosing with varying strengths of a Nitricil.TM.
NVN1 Admixture. In this experiment, 1.6% and 16.0% Nitricil.TM.
NVN1 Gel Admixture (having a formulation consistent with those
described in Example 6) were applied topically to infected nail
mounted in ChubTur cells and fungal viability was assessed via ATP
luminescence as described following 1, 3, or 7 days of daily
topical application and compared to the ATP levels of non-infected
and infected control nails incubated for the same durations.
[0224] Results
[0225] The broad-spectrum antifungal activity of Nitricil.TM. NVN1
was assessed via growth inhibition experiments against 40 different
fungal strains per CLSI M27-A2 and M38-A2 methodology (CLSI, 2008)
for assessment of yeasts and filamentous fungi respectively
utilizing ketoconazole as the antifungal comparator. The MIC values
for Nitricil.TM. NVN1 are summarized in Table 7 and ranged from 0.5
mg/mL to 8.0 mg/mL, equating to 75.5-1208 .mu.g NO/mL,
demonstrating a 16-fold range for all fungal species tested. The
ketoconazole MIC values for all fungal species ranged by
>500-fold under the same assay conditions (<0.063->32.0
ug/mL). The fungicidal activity of Nitricil.TM. NVN1 against a
panel of fungal species was examined utilizing the time-kill assay
to assess the rate and extent of fungal reduction following
exposure to Nitricil.TM. NVN1 under static growth conditions. The
time-kill curves following 24 hours of exposure to Nitricil.TM.
NVN1 are shown in FIG. 6. The dermatophytes T. mentagrophytes, E.
floccosum, and T. rubrum were especially susceptible to
NITRICIL.TM. NVN1, exhibiting a 99.9% fungal reduction following
challenge with 2 mg/mL of NITRICIL.TM. NVN1 (302 .mu.g NO/mL) in as
little as 4 hours exhibiting a rapid and robust effect following NO
exposure. Following 24 hours of exposure, apart from Fusarium
solani, fungicidal activity (99.9% fungal reduction) was observed
for all tested species challenged with 302 .mu.g NO/mL revealing
the lingering antimicrobial effect of NO despite its short
half-life.
TABLE-US-00007 TABLE 7 Antifungal activity of Nitricil .TM. NVN1
(.mu.g NO/ml) and ketoconazole (.mu.g/ml) against a panel of fungal
isolates. Nitricil .TM. Ketoconazole NVN1 MIC MIC Fungal Strain
(.mu.g NO/mL) (.mu.g/mL) Trichophyton rubrum NCPF #0113 75.5
>32.0 NCPF #0118 302 <0.063 NCPF #0295 604 >32.0 NCPF
#5025 302 >32.0 ATCC #MYA-4438 302 >32.0 ATCC #10218 75.5
<0.063 ATCC #22402 151 <0.063 ATCC #28188 604 0.125 ATCC
#44697 302 >32.0 Trichophyton mentagrophytes NCPF #0224 604 0.25
NCPF #5024 1208 0.5 ATCC #9533 151 1.0 ATCC #18749 75.5 0.125 ATCC
#28939 75.5 1.0 Epidermophyton floccosum NCPF #5011 1208 >32.0
NCPF #5012 302 >32.0 ATCC #38826 151 4.0 ATCC #44685 604 0.125
ATCC #52061 604 1.0 ATCC #52063 302 >32.0 ATCC #52066 604
>32.0 Fusarium species Fusarium keratoplasticum 604 >32.0
ATCC #36031 Fusarium oxysporum 302 >32.0 ATCC #62705 Fusarium
solani 604 >32.0 ATCC #56480 Malassezia furfur NCPF #3349 75.5
>32.0 NCPF #8211 151 16.0 ATCC #14521 151 >32.0 Candida
albicans ATCC #10231 151 <0.063 ATCC #58716 151 16.0 ATCC #96901
151 >32.0 BLSI #112613Ca1 151 >32.0 BLSI #112613Ca2 151
>32.0 Candida species Candida lusitaniae ATCC #200950 151
<0.063 Candida tropicalis NCPF #8760 1208 32.0
[0226] For the topical treatment of superficial fungal infections,
the Nitricil.TM. NVN1 drug substance was formulated into a variety
of topical products (gel, cream, or lacquer). Given the rapid
fungicidal activity of Nitricil.TM. NVN1 observed in time-kill
assays against the dermatophyte species, we sought to further
explore the effectiveness of formulated NO-releasing drug products
in an infected nail assay that simulates onychomycosis. The ability
of various Nitricil.TM. NVN1-containing topical formulations to
effectively penetrate the nail and exhibit antifungal activity was
evaluated in vitro utilizing the infected nail assay (ChubTur test
system) developed by MedPharm Ltd as this assay most accurately
mimics the conditions of onychomycosis (Traynor, 2010). In this
assay, T. rubrum was inoculated on the underside of a donor human
nail plate and the infection was allowed to establish for 2 weeks.
