U.S. patent application number 16/779884 was filed with the patent office on 2020-07-16 for foamable vehicles and pharmaceutical compositions comprising aprotic polar solvents and uses thereof.
The applicant listed for this patent is Foamix Pharmaceuticals Ltd.. Invention is credited to Tal Berman, Yohan Hazot, David Schuz, Dov Tamarkin.
Application Number | 20200222320 16/779884 |
Document ID | / |
Family ID | 42790900 |
Filed Date | 2020-07-16 |
United States Patent
Application |
20200222320 |
Kind Code |
A1 |
Tamarkin; Dov ; et
al. |
July 16, 2020 |
FOAMABLE VEHICLES AND PHARMACEUTICAL COMPOSITIONS COMPRISING
APROTIC POLAR SOLVENTS AND USES THEREOF
Abstract
The present invention teaches a foamable pharmaceutical and
cosmetic compositions comprising an aprotic polar solvent; foam
compositions and uses thereof.
Inventors: |
Tamarkin; Dov; (Ness Ziona,
IL) ; Schuz; David; (Gimzu, IL) ; Berman;
Tal; (Rishon Le Ziyyon, IL) ; Hazot; Yohan;
(Rehovot, IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Foamix Pharmaceuticals Ltd. |
Rehovot |
|
IL |
|
|
Family ID: |
42790900 |
Appl. No.: |
16/779884 |
Filed: |
February 3, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16443649 |
Jun 17, 2019 |
10588858 |
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16779884 |
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16236704 |
Dec 31, 2018 |
10363216 |
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16443649 |
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15883134 |
Jan 30, 2018 |
10213384 |
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16236704 |
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15639114 |
Jun 30, 2017 |
9884017 |
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15883134 |
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13263201 |
Dec 28, 2011 |
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PCT/IB10/01126 |
Apr 28, 2010 |
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15639114 |
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61173378 |
Apr 28, 2009 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 47/38 20130101;
A61P 29/00 20180101; A61K 47/26 20130101; A61K 8/046 20130101; A61K
47/14 20130101; A61K 2800/31 20130101; A61K 9/122 20130101; A61K
9/0014 20130101; A61K 8/46 20130101; A61K 47/20 20130101; A61P
17/00 20180101; A61Q 19/00 20130101 |
International
Class: |
A61K 9/12 20060101
A61K009/12; A61K 8/04 20060101 A61K008/04; A61K 8/46 20060101
A61K008/46; A61K 9/00 20060101 A61K009/00; A61K 47/14 20060101
A61K047/14; A61K 47/20 20060101 A61K047/20; A61K 47/26 20060101
A61K047/26; A61K 47/38 20060101 A61K047/38; A61Q 19/00 20060101
A61Q019/00 |
Claims
1-45. (canceled)
46. A composition formulated for administration to skin, comprising
a carrier composition comprising: a) a short chain alcohol
comprising ethanol present at a concentration of at least 55% by
weight of the carrier; b) about 2% to about 50% by weight of the
carrier of a protic polar solvent comprising propylene glycol; c) a
polymeric agent comprising a cellulose ether, wherein the cellulose
ether is a hydroxypropyl cellulose present at a concentration of
about 0.5% to about 1% by weight of the carrier; d) a modulating
agent comprising an antioxidizing agent present at a concentration
of about 0.1% to about 10% by weight of the carrier; e) a metal; f)
an essential oil; and g) tetracycline in a therapeutically
effective amount of about 1% to about 5% by weight of the carrier;
wherein the composition is substantially nonaqueous and free or
essentially free of fatty alcohol.
47. The composition of claim 46, wherein the protic polar solvent
is at a concentration of about 12% to about 30% by weight of the
carrier.
48. The composition of claim 46, further comprising a liquefied or
compressed gas propellant present at a concentration of about 3% to
about 25% by weight of the composition.
49. A composition formulated for administration to skin, comprising
a carrier composition comprising: a) a short chain alcohol
comprising ethanol; b) about 2% to about 50% by weight of the
carrier of a protic polar solvent comprising propylene glycol; c) a
polymeric agent comprising a cellulose ether; d) a modulating agent
comprising an antioxidizing agent; e) a metal; f) an essential oil;
and g) tetracycline in a therapeutically effective amount of about
1% to about 5% by weight of the carrier; wherein the composition is
surfactant free, and free or essentially free of fatty alcohol.
50. The composition of claim 49, wherein the short chain alcohol is
present at a concentration of at least 55% by weight of the
carrier.
51. The composition of claim 49, wherein the cellulose ether is a
hydroxypropyl cellulose.
52. The composition of claim 49, wherein the cellulose ether is
present in a concentration of about 0.5% to about 1% by weight of
the carrier.
53. The composition of claim 49, wherein the modulating agent is
present at a concentration of about 0.1% to about 10% by weight of
the carrier.
54. The composition of claim 49, further comprising a liquefied or
compressed propellant at a concentration of about 3% to about 25%
by weight of the composition.
