U.S. patent application number 13/977461 was filed with the patent office on 2016-09-08 for treatment of erectile dysfunction and other indications.
This patent application is currently assigned to Strategic Science & Technologies, LLC. The applicant listed for this patent is Eric T. Fossel. Invention is credited to Eric T. Fossel.
Application Number | 20160256381 13/977461 |
Document ID | / |
Family ID | 46383543 |
Filed Date | 2016-09-08 |
United States Patent
Application |
20160256381 |
Kind Code |
A9 |
Fossel; Eric T. |
September 8, 2016 |
TREATMENT OF ERECTILE DYSFUNCTION AND OTHER INDICATIONS
Abstract
The present invention generally relates to the transdermal
delivery of various compounds. In some aspects, transdermal
delivery may be facilitated by the use of a hostile biophysical
environment. One set of embodiments provides a composition for
topical delivery comprising a phosphodiesterase type 5 inhibitor
and/or a salt thereof, and optionally, a hostile biophysical
environment and/or a nitric oxide donor. In some cases, the
composition may be stabilized using a combination of a
stabilization polymer (such as xanthan gum, KELTROL.RTM. BT and/or
KELTROL.RTM. RD), propylene glycol, and a polysorbate surfactant
such as Polysorbate 20, which combination unexpectedly provides
temperature stability to the composition, e.g., at elevated
temperatures such as at least 40.degree. C. (at least about
104.degree. F.), as compared to compositions lacking one or more of
these.
Inventors: |
Fossel; Eric T.; (Cambridge,
MA) |
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Applicant: |
Name |
City |
State |
Country |
Type |
Fossel; Eric T. |
Cambridge |
MA |
US |
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Assignee: |
Strategic Science &
Technologies, LLC
Cambridge
MA
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Prior
Publication: |
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Document Identifier |
Publication Date |
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US 20140086980 A1 |
March 27, 2014 |
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Family ID: |
46383543 |
Appl. No.: |
13/977461 |
Filed: |
December 29, 2011 |
PCT Filed: |
December 29, 2011 |
PCT NO: |
PCT/US11/67993 PCKC 00 |
371 Date: |
September 25, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12812187 |
Mar 28, 2011 |
8604081 |
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PCT/US09/03749 |
Jun 24, 2009 |
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13977461 |
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61427999 |
Dec 29, 2010 |
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61428123 |
Dec 29, 2010 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 47/10 20130101;
A61K 31/506 20130101; A61K 9/0014 20130101; A61K 47/06 20130101;
A61P 15/00 20180101; A61K 47/14 20130101; A61K 9/107 20130101; A61K
47/36 20130101; A61K 9/0034 20130101; A61K 47/183 20130101; A61K
31/198 20130101; A61K 31/53 20130101; A61K 31/4985 20130101; A61K
9/06 20130101; A61K 47/16 20130101; A61P 15/10 20180101; A61K
31/495 20130101; A61P 43/00 20180101; A61K 47/02 20130101; A61K
47/26 20130101; A61K 47/22 20130101; A61K 31/519 20130101; A61K
47/12 20130101; A61K 31/198 20130101; A61K 2300/00 20130101; A61K
31/519 20130101; A61K 2300/00 20130101; A61K 31/495 20130101; A61K
2300/00 20130101; A61K 31/506 20130101; A61K 2300/00 20130101 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61K 31/506 20060101 A61K031/506; A61K 31/53 20060101
A61K031/53; A61K 31/519 20060101 A61K031/519; A61K 31/4985 20060101
A61K031/4985 |
Claims
1. A composition for topical delivery to the skin of a subject, the
composition comprising: a nitric oxide donor comprising L-arginine
and/or L-arginine hydrochloride; a hostile biophysical environment
comprising an ionic salt; a stabilization polymer comprising
xanthan gum; propylene glycol; a polysorbate surfactant comprising
Polysorbate 20; and a phosphodiesterase type 5 inhibitor and/or a
salt thereof.
2. (canceled)
3. The composition of claim 1, wherein the composition is stable
when exposed to a temperature of 40.degree. C. for at least about 4
weeks.
4-5. (canceled)
6. The composition of claim 1, wherein the composition is a
cream.
7-8. (canceled)
9. The composition of claim 1, wherein the composition is contained
within a transdermal patch.
10-12. (canceled)
13. The composition of claim 1, wherein the nitric oxide donor is
present at a concentration of at least about 0.5% by weight of the
composition.
14-17. (canceled)
18. The composition of claim 1, wherein the ionic salt is present
at a concentration of at least about 5% by weight of the
composition.
19-20. (canceled)
21. The composition of claim 1, wherein the hostile biophysical
environment comprises one or more salts selected from the group
consisting of sodium chloride, choline chloride, magnesium
chloride, and calcium chloride.
22-24. (canceled)
25. The composition of claim 1, wherein the hostile biophysical
environment has an ionic strength of at least about 0.25 M.
26. The composition of claim 1, wherein the hostile biophysical
environment has an ionic strength of at least about 1 M.
27-31. (canceled)
32. The composition of claim 1, wherein the composition further
comprises a package containing the nitric oxide donor, the package
being selected from the group consisting of liposomes, emulsions of
collagen, collagen peptides and combinations thereof.
33-37. (canceled)
38. The composition of claim 1, wherein the stabilization polymer
is present at a concentration of at least about 0.5% by weight of
the composition.
39. (canceled)
40. The composition of claim 1, wherein the propylene glycol is
present at a concentration of at least about 1% by weight of the
composition.
41-43. (canceled)
44. The composition of claim 1, wherein the polysorbate surfactant
is present at a concentration of at least about 1% by weight of the
composition.
45-52. (canceled)
53. The composition of claim 1, wherein the phosphodiesterase type
5 inhibitor is avanafil.
54. The composition of claim 1, wherein the phosphodiesterase type
5 inhibitor is lodenafil.
55. The composition of claim 1, wherein the phosphodiesterase type
5 inhibitor is mirodenafil.
56. The composition of claim 1, wherein the phosphodiesterase type
5 inhibitor is sildenafil.
57. The composition of claim 1, wherein the phosphodiesterase type
5 inhibitor is tadalafil.
58. The composition of claim 1, wherein the phosphodiesterase type
5 inhibitor is vardenafil.
59. The composition of claim 1, wherein the phosphodiesterase type
5 inhibitor is udenafil.
60. The composition of claim 1, wherein the phosphodiesterase type
5 inhibitor is acetildenafil.
61. The composition of claim 1, wherein the phosphodiesterase type
5 inhibitor is thiomethisosildenafil.
62. The composition of claim 1, wherein the a phosphodiesterase
type 5 inhibitor and/or salt thereof is present at a concentration
of at least about 0.1% by weight of the composition.
63-65. (canceled)
66. A method, comprising applying the composition of claim 1 to a
subject.
67-169. (canceled)
170. The composition of claim 1, wherein the hostile biophysical
environment is capable of driving the phosphodiesterase type 5
inhibitor and/or salt thereof through stratum corneum.
171. The composition of claim 1, wherein the composition has a pH
of between about 5 and about 9.
172. A composition for topical delivery to the skin of a subject,
wherein at least about 80% by weight of the composition comprises:
water; at least one chloride salt; a nitric oxide donor; a
stabilization polymer; propylene glycol; a polysorbate surfactant;
and a phosphodiesterase type 5 inhibitor and/or a salt thereof.
173. The composition of claim 172, wherein the composition further
comprises glyceryl stearate.
174. The composition of claim 172, wherein the composition further
comprises cetyl alcohol.
175. The composition of claim 172, wherein the composition further
comprises squalane.
176. The composition of claim 172, wherein the composition further
comprises isopropyl myristate.
177. The composition of claim 172, wherein the composition further
comprises oleic acid.
178. The composition of claim 172, wherein the water is present at
a concentration of at least about 35% by weight of the
composition.
179. The composition of claim 172, wherein the water is present at
a concentration of at least about 40% by weight of the
composition.
180. The composition of claim 172, wherein the composition has a pH
of between about 5 and about 8.5.
181. A composition for topical delivery to the skin of a subject,
the composition consisting essentially of: water; sodium chloride;
a nitric oxide donor; glyceryl stearate; cetyl alcohol; magnesium
chloride; squalane; a stabilization polymer; isopropyl myristate;
oleic acid; propylene glycol; a polysorbate surfactant; and a
phosphodiesterase type 5 inhibitor and/or a salt thereof.
182. A composition for topical delivery to the skin of a subject,
the composition comprising each of the following compounds at
concentrations of no more than .+-.20% of the stated
concentrations: water at a concentration of about 35% to about 55%
by weight; sodium chloride at a concentration of about 2.5% to
about 15% by weight; a nitric oxide donor at a concentration of
about 2.5% to about 15% by weight; glyceryl stearate at a
concentration of about 4% to about 10% by weight; cetyl alcohol at
a concentration of about 4% to about 10% by weight; magnesium
chloride at a concentration of about 0.1% to about 5% by weight;
squalane at a concentration of about 1% to about 8% by weight; a
polysorbate surfactant at a concentration of about 0.2% to about 2%
by weight; isopropyl myristate at a concentration of about 0.1% to
about 5% by weight; oleic acid at a concentration of about 0.1% to
about 5% by weight; propylene glycol at a concentration of about 1%
to about 10% by weight; a stabilization polymer at a concentration
of about 1% to about 10% by weight; and a phosphodiesterase type 5
inhibitor and/or a salt thereof at a concentration of about 1% to
about 10% by weight.
Description
RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Patent Application Ser. No. 61/427,999, filed Dec. 29, 2010,
entitled "Treatment of Erectile Dysfunction and Other Indications,"
by E. T. Fossel; and of U.S. Provisional Patent Application Ser.
No. 61/428,213, filed Dec. 29, 2010, entitled "Methods and
Compositions for Preparing Emulsions for Topical Drug Delivery," by
E. T. Fossel. Each of these is incorporated herein by reference in
its entirety.
FIELD OF INVENTION
[0002] The present invention generally relates to transdermal
delivery and, in particular, to the transdermal delivery of
phosphodiesterase type 5 inhibitors and other compounds.
BACKGROUND
[0003] Phosphodiesterase type 5 inhibitors are drugs used to block
the degradative action of phosphodiesterase type 5 on cyclic GMP in
the smooth muscle cells lining the blood vessels supplying the
corpus cavernosum of the penis. These drugs are commonly used in
the treatment of erectile dysfunction.