Infected fingernails were then mounted into modified vertical
diffusion cells for the assessment of topical dosing. As a
surrogate for fungal viability, ATP levels were assessed following
topical application of candidate test formulations as ATP levels
are inversely proportional to the percent fungal killing. This
assay has been utilized previously to compare the effectiveness of
Penlac, Loceryl, and a terbinafine spray formulation (Traynor,
2010). In this assay, fungicidal efficacy can only result from
penetration of the applied topical solution through the nail to the
resident fungal infection established beneath the nail. Initially a
single topical application of the various Nitricil.TM.
NVN1-containing formulations was assessed in this model to compare
the nail penetration and fungicidal activity of each formulation.
For comparison, the antifungal efficacy following a single
application of 10% efinaconazole solution was also examined in this
assay. Following a single 24-hr topical application there was no
significant difference in the ATP recovery (surrogate for fungal
viability) from any of the Nitricil.TM. NVN1-containing topical
formulations or 10% efinaconazole solution. All tested
formulations, including the positive control, demonstrated a mean
percent fungal kill of 82% or higher after a single topical
application (Table 8).
TABLE-US-00008 TABLE 8 Percentage kill of T. rubrum in the ChubTur
.RTM. infected nail investigation following a single topical
application of various Nitricil .TM. NVN1-containing topical
formulations. Mean Percentage Kill of T. rubrum vs. Infected
Control, Test Formulation n = 6 .+-. SEM 16% Nitricil .TM. NVN1 Gel
Admixture 88.67 .+-. 4.72 16% Nitricil .TM. NVN1 Cream 91.62 .+-.
2.09 16% Nitricil .TM. NVN1 Lacquer 99.02 .+-. 0.30 Jublia (10%
efinaconazole solution) 82.49 .+-. 6.71
[0227] Nitricil.TM. NVN1 Gel Admixtureis the drug product admixture
formulation that results from the 1:1 mixing of the Nitricil.TM.
NVN1-containing active gel phase and a hydrogel phase. Nitricil.TM.
NVN1 Gel Admixture was selected for further characterization based
on its physiochemical properties allowing for the concurrent
application to cutaneous soft tissues, as well as the nail plate,
for the treatment of onychomycosis and the ability of this
formulation to be used for the treatment of large surface areas.
This formulation was further optimized during development to reduce
the alcohol content of the active phase in an effort to improve the
tolerability in the intended patient population. The infected nail
assay utilizing the ChubTur cells was performed a second time to
determine the efficacy of low (1.6%) and high (16.0%) strength
optimized Nitricil.TM. NVN1 formulations against T. rubrum after
repeat daily dosing for up to 7 days. FIG. 7 presents the percent
fungal kill observed when T. rubrum-infected nails were treated
with varying strengths of the Nitricil.TM. NVN1 Gel Admixture. The
mean percentages of ATP recovered from the T. rubrum infected nails
compared to the infected control after a single dose and 24-hour
exposure were 77.15% and 9.78% for the low (1.6%) and the high
(16%) Nitricil.TM. NVN1 Gel Admixture formulation, respectively
equating to a 23% and 90% inhibition of fungal growth. Thus, there
was a statistically significant (p.ltoreq.0.05) difference in the
ATP recovery observed following a single topical application with
either strength Nitricil.TM. NVN1 Gel Admixture formulation when
compared to the ATP recovery from untreated infected nails. Despite
the potent antifungal activity observed with high strength (16.0%)
Nitricil.TM. NVN1 Gel Admixture on Day 1, the ATP recovery was
statistically different (p.ltoreq.0.05) from the Day 1 non-infected
control, indicating that complete fungal kill was not yet achieved.
Following 3 days of daily treatment, comparable antifungal efficacy
was observed following topical application of low (1.6%) and high
(16.0%) strength Nitricil.TM. NVN1 Gel Admixtures with 80% and
93.6% fungal growth inhibition achieved, respectively (FIG. 7).
However, only the high strength (16.0%) Nitricil.TM. NVN1 Gel
Admixture was statistically equivalent (p >0.05) to the Day 3
non-infected control, indicating that this formulation had achieved
complete fungal kill under the limitations of this assay. After 7
days of daily dosing, both the low (1.6%) and the high (16.0%)
strength Nitricil.TM. NVN1 Gel Admixtures achieved complete fungal
kill as determined by ATP recovery values that were equivalent to
the Day 7 non-infected controls (p >0.05) (FIG. 7).
[0228] MIC assay results indicated a broad-spectrum of Nitricil.TM.