55. The composition of claim 49, wherein the composition is
substantially nonaqueous.
56. The composition of claim 49, further comprising a retinoid.
57. The composition of claim 56, wherein the retinoid comprises
adapalene or tazarotene.
58. A method of treating acne or rosacea, comprising administering
to skin a carrier composition comprising: a) a short chain alcohol
comprising ethanol; b) about 2% to about 50% by weight of the
carrier of a protic polar solvent comprising propylene glycol; c) a
polymeric agent comprising a cellulose ether; d) a modulating agent
comprising an antioxidizing agent; e) a metal; f) an essential oil;
and g) tetracycline in a therapeutically effective amount of about
1% to about 5% by weight of the carrier; wherein the composition is
surfactant free, and free or essentially free of fatty alcohol.
59. The method of claim 58, wherein the tetracycline is a
doxycycline or a minocycline.
60. The composition of claim 46, wherein the tetracycline is a
doxycycline or a minocycline.
61. The composition of claim 49, wherein the tetracycline is a
doxycycline or a minocycline.
62. The composition of claim 56, wherein the tetracycline is a
doxycycline or a minocycline.
63. The method of claim 58, wherein the cellulose ether is a
hydroxypropyl cellulose present in a concentration of about 0.5% to
about 1% by weight of the carrier.
64. The method of claim 58, wherein the modulating agent is present
at a concentration of about 0.1% to about 10% by weight of the
carrier.
Description
BACKGROUND
[0001] This invention relates to foamable pharmaceutical and
cosmetic compositions and foams, containing aprotic polar solvents
and uses.
[0002] External topical administration is an important route for
the administration of drugs in disease treatment. Administration
into body cavities is gaining in importance. Many groups of drugs,
including, for example, antibiotic, anti-fungal, anti-inflammatory,
anesthetic, analgesic, anti-allergic, corticosteroid, retinoid and
anti-proliferative medications are preferably administered in
creams and ointment.
[0003] There are many different types of foams and within each foam
type there are many levels of qualities. For example, the froth on
the head of beer, lather of shampoo, and lather of shaving cream
have been loosely described as foam but all are different from one
another. Such differences speak to usability applicability. At one
end of the cosmetic or pharmaceutical foam spectrum, the foam can
be long-lasting and not readily breakable upon mechanical
stimulation like shaving foams. Such foams lack suitability for
pharmaceutical use since they lather with mechanical stimulation
and require washing off. At the other end of the spectrum, the foam
can be quick breaking without mechanical stimulation and collapse
upon release. Such foams can be inconvenient since they can
disappear rapidly before they can be conveniently applied to the
intended target. Yet another type of foam is delayed foaming gel
which is expelled as a gel but is said to expand into a type of
foam on exposure to body temperature. Such expansion can be slow or
delayed and inconvenient. Foams are considered a more convenient
vehicle for topical delivery of active agents. There are several
types of topical foams, including aqueous foams, such as commonly
available shaving foams; hydroalcoholic foams; emulsion-based
foams, comprising oil and water components; and oleaginous foams,
which consist of high oil content. In skin therapy, oil containing
foams are preferred, since oil contributes to skin protection and
moisturization, which improve the therapeutic effect of the
formulation. Typically foams are made using liquefied hydrocarbon
gas propellant, such as propane, butane and isobutene, or
hydro-fluoro carbon propellants.
[0004] Formulations containing aprotic polar solvents, such as
Dimethyl sulfoxide ("DMSO"), have been occasionally known. However,
these formulations have only been known as creams, gels or liquid
formulations. Yet, despite the many benefits of pharmaceutical and
cosmetic foam formulations, until now DMSO-containing formulations
have not been developed in a commercial foam form.
SUMMARY
[0005] The present invention relates to foamable pharmaceutical and
cosmetic compositions and foams, comprising aprotic polar
solvents.
[0006] There is provided, easy to use, stable foamable formulations
and foams containing aprotic polar solvents, with improved delivery
properties, especially for treatment of dermal and mucosal
tissues.
[0007] In one or more embodiments waterless formulations comprising
at least one aprotic polar solvent are provided. In certain
embodiments the waterless formulations are formulated with
surfactant. In some embodiments they may also comprise a polymer
and or a foam adjuvant. In certain other embodiments they are
formulated without surfactant. Surfactant free formulations may in
one or more embodiments comprise a polymer and or a foam adjuvant
and preferably both. In one or more embodiments the aprotic
waterless formulation comprises a short chain alcohol. In one or
more embodiments the waterless formulation may form an emulsion,
for example between a hydrophobic phase and an aprotic phase. In
certain embodiments the formulation may be a single phase until
addition of propellant. In one or more embodiments an emulsion is
formed or reformed after addition of hydrophobic propellant.