[0004] Phosphodiesterase type 5 inhibitors are commonly delivered
orally. Currently, no transdermal formulations of phosphodiesterase
type 5 inhibitors have been approved by the FDA. Accordingly,
systems and methods for transdermally delivering clinically useful
amounts of phosphodiesterase type 5 inhibitors are needed.
SUMMARY OF THE INVENTION
[0005] The present invention generally relates to the transdermal
delivery of phosphodiesterase type 5 inhibitors and other
compounds. The subject matter of the present invention involves, in
some cases, interrelated products, alternative solutions to a
particular problem, and/or a plurality of different uses of one or
more systems and/or articles.
[0006] Several methods are disclosed herein of administering a
subject with a composition for prevention or treatment of a
particular condition. It is to be understood that in each such
aspect of the invention, the invention specifically includes, also,
the composition for use in the treatment or prevention of that
particular condition, as well as use of the composition for the
manufacture of a medicament for the treatment or prevention of that
particular condition.
[0007] In some embodiments, aspects of the invention relate to
compositions for delivering a phosphodiesterase type 5 inhibitor
and/or a salt thereof to a subject. In some embodiments, a
composition comprises a phosphodiesterase type 5 inhibitor and/or a
salt thereof in a hostile biophysical environment for topical
delivery to the skin of a subject. In some embodiments, a
composition also comprises a nitric oxide donor. In some
embodiments, a composition further comprises one or more compounds
that stabilize and/or otherwise promote the efficacy of storage
and/or delivery (e.g., with or without a nitric oxide donor).
[0008] In some embodiments, compositions of the invention increase
the efficiency of direct compound delivery to a target site by
using transdermal delivery thereby significantly lowering the
systemic exposure and reducing potential side effects. For example,
a transdermal delivery according to the invention can reduce
systemic exposure to less than 10% (e.g., less than 5%, or between
0.1% and 1%, or even less) of the systemic exposure resulting from
an oral dosage required for effective delivery of the compound. For
example, the systemic exposure of a phosphodiesterase type 5
inhibitor (e.g., sildenafil) that is delivered topically according
to the invention can be about 0.3% of the systemic exposure
resulting from oral formulations. Also, in some embodiments,
compositions of the invention provide for unexpectedly high speeds
of action of the compound being delivered (e.g., relative to oral
delivery or other delivery techniques used for the compound).
Accordingly, in some embodiments, aspects of the invention are
useful for rapid therapy when delivery of a therapeutic amount of a
compound within a short period of time is required. Topical
delivery formulations described herein can deliver a compound to a
target tissue more rapidly than an oral formulation, for example.
Topical delivery formulations also allow for targeted local
delivery of a therapeutically effective amount of compound without
requiring a significant systemic increase in the amount of
compound. However, it should be appreciated that topical
formulations can be used for systemic delivery if so required.
[0009] One aspect of the present invention is generally directed to
a composition, e.g., a composition for topical delivery to the skin
of a subject. In accordance with one set of embodiments, the
composition includes a nitric oxide donor, a hostile biophysical
environment, a stabilization polymer, propylene glycol, a
polysorbate surfactant, and a phosphodiesterase type 5 inhibitor
and/or a salt thereof.
[0010] In another set of embodiments, at least about 80% by weight
of the composition comprises water, at least one chloride salt, a
nitric oxide donor, a stabilization polymer, propylene glycol, a
polysorbate surfactant, and a phosphodiesterase type 5 inhibitor
and/or a salt thereof.
[0011] The composition, in accordance with yet another set of
embodiments, includes a nitric oxide donor, a hostile biophysical
environment, and a phosphodiesterase type 5 inhibitor and/or a salt
thereof.
[0012] According to still another set of embodiments, the
composition comprises or consists essentially of water, sodium
chloride, a nitric oxide donor, glyceryl stearate, cetyl alcohol,
magnesium chloride, squalane, a stabilization polymer, isopropyl
myristate, oleic acid, propylene glycol, a polysorbate surfactant,
and a phosphodiesterase type 5 inhibitor and/or a salt thereof.
[0013] In yet another set of embodiments, the composition comprises
each of the following compounds at concentrations of no more than
+20% of the stated concentrations: water at a concentration of
about 35% to about 55% by weight, sodium chloride at a
concentration of about 2.5% to about 15% by weight, a nitric oxide
donor at a concentration of about 2.5% to about 15% by weight,
glyceryl stearate at a concentration of about 4% to about 10% by
weight, cetyl alcohol at a concentration of about 4% to about 10%
by weight, magnesium chloride at a concentration of about 0.1% to
about 5% by weight, squalane at a concentration of about 1% to
about 8% by weight, a polysorbate surfactant at a concentration of
about 0.2% to about 2% by weight, isopropyl myristate at a
concentration of about 0.1% to about 5% by weight, oleic acid at a
concentration of about 0.1% to about 5% by weight, propylene glycol
at a concentration of about 1% to about 10% by weight, a
stabilization polymer at a concentration of about 1% to about 10%
by weight, and a phosphodiesterase type 5 inhibitor and/or a salt
thereof at a concentration of about 1% to about 10% by weight.
[0014] In some embodiments, a composition comprises approximately
5% (e.g., 1% to 15%, or more or less) by weight of inhibitor (e.g.,
sildenafil or other inhibitor) in an oil/water emulsion further
comprising about 10% sodium chloride, 5% potassium chloride, and
about 2.5% magnesium chloride. For example, the inhibitor may be a
phosphodiesterase type 5 inhibitor and/or a salt thereof.
[0015] In some embodiments, the pH of a composition is optimized to
ionize the inhibitor while remaining compatible with acceptable pH
ranges for contact with the skin (e.g., within a range of about pH
5 to about pH 8). In some embodiments, a pH below 10 is sufficient
to ionize an inhibitor such as sildenafil or related compounds. In
some embodiments, a pH of 5-8 (+/-0.5) is effective. In some
embodiments, a pH of 6.5 (e.g., +/-0.5) is particularly effective.
In some embodiments, a pH at least about 1 pH unit above or below
(e.g., at least about 2 pH units above or below) the pKa of an
inhibitor may be used, particularly if the pH is within the range
of about pH 5.0-8.0 that is particularly compatible for direct
topical contact with skin. The inhibitor may be, for instance, a
phosphodiesterase type 5 inhibitor and/or a salt thereof, or any
inhibitor discussed herein.
[0016] According to aspects of the invention, a relatively high
salt concentration, for example at least about 2% (e.g., about 5%,
about 10% about 15%, about 20% about 25%, about 25-50%, weight %)
is useful to provide a hostile biophysical environment that
promotes transdermal migration of an inhibitor (e.g., sildenafil).
In some embodiments, emulsions described herein, for example,
containing a stabilization polymer and/or a polysorbate surfactant
and/or propylene glycol (or a low molecular weight glycol, or a
polyglycol such as polyethylene glycol or other polyglycol--however
it should be appreciated that glycols with even numbers of carbons
can be toxic, particularly for smaller glycols such as ethylene
glycol and butylene glycol, and should be avoided or excluded) are
unexpectedly effective at stabilizing the inhibitor in the high
salt composition in a form that remains effective for an extended
period--for example, retaining rapid transdermal delivery of the
inhibitor for at least several weeks or months. In some cases, the
inhibitor is a phosphodiesterase type 5 inhibitor and/or a salt
thereof.
[0017] In some embodiments, a composition also includes a nitric
oxide donor (e.g., L-Arg) that can be useful to increase local
blood flow and further promote delivery of the compound. In
accordance with another set of embodiments, the composition
comprises a stabilization polymer, propylene glycol, a polysorbate
surfactant, and a phosphodiesterase type 5 inhibitor and/or a salt
thereof.
[0018] In still another set of embodiments, at least about 80% by
weight of the composition comprises water, at least one chloride
salt, a stabilization polymer, propylene glycol, a polysorbate
surfactant, and a phosphodiesterase type 5 inhibitor and/or a salt
thereof.
[0019] The invention, in accordance with another aspect, is
generally directed to a method. In one set of embodiments, the
method is a method of applying any of the compositions described
herein to a subject, e.g., to the skin of a subject. The method, in
accordance with another set of embodiments, includes an act of
applying, to a portion of the skin of a subject, a delivery vehicle
comprising a phosphodiesterase type 5 inhibitor and/or a salt
thereof in a hostile biophysical environment.
[0020] The method, in yet another set of embodiments, includes an
act of applying, to at least a portion of the skin of a subject, a
composition comprising a nitric oxide donor, a hostile biophysical
environment, a stabilization polymer, propylene glycol, a
polysorbate surfactant, and a phosphodiesterase type 5 inhibitor
and/or a salt thereof.
[0021] In another aspect, the present invention encompasses methods
of making one or more of the embodiments described herein, for
example, a composition comprising a phosphodiesterase type 5
inhibitor. In still another aspect, the present invention
encompasses methods of using one or more of the embodiments
described herein, for example, a composition comprising a
phosphodiesterase type 5 inhibitor. In yet another aspect, the
present invention encompasses various uses of a composition
including a phosphodiesterase type 5 inhibitor. For example, the
composition may be used to treat erectile dysfunction.
[0022] In some embodiments, aspects of the invention relate to a
patch that comprises a composition of the invention (e.g., with or
without a nitric oxide donor, and with or without one or more
stabilizing compounds). In some embodiments, a composition is in
the form of a cream or ointment that is incorporated into the
patch. However, other configurations also may be used.
[0023] In some embodiments, aspects of the invention relate to
methods and formulations for delivering a compound locally at a
fraction of the systemic dose required using oral delivery. In some
embodiments, a hostile biophysical environment may be evaluated for
enhancing local delivery through a topical application. Depending
on the therapeutic application, an appropriate delivery
configuration (e.g., a combination of compound concentration,
hostile biophysical environment, cream, patch, etc.) can be used to
reduce the systemic amount of the compound required for an
effective therapeutic application.
[0024] In some embodiments, aspects of the invention relate to
reducing or avoiding the side effects (in males and in females
where side effects have caused the FDA to refuse approval)
associated with systemic levels of phosphodiesterase type 5
inhibitors required to produce a desired local effect when
administered orally. In some embodiments, aspects of the invention
can be used to treat sexual dysfunction in males and/or females by
providing a topical formulation of one or more phosphodiesterase
type 5 inhibitors. The topical formulation can be used to provide
local levels that are effective (e.g., by applying topically to the
male or female genitalia) without causing high systemic levels that
are associated with the dosages required for effective oral
administration. In some embodiments, aspects of the invention
provide a topical delivery formulation that is effective within
about 5 minutes (e.g., within less than about 30, less than about
20, less than about 15, less than about 10, or less than about 5
minutes) after topical application as opposed to waiting for 30
minutes to 1 hour or more for an oral administration to have an
effect.