NVN1 antifungal activity against a wide panel of yeast and
filamentous fungi. All Nitricil.TM. NVN1 MIC values listed in Table
7 fell within a 16-fold range (0.5 mg/mL-8.0 mg/mL NV1000;
75.5-1208 .mu.g NO/mL), demonstrating a narrow susceptibility
profile over a diverse panel of fungi responsible for a large
percentage of cutaneous infections in man. The ketoconazole results
demonstrated a much wider concentration range (<0.063->32
ug/mL) needed to affect the same species of fungi. Additionally,
unlike Nitricil.TM. NVN1, individual strains within a given fungal
species showed disparate susceptibility to ketoconazole. Comparison
between the two molecules reveal that the concentration of
Nitricil.TM. NVN1 needed to inhibit fungal growth was an order of
magnitude higher than the micromolar concentration observed
following exposure to ketoconazole. This result is not unexpected
as unlike ketoconazole NO is a highly reactive gaseous species
exhibiting a short half-life, measured in seconds, in the
physiological milieu. While wishing not to be bound to any
particular theory, it is believed that the antimicrobial activity
of Nitricil.TM. NVN1 is associated with the release of NO. Nitric
oxide in Nitricil.TM. NVN1 represents 15% of the overall
macromolecule on a weight-weight basis. Further, as a gaseous
species NO will readily diffuse in all directions following
proton-initiated release from the macromolecular backbone and a
measurable proportion of the liberated NO is expected to be lost to
the atmosphere upon topical application.
[0229] As both tinea pedis and onychomycosis have high rates of
recurrence, the fungicidal activity of a novel therapy provides
perhaps even more meaningful information about the potential for
treatment success than the growth inhibitory concentration
determined by MIC assay. Therefore, the fungicidal efficacy of
Nitricil.TM. NVN1 was evaluated against six representative
dermatophytes and yeasts via time-kills studies using a similar
concentration range employed in the MIC experiments.
[0230] As shown in FIG. 6 and Table 9, three of the six fungal
species were effectively killed (>4-log reduction in CFU/mL) by
Nitricil.TM. NVN1 concentrations of .ltoreq.604 NO/mL at the
earliest 4 hour timepoint. The other three species showed complete
kill by 24 hr exposure at Nitricil.TM. NVN1 concentrations of
.ltoreq.1208 .mu.g NO/mL. Despite the short half-life of NO, the
MIC and kill curve results demonstrate the rapid and broad
fungicidal potential of Nitricil.TM. NVN1.
TABLE-US-00009 TABLE 9 Percent fungal killing achieved following 4
hours of exposure to Nitricil .TM. NVN1 for representative fungal
isolates. 151 .mu.g 302 .mu.g 604 .mu.g 1208 .mu.g 4 hrs NO/mL
NO/mL NO/mL NO/mL T. rubrum 99.97% 99.99% 99.99% 99.99% T.
mentagrophytes 99.63% 99.98% 99.999% 99.999% E. floccosum 99.70%
99.70% 99.70% 99.70% F. solani 64.21% 77.35% 87.83% 78.30% C.
albicans 31.49% 73.96% 81.29% 87.94% C. tropicalis 99.99% 99.99%
99.99% 99.99%
[0231] Successful treatment of onychomycosis is fraught with
difficulty due to several factors; the location of the fungal
infection within the nail bed, the unique physical and chemical
properties of the nail, and the co-existence of tinea pedis which
aids in recurrence of fungal infection. Among these factors,
difficulty in finding compounds with the
pharmacologic/pharmacokinetic profile to allow for adequate nail
penetration and achieving therapeutic of drug levels, particularly
after topical administration is the most challenging. The newest
topical antifungal treatments, efinaconazole 10% solution and
tavaborole 5% solution, specifically developed for the treatment of
dermatophyte onychomycosis still only achieved complete cure rates
of approximately 17% and 9%, respectively in pivotal phase 3
clinical trials (Gupta et al., J Drugs Dermatol. 2014,
13(7):815-20; Elewski, et al., J Am. Acad. Dermatol. 2015
73(1):62-9). The results of these studies with Nitricil.TM. NVN1
demonstrate the benefits of topical treatment with a formulation
engineered to release gaseous NO that can be directly applied to
the nail plate and surrounding cutaneous tissues. T. rubrum and T.
mentagrophytes, the primary pathogens associated with both
onychomycosis and tinea pedis, were particularly susceptible to NO
exposure. The results of the preliminary study assessing various
Nitricil.TM. NVN1-containing topical formulations indicated that
all topical NO-releasing formulations were equally effective, as no
statistically significant differences in fungicidal efficacy based
upon topical formulation (gel, cream, or lacquer) were observed.
Each test article formulation demonstrated a mean percent fungal
kill of at least 82% following a single topical application.
[0232] Most topical antifungal drugs that successfully treat
cutaneous fungal infections do not effectively penetrate the nail
plate and bed, thus limiting the ability to concurrently treat
tinea pedis and onychomycosis with a single topical antifungal
agent (Hui, et al., J Pharm. Sci. 2007, 96(10):2622-31). The
Nitricil.TM. NVN1 Gel Admixture formulation was selected for
further development as it would allow for the concurrent treatment
of both the nail and surrounding soft tissue of the foot, which
might enhance the overall mycological cure rate observed following
topical treatment in the clinical setting. Both the low (1.6%) and
the high (16.0%) strength Nitricil.TM. NVN1 Gel Admixture
formulations exhibited fungicidal activity as early as 24 hours
following the first topical application. The 16.0% Nitricil.TM.