[0008] In one or more other embodiments water comprising
formulations comprising at least one aprotic polar solvent are
provided. In certain embodiments the water comprising formulations
are formulated with surfactant. In some embodiments they may also
comprise a polymer and or a foam adjuvant. In certain other
embodiments they are formulated without surfactant. Surfactant free
formulations may in one or more embodiments comprise a polymer and
or a foam adjuvant and preferably both. In one or more embodiments
the aprotic-aqueous formulation comprises a short chain alcohol. In
one or more embodiments the water comprising formulation may form
an emulsion, for example between a hydrophobic phase and an aqueous
aprotic phase. In certain embodiments the formulation may be a
single phase until addition of propellant. In one or more
embodiments an emulsion is formed or reformed after addition of
hydrophobic propellant.
[0009] According to one or more embodiments the foamable carrier
comprises: [0010] 1. An aprotic polar solvent; [0011] 2. At least
one foaming or stabilizing member, selected from the group,
consisting of: [0012] a. a surface-active agent; [0013] b. a foam
adjuvant; and [0014] c. a polymeric agent; [0015] and [0016] 3. A
liquefied or compressed gas propellant at a concentration of about
3% to about 25% by weight of the total composition.
[0017] According to one or more embodiments the foamable carrier
comprises: [0018] 1. An aprotic polar solvent; [0019] 2. At least
one foaming or stabilizing member, selected from the group,
consisting of: [0020] a. a surface-active agent; [0021] b. a foam
adjuvant; and [0022] c. a polymeric agent; [0023] 3. At least one
solvent, selected from the group, consisting of: [0024] a. water
[0025] b. a protic polar solvent; and [0026] c. a hydrophobic
carrier; [0027] and [0028] 4. A liquefied or compressed gas
propellant at a concentration of about 3% to about 25% by weight of
the total composition.
[0029] According to one or more embodiments the foamable
composition is aqueous and comprises two or more of the foaming or
stabilizing members. In one or more embodiments the composition
further comprises one of a protic polar solvent or a hydrophobic
carrier or mixtures thereof.
[0030] According to one or more embodiments the foamable carrier is
water-containing (aqueous) and comprises: [0031] 1. An aprotic
polar solvent [0032] 2. At least two foaming or stabilizing
members, selected from the group, consisting of: [0033] a. a
surface-active agent; [0034] b. a foam adjuvant; and [0035] c. a
polymeric agent; [0036] 3. Water and optionally at least one
solvent, selected from the group, consisting of: [0037] a. a protic
polar solvent; and [0038] b. a hydrophobic carrier; [0039] and
[0040] 4. A liquefied or compressed gas propellant at a
concentration of about 3% to about 25% by weight of the total
composition.
[0041] According to one or more certain embodiments the aqueous
foamable carrier is aqueous without a hydrophobic carrier and
comprises one stabilizing member comprising a non ionic surfactant
with a HLB between about 9 to about 16.
[0042] According to one or more embodiments, the foamable
composition, comprises a therapeutically effective concentration of
an aprotic polar solvent, which possesses inherent therapeutic
properties.
[0043] In preferred embodiments, the therapeutic aprotic polar
solvent comprises Dimethyl sulfoxide (DMSO).
[0044] The carrier or pharmaceutical or cosmetic composition is
stored in a pressurized canister and when released a foam is formed
that is thermally stable, yet breaks easily upon application of
shear force. So in one or more embodiments the foam composition is
breakable. The breakable foam is thermally stable, yet breaks
easily upon application of shear force. By thermally stable is
meant that the foam is stable for a sufficient period of time--both
at room temperature and when applied to the skin or subjected to at
temperature of about 36 C--to facilitate easy and relaxed use and
allow for possible distractions or interruptions. In one or more
embodiments the foam is stable for at least about 30 secs, at least
about 40 secs, at least about 50 secs, at least about 60 secs, at
least about 80 secs, at least about 100 secs, at least about 120
secs, at least about 140 secs, at least about 160 secs, at least
about 180 secs, at least about 210 secs, at least about 240 secs,
at least about 270 secs or at least about 300 secs.
[0045] In one or more alternative embodiments the foam composition
is quick-break or thermolabile. The quick-breaking foam is
thermally instable, and collapses easily upon exposure to body
temperature without the need to apply shear force. In one or more
embodiments the foam has low stability or is unstable and collapses
in less than about 30 secs, in less than about 25 secs, in less
than about 20 secs, in less than about 15 secs, in less than about
10 secs, or in less than about 5 secs. Foam can be quick-breaking,
for example, wherein the foam formulation comprises high levels of
a short chain alcohol, such as, ethanol.
[0046] According to one or more embodiments the concentration of
the aprotic polar solvent, about 3% to about 97% by weight of the
total composition.
[0047] According to one or more embodiments, the composition
comprises a hydrophobic carrier; and the composition is an emulsion
between the water/aprotic polar solvent mixture and the hydrophobic
carrier.
[0048] According to one or more embodiments, the composition is
waterless. In some embodiments the composition is waterless and
comprises a protic polar solvent or a hydrophobic carrier or
mixtures thereof. In certain embodiments, the composition is
waterless, and the composition is a waterless emulsion between the
aprotic polar solvent and the hydrophobic carrier.