[0025] Other advantages and novel features of the present invention
will become apparent from the following detailed description of
various non-limiting embodiments of the invention when considered
in conjunction with the accompanying figures. In cases where the
present specification and a document incorporated by reference
include conflicting and/or inconsistent disclosure, the present
specification shall control in the absence of clear error. If two
or more documents incorporated by reference include conflicting
and/or inconsistent disclosure with respect to each other, then the
document having the later effective date shall control.
DETAILED DESCRIPTION
[0026] The present invention generally relates to the transdermal
delivery of various compounds. In some aspects, transdermal
delivery may be facilitated by the use of a hostile biophysical
environment. One set of embodiments provides a composition for
topical delivery comprising a phosphodiesterase type 5 inhibitor
and/or a salt thereof, and optionally, a hostile biophysical
environment and/or a nitric oxide donor. In some cases, the
composition may be stabilized using a combination of a
stabilization polymer (such as xanthan gum, KELTROL.RTM. BT and/or
KELTROL.RTM. RD), propylene glycol, and a polysorbate surfactant
such as Polysorbate 20, which combination unexpectedly provides
temperature stability to the composition, e.g., at elevated
temperatures such as at least 40.degree. C. (at least about
104.degree. F.), as compared to compositions lacking one or more of
these.
[0027] According to aspects of the invention, compositions
comprising a relatively high salt composition (e.g., high chloride
content) are unexpectedly effective for topical delivery of a
phosphodiesterase type 5 inhibitor (e.g., sildenafil or other
inhibitor, including salts thereof). In some embodiments, a
salt-enhanced delivery (e.g., in a composition having at least 2%
salt, at least 5% salt, at least 10% salt, at least 15% salt, or
higher as described herein) is particularly effective when the pH
of the composition is optimized to ionize the compound being
delivered (e.g., at least about 80%, at least about 90%, at least
about 95%, or about 99% or more) is ionized. It should be
appreciated that depending on the pKa of the compound and the pH of
the composition, the ionized form may be anionic or cationic (e.g.,
due to protonation). In some embodiments, a compound may contain
several ionizable groups each having a different pKa. In some
embodiments, it is sufficient for at least 1, 2, or 3 of the groups
to be ionized for the salt-enhanced delivery to be effective. In
some embodiments, an ionizable group is sufficiently ionized if the
pH of the composition is at least 1 pH unit, or at least 2 pH units
(e.g., 1, 1-2, 2-3, or more pH units) below the pKa of the group
and it is cationic (due to protonation) below its pKa. Similarly,
in some embodiments, an ionizable group is sufficiently ionized if
the pH of the composition is at least 1 pH unit, or at least 2 pH
units (e.g., 1, 1-2, 2-3, or more pH units) above the pKa of the
group and it is anionic (due to deprotonation) above its pKa. In
some embodiments, the presence of magnesium chloride, for example
at 0.1-5% by weight, can help stabilize compositions containing
compounds with relatively high pKas (e.g., above 8.0, above 9.0,
above 10.0 or higher). In some embodiments, the pH of a composition
may be maintained using a buffer. However, the pH of compositions
of the invention are surprisingly stable without a buffer. In some
embodiments, a desired pH can be established by titrating the
mixture with an acid (e.g., HCl) or a base (e.g., NaOH). The pH of
the resulting composition (e.g., when formulated as an emulsion as
described herein) can be stable (e.g., sufficiently for the
composition to be effective for transdermal delivery) for extended
periods of time (e.g., weeks, months, or 1 or more years).
[0028] According to other aspects of the invention, a high salt
composition containing a phosphodiesterase type 5 inhibitor is
unexpectedly stable when formulated as an emulsion (e.g., a water
in oil emulsion or an oil in water emulsion, for example, including
one or more of a stabilization polymer and/or a polysorbate
surfactant and/or propylene glycol (or other low molecular weight
glycol, or a polyglycol) as described herein). In some embodiments,
the pH of the composition comprising the emulsion and high salt
concentration is selected to ionize the compound being delivered as
described herein.
[0029] In some embodiments, topical delivery according to the
invention (e.g., topical delivery of phosphodiesterase type 5
inhibitor, for example sildenafil) provides a surprisingly rapid
effect (within about 1-5 minutes). In contrast, an oral counterpart
requires about 60 minutes or more to produce an effect.
Accordingly, aspects of the invention provide methods and
compositions for delivering an effective treatment to a subject to
treat or prevent erectile dysfunction. In some embodiments, a
topical composition provided that can be applied to a genital
region of a female or male subject (e.g., the penis of a male
subject) to treat an erectile dysfunction (e.g., promote an
erection) within less than 60 minutes, less than 45 minutes, less
than 30 minutes, or less than 15 minutes of application.
[0030] One aspect of the invention provides compositions for the
topical delivery of substances such as pharmaceutical agents (e.g.,
drugs, biological compounds, etc.). The pharmaceutical agents may
be applied to the skin of a subject, e.g. a human, to aid in
treatment of medical conditions or diseases, and/or the symptoms
associated thereof. In some embodiments, the invention provides for
the treatment of medical conditions or diseases and/or ailments
using pharmaceutical agents (for example, to treat a subject
diagnosed with a medical condition or disease, as described
herein), and in some cases, the invention provides for the delivery
of a minimum amount of pharmaceutical agents to provide effective
levels of medication to an effected area topically while limiting
side effects. In some cases, the effective dosage of the
pharmaceutical agent may be lower than the effective dosage of the
pharmaceutical agent when taken orally.
[0031] For example, in one set of embodiments, the pharmaceutical
agent is a phosphodiesterase type 5 inhibitor and/or a salt
thereof. A phosphodiesterase type 5 inhibitor is a drug that blocks
the degradative action of phosphodiesterase type 5 on cyclic GMP,
e.g., in the smooth muscle cells lining the blood vessels supplying
the corpus cavernosum of the penis. Part of the physiological
process of erection involves the release of nitric oxide (NO) in
vasculature of the corpus cavernosum as a result of sexual
stimulation. NO activates the enzyme guanylate cyclase which
results in increased levels of cyclic guanosine monophosphate
(cGMP), leading to smooth muscle relaxation in blood vessels
supplying the corpus cavernosum, resulting in increased blood flow
and an erection. Accordingly, PDES inhibitors inhibit the
degradation of cGMP by phosphodiesterase type 5, increasing
bloodflow to the penis during sexual stimulation.
[0032] Non-limiting examples of phosphodiesterase type 5 inhibitors
include, but are not limited to, avanafil, lodenafil, mirodenafil
(pKa of 6.0), sildenafil (or analogs thereof, for example,
actetildenafil, hydroxyacetildenafil, or dimethylsildenafil),
tadalafil (pKa of 18), vardenafil (pKas of 3.4, 6.7, 8.8, and 14),
udenafil (pKa of 10.53), acetildenafil, or thiomethisosildenafil.
The structures of these compounds are respectively shown below:
##STR00001## ##STR00002##
[0033] Accordingly, various aspects of the invention are directed
to compositions including a phosphodiesterase type 5 inhibitor for
transdermal delivery or topical application to a subject. Other
compounds such as salts or derivatives of phosphodiesterase type 5
inhibitors (including salts or derivatives of the above compounds)
are also included in other embodiments; thus, it should be
understood that in any embodiment described herein using a
phosphodiesterase type 5 inhibitor, this is by way of example only,
and other embodiments of the invention are directed to
phosphodiesterase type 5 inhibitor salts, phosphodiesterase type 5
inhibitor derivatives, etc., instead of and/or in addition to
phosphodiesterase type 5 inhibitors.
[0034] Phosphodiesterase type 5 inhibitors or other pharmaceutical
agents (e.g., salts or derivatives of phosphodiesterase type 5
inhibitors, etc.) may be present at any suitable concentration. For
instance, in some cases, the pharmaceutical agent may be present at
a concentration of at least about 0.1%, at least about 0.3%, at
least about 0.5%, at least about 0.7%, at least about 1%, at least
about 2%, at least about 3%, at least about 4%, at least about 5%,
at least about 6%, at least about 7%, at least about 7.5%, at least
about 8%, at least about 9%, or at least about 10% by weight of the
composition. In certain embodiments, the pharmaceutical agent may
be present at a concentration of no more than about 1%, no more
than about 2%, no more than about 3%, no more than about 4%, no
more than about 5%, no more than about 6%, no more than about 7%,
no more than about 8%, no more than about 9%, no more than about
10%, no more than about 12%, no more than about 15%, or no more
than about 20% by weight of the composition. In addition, the
pharmaceutical agent may be present in native form and/or as one or
more salts. For example, if a phosphodiesterase type 5 inhibitor is
present, it may be used in its native form, and/or as one or more
salts, e.g., the sodium salt, the potassium salt, the magnesium
salt, the lysine salt, the arginine salt, the lactate salt, or the
citrate salt of a phosphodiesterase type 5 inhibitor, e.g.,
avanafil, lodenafil, mirodenafil, sildenafil, tadalafil,
vardenafil, udenafil, acetildenafil, thiomethisosildenafil, etc.
For salt forms of the pharmaceutical agent, "by weight of the
composition" includes the entire salt form of the pharmaceutical
agent, e.g., the agent itself as well as any counterions such as
sodium, potassium, etc. The amount of the pharmaceutical agent may
be determined in a composition, for example, using techniques such
as HPLC or HPLC/MS that are known to those of ordinary skill in the
art.
[0035] Many phosphodiesterase type 5 inhibitors are readily
commercially available. In some cases, the phosphodiesterase type 5
inhibitor may be obtained as a racemic mixture, for example, of
tadalafil (e.g., (R,R)-tadalafil, (R,S)-tadalafil, (S,R)-tadalafil,
and (S,S)-tadalafil). However, in other cases, one of the
enantiomers may be present in an amount greater than the other. For
example, at least about 60%, at least about 70%, at least about
80%, at least about 90%, or at least about 95% of the
phosphodiesterase type 5 inhibitor within the composition may be
present as one of the enantiomers. Techniques for preparing or
separating racemic phosphodiesterase type 5 inhibitors are known;
see, for example, Gao, et al., "Chiral Separation of Two Pairs of
Enantiomers of Tadalafil by High-Performance Liquid
Chromatography," J. Chromatogr. Sci., 45:540-543, 2007.