NVN1 Gel Admixture formulation completely eradicated the fungal
infection in the ChubTur model following 3 daily topical
applications. Similarly, following a week of daily topical
application, complete fungal eradication was also observed with
1.6% Nitricil.TM. NVN1 Gel Admixture. These findings demonstrate
that repeated topical applications, as would occur clinically, can
achieve comparable antifungal efficacy following treatment with
Nitricil.TM. NVN1 Gel Admixture.
[0233] These results suggest that the unique mechanism of action
and molecular characteristics of a topical NO-releasing gel may
produce high rates of fungicidal efficacy against a wide range of
fungal species. NO's antimicrobial activities include generation of
both oxidative and nitrosative species. These species interact with
a variety of molecular targets including iron-sulfur thiols,
tyrosine residues, membrane lipids, and DNA bases providing
numerous fungal targets to act upon. While not wishing to be bound
to any particular theory, the ability of NO and its associated
gaseous species to rapidly migrate through the nail plate, and
through microbial lipid membranes, demonstrates that Nitricil.TM.
NVN1 Gel Admixture may be an effective topical treatment for
superficial fungal infections such as onychomycosis. The potential
to simultaneously treat both the nail plate and the surrounding
cutaneous tissues with a single topical formulation could improve
the clinical outcome as compared to the standard of care for both
tinea pedis and onychomycosis, which is particularly important as
the prevalence of onychomycosis is increasing in the elderly and
diabetic populations where more advanced disease occurs with
associated morbidities such as wounds, cellulitis, and compromised
ambulation.
Example 5
[0234] A phase 2, multi-center, double-blind, randomized,
vehicle-controlled study is conducted in approximately 220non
immunocompromised adult subjects with interdigital tinea pedis.
Subjects will apply the investigational product (IP) (Nitricil.TM.
NVN1 Gel Admixture or Vehicle Gel) to the interdigital areas and
all affected and immediate surrounding areas of one or both feet
once daily for 2 weeks, followed by a 4-week post-treatment
observation period.
[0235] Study Type: Interventional
[0236] Study Design: Allocation: Randomized
[0237] Intervention Model: Parallel Assignment
[0238] Masking: Double Blind (Subject, Investigator)
[0239] Primary Purpose: Treatment
[0240] Primary Outcome Measures:
[0241] Fungal culture result [Time Frame: 14 days], Negative fungal
culture from target lesion
[0242] Secondary Outcome Measures:
[0243] Clinical cure [Time Frame: 42 days], Amelioration of signs
and symptoms of tinea pedis
[0244] Mycological cure [Time Frame: 42 days], No evidence of
fungal infection based on skin scraping and culture
[0245] Other Outcome Measures:
[0246] Incidence of treatment-emergent adverse events [Time Frame:
42 days], Summary of treatment emergent adverse events by treatment
group
TABLE-US-00010 Arms Assigned Interventions Experimental: 2%
Nitricil .TM. NVN1 Drug: 2% Nitricil .TM. NVN1 Gel Gel Admixture
Admixture once daily (provided in Example 6) Experimental: 4%
Nitricil .TM. NVN1 Drug: 4% Nitricil .TM. NVN1 Gel Gel Admixture
(provided in Example 6) Admixture once daily Experimental: 16%
Nitricil .TM. NVN1 Drug: 16% Nitricil .TM. NVN1 Gel Admixture Gel
Admixture once daily (provided in Example 6) Placebo Comparator:
Vehicle Gel Drug: Vehicle Gel once daily
[0247] Eligibility
[0248] Ages Eligible for Study: 18 Years to 70 Years (Adult,
Senior)
[0249] Sexes Eligible for Study: All
[0250] Accepts Healthy Volunteers: No
[0251] Inclusion Criteria: Otherwise healthy male and female
subjects with clinical diagnosis of interdigital t. pedis. T. pedis
provisionally confirmed at baseline by a positive KOH wet mount for
segmented fungal hyphae on skin scraping from the target site
[0252] Exclusion Criteria: Women who are pregnant or nursing or
planning on becoming pregnant. Subjects with onychomycosis or
moccasin-type t. pedis. Subjects using topical or systemic
anti-fungal agents.
[0253] Enrollment: 222
[0254] Results from the Primary Outcome Measures: The results from
the primary outcome measures are provided in Tables 10 and 11. In
pre-specified populations including the per protocol population,
subjects treated with SB208 4% and 16% once daily demonstrated a
statistically significant (p.ltoreq.0.05) difference from vehicle
on the primary efficacy outcome, a negative fungal culture at Day
14. No subjects discontinued treatment due to adverse events.
[0255] Results from the Secondary Outcome Measures: The results
from the secondary outcome measures are provided in Tables
12-17.