[0049] According to one or more embodiments, the composition is
substantially waterless.
[0050] According to one or more embodiments the foamable carrier is
non-aqueous (waterless) and comprises: [0051] 1. An aprotic polar
solvent [0052] 2. At least one foaming or stabilizing member,
selected from the group, consisting of: [0053] a. a surface-active
agent; [0054] b. a foam adjuvant; and [0055] c. a polymeric agent;
[0056] 3. Optionally at least one solvent, selected from the group,
consisting of: [0057] a. a protic polar solvent; and [0058] b. a
hydrophobic carrier; [0059] and [0060] 4. A liquefied or compressed
gas propellant at a concentration of about 3% to about 25% by
weight of the total composition.
[0061] According to one or more embodiments, the foamable carrier
is substantially non-aqueous (substantially waterless), and
comprises: [0062] a) An aprotic polar solvent [0063] b) At least
one member, selected from the group, consisting of: [0064] I. a
surface-active agent; [0065] II. a foam adjuvant; and [0066] III. a
polymeric agent; [0067] c) Up to about 5% water and optionally a
solvent, selected from the group, consisting of: [0068] I. a protic
polar solvent; and [0069] II. a hydrophobic carrier; [0070] and
[0071] d) A liquefied or compressed gas propellant at a
concentration of about 3% to about 25% by weight of the total
composition.
[0072] According to one or more embodiments, the foamable carrier
is substantially waterless, and comprises: [0073] a) An aprotic
polar solvent [0074] b) At least one member, selected from the
group, consisting of: [0075] I. a surface-active agent; [0076] II.
a foam adjuvant; and [0077] III. a polymeric agent; [0078] c) At
least two solvents, one of which is water selected from the group,
consisting of: [0079] IV. Up to about 5% water; [0080] V. a protic
polar solvent; and [0081] VI. a hydrophobic carrier; [0082] and
[0083] d) A liquefied or compressed gas propellant at a
concentration of about 3% to about 25% by weight of the total
composition.
[0084] According to one or more embodiments, the composition is
alcohol-free, or substantially alcohol-free. According to one or
more other certain embodiments the composition is alcoholic.
[0085] According to one or more embodiments, the composition is a
waterless foamable carrier comprising: [0086] a. DMSO [0087] b. At
least one foaming or stabilizing member, selected from the group,
consisting of: [0088] i. a solid surface-active agent at room
temperature having a HLB of less than about 5; [0089] ii. a foam
adjuvant; [0090] iii. hydroxypropyl methyl cellulose; [0091] iv. a
surface active agent and a foam adjuvant and or hydroxypropyl
methyl cellulose; [0092] v. a surface active agent and a foam
adjuvant and a polymeric agent; and [0093] vi. a foam adjuvant and
a polymeric agent; [0094] c. Optionally or at least one solvent,
selected from the group, consisting of: [0095] i. a protic polar
solvent; and [0096] ii. a hydrophobic carrier; [0097] and [0098] d.
A liquefied or compressed gas propellant at a concentration of
about 3% to about 25% by weight of the total composition. wherein
the resultant foam formed from the carrier is thermally stable, yet
breaks easily upon application of shear force.
[0099] According to one or more embodiments, the hydrophobic
solvent comprises a petrolatum.
[0100] According to one or more embodiments, the protic polar
solvent comprises ethanol.
[0101] According to one or more embodiments, the composition
further comprises urea.
[0102] According to one or more embodiments, the composition is a
water containing foamable carrier comprising: [0103] a. DMSO [0104]
b. At least two foaming or stabilizing members, selected from the
group, consisting of: [0105] i. a surface-active agent; [0106] ii.
a foam adjuvant; [0107] iii. a polymeric agent; and [0108] iv. a
foam adjuvant and a polymeric agent; [0109] c. Water and optionally
or at least one solvent, selected from the group, consisting of:
[0110] i. a protic polar solvent; and [0111] ii. a hydrophobic
carrier; [0112] and [0113] d. A liquefied or compressed gas
propellant at a concentration of about 3% to about 25% by weight of
the total composition. wherein the resultant foam formed from the
carrier is thermally stable, yet breaks easily upon application of
shear force.
[0114] According to one or more embodiments, the water is less than
about 5% and the formulation is substantially waterless.
[0115] According to one or more embodiments the foamable carrier,
further comprises an active agent; In one or more additional
embodiments, the aprotic polar solvents possesses inherent
therapeutic properties and therefore it can be considered as an
"active agent".
[0116] According to one or more embodiments the method of treating
a disorder of a mammalian subject, includes:
[0117] administering a foamable therapeutic composition to a target
site, the composition comprising: [0118] a. An aprotic polar
solvent [0119] b. At least one foaming or stabilizing member,
selected from the group, consisting of: [0120] i. a surface-active
agent; [0121] ii. a foam adjuvant; and [0122] iii. a polymeric
agent; [0123] c. Optionally or at least one solvent, selected from
the group, consisting of: [0124] i. water; [0125] ii. a protic
polar solvent; and [0126] iii. a hydrophobic carrier; and [0127] d.