[0036] The composition may also comprise a nitric oxide donor in
some embodiments, for example, L-arginine and/or L-arginine
hydrochloride. In some cases, such a nitric oxide donor may be used
to increase localized blood flow at the site where the composition
is applied, which may enhance delivery of the pharmaceutical agent.
The nitric oxide donor may be present at any suitable concentration
within the composition. For instance, in some cases, the nitric
oxide donor is present at a concentration of at least about 1%, at
least about 2%, at least about 3%, at least about 4%, at least
about 5%, at least about 6%, at least about 7%, at least about
7.5%, at least about 8%, at least about 9%, or at least about 10%
by weight of the composition. In some cases, one or more nitric
oxide donors (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, etc. nitric oxide
donors) may be used. In some cases, there may be no more than 3, 5,
7, or 10 nitric oxide donors present within the composition.
[0037] A "nitric oxide donor," as used herein, is a compound that
is able to release nitric oxide and/or chemically transfer the
nitric oxide moiety to another molecule, directly or indirectly,
for example, through a biological process. The nitric oxide donor
may release nitric oxide into the skin, and/or tissues such as
muscles and/or elements of the circulatory system in close
proximity to the surface of the skin. Non-limiting examples of
nitric oxide donors include arginine (e.g., L-arginine and/or
D-arginine), arginine derivatives (e.g., L-arginine hydrochloride
and/or D-arginine hydrochloride), nitroglycerin,
polysaccharide-bound nitric oxide-nucleophile adducts,
N-nitroso-N-substituted hydroxylamines,
1,3-(nitrooxymethyl)phenyl-2-hydroxybenzoate, etc., and/or any
combination of these and/or other compounds.
[0038] Besides L-arginine and L-arginine hydrochloride, other
non-limiting examples of nitric oxide donors include D,L-arginine,
D-arginine, or alkyl (e.g., ethyl, methyl, propyl, isopropyl,
butyl, isobutyl, tert-butyl, etc.) esters of L-arginine and/or
D-arginine (e.g., a methyl ester, an ethyl ester, a propyl ester, a
butyl ester, etc.) and/or salts thereof, as well as other
derivatives of arginine and other nitric oxide donors. For
instance, non-limiting examples of pharmaceutically acceptable
salts include hydrochloride, glutamate, butyrate, or glycolate
(e.g., resulting in L-arginine glutamate, L-arginine butyrate,
L-arginine glycolate, D-arginine hydrochloride, D-arginine
glutamate, etc.). Still other examples of nitric oxide donors
include L-arginine-based compounds such as, but not limited to,
L-homoarginine, N-hydroxy-L-arginine, nitrosylated L-arginine,
nitrosylated L-arginine, nitrosylated N-hydroxy-L-arginine,
nitrosylated N-hydroxy-L-arginine, citrulline, ornithine,
linsidomine, nipride, glutamine, etc., and salts thereof (e.g.,
hydrochloride, glutamate, butyrate, glycolate, etc.), and/or any
combination of these and/or other compounds. Still other
non-limiting examples of nitric oxide donors include
S-nitrosothiols, nitrites, 2-hydroxy-2-nitrosohydrazines, or
substrates of various forms of nitric oxide synthase. In some
cases, the nitric oxide donor may be a compound that stimulates
endogenous production of nitric oxide in vivo. Examples of such
compounds include, but are not limited to, L-arginine, substrates
of various forms of nitric oxide synthase, certain cytokines,
adenosine, bradykinin, calreticulin, bisacodyl, phenolphthalein,
OH-arginine, or endothelein, and/or any combination of these and/or
other compounds.
[0039] Accordingly, it should be understood that, in any of the
embodiments described herein that describe L-arginine and/or
L-arginine hydrochloride, other nitric oxide donors may also be
used instead, or in combination with, L-arginine and/or L-arginine
hydrochloride, in other embodiments of the invention.
[0040] In some cases, the concentration of the nitric oxide donor
within the composition may be tailored to have a duration of
effective treatment of at least about 3 hours, at least about 5
hours, or at least about 8 hours or more in certain instances. The
duration may also be controlled, for instance, by controlling the
concentration of a penetrating agent used in conjunction with the
nitric oxide donor. Penetration agents are discussed in detail
herein. The actual concentration for a particular application can
be determined by those of ordinary skill in the art using no more
than routine experimentation, for example, by measuring the amount
of transport of the nitric oxide donor as a function of
concentration in vitro across cadaver skin or suitable animal
models, skin grafts, synthetic model membranes, human models, or
the like.
[0041] As a particular non-limiting example, in certain
embodiments, nitric oxide is provided using L-arginine, for
example, at a concentration of at least about 0.5% by weight (wt %
or w/v) of L-arginine (optionally with one or more penetrating
agents as discussed herein, for example, a penetrating agent able
to create a hostile biophysical environment), at least about 0.75
wt %, at least about 1 wt %, at least about 2 wt %, at least about
3 wt %, at least about 5 wt %, at least about 7 wt %, at least
about 10 wt %, or at least about 15 wt %. The L-arginine may be
present in a suitable delivery vehicle, such as a cream or a
lotion. L-arginine may be particularly useful in some cases due to
its low toxicity, its high solubility, and/or its low cost. Other
examples of nitric oxide donors are discussed in International
Patent Application No. PCT/US2005/005726, filed Feb. 23, 2005,
entitled "Topical Delivery of a Nitric Oxide Donor to Improve Body
and Skin Appearance," by E. T. Fossel, published as WO 2005/081964
on Sep. 9, 2005, incorporated herein by reference.
[0042] Without wishing to be bound to any theory, it is generally
believed that the flow of the pharmaceutical agent across the skin
may slow as it builds up within the tissue. Fick's first law of
diffusion suggests that when the concentration inside becomes
substantially equal to that outside, passive flow stops. The
increased local blood flow may prevent or at least decrease the
stoppage of the flow of the pharmaceutical agent. Thus, when the
composition is applied to the skin, the pharmaceutical agent exits
the vehicle into the tissue more readily, as the pharmaceutical
agent is dispersed by flow and does not build up in concentration
in the tissue. Thus, in certain embodiments, pharmaceutical agents
may be introduced into the skin, for example, a phosphodiesterase
type 5 inhibitor and/or a salt or derivative of a phosphodiesterase
type 5 inhibitor, such as avanafil, lodenafil, mirodenafil,
sildenafil, tadalafil, vardenafil, udenafil, acetildenafil, or
thiomethisosildenafil. Accordingly, the composition may be
delivered locally and/or systemically; initially, much of the
delivery is at first local (i.e., through the skin), but in some
cases, the pharmaceutical agents may also be distributed
systemically, e.g., upon reaching the blood supply.
[0043] The composition may also comprise a hostile biophysical
environment to a phosphodiesterase type 5 inhibitor in some
embodiments. In a hostile biophysical environment, the environment
surrounding the pharmaceutical agent (e.g., a phosphodiesterase
type 5 inhibitor, etc.) may be such that the pharmaceutical agent
is in a chemically and/or energetically unfavorable environment,
relative to the skin (e.g., the chemical potential and/or the free
energy of the pharmaceutical agent within the hostile biophysical
environment is significantly greater than the chemical potential
and/or the free energy of the pharmaceutical agent within the skin,
thus energetically favoring transport into the skin), especially
the stratum corneum.
[0044] Examples of such compositions are discussed in International
Patent Application No. PCT/US2005/013228, filed Apr. 19, 2005,
entitled "Transdermal Delivery of Beneficial Substances Effected by
a Hostile Biophysical Environment," by E. Fossel, published as WO
2005/102282 on Nov. 3, 2005, incorporated herein by reference.
Other techniques for hostile biophysical environments are discussed
in detail herein. Accordingly, certain embodiments of the invention
are generally directed to compositions for topical delivery to the
skin of a subject comprising a nitric oxide donor, a hostile
biophysical environment, and a pharmaceutical agent such as a
phosphodiesterase type 5 inhibitor, or a salt or a derivative of a
phosphodiesterase type 5 inhibitor, or the like.
[0045] A hostile biophysical environment of the invention can
comprise, in various embodiments, high ionic strength, a high
concentration of osmotic agents such as ureas, sugars, or
carbohydrates, a high pH environment (e.g., greater than about 7,
greater than about 8, greater than about 9, greater than about 10,
greater than about 11, greater than about 12, or greater than about
13), a low pH environment (less than about 5, less than about 4,
less than about 3 or less than about 2), highly hydrophobic
components, or highly hydrophilic components or other substances
that cause an increase in the chemical potential and/or free energy
of the pharmaceutical agent, or any combination of two or more of
these and/or other compounds. A hydrophobic component may, in some
embodiments, have an octanol-water partition coefficient of at
least about 100, at least about 1000, at least about 10.sup.4, at
least about 10.sup.5, or more in some cases. Similarly, a
hydrophilic component may have an octanol-water partition
coefficient of less than about 0.01, less than about 10.sup.-3,
less than about 10.sup.-4, or less than about 10.sup.-5 in some
cases.
[0046] In some cases, the composition defines the biophysical
hostile environment. In other cases, a pharmaceutical agent may be
packaged in such a way that it is carried into tissue and/or its
charge is neutralized by derivitization and/or by forming a neutral
salt. Examples of biophysically hostile environments include, but
are not limited to, high ionic strength environments (e.g., by the
addition of ureas, sugars, carbohydrates, and/or ionic salts such
as lithium chloride, sodium chloride, potassium chloride, calcium
chloride, magnesium chloride, choline chloride, sodium fluoride,
lithium bromide, etc.), as well as combinations of these and/or
other agents, for instance at high ionic strengths (for example,
greater than about 0.25 M, greater than about 1 M, greater than
about 2 M, greater than about 3 M, greater than about 5 M, greater
than about 10 M, greater than about 15 M, greater than about 20 M,
greater than about 25 M, etc., or in some cases, between about 0.25
M and about 15 M, between about 5 M and about 15 M, between about
10 M and about 15 M, etc.); high or low pH environments (e.g., by
adding pharmaceutically acceptable acids or bases, for example,
such that the pH is between about 3 and about 7, between about 3
and about 6, between about 3 and about 5, between about 4 and 8,
between about 5 and about 8, between about 5 and 8.5, between about
7 and about 11, between about 8 and about 11, between about 9 and
about 11, etc.); or highly hydrophobic environments (e.g., by
decreasing water content and increasing lipid, oil and/or wax
content of the environment). In some embodiments, the ionic
strength is any amount greater than two times the physiological
ionic strength of blood. The ionic strength of a composition can be
readily controlled in certain embodiments by controlling the
amounts or concentrations of one or more of the salts present in
the composition, e.g., by controlling the amount of sodium
chloride, magnesium chloride, choline chloride, etc., and/or other
salts.