TABLE-US-00011 TABLE 10 Subject Disposition (All Randomized
Subjects) SB208 SB208 SB208 SB208 Disposition 2% 4% 16% Total
Vehicle Total Subjects Randomized 56 55 55 166 56 222 Subjects
Included in Intent-to-Treat 56 (100.0%) 55 (100.0%) 55 (100.0%) 166
(100.0%) 56 (100.0%) 222 (100.0%) (Safety) Analysis Subjects
Included in Modified 35 (62.5%) 37 (67.3%) 36 (65.5%) 108 (65.1%)
35 (62.5%) 143 (64.4%) Intent-to-Treat Analysis Subjects Included
in Per-Protocol Analysis 29 (51.8%) 29 (52.7%) 30 (54.5%) 88
(53.0%) 31 (55.4%) 119 (53.6%) Subjects Completed study 40 (71.4%)
45 (81.8%) 41 (74.5%) 126 (75.9%) 42 (75.0%) 168 (75.7%) Subjects
Discontinued 16 (28.6%) 10 (18.2%) 14 (25.5%) 40 (24.1%) 14 (25.0%)
54 (24.3%) Reason for Discontinuation: Negative baseline culture 15
(26.8%) 9 (16.4%) 14 (25.5%) 38 (22.9%) 14 (25.0%) 52 (23.4%)
Adverse event 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%)
Subject decision/withdrawal of consent 0 (0.0%) 1 (1.8%) 0 (0.0%) 1
(0.6%) 0 (0.0%) 1 (0.5%) Significant protocol violation or 0 (0.0%)
0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) non-compliance with
protocol Non-compliant use of IP 0 (0.0%) 0 (0.0%) 0 (0.0%) 0
(0.0%) 0 (0.0%) 0 (0.0%) Condition worsens and requires 0 (0.0%) 0
(0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) alternative or
supplemental therapy for treatment of tinea pedis during the study
Lost to follow-up 1 (1.8%) 0 (0.0%) 0 (0.0%) 1 (0.6%) 0 (0.0%) 1
(0.5%) Subject's IP code is unblinded 0 (0.0%) 0 (0.0%) 0 (0.0%) 0
(0.0%) 0 (0.0%) 0 (0.0%) Subject became pregnant 0 (0.0%) 0 (0.0%)
0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) Investigator discretion 0
(0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) Other 0 (0.0%)
0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%)
TABLE-US-00012 TABLE 11 Primary Efficacy Analysis: Proportion of
Subjects with Negative Fungal Culture at Visit 2/Day 14 Missing
p-value of Data SB208 SB208 SB208 SB208 SB208 Total Handling
Statistics 2% 4% 16% Total Vehicle vs. Vehicle.sup.1 Modified
Intent-to-Treat Population Confirmed N 31 31 31 93 33 n (%)
Subjects with Negative 19 (61.3%) 25 (80.6%) 23 (74.2%) 67 (72.0%)
15 (45.5%) 0.004 Fungal Culture p-value of SB208 vs. Vehicle.sup.1
0.209 0.002 0.016 Per-Protocol Population LOCF N 29 29 30 88 31 n
(%) Subjects with Negative 17 (58.6%) 23 (79.3%) 23 (76.7%) 63
(71.6%) 13 (41.9%) 0.003 Fungal Culture p-value of SB208 vs.
Vehicle.sup.1 0.204 0.002 0.008 Modified Intent-to-Treat: subjects
with a positive fungal culture at Baseline. Confirmed analysis only
includes subjects with evaluable culture result at Day 14.
Per-Protocol: Subjects with no significant protocol violations.
LOCF: last observation carried forward. .sup.1P-values for
treatment comparisons from Cochran-Mantel-Haenszel test for general
association adjusting for site.
TABLE-US-00013 TABLE 12 Secondary Efficacy Analysis: Proportion of
Subjects with Clinical Cure at Visit 3/Day 42 Missing p-value of
Data SB208 SB208 SB208 SB208 SB208 Total Handling Statistics 2% 4%
16% Total Vehicle vs. Vehicle.sup.1 Modified Intent-to-Treat
Population LOCF N 35 37 36 108 35 n (%) Subjects with Clinical
Cure* 5 (14.3%) 11 (29.7%) 9 (25.0%) 25 (23.1%) 5 (14.3%) 0.280
p-value of SB208 vs. Vehicle.sup.1 1.000 0.152 0.253 Observed N 34
37 36 107 35 n (%) Subjects with Clinical Cure* 5 (14.7%) 11
(29.7%) 9 (25.0%) 25 (23.4%) 5 (14.3%) 0.279 p-value of SB208 vs.
Vehicle.sup.1 0.988 0.152 0.253 Per-Protocol Population LOCF N 29
29 30 88 31 n (%) Subjects with Clinical Cure* 5 (17.2%) 10 (34.5%)
8 (26.7%) 23 (26.1%) 5 (16.1%) 0.224 p-value of SB208 vs.
Vehicle.sup.1 0.887 0.120 0.234 Observed N 29 29 30 88 31 n (%)
Subjects with Clinical Cure* 5 (17.2%) 10 (34.5%) 8 (26.7%) 23
(26.1%) 5 (16.1%) 0.224 p-value of SB208 vs. Vehicle.sup.1 0.887
0.120 0.234 *Clinical cure is defined as a total signs/symptoms
severity score of no more than 2 with no individual severity score
greater than 1 on the 4-point scale. .sup.1P-values for treatment
comparisons from Cochran-Mantel-Haenszel test for general
association adjusting for site.