A liquefied or compressed gas propellant at a concentration of
about 3% to about 25% by weight of the total composition.
[0128] According to one or more embodiments the method of treating
a disorder of a mammalian subject, includes: [0129] administering a
foamable therapeutic composition to a target site, the composition
comprising: [0130] 1. An aprotic polar solvent; [0131] 2. At least
two members, selected from the group, consisting of: [0132] i. a
surface-active agent; [0133] ii. a foam adjuvant; and [0134] iii. a
polymeric agent; [0135] 3. At least one solvent, selected from the
group, consisting of: [0136] i. water; [0137] ii. a protic polar
solvent; and [0138] iii. a hydrophobic carrier; [0139] and [0140]
4. A liquefied or compressed gas propellant at a concentration of
about 3% to about 25% by weight of the total composition.
[0141] According to one or more embodiments, the method comprises a
waterless foamable carrier or composition with at least one of a
surfactant, a polymer and a foam adjuvant. According to one or more
other embodiments, the method comprises a substantially waterless
foamable carrier or composition with at least one of a surfactant,
a polymer and a foam adjuvant and up to about 5% water. According
to one or other embodiments, the method comprises an aqueous
carrier or composition with at least two of a surfactant, a polymer
and a foam adjuvant.
[0142] According to one or more embodiments, the method comprises
foamable carrier or composition, further comprises an active
agent.
[0143] According to one or more embodiments, the method comprises
pre-treating the target area with a foamable carrier or composition
comprising an agent that can ameliorate or prevent a taste or odor
being experienced after a DMSO foam is applied to a target.
According to one or more other embodiments, the method comprises
treating the target area with a foamable carrier or composition
further comprising an agent that can ameliorate or prevent a taste
or odor being experienced after a DMSO foam is applied to a
target.
[0144] According to one or more embodiments the foamable
composition, comprises a therapeutically effective concentration of
an aprotic polar solvent, which possesses inherent therapeutic
properties.
[0145] All % values herein are provided on a weight (w/w)
basis.
BRIEF DESCRIPTION OF THE DRAWING
[0146] The patent or application file contains at least one drawing
executed in color. Copies of this patent or patent application
publication with color drawing(s) will be provided by the Office
upon request and payment of the necessary fee.
[0147] FIG. 1 is a Table illustrating increase in skin hydration 4
hours after application of DMSO foamable carriers.
[0148] FIG. 2 is a color bar chart illustrating increase in skin
hydration 4 hours after application of DMSO foamable carriers.
[0149] FIG. 3 is a color microscope picture of a foam produced from
formulation D30 comprising DMSO and mineral oil.
[0150] FIG. 4 is a microscope picture at .times.200 of a waterless
DMSO foam sample from formulation D24 showing a single-phase
homogeneous preparation free of crystals or agglomerations.
[0151] FIG. 5 is a Microscope picture at .times.200 of an aqueous
DMSO foam sample from formulation D33 showing a single-phase
homogeneous preparation free of crystals or agglomerations.
DETAILED DESCRIPTION
[0152] According to one or more embodiments the present invention
includes the embodiments described above in the Summary of the
Invention as more particularly detailed, specified and exemplified
below.
Aprotic Polar Solvent
[0153] Solvents can be broadly classified into polar (hydrophilic)
and nonpolar (lipophilic). The polarity can be measured as the
dielectric constant or the dipole moment of a compound.
[0154] An aprotic solvent is an organic solvent that does not
contain an O--H or N--H bond; or does not exchange protons with a
substance dissolved in it. In the context herein, the aprotic polar
solvent is a solvent with a comparatively high relative
permittivity (or dielectric constant), greater than about 15, and a
sizable permanent dipole moment, that cannot donate suitably labile
hydrogen atoms to form strong hydrogen bonds; and it is miscible in
water. Examples of aprotic polar solvents, suitable according to
the present invention include, but are not limited to dimethyl
sulfoxide (DMSO), dimethylformamide (DMF), acetonitrile, acetone,
methyl ethyl ketone, 1,4-Dioxane and tetrahydrofuran (THF).
Additional non-limiting examples include N-methylpyrrolidone,
pyridine, piperidine, dimethyl ether, hexamethylphosphorotriamide,
dimethylformanide, methyl dodecyl sulfoxide, N-methyl-2-pyrrolidone
and 1-methyl-2-pyrrolidinone) and azone
(1-dodecylazacycloheptan-2-one).
[0155] An aprotic solvent can be a defoamer in certain embodiments.
It can in certain embodiments act to accelerate the breakdown of
the foam and reduce its stability. To an extent this may be
countered by adding one or more agents that can stabilize the foam
and boost its stability. For example, addition of a polymer and or
a foam adjuvant can help to improve the collapse time and likewise
slow liquid drainage driven by gravity, which otherwise can and
will cause the walls of bubbles to thin and ultimately collapse
into adjacent bubble walls that are likewise thinning to form
larger bubbles. Examples 1 and 2 indicate, for example, that DMSO
is not prone to foaming.