[0047] Other highly charged molecules such as polylysine,
polyglutamine, polyaspartate, etc., or copolymers of such highly
charged amino acids may also be used in certain embodiments to
create the hostile biophysical environment. Non-limiting examples
of delivery vehicles which would be carried into tissue includes
liposomes or emulsions of collagen, collagen peptides or other
components of skin or basement membrane. Non-limiting examples of
neutralization of charge include delivery of the pharmaceutical
agent in the form or an ester or salt which is electronically
neutral. In some embodiments, the hostile biophysical environment
may include any two or more of these conditions. For instance, the
hostile biophysical environment may include high ionic strength and
a high pH or a low pH, a highly hydrophobic environment and a high
pH or a low pH, a highly hydrophobic environment that includes
liposomes, or the like.
[0048] A hostile biophysical environment may also be created in
some embodiments by placing a pharmaceutical agent that is
relatively highly charged into a hydrophobic, oily environment such
as in an oil-based cream or lotion containing little or no water.
Absorption may further be aided by combining the use of hostile
biophysical environments with the use of penetrating agents, as
further described herein.
[0049] In one set of embodiments, the composition may be present as
an emulsion. As known by those of ordinary skill in the art, an
emulsion typically includes a first phase (e.g., a discontinuous
phase) contained within a second fluid phase (e.g., a continuous
phase). The pharmaceutical agent (e.g., a phosphodiesterase type 5
inhibitor) may be present in either or both phases. In addition,
other materials such as those described herein may be present in
the same phase as the pharmaceutical agent.
[0050] In some embodiments, an emulsion may be prepared to contain
a drug (or other pharmaceutical agent) of interest in a hostile
biophysical environment, and optionally one or more of a
stabilization polymer, propylene glycol, and/or a polysorbate
surfactant. An emulsion may also comprise a nitric oxide donor in
some embodiments, for example, L-arginine and/or L-arginine
hydrochloride.
[0051] In some embodiments, various aspects of the invention relate
to methods and compositions for preparing and/or manufacturing drug
formulations for topical delivery. In one set of embodiments, the
present invention is generally directed to emulsions that contain
one or more drugs or other pharmaceutical agents described herein
for topical application. In some embodiments, certain aspects of
the invention are useful for preparing emulsions that contain one
or more drugs (or other pharmaceutical agents) in a hostile
biophysical environment. In some embodiments, the hostile
biophysical environment is a high salt concentration (e.g., a high
concentration of one or more salts), for example, as described
herein.
[0052] In some embodiments, an emulsion is prepared by mixing a
first aqueous preparation (e.g., a water phase) with a second
non-aqueous preparation (e.g., an oil or lipid phase). Drugs or
other pharmaceutical agents that are water-soluble may be added to
the first aqueous preparation (e.g., prior to mixing with the
second non-aqueous preparation). Drugs or other pharmaceutical
agents that are water insoluble (or relatively water insoluble) may
be added to the second non-aqueous preparation (e.g., prior to
mixing with the first aqueous preparation). Drugs or other
pharmaceutical agents that are partially water soluble may be added
to one phase, or may be split between the two phases prior to
mixing. The split between the two phases will depend on the amount
of drug (or other pharmaceutical agent) that is being added, the
composition (e.g., the nature and the amount of other chemicals or
agents) of the first and second preparations, the pH, the
temperature, other physical or chemical factors, and/or a
combination thereof. For example, if a drug of interest is soluble
at a 1% level in the aqueous (e.g., water or buffer) phase, but a
2% level of the drug is required in the emulsion, then the drug may
also be added to the non-aqueous (e.g., lipid) phase at a 1% level.
In some embodiments, a drug that is less than 1% soluble in an
aqueous phase is provided in the non-aqueous phase prior to mixing.
However, it should be appreciated that other percentages and/or
splits between the two phases may be used.
[0053] In some embodiments, the pH of one or both of the first and
second preparations is adjusted to optimize the solubility of the
drug being used. In some embodiments, a high salt concentration is
used. In order to prevent a high salt concentration from breaking
down an emulsion, one or more emulsifying agents may be used in
some cases. In some embodiments, the mixing time may be adjusted to
promote appropriate mixing and/or emulsion formation.
[0054] In some embodiments, the temperature of the first and/or
second preparation may be controlled to promote solubility, mixing,
and/or emulsion formation. In some embodiments, the temperature of
one or both preparations and/or of the mixing may be set at
25.degree. C. or higher (e.g., 30.degree. C. or higher, 40.degree.
C. or higher, 50.degree. C. or higher, 60.degree. C. or higher,
70.degree. C. or higher, or 80.degree. C. or higher). For example,
the temperature may be at between 30.degree. C. and 90.degree. C.,
between 40.degree. C. and 80.degree. C., at around 50.degree. C.,
at around 60.degree. C., or at around 70.degree. C.
[0055] It should be appreciated that methods and compositions of
the invention may be used with any suitable drug or pharmaceutical
agent. In some embodiments, for example, an oral drug may be
formulated for topical delivery using one or more compositions or
methods described herein. A topical formulation may be useful to
deliver a locally effective amount of a drug (or other
pharmaceutical agent) to a subject (e.g., a human) without causing
unwanted side effects associated with systemic levels required for
effectiveness when the drug is administered orally. Accordingly, a
topical formulation may be useful to deliver an amount of a drug
that is sufficient to cause a desired effect (e.g., a therapeutic
effect) but that is lower than the total amount of the drug that
would be administered to a subject (e.g., a human) if it were
provided orally.
[0056] Emulsions of the invention may be packaged using any
suitable format (e.g., in a tube, a pump-actuated container, or any
other suitable form), in certain embodiments of the invention. For
example, in some embodiments, an emulsion may be added to a surface
of a patch or bandage. The emulsion may also be applied to the skin
of a subject as a cream, gel, liquid, lotion, spray, aerosol, or
the like.
[0057] Methods and compositions such as any of those discussed
herein may be used to prepare a composition that is sterile or that
has a low microbial content, in some embodiments.
[0058] In some aspects of the invention, a composition of the
invention is administered to a subject using a delivery vehicle
such as a cream, gel, liquid, lotion, spray, aerosol, or
transdermal patch. In one set of embodiments, a composition of the
invention may be applied or impregnated in a bandage or a patch
applied to the skin of a subject. In some embodiments, a patch has
a skin contacting portion made of any suitable material that is
covered or impregnated with a cream or emulsion described herein,
wherein the skin contacting portion may be supported by a backing,
one or both of which may have an adhesive segment or other
configuration for attaching to the skin surface of a subject. A
"subject," as used herein, means a human or non-human animal.
Examples of subjects include, but are not limited to, a mammal such
as a dog, a cat, a horse, a donkey, a rabbit, a cow, a pig, a
sheep, a goat, a rat (e.g., Rattus Norvegicus), a mouse (e.g., Mus
musculus), a guinea pig, a hamster, a primate (e.g., a monkey, a
chimpanzee, a baboon, an ape, a gorilla, etc.), or the like. Such
delivery vehicles may be applied to the skin of a subject, such as
a human subject. Examples of delivery vehicles are discussed
herein. The delivery vehicle may promote transfer into the skin of
an effective concentration of the nitric oxide donor and/or the
pharmaceutical agent, directly or indirectly. For instance, the
delivery vehicle may include one or more penetrating agents, as
further described herein. Those of ordinary skill in the art will
know of systems and techniques for incorporating a nitric oxide
donor and/or a pharmaceutical agent within delivery vehicles such
as a cream, gel, liquid, lotion, spray, aerosol, or transdermal
patch. In some cases, the concentration of the nitric oxide donor,
and/or a pharmaceutical agent in the delivery vehicle can be
reduced with the inclusion of a greater amount or concentration of
penetrating agent, or increased to lengthen the beneficial effect.
In one set of embodiments, the nitric oxide donor and/or the
pharmaceutical agent may be used in conjunction with an adjunct,
such as theophylline (for example, at 10% weight by volume).
[0059] Other materials may be present within the delivery vehicle,
for example, buffers, preservatives, surfactants, etc. For
instance, the cream may include one or more of water, mineral oil,
glyceryl stereate, squalene, propylene glycol stearate, wheat germ
oil, glyceryl stearate, isopropyl myristate, steryl stearate,
polysorbate 60, propylene glycol, oleic acid, tocopherol acetate,
collagen, sorbitan stearate, vitamin A and D, triethanolamine,
methylparaben, aloe vera extract, imidazolidinyl urea,
propylparaben, PND, and/or BHA.
[0060] As specific non-limiting examples, a cream may have one or
more of (w/v): water (20-80%), white oil (3-18%), glyceryl stearate
(0.25-12%), squalene (0.25-12%), cetyl alcohol (0.1-11%), propylene
glycol stearate (0.1-11%), wheat germ oil (0.1-6%), polysorbate 60
(0.1-5%), propylene glycol (0.05-5%), collagen (0.05-5%), sorbitan
stearate (0.05-5%), vitamin A (0.02-4%), vitamin D (0.02-4%),
vitamin E (0.02-4%), triethanolamine (0.01-4%), methylparaben
(0.01-4%), aloe vera extract (0.01-4%), imidazolidinyl urea
(0.01-4%), propylparaben (0.01-4%), BHA (0.01-4%), L-arginine
hydrochloride (0.25-25%), sodium chloride (0.25-25%), magnesium
chloride (0.25-25%), and/or choline chloride (0.25-25%). The
percentages of each compound can vary (or the compound may be
absent in some cases), for example, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%,
9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, etc.