TABLE-US-00014 TABLE 13 Secondary Efficacy Analysis: Proportion of
Subjects with Mycological Cure at Visit 3/Day 42 Missing p-value of
Data SB208 SB208 SB208 SB208 SB208 Total Handling Statistics 2% 4%
16% Total Vehicle vs. Vehicle.sup.1 Modified Intent-to-Treat
Population LOCF N 35 37 36 108 35 n (%) Subjects with Mycological
Cure* 12 (34.3%) 18 (48.6%) 21 (58.3%) 51 (47.2%) 11 (31.4%) 0.079
p-value of SB208 vs. Vehicle.sup.1 0.798 0.103 0.019 Confirmed N 34
35 34 103 34 n (%) Subjects with Mycological Cure* 12 (35.3%) 18
(51.4%) 20 (58.8%) 50 (48.5%) 11 (32.4%) 0.071 p-value of SB208 vs.
Vehicle.sup.1 0.795 0.076 0.020 Per-Protocol Population LOCF N 29
29 30 88 31 n (%) Subjects with Mycological Cure* 8 (27.6%) 16
(55.2%) 17 (56.7%) 41 (46.6%) 10 (32.3%) 0.166 p-value of SB208 vs.
Vehicle.sup.1 0.673 0.054 0.074 Confirmed N 29 28 29 86 31 n (%)
Subjects with Mycological Cure* 8 (27.6%) 16 (57.1%) 16 (55.2%) 40
(46.5%) 10 (32.3%) 0.166 p-value of SB208 vs. Vehicle.sup.1 0.673
0.042 0.086 *Mycological cure is defined as a negative KOH wet
mount and a negative fungal culture. .sup.1P-values for treatment
comparisons from Cochran-Mantel-Haenszel test for general
association adjusting for site.
TABLE-US-00015 TABLE 14 Secondary Efficacy Analysis: Proportion of
Subjects with Therapeutic Cure at Visit 3/Day 42 Missing p-value of
Data SB208 SB208 SB208 SB208 SB208 Total Handling Statistics 2% 4%
16% Total Vehicle vs. Vehicle.sup.1 Modified Intent-to-Treat
Population LOCF N 35 37 36 108 35 n (%) Subjects with Therapeutic
Cure* 2 (5.7%) 7 (18.9%) 4 (11.1%) 13 (12.0%) 3 (8.6%) 0.606
p-value of SB208 vs. Vehicle.sup.1 0.646 0.247 0.729 Confirmed N 34
37 36 107 35 n (%) Subjects with Therapeutic Cure* 2 (5.9%) 7
(18.9%) 4 (11.1%) 13 (12.1%) 3 (8.6%) 0.604 p-value of SB208 vs.
Vehicle.sup.1 0.660 0.247 0.729 Per-Protocol Population LOCF N 29
29 30 88 31 n (%) Subjects with Therapeutic Cure* 2 (6.9%) 7
(24.1%) 3 (10.0%) 12 (13.6%) 3 (9.7%) 0.547 p-value of SB208 vs.
Vehicle.sup.1 0.706 0.152 0.919 Confirmed N 29 29 30 88 31 n (%)
Subjects with Therapeutic Cure* 2 (6.9%) 7 (24.1%) 3 (10.0%) 12
(13.6%) 3 (9.7%) 0.547 p-value of SB208 vs. Vehicle.sup.1 0.706
0.152 0.919 *Therapeutic cure is defined as having both clinical
cure and mycological cure. .sup.1P-values for treatment comparisons
from Cochran-Mantel-Haenszel test for general association adjusting
for site.
TABLE-US-00016 TABLE 15 Secondary Efficacy Analysis: Proportion of
Subjects with Clinical Cure at Visit 2/Day 14 Missing p-value of
Data SB208 SB208 SB208 SB208 SB208 Total Handling Statistics 2% 4%
16% Total Vehicle vs. Vehicle.sup.1 Modified Intent-to-Treat
Population LOCF N 35 37 36 108 35 n (%) Subjects with Clinical
Cure* 4 (11.4%) 1 (2.7%) 4 (11.1%) 9 (8.3%) 2 (5.7%) 0.649 p-value
of SB208 vs. Vehicle.sup.1 0.386 0.463 0.418 Observed N 35 36 36
107 35 4 (11.4%) 1 (2.8%) 4 (11.1%) 9 (8.4%) 2 (5.7%) 0.649 n (%)
Subjects with Clinical Cure* p-value of SB208 vs. Vehicle.sup.1
0.386 0.463 0.418 Per-Protocol Population LOCF N 29 29 30 88 31 3
(10.3%) 1 (3.4%) 4 (13.3%) 8 (9.1%) 2 (6.5%) 0.626 n (%) Subjects
with Clinical Cure* p-value of SB208 vs. Vehicle.sup.1 0.564 0.555
0.292 Observed N 29 29 30 88 31 n (%) Subjects with Clinical Cure*
3 (10.3%) 1 (3.4%) 4 (13.3%) 8 (9.1%) 2 (6.5%) 0.626 p-value of
SB208 vs. Vehicle.sup.1 0.564 0.555 0.292 *Clinical cure is defined
as a total signs/symptoms severity score of no more than 2 with no
individual severity score greater than 1 on the 4-point scale.