DMSO
[0156] Dimethyl sulfoxide (DMSO) is the chemical compound with the
formula (CH.sub.3).sub.2SO. This colorless liquid is an important
aprotic polar solvent that dissolves both polar and nonpolar
compounds and is miscible in a wide range of organic solvents as
well as water. It has a distinctive property of penetrating the
skin very readily, so that some people report that one can taste it
soon after it comes into contact with the skin. In this connection,
taking DMSO internally is reported to cause a fish- or oyster-like
taste or odor in the mouth. With its high polarity combined with a
high dielectric constant, DMSO is known to be an excellent solvent
for polar or polarizable organic compounds, but also many acids,
alkalis and mineral salts. DMSO is miscible with most co-solvents.
The following table provides certain physical characteristics of
DMSO and DMF.
TABLE-US-00001 DMSO DMF Dielectric constant (25.degree. C.) 46.4
36.7 Polarity (Debye, 25.degree. C.) 4.3 3.8 Boiling point
(.degree. C.) 189 153 Flash point (closed cup, .degree. C.) 87
58
[0157] DMSO can penetrate the skin and other membranes without
damaging them and could carry other compounds into a biological
system. DMSO has been used most widely as a topical analgesic, in a
70% DMSO, 30% water solution. Laboratory studies suggest that DMSO
reduces pain by blocking peripheral nerve C fibers. DMSO also is
said to reduce inflammation by several mechanisms. It is further an
antioxidant--a scavenger of the free radicals that gather at the
site of injury. DMSO also stabilizes membranes and slows or stops
leakage from injured cells and is recommended for many inflammatory
conditions not caused by infection or tumor. Because DMSO increases
the rate of absorption of some compounds through organic tissues
including skin and nails, it can be used as a drug delivery
system.
[0158] In one or more embodiments a method is provided to
ameliorate or prevent possible side effects of DMSO such as a
taste, which has been described as "garlicy" and a breath odor. As
an initial observation although a high proportion of DMSO can be
present in the formulations because they are presented as a low
density foam it is possible to apply a much thinner layer and cover
the same area with a substantially or much smaller amount than a
cream or ointment. That being said the position can be further
improved by first applying to the target area a composition
containing one or more of urea, ethanol, and or lipophilic
compounds and then subsequently applying the DMSO foam to the
target area. The time interval between the first application and
the second application can be about almost immediately afterwards,
about 30 secs afterwards, about 1minute afterwards, about 2 minutes
afterwards, about 5 minutes afterwards, about 10 minutes
afterwards, about 20 minutes afterwards, about 30 minutes
afterwards, about 40 minutes afterwards, about 50 minutes
afterwards, about 60 minutes afterwards, or sometimes longer. In
one or more embodiments the DMSO presented to the target area
simultaneously with another foam containing one or more ingredients
known to ameliorate or prevent the taste and odor by using a dual
chamber device to apply the two foams such as is described in US
publication 2007/0069046 entitled "MEASURE OF CONTENT FROM A
PLURALITY OF CONTAINERS" and incorporated herein by reference. In
an alternative approach the formulation may itself include one or
more ingredients known to ameliorate or prevent the taste and
odor.
Concentration
[0159] In an embodiment the aprotic polar solvent can be
incorporated in the foamable composition of the present invention
in a concentration between about 3% and about 98% or between about
10% and about 97%, for example above aboutl5%, above about 20%,
above about 25%, above about 30%, above about 35%;,above about;
40%, above about 45%, above about 50%, above about 55%, above
about, 60%; above about 70%, above about 80%, above about 90%, or
any range between any of the aforesaid amounts; and more preferably
from about 10% to about 60% of at least one aprotic polar
solvent.
[0160] In certain embodiments, the aprotic polar solvent is DMSO
and its concentration is in the range between about 30% and about
60%. In an embodiment it is between about 40% to about 50%. In an
embodiment, aprotic polar solvent is DMSO and its concentration is
about 45%.
[0161] In other embodiments, the composition contains more than 60%
aprotic polar solvent, and in certain cases, up to about 98% of at
least one aprotic polar solvent.
[0162] In one or more embodiments where ever a phrase is used to
refer to a concentration of above X% or below X% it can also
include X% or of above about X% or below about X% it can also
include about X%.
General
[0163] In one or more embodiments, the aprotic polar solvent is a
combination of two or more aprotic solvents. In certain embodiments
the main aprotic solvent is DMSO.
[0164] In one or more embodiments, the aprotic polar solvent is
used in combination with a solid aprotic compound. Non limiting
examples of solid aprotic compounds are octyl methyl sulfoxide,
nonyl methyl sulfoxide, decyl methyl sulfoxide, undecyl methyl
sulfoxide, and dodecyl methyl sulfoxide.