[0061] In another embodiment, the cream may include a
pharmaceutical agent, for instance, a phosphodiesterase type 5
inhibitor such as those described herein, and one or more of the
following, in any suitable amount: water (e.g., 20-80%), L-arginine
hydrochloride (e.g., 0-25%), sodium chloride (e.g., 0-25%),
potassium chloride (e.g., 0-25%), glyeryl steareate (e.g., 0-15%),
cetyl alcohol (e.g., 0-15%), squalene (e.g., 0-15%), isopropyl
mysterate (e.g., 0-15%), oleic acid (e.g., 0-15%), Tween 20 (e.g.,
0-10%), and/or butanediol (e.g., 0-10%). The percentages of each
compound can vary (or the compound may be absent in some cases),
for example, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%,
13%, 14%, 15%, 20%, etc.
[0062] In some embodiments, the cream may include a pharmaceutical
agent, and one or more ionic salts at a concentration at least
sufficient to produce a hostile biophysical environment with
respect to the pharmaceutical agent. For example, the cream may
include one or more of (w/v): a charged and/or hydrogen bonding
entity (0.001-30%), choline chloride (1-30%), sodium chloride
(2-30%), and/or magnesium chloride (1-20% w/v). In another example,
the cream may include one or more of (w/v): L-arginine
hydrochloride (2.5-25%), choline chloride (10-30%), sodium chloride
(5-20%), and/or magnesium chloride (5-20%). In still another
example, the cream may include one or more of (w/v): creatine
(0.001-30%), inosine (0.001-30%), choline chloride (1-30%), sodium
chloride (2-30%), magnesium chloride (1-20%), L-arginine (0.1-25%),
and/or theophylline (0.1-20%). In some cases, the cream may also
contain L-arginine hydrochloride (0-12.5% w/v) and/or theophylline
(0-10% w/v). The percentages of each compound can vary (or the
compound may be absent in some cases), for example, 1%, 2%, 3%, 4%,
5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, etc. In
these examples, choline chloride, sodium chloride, and/or magnesium
chloride can be used to provide a high ionic strength
environment.
[0063] In some embodiments, the composition may include an
antioxidant, which may be able to reduce or inhibit the oxidation
of other molecules within the composition. Examples of suitable
antioxidants include, but are not limited to, glutathione, vitamin
C, and vitamin E as well as enzymes such as catalase, superoxide
dismutase and various peroxidases. The antioxidant may be present
in any suitable concentration. For example, the antioxidant may be
present at a concentration of at least about 0.1%, at least about
0.3%, at least about 0.5%, at least about 0.7%, at least about 1%,
at least about 2%, at least about 3%, at least about 4%, or at
least about 5% by weight of the composition. In certain
embodiments, the pharmaceutical agent may be present at a
concentration of no more than about 0.2%, no more than about 0.5%,
no more than about 1%, no more than about 2%, no more than about
3%, no more than about 4%, or no more than about 5% by weight of
the composition.
[0064] Another set of embodiments is generally directed to
compositions having relatively high temperature stability. For
example, the composition may be stable at elevated temperatures
such as at least 40.degree. C. (at least about 104.degree. F.) for
periods of time of at least about a day. In some embodiments, for
instance, a composition of the present invention may further
include a stabilization polymer, propylene glycol, and a
polysorbate surfactant. Non-limiting examples of stabilization
polymers include xanthan gum, KELTROL.RTM. BT and/or KELTROL.RTM.
RD; an example of a polysorbate surfactant is Polysorbate 20.
Additional examples are discussed herein.
[0065] Such a combination of components to create high temperature
stability are surprising, since compositions involving any two of
these components (but not the third) were found to lack such high
temperature stabilization properties. It is not currently known why
this combination of components is remarkably effective at
facilitating relatively high temperature stability of the
compositions discussed herein, as these components are not known to
participate in any significant chemical reactions with each other,
and high temperature stability is greatly reduced when one of the
components is removed. In addition, propylene glycol is not known
to work in pharmaceutical compositions as a stabilizing agent.
[0066] For instance, in one set of embodiments, a composition may
be determined to be one that has high temperature stability by
determining whether the composition exhibits phase separation over
a relatively long period of time, e.g., over at least an hour, at
least about 2 hours, at least a day, at least about a week, at
least about 4 weeks, etc. For example, in some embodiments, a
composition is exposed to ambient temperature and pressure for at
least 1 hour, and the composition is then analyzed to determine
whether the composition exhibits phase separation or a change in
phase. A stable compound is one that exhibits no phase separation,
whereas an unstable compound may exhibit phase separation. Such
stability may be useful, for example, for storage of the
composition, transport of the composition, shelf life, or the
like.
[0067] As used herein, a "stabilization polymer" is a polymer that
comprises xanthan gum, a xanthan gum derivative, and/or a xanthan
gum equivalent, for example, KELTROL.RTM. BT and/or KELTROL.RTM.
RD, KELZAN.RTM. XC, KELZAN.RTM. XCD, KELZAN.RTM. D, KELZAN.RTM. CC,
XANTURAL.RTM. 180, XANTURAL.RTM. 75, or the like, all of which can
be obtained commercially from various suppliers. In some
embodiments, combinations of these and/or other polymers are also
possible. In some cases, the stabilization polymer is chosen to be
one which is at least generally regarded as safe for use in humans.
In addition, in certain embodiments, the stabilization polymer is
produced synthetically, and/or one which has been purified to some
degree. The stabilization polymer may have any suitable molecular
weight, for example, at least about 1 million, at least about 2
million, at least about 5 million, at least about 10 million, at
least about 25 million, or at least about 50 million.
[0068] The stabilization polymer may be present at any suitable
concentration within the composition. For example, the
stabilization polymer may be present at a concentration of at least
about 0.1%, at least about 0.2%, at least about 0.3%, at least
about 0.4%, at least about 0.5%, at least about 0.6%, at least
about 0.7%, at least about 0.8%, at least about 0.9%, or at least
about 1% by weight of the composition. In some embodiments, the
stabilization polymer may be present at a concentration of no more
than about 0.1%, no more than about 0.2%, no more than about 0.4%,
no more than about 0.6%, no more than about 0.8%, no more than
about 1%, no more than about 2%, no more than about 3%, no more
than about 4%, no more than about 5%, no more than about 7%, no
more than about 10%, no more than about 12%, no more than about
15%, or no more than about 20% by weight of the composition. In
some cases, more than one stabilization polymer may be present, and
each stabilization polymer may be present in any suitable amount.
As a specific example, in certain embodiments, the stabilization
polymer consists essentially of KELTROL.RTM. BT and/or KELTROL.RTM.
RD. In certain instances, the stabilization polymer may have a
fixed ratio of KELTROL.RTM. BT and/or KELTROL.RTM. RD, for example,
1:1 or 3:5 by weight. In another example, the KELTROL.RTM. BT may
be present at a concentration of about 0.3% by weight and the
KELTROL.RTM. RD may be present at a concentration of 0.5% by weight
of the composition, or one or both of these may be present at one
of the other concentrations described above. Combinations of these
and/or other stabilization polymers are also contemplated in other
embodiments, e.g., KELTROL.RTM. BT and xanthan gum, KELTROL.RTM. RD
and xanthan gum, etc. In some cases, thickening agents can be used
instead of, or in conjunction with a stabilization polymer. Many
thickening agents can be obtained commercially. Thickening agents
include those used in the food industry, or are GRAS agents
(generally regarded as safe), e.g., alginin, guar gum, locust bean
gum, collagen, egg white, furcellaran, gelatin, agar, and/or
carrageenan, as well as combinations of these and/or other
stabilization polymers. It should thus be appreciated that, in the
specification herein, references to stabilization polymers, in
other embodiments, should be understood to also include thickening
agents in conjunction or instead of stabilization polymers,
[0069] Propylene glycol can be obtained commercially, and can be
present as any stereoisomer or racemic mixture of isomers. It may
also be present at any suitable concentration. For instance,
propylene glycol may be present at a concentration of at least
about 1%, at least about 2%, at least about 3%, at least about 4%,
at least about 5%, at least about 6%, at least about 7%, at least
about 8%, at least about 9%, or at least about 10% by weight of the
composition. In some embodiments, propylene glycol may be present
at a concentration of no more than about 2%, no more than about 4%,
no more than about 6%, no more than about 8%, no more than about
10%, no more than about 12%, no more than about 15%, no more than
about 20%, or no more than about 25% by weight of the composition.
In some cases, other glycols can be used in conjunction or instead
of propylene glycol, such as butylene glycol. Accordingly, it
should thus be appreciated that, in the specification herein,
references to propylene glycol, in other embodiments, should be
understood to also include other glycols (e.g., a low molecular
weight glycol, or a polyglycol, as described herein) in conjunction
or instead of propylene glycol.
[0070] In addition, a polysorbate surfactant can also be present
any suitable concentration within the composition. For instance, in
some cases, the polysorbate surfactant may be present at a
concentration of at least about 1%, at least about 2%, at least
about 3%, at least about 4%, at least about 5%, at least about 6%,
at least about 7%, at least about 8%, at least about 9%, or at
least about 10% by weight of the composition. In certain
embodiments, the polysorbate surfactant may be present at a
concentration of no more than about 2%, no more than about 4%, no
more than about 6%, no more than about 8%, no more than about 10%,
no more than about 12%, no more than about 15%, no more than about
20%, or no more than about 25% by weight of the composition A
"polysorbate surfactant," as used herein, is a surfactant
comprising a polysorbate. For example, the surfactant may comprise
sorbitan monolaurate, sorbitan monopalmitate, sorbitan
monostearate, sorbitan monooleate, or another sorbitan salt. In
some cases, the polysorbate surfactant has a molecular formula:
##STR00003##
where w, x, y, and z are any suitable positive integers. w, x, y,
and z may also each be independently the same or different. In one
set of embodiments, w+x+y+z is 20 (e.g., as in Polysorbate 20). In
some cases, other polymeric sugars can be used instead of, or in
conjunction with, a polysorbate surfactant. Thus, it should be
appreciated that, in the specification herein, references to a
polysorbate surfactant are by way of example, and in other
embodiments, it should be understood that references to a
polysorbate surfactant may include other polymeric sugars in
conjunction or instead of a polysorbate surfactant.
[0071] In some cases, the composition may have a fixed ratio of the
stabilization polymer to propylene glycol to the polysorbate
surfactant. For instance, the ratio of these may be about 1:1:1,
about 1:6:3, about 1:6:2, about 1:7:2, about 1:7:3, about 1.5:1:1,
about 1.5:6:3, about 1.5:6:4, about 1:6:2.5, about 1:6.25:2.5,
about 1:6.25:2.5, etc. As mentioned above, such ratios may be
useful, in certain embodiments of the invention, in providing
temperature stability to the composition.