.sup.1P-values for treatment comparisons from
Cochran-Mantel-Haenszel test for general association adjusting for
site.
TABLE-US-00017 TABLE 16 Secondary Efficacy Analysis: Proportion of
Subjects with Mycological Cure at Visit 2/Day 14 Missing p-value of
Data SB208 SB208 SB208 SB208 SB208 Total Handling Statistics 2% 4%
16% Total Vehicle vs. Vehicle.sup.1 Modified Intent-to-Treat
Population LOCF N 35 37 36 108 35 n (%) Subjects with Mycological
Cure* 11 (31.4%) 16 (43.2%) 17 (47.2%) 44 (40.7%) 8 (22.9%) 0.038
p-value of SB208 vs. Vehicle.sup.1 0.414 0.035 0.022 Confirmed N 32
32 32 96 34 n (%) Subjects with Mycological Cure* 11 (34.4%) 16
(50.0%) 17 (53.1%) 44 (45.8%) 8 (23.5%) 0.013 p-value of SB208 vs.
Vehicle.sup.1 0.305 0.009 0.010 Per-Protocol Population LOCF N 29
29 30 88 31 n (%) Subjects with Mycological Cure* 10 (34.5%) 14
(48.3%) 17 (56.7%) 41 (46.6%) 6 (19.4%) 0.005 p-value of SB208 vs.
Vehicle.sup.1 0.194 0.007 0.003 Confirmed N 29 29 30 88 31 n (%)
Subjects with Mycological Cure* 10 (34.5%) 14 (48.3%) 17 (56.7%) 41
(46.6%) 6 (19.4%) 0.005 p-value of SB208 vs. Vehicle.sup.1 0.194
0.007 0.003 *Mycological cure is defined as a negative KOH wet
mount and a negative fungal culture. .sup.1P-values for treatment
comparisons from Cochran-Mantel-Haenszel test for general
association adjusting for site.
TABLE-US-00018 TABLE 17 Secondary Efficacy Analysis: Proportion of
Subjects with Therapeutic Cure at Visit 2/Day 14 Missing p-value of
Data SB208 SB208 SB208 SB208 SB208 Total Handling Statistics 2% 4%
16% Total Vehicle vs. Vehicle.sup.1 Modified Intent-to-Treat
Population LOCF N 35 37 36 108 35 n (%) Subjects with Therapeutic
Cure* 2 (5.7%) 1 (2.7%) 4 (11.1%) 7 (6.5%) 1 (2.9%) 0.439 p-value
of SB208 vs. Vehicle.sup.1 0.555 0.909 0.176 Confirmed N 34 36 36
106 35 n (%) Subjects with Therapeutic Cure* 2 (5.9%) 1 (2.8%) 4
(11.1%) 7 (6.6%) 1 (2.9%) 0.430 p-value of SB208 vs. Vehicle.sup.1
0.528 0.909 0.176 Per-Protocol Population LOCF N 29 29 30 88 31 n
(%) Subjects with Therapeutic Cure* 2 (6.9%) 1 (3.4%) 4 (13.3%) 7
(8.0%) 1 (3.2%) 0.351 p-value of SB208 vs. Vehicle.sup.1 0.501
1.000 0.114 Confirmed N 29 29 30 88 31 n (%) Subjects with
Therapeutic Cure* 2 (6.9%) 1 (3.4%) 4 (13.3%) 7 (8.0%) 1 (3.2%)
0.351 p-value of SB208 vs. Vehicle.sup.1 0.501 1.000 0.114
*Therapeutic cure is defined as having both clinical cure and
mycological cure. .sup.1P-values for treatment comparisons from
Cochran-Mantel-Haenszel test for general association adjusting for
site.
Example 6
[0256] In vitro nitric oxide release profiles for 4%, 8%, and 16%
Nitricil.TM. NVN1 Gel Admixture are shown in FIGS. 8 and 9 and are
summarized in Table 18 below.
TABLE-US-00019 TABLE 18 In Vitro Nitric Oxide Release Summary.