[0165] In one or more embodiments, the aprotic polar solvent is
used in combination with a sulfoxide derivative which is not
aprotic. Non limiting examples of non aprotic sulfoxide compounds
having hydroxyl groups are 2-hydroxydecyl methyl sulfoxide,
2-hydroxyundecyl methyl sulfoxide and hydroxydodecyl methyl
sulfoxide.
[0166] In one or more embodiments, formulations comprising DMSO can
produce a quality foam with one or more surfactants without the
addition of a polymer and or without the addition of a foam
adjuvant. Aprotic solvents are not oil so which surfactants are
preferred is not obvious. In one or more embodiments preferred
surfactants or surfactant combinations include polyoxyethylene
fatty acid ethers, polyoxyethylene fatty acid esters, polysorbates,
sucrose esters, glycerides esters, sorbitol esters.
[0167] In one or more embodiments, formulations comprising DMSO can
unexpectedly produce a quality foam without one or more
surfactants. In one or more embodiments good quality waterless
foams comprising DMSO can be achieved with a combination of a
polymeric agent and a fatty alcohol. In an embodiment the fatty
alcohol may be replaced by the fatty acid. In an embodiment a
combination of fatty alcohol and fatty acid may be applied together
with the polymeric agent.
[0168] In one or more embodiments good quality aqueous foams
comprising DMSO can be achieved with a combination of a polymeric
agent and a fatty alcohol. In one or more embodiments good quality
aqueous foams comprising DMSO can be achieved with the addition of
a short chain alcohol, such as ethanol, even in high
concentrations.
[0169] By the term "aqueous" in relation to formulations herein it
is intended to indicate and describe a multiplicity of formulations
containing some water including formulations comprising low
amounts, medium amounts or high amounts of water so as to apply a
wide meaning to the term.
Foamable Composition and Foam Properties
[0170] The ability to achieve quality foam with substantial
concentration of at least one aprotic polar solvent, is surprising,
because usually, such solvents are not prone to create a foam. The
challenge is not just to achieve a quality foam but also to attain
a formulation that will satisfy a plurality of two, three, four,
five, six or more of property specifications simultaneously. [0171]
1. Uniformity: The composition should be formulated so that it is
and can remain uniform without phase separation or precipitation
over time. This property is of high importance when the product is
intended to be a pharmaceutical product. [0172] 2. Flowability: The
composition, when placed in an aerosol container and pressurized
should be flowable such that it can be expelled through the
canister valve. It should preferably also be shakable inside the
container. These requirements create a formulation challenge,
because low or non-viscous flowable and shakable compositions are
prone to undergo phase separation or precipitation. [0173] 3.
Quality: Upon release from the can, the composition should generate
a foam of about good or excellent quality having low density and
small bubble size. [0174] 4. Stability/Breakability: The fine
balance between stability and breakability of the foam coming out
of the container is very delicate: on one hand the foam should not
be "quick breaking", i.e., it should be at least short term stable
upon release from the pressurized container and not break as a
result of exposure to skin temperature; and on the other hand, it
should be "breakable", i.e., it should spread easily, break down
and absorb into the skin or membrane upon application of mild shear
force. [0175] 5. Skin Feeling: To ensure patient compliance the
skin feeling after application should be pleasant, and greasy or
waxy residues should be minimalized. [0176] 6. Non irritating: The
above requirements should be achieved with the awareness that
formulation excipients, especially surfactants, can be irritating,
and should be used in low concentrations. [0177] 7. Delivery:
Finally, the composition should also be designed to ensure
efficient delivery of a therapeutic agent (other than the aprotic
polar solvent) into the target site of treatment.
[0178] Based on extensive investigations and trial and error
experiments, it has been found that such properties can be achieved
for formulations comprising water by incorporating into the
composition at least two stabilizing members, and also for
formulations that are substantially waterless by incorporating into
the composition at least one stabilizing member selected from the
group consisting of: [0179] i. a surface-active agent; [0180] ii. a
foam adjuvant [0181] iii. a polymeric agent It has further been
discovered that such properties can be achieved for waterless
formulations by incorporating into the composition at least one
stabilizing member, selected from the group, consisting of: [0182]
i. a surface-active agent; [0183] ii. a foam adjuvant [0184] iii. a
polymeric agent
[0185] The type, quality, properties and mechanism of foam
formation for aprotic formulations cannot be predicted or deduced
based on the literature or on existing product experience. The
challenge to achieve such foam formulations may be even more
pronounced when the aprotic polar solvent composition is waterless
or substantially waterless.
[0186] As detailed and exemplified below, the aqueous or water
containing compositions containing aprotic polar solvents, such as
DMSO, conform with the desirable and favorable sensory properties
of foam. They further deliver efficacious therapy, as exemplified
herein.
[0187] As further detailed and exemplified below, even waterless or
substantially waterless compositions, containing aprotic polar
solvents, such as DMSO, provide favorable sensory properties of
foam.