[0072] In certain aspects of the invention, a pharmaceutical agent
may be combined with a penetrating agent, i.e., an agent that
increases transport of the pharmaceutical agent into the skin,
relative to transport in the absence of the penetrating agent. In
some embodiments, the penetrating agent may define and/or be
combined with a hostile biophysical environment. Examples of
penetrating agents include oleoresin capsicum or its constituents,
or certain molecules containing heterocyclic rings to which are
attached hydrocarbon chains.
[0073] Non-limiting examples of penetrating agents include, but are
not limited to, cationic, anionic, or nonionic surfactants (e.g.,
sodium dodecyl sulfate, polyoxamers, etc.); fatty acids and
alcohols (e.g., ethanol, oleic acid, lauric acid, liposomes, etc.);
anticholinergic agents (e.g., benzilonium bromide, oxyphenonium
bromide); alkanones (e.g., n-heptane); amides (e.g., urea,
N,N-dimethyl-m-toluamide); fatty acid esters (e.g., n-butyrate);
organic acids (e.g., citric acid); polyols (e.g., ethylene glycol,
glycerol); sulfoxides (e.g., dimethylsulfoxide); terpenes (e.g.,
cyclohexene); ureas; sugars; carbohydrates or other agents. In
certain embodiments, the penetrating agent includes a salt, e.g.,
as described herein.
[0074] Thus, another aspect of the invention provides for the
delivery of pharmaceutical agents (e.g., drugs, biological
compounds, etc.) into the body, and such treatments may be systemic
or localized, e.g., directed to a specific location of the body of
a subject, such as the head, one or more specific muscles, an arm,
a leg, the genitals, etc., depending on the specific
application.
[0075] In one set of embodiments, pharmaceutical agents are
introduced to aid in treatment of medical conditions or diseases,
and the symptoms associated thereof. In some embodiments, the
invention provides for the treatment of medical conditions or
diseases and/or ailments using pharmaceutical agents (for example,
to treat a subject diagnosed with a medical condition or disease),
and in some cases, the invention provides for the delivery of a
minimum amount of pharmaceutical agents to provide effective levels
of medication to an effected area topically while limiting side
effects. In some cases, the effective dosage of the pharmaceutical
agent may be lower than the effective dosage of the pharmaceutical
agent when taken orally. Other embodiments of the invention provide
methods for treating erectile dysfunction. Accordingly, in some
embodiments, a composition may be topically applied to a specific
location of the body, e.g., to the penis. Also, in certain cases, a
composition as described herein may be used in the preparation of a
medicament for treatment of erectile dysfunction, or other diseases
or conditions as discussed herein.
[0076] In another aspect, the present invention is directed to a
kit including one or more of the compositions discussed herein. A
"kit," as used herein, typically defines a package or an assembly
including one or more of the compositions of the invention, and/or
other compositions associated with the invention, for example, as
described herein. Each of the compositions of the kit may be
provided in liquid form (e.g., in solution), or in solid form
(e.g., a dried powder). In certain cases, some of the compositions
may be constitutable or otherwise processable (e.g., to an active
form), for example, by the addition of a suitable solvent or other
species, which may or may not be provided with the kit. Examples of
other compositions or components associated with the invention
include, but are not limited to, solvents, surfactants, diluents,
salts, buffers, emulsifiers, chelating agents, fillers,
antioxidants, binding agents, bulking agents, preservatives, drying
agents, antimicrobials, needles, syringes, packaging materials,
tubes, bottles, flasks, beakers, dishes, frits, filters, rings,
clamps, wraps, patches, containers, and the like, for example, for
using, administering, modifying, assembling, storing, packaging,
preparing, mixing, diluting, and/or preserving the compositions
components for a particular use, for example, to a sample and/or a
subject.
[0077] A kit of the invention may, in some cases, include
instructions in any form that are provided in connection with the
compositions of the invention in such a manner that one of ordinary
skill in the art would recognize that the instructions are to be
associated with the compositions of the invention. For instance,
the instructions may include instructions for the use,
modification, mixing, diluting, preserving, administering,
assembly, storage, packaging, and/or preparation of the
compositions and/or other compositions associated with the kit. In
some cases, the instructions may also include instructions for the
delivery and/or administration of the compositions, for example,
for a particular use, e.g., to a sample and/or a subject. The
instructions may be provided in any form recognizable by one of
ordinary skill in the art as a suitable vehicle for containing such
instructions, for example, written or published, verbal, audible
(e.g., telephonic), digital, optical, visual (e.g., videotape, DVD,
etc.) or electronic communications (including Internet or web-based
communications), provided in any manner.
[0078] In some embodiments, the present invention is directed to
methods of promoting one or more embodiments of the invention as
discussed herein, for example, methods of promoting the making or
use of compositions such as those discussed above, methods of
promoting kits as discussed above, or the like. As used herein,
"promoted" includes all methods of doing business including, but
not limited to, methods of selling, advertising, assigning,
licensing, contracting, instructing, educating, researching,
importing, exporting, negotiating, financing, loaning, trading,
vending, reselling, distributing, repairing, replacing, insuring,
suing, patenting, or the like that are associated with the systems,
devices, apparatuses, articles, methods, compositions, kits, etc.
of the invention as discussed herein. Methods of promotion can be
performed by any party including, but not limited to, personal
parties, businesses (public or private), partnerships,
corporations, trusts, contractual or sub-contractual agencies,
educational institutions such as colleges and universities,
research institutions, hospitals or other clinical institutions,
governmental agencies, etc. Promotional activities may include
communications of any form (e.g., written, oral, and/or electronic
communications, such as, but not limited to, e-mail, telephonic,
Internet, Web-based, etc.) that are clearly associated with the
invention.
[0079] In one set of embodiments, the method of promotion may
involve one or more instructions. As used herein, "instructions"
can define a component of instructional utility (e.g., directions,
guides, warnings, labels, notes, FAQs or "frequently asked
questions," etc.), and typically involve written instructions on or
associated with the invention and/or with the packaging of the
invention. Instructions can also include instructional
communications in any form (e.g., oral, electronic, audible,
digital, optical, visual, etc.), provided in any manner such that a
user will clearly recognize that the instructions are to be
associated with the invention, e.g., as discussed herein.
[0080] The following documents are incorporated herein by
reference: International Patent Application No. PCT/US98/19429,
filed Sep. 17, 1998, entitled "A Delivery of Arginine to Cause
Beneficial Effects," by E. T. Fossel, published as WO 99/13717 on
Mar. 25, 1999; U.S. patent application Ser. No. 11/587,323, filed
Oct. 19, 2006, entitled "Transdermal Delivery of Beneficial
Substances Effected by a Hostile Biophysical Environment," by E. T.
Fossel, published as U.S. Patent Application Publication No.
2008/0280984 on Nov. 13, 2008; and U.S. patent application Ser. No.
11/587,328, filed Oct. 19, 2006, entitled "Beneficial Effects of
Increasing Local Blood Flow," by E. T. Fossel, published as U.S.
Patent Application Publication No. 2009/0105336 on Apr. 23,
2009.
[0081] Also incorporated herein by reference are International
Patent Application No. PCT/US2005/005726, filed Feb. 23, 2005,
entitled "Topical Delivery of a Nitric Oxide Donor to Improve Body
and Skin Appearance," by E. Fossel, published as WO 2005/081964 on
Sep. 9, 2005; International Patent Application No.
PCT/US2005/013228, filed Apr. 19, 2005, entitled "Transdermal
Delivery of Beneficial Substances Effected by a Hostile Biophysical
Environment," by E. Fossel, published as WO 2005/102282 on Nov. 3,
2005; International Patent Application No. PCT/US2005/013230, filed
Apr. 19, 2005, entitled "Beneficial Effects of Increasing Local
Blood Flow," by E. Fossel, published as WO 2005/102307 on Nov. 3,
2005; U.S. patent application Ser. No. 08/932,227, filed Sep. 17,
1997, entitled "Topical Delivery of Arginine of Cause Beneficial
Effects," by E. T. Fossel, published as 2002/0041903 on Apr. 11,
2002; U.S. patent application Ser. No. 10/201,635, filed Jul. 22,
2002, entitled "Topical Delivery of L-Arginine to Cause Beneficial
Effects," by E. T. Fossel, published as 2003/0028169 on Feb. 6,
2003; U.S. patent application Ser. No. 10/213,286, filed Aug. 5,
2002, entitled "Topical and Oral Arginine to Cause Beneficial
Effects," by E. T. Fossel, published as 2003/0018076 on Jan. 23,
2003; U.S. Pat. No. 5,895,658, issued Apr. 20, 1999, entitled
"Topical Delivery of L-Arginine to Cause Tissue Warming," by E. T.
Fossel; U.S. Pat. No. 5,922,332, issued Jul. 13, 1999, entitled
"Topical Delivery of Arginine to Overcome Pain," by E. T. Fossel;
U.S. Pat. No. 6,207,713, issued Mar. 27, 2001, entitled "Topical
and Oral Delivery of Arginine to Cause Beneficial Effects," by E.
T. Fossel; and U.S. Pat. No. 6,458,841, issued Oct. 1, 2002,
entitled "Topical and Oral Delivery of Arginine to Cause Beneficial
Effects," by E. T. Fossel.
[0082] In addition, incorporated by reference herein in their
entireties are U.S. Provisional Patent Application Ser. No.
61/427,999, filed Dec. 29, 2010, entitled "Treatment of Erectile
Dysfunction and Other Indications," by E. T. Fossel; and U.S.
Provisional Patent Application Ser. No. 61/428,213, filed Dec. 29,
2010, entitled "Methods and Compositions for Preparing Emulsions
for Topical Drug Delivery," by E. T. Fossel.
[0083] The following examples are intended to illustrate certain
embodiments of the present invention, but do not exemplify the full
scope of the invention.
EXAMPLE 1
[0084] This prophetic example illustrates one method of preparing a
transdermal formula of the invention including sildenafil,
tadalafil, or vardenafil. The final composition is shown in Table
1. Of course, those of ordinary skill in the art will understand
that percentages other than the ones listed below are also
possible, according to other embodiments of the invention.