Product 4% Nitricil .TM. NVN1 8% Nitricil .TM. NVN1 16% Nitricil
.TM. NVN1 Gel Admixture Gel Admixture Gel Admixture Components 8%
Nitricil .TM. NVN1 16% Nitricil .TM. NVN1 32% Nitricil .TM. NVN1
Gel + pH 4 Hydrogel Gel + pH 4 Hydrogel Gel + pH 4 Hydrogel Cmax
(pmol NO) 868 1742 2114 Total NO (nmol NO/mg Gel) 253 514 851 Tmax
(min) 0.6 1.8 1.8 [NO] [NO] [NO] Released Total NO Released Total
NO Released Total NO Time (hr) (pmol/mg) (nmol/mg) (pmol/mg)
(nmol/mg) (pmol/mg) (nmol/mg) 0.00 119.69 0.67 0.67 0.01 1.47 0.01
0.01 867.87 20.21 59.12 0.43 761.26 0.01 0.03 693.52 53.56 1742.17
141.35 2114.28 0.17 0.05 336.37 99.10 448.68 214.58 973.29 75.46
0.10 178.19 143.82 141.24 303.60 287.69 158.04 0.20 60.04 178.63
42.70 398.91 104.72 257.67 0.40 22.71 206.68 21.02 408.82 55.74
343.42 0.60 10.39 217.94 12.48 416.21 38.96 409.01 0.80 8.08 224.58
9.20 424.31 30.29 458.72 1.00 5.30 228.85 10.51 446.07 24.18 500.18
1.50 2.34 234.85 7.11 452.58 14.74 571.84 1.75 2.02 236.84 4.60
458.18 12.38 598.47 2.00 1.61 238.46 4.21 467.10 11.26 619.69 2.50
1.25 241.11 3.92 470.94 8.66 659.85 2.75 1.08 242.18 3.77 474.32
7.77 677.57 3.00 1.03 243.15 3.53 480.35 7.27 692.82 3.50 0.87
244.92 2.80 483.09 6.36 715.74 3.75 0.84 245.69 2.63 485.65 6.14
727.21 4.00 0.77 246.41 2.14 490.19 5.86 738.64 4.50 0.71 247.74
2.38 492.26 4.99 760.36 4.75 0.67 248.36 1.92 494.16 4.60 770.28
5.00 0.62 248.93 1.88 497.73 4.19 779.54 5.50 0.54 249.98 1.94
499.49 3.90 795.94 5.75 0.49 250.44 1.83 501.14 3.72 803.27 6.00
0.45 250.87 1.83 504.25 3.56 810.22 6.50 0.41 251.66 1.50 505.69
3.15 822.38 6.75 0.40 252.02 1.46 507.07 2.94 827.86 7.00 0.38
252.36 1.27 509.60 2.87 832.93 7.50 0.36 253.01 1.39 510.80 2.76
842.22 7.75 0.32 253.31 1.18 511.94 2.69 846.59 8.00 0.33 253.61
1.24 514.18 2.56 850.86
[0257] The composition of the pH 4 Hydrogel is shown in Table 19
below.
TABLE-US-00020 TABLE 19 Composition of pH 4 Hydrogel. Ingredient %
w/w Purified Water 55.10 Decon, or equivalent Methylvinyl
Ether/Maleic Anhydride Copolymer 18.00 Gantrez S-97 HSU, Ashland
Potassium Phosphate, Monobasic 11.50 Fisher, or equivalent Ethanol,
Anhydrous 5.00 Decon, or equivalent Cyclomethicone 5.00
ST-Cyclomethicone-5, Dow Corning Carboxymethylcellulose, Sodium
2.00 Aqualon CMC 7M85F PH, Ashland Benzyl Alcohol 2.50 J.T. Baker,
or equivalent Carbomer Interpolymer Type B 0.80 Carbopol 2020 ETD,
Lubrizol Benzoic Acid Spectrum, or equivalent 0.10 100.00
[0258] The compositions of the 8%, 16%, and 32% Nitricil.TM. NVN1
Gels are shown in Table 20 below.
TABLE-US-00021 TABLE 20 Compositions of 4%, 8%, 16% and 32%
Nitricil .TM. NVN1 Gels. % w/w Ingredient 4% 8% 16% 32% Diethylene
Glycol 34.00 33.00 30.00 26.00 Monoethyl Ether Transcutol, P,
Gattefosse Hexylene Glycol Amresco 25.00 23.00 20.00 14.00
Cyclomethicone ST- 18.00 18.00 18.00 17.00 Cyclomethicone-5, Dow
Corning Ethanol, Anhydrous .sup.(1) 15.40 14.70 12.90 8.40 Decon,
or equivalent Nitricil .TM. NVN1 Drug 4.00 8.00 16.00 32.00
Substance .sup.(1) Novan, Inc. Cyclopentasiloxane/ 2.00 2.00 2.00
1.75 Dimethicone Crosspolymer ST-Elastomer-10, Dow Corning
Hydroxypropyl Cellulose 1.50 1.20 1.00 0.75 Klucel MF Pharm,
Ashland Titanium Dioxide Spectrum, or equivalent 0.10 0.10 0.10
0.10 100.00 100.00 100.00 .sup.(1) The dispensed amount of Nitricil
.TM. NVN1 Drug Substance is based on the potency of MAP3-NONOate of
the drug substance and will be adjusted when the content of the
respective Nitricil .TM. NVN1Drug Substance batch is < 56.8%.
The dispensed amount of Ethanol, Anhydrous will be equally adjusted
based on the final calculated adjustment of Nitricil .TM. NVN1 Drug
Substance to equal 100.0 %.
[0259] 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.
* * * * *