TABLE-US-00001 TABLE 1 Ingredient % w/w Water 35-55 Sodium Chloride
2.5-15 L-Arginine Hydrochloride 2.5-15 Sildenafil, Tadalafil, or
Vardenafil 1-10 Glyceryl Stearate (SE) 4-10 Cetyl Alcohol 4-10
Magnesium Chloride 0.1-5 Squalane 1-8 Xanthan Gum 0.2-2 Isopropyl
Myristate 0.1-5 Oleic Acid 0.1-5 Propylene Glycol 1-10
Polysorbate-20 0.1-5
[0085] To prepare the formulation in this example, sodium chloride,
potassium chloride, L-arginine and sildenafil, tadalafil, or
vardenafil were mixed in water, then heated to 74.degree. C. with
rapid mixing. In a separate container, the remaining ingredients
were mixed together and heated to 74.degree. C. The other
ingredients were then added to the water phase at 74.degree. C.
with rapid mixing. The mixture was then cooled to room temperature
with continued mixing. At this point, an emulsion formed with a
relatively thin consistency. The emulsion was then homogenized at
high speed at room temperature to thicken the consistency.
EXAMPLE 2
[0086] Initially, it should be appreciated that the compositions
described in this example for the first aqueous and second
non-aqueous preparations for use with ibuprofen may be used for
other drugs or other pharmaceutical agents such as those described
herein (e.g., a phosphodiesterase type 5 inhibitor), or may be
modified to contain equivalent or similar compounds (or a subset
thereof) for use with different drugs or other pharmaceutical
agents, and each drug or other pharmaceutical agent may
individually be provided in the first preparation, the second
preparation, or both.
[0087] Ibuprofen sodium salt is water soluble at pH 7.0 and is
added to the water phase. Any suitable ibuprofen salt may be used.
For example, a commercially available ibuprofen salt may be used.
In some embodiments, an ibuprofen preparation is manufactured to
have the following relative composition (Table 2).
TABLE-US-00002 TABLE 2 Ingredient Quality % w/w Water USP 40.9
Sodium Chloride USP 10.0 L-Arginine Hydrochloride USP 7.5 Ibuprofen
USP 7.5 Sodium Hydroxide USP 1.3 Glyceryl Stearate (SE) 7.0 Cetyl
Alcohol NF 7.0 Potassium Chloride USP 5.0 Squalane NF 4.0 Xanthan
Gum FCC 0.8 Isopropyl Myristate NF 1.0 Oleic Acid NF 1.0 Propylene
Glycol USP 5.0 Polysorbate-20 NF 2.0
[0088] The basic manufacturing process is to form an emulsion by
mixing a water phase and an oil phase at elevated temperature with
rapid mixing. Once the two phases are mixed the mixture is cooled
to room temperature. While cooling is being accomplished homomixing
is accomplished with a vertical colloid mill. For example, in one
set of embodiments, the following manufacturing steps can be
used:
[0089] Step 1: disperse xanthan gum in the propylene glycol and
water and mix to fully hydrate.
[0090] Step 2: To the above mixture add ibuprofen and sodium
hydroxide to produce sodium ibuprofen, add sodium chloride,
potassium chloride and 1-arginine HCl. Heat this mixture to
75.degree. C. to 80.degree. C.
[0091] Step 3: Add glyceryl stearate SE, cetyl alcohol, squalane,
isopropyl myristate, oleic acid and polysorbate-20 and heat this
mixture to 75.degree. C. to 80.degree. C.
[0092] Step 4: Combine the mixtures produced in Step 2 and Step 3
and mix well maintaining temperature.
[0093] Step 5: Cool the mixture of Step 4 to 25.degree. C. to
30.degree. C. while circulating through the vertical colloid
mill.
[0094] The resulting smooth emulsion has a pH of 6.50 to 7.50. In
some cases, the preparation can be manufactured under conditions to
minimize microbial content (e.g., completely sterile or with a
microbiological content of less than about 100 CFU/g).
[0095] In some embodiments, a transdermal ibuprofen cream is
packaged in 100 ml "Magic Star Dispensers" which are airless pumps.
The pump dispenses 1.45 ml with each depression of the pump
head.
[0096] Similar procedures may be used for preparing emulsions of
other compounds described herein. In some embodiments, the compound
is added to the oil phase prior to mixing with the aqueous phase.
In some embodiments, the compound is added to the aqueous phase
prior to mixing with the oil phase.
EXAMPLE 3
Use of a Topical Sildenafil Composition:
[0097] A 66 year old male with erectile dysfunction was given a
cream containing 5% sildenafil in an oil/water emulsion to which
was added 10% sodium chloride, 5% potassium chloride and 2.5%
magnesium chloride. The pH was 6.5. 15 minutes before initiating
sexual activity he applied 1 gram of cream to his penis and gently
rubbed it in until absorbed. Upon engaging in sexual activity he
achieved a full and functional erection and sexual activity
proceeded until successfully concluded.
[0098] The formula for the topical composition that was used for
sildenafil is provided in Table 3 below (shown as % weight). It
should be appreciated that the relative amounts of each component
may be varied (e.g., by about 10%) in some embodiments. It also
should be appreciated that this topical composition may be used for
other inhibitors (e.g., one or more examples of phosphodiesterase
type 5 inhibitors including, but not limited to, avanafil,
lodenafil, mirodenafil, tadalafil, vardenafil, udenafil,
acetildenafil, or thiomethisosildenafil). In some embodiments, the
active compound (e.g., sildenafil) may be added to the oil phase
prior to mixing with the aqueous phase. However, other compounds
may be added to the aqueous phase prior to mixing with the oil
phase.
TABLE-US-00003 TABLE 3 Ingredient % by weight purified water 41
propylene glycol 5 xanthum gum 0.8 active ingredient 5 sodium
chloride 10 potassium chloride 5 magnesium chloride 2.5 L-Arginine
HCl 7.5 Glyceryl Stearate SE 6.5 Cetyl Alcohol 6.5 Squalane 3.5
Isopropyl Myrstate 2 Oleic Acid 2 Polysorbate 20 2
[0099] While several embodiments of the present invention have been
described and illustrated herein, those of ordinary skill in the
art will readily envision a variety of other means and/or
structures for performing the functions and/or obtaining the
results and/or one or more of the advantages described herein, and
each of such variations and/or modifications is deemed to be within
the scope of the present invention. More generally, those skilled
in the art will readily appreciate that all parameters, dimensions,
materials, and configurations described herein are meant to be
exemplary and that the actual parameters, dimensions, materials,
and/or configurations will depend upon the specific application or
applications for which the teachings of the present invention
is/are used. Those skilled in the art will recognize, or be able to
ascertain using no more than routine experimentation, many
equivalents to the specific embodiments of the invention described
herein. It is, therefore, to be understood that the foregoing
embodiments are presented by way of example only and that, within
the scope of the appended claims and equivalents thereto, the
invention may be practiced otherwise than as specifically described
and claimed. The present invention is directed to each individual
feature, system, article, material, kit, and/or method described
herein. In addition, any combination of two or more such features,
systems, articles, materials, kits, and/or methods, if such
features, systems, articles, materials, kits, and/or methods are
not mutually inconsistent, is included within the scope of the
present invention.
[0100] All definitions, as defined and used herein, should be
understood to control over dictionary definitions, definitions in
documents incorporated by reference, and/or ordinary meanings of
the defined terms.
[0101] The indefinite articles "a" and "an," as used herein in the
specification and in the claims, unless clearly indicated to the
contrary, should be understood to mean "at least one."
[0102] The phrase "and/or," as used herein in the specification and
in the claims, should be understood to mean "either or both" of the
elements so conjoined, i.e., elements that are conjunctively
present in some cases and disjunctively present in other cases.
Multiple elements listed with "and/or" should be construed in the
same fashion, i.e., "one or more" of the elements so conjoined.
Other elements may optionally be present other than the elements
specifically identified by the "and/or" clause, whether related or
unrelated to those elements specifically identified. Thus, as a
non-limiting example, a reference to "A and/or B", when used in
conjunction with open-ended language such as "comprising" can
refer, in one embodiment, to A only (optionally including elements
other than B); in another embodiment, to B only (optionally
including elements other than A); in yet another embodiment, to
both A and B (optionally including other elements); etc.
[0103] As used herein in the specification and in the claims, "or"
should be understood to have the same meaning as "and/or" as
defined above. For example, when separating items in a list, "or"
or "and/or" shall be interpreted as being inclusive, i.e., the
inclusion of at least one, but also including more than one, of a
number or list of elements, and, optionally, additional unlisted
items. Only terms clearly indicated to the contrary, such as "only
one of" or "exactly one of," or, when used in the claims,
"consisting of," will refer to the inclusion of exactly one element
of a number or list of elements. In general, the term "or" as used
herein shall only be interpreted as indicating exclusive
alternatives (i.e. "one or the other but not both") when preceded
by terms of exclusivity, such as "either," "one of," "only one of,"
or "exactly one of." "Consisting essentially of," when used in the
claims, shall have its ordinary meaning as used in the field of
patent law.
[0104] As used herein in the specification and in the claims, the
phrase "at least one," in reference to a list of one or more
elements, should be understood to mean at least one element
selected from any one or more of the elements in the list of
elements, but not necessarily including at least one of each and
every element specifically listed within the list of elements and
not excluding any combinations of elements in the list of elements.
This definition also allows that elements may optionally be present
other than the elements specifically identified within the list of
elements to which the phrase "at least one" refers, whether related
or unrelated to those elements specifically identified. Thus, as a
non-limiting example, "at least one of A and B" (or, equivalently,
"at least one of A or B," or, equivalently "at least one of A
and/or B") can refer, in one embodiment, to at least one,
optionally including more than one, A, with no B present (and
optionally including elements other than B); in another embodiment,
to at least one, optionally including more than one, B, with no A
present (and optionally including elements other than A); in yet
another embodiment, to at least one, optionally including more than
one, A, and at least one, optionally including more than one, B
(and optionally including other elements); etc.
[0105] It should also be understood that, unless clearly indicated
to the contrary, in any methods claimed herein that include more
than one step or act, the order of the steps or acts of the method
is not necessarily limited to the order in which the steps or acts
of the method are recited.
[0106] In the claims, as well as in the specification above, all
transitional phrases such as "comprising," "including," "carrying,"
"having," "containing," "involving," "holding," "composed of," and
the like are to be understood to be open-ended, i.e., to mean
including but not limited to. Only the transitional phrases
"consisting of" and "consisting essentially of" shall be closed or
semi-closed transitional phrases, respectively, as set forth in the
United States Patent Office Manual of Patent Examining Procedures,
Section 2111.03.
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