Surface Active Agent
[0188] The composition of the present invention contains a
surface-active agent. Surface-active agents (also termed
"emulsifiers" or "surfactants") include any agent linking oil and
water in the composition, in the form of emulsion. A surfactant's
hydrophilic/lipophilic balance (HLB) describes the emulsifier's
affinity toward water or oil. HLB is defined for non-ionic
surfactants. The HLB scale ranges from 1 (totally lipophilic) to 20
(totally hydrophilic), with 10 representing an equal balance of
both characteristics. The HLB of a blend of two emulsifiers equals
the weight fraction of emulsifier A times its HLB value plus the
weight fraction of emulsifier B times its HLB value (weighted
average). In many cases a single surfactant may suffice. In other
cases a combination of two or more surfactants is desired.
Reference to a surfactant in the specification can also apply to a
combination of surfactants or a surfactant system. As will be
appreciated by a person skilled in the art which surfactant or
surfactant system is more appropriate is related to the vehicle and
intended purpose. In general terms a combination of surfactants is
usually preferable where the vehicle is an emulsion. In an emulsion
environment a combination of surfactants can be significant in
producing breakable foams of good quality. It has been further
discovered that the generally thought considerations for HLB values
for selecting a surfactant or surfactant combination are not always
binding for emulsions and that good quality foams can be produced
with a surfactant or surfactant combination both where the HLB
values are in or towards the lipophilic side of the scale and where
the HLB values are in or towards the hydrophilic side of the scale.
Surfactants also play a role in foam formation where the foamable
formulation is a single phase composition.
[0189] According to one or more embodiments the composition
contains a single surface active agent having an HLB value between
about 2 and 9, or more than one surface active agent and the
weighted average of their HLB values is between about 2 and about
9. Lower HLB values may in certain embodiments be more applicable,
especially in compositions with low water content, or non-aqueous
compositions.
[0190] According to one or more embodiments the composition
contains a single surface active agent having an HLB value between
about 7 and 14, or more than one surface active agent and the
weighted average of their HLB values is between about 7 and about
14. Mid range HLB values may in certain embodiments be more
suitable for oil in water emulsions.
[0191] According to one or more other embodiments the composition
contains a single surface active agent having an HLB value between
about 9 and 20, or more than one surface active agent and the
weighted average of their HLB values is between about 9 and about
20.
[0192] In a waterless or substantially waterless environment a wide
range of HLB values may be suitable; however, surfactants of the
low range are sometimes preferred.
[0193] Preferably, the composition of the present invention
contains a non-ionic surfactant. Nonlimiting examples of possible
non-ionic surfactants include: [0194] Polyoxyethylene sorbitan
esters (polysorbates), such as Polysorbate 20 (polyoxyethylene (20)
sorbitan monolaurate), Polysorbate 40 (polyoxyethylene (20)
sorbitan monopalmitate), Polysorbate 60 (polyoxyethylene (20)
Sorbitan monostearate) and Polysorbate 80 (polyoxyethylene (20)
sorbitan monooleate). [0195] Sorbitan esters, such as Span 20
(Sorbitan monolaurate), Span 40 (Sorbitan monopalmitate), Span 60
(Sorbitan monostearate), Span 65 (Sorbitan tristearate), Span 80
(Sorbitan monooleate). [0196] Polyoxyethylene fatty acid esters,
such as, PEG-8 Stearate, PEG-20 Stearate, PEG-40 Stearate, PEG-100
Stearate, PEG-150 Distearate, PEG-8 laurate, PEG-10 laurate, PEG-12
laurate, PEG-20 laurate, PEG-8 oleate, PEG-9 oleate, PEG-10 oleate,
PEG-12 oleate, PEG-15 oleate and PEG-20 oleate. [0197] PEG-Fatty
Acid Diesters, such as PEG-20 dilaurate, PEG-20 dioleate, PEG-20
distearate, PEG-32 dilaurate and PEG-32 dioleate. [0198]
Polyethylene glycol (PEG) ethers of fatty alcohols, e.g.,
Isoceteth-20, Laureth-4, Laureth-9, Laureth-23, Ceteth-2,
Ceteth-10, Ceteth-20, Steareth-2, Steareth-7, Steareth-10,
Steareth-20, Steareth-21, Steareth-100, Steareth-200, Oleth-2,
Oleth-3, Oleth-5, Oleth-10, Oleth-20, Ceteareth-6, Ceteareth-12,
Ceteareth-17, Ceteareth-20, Ceteareth-25, Ceteareth-50,
Ceteareth-80, Cetoleth-5, Cetoleth-10, Pareth-12, Pareth-23, C12-13
Pareth-3, C12-13 Pareth-4. [0199] Glycerol esters, such as glyceryl
monostearate, glyceryl monolaurate, glyceryl monopalmitate and
glyceryl monooleate [0200] PEG-fatty Acid Mono- and di-ester
Mixtures--several PEG-fatty acid esters are marketed commercially
as mixtures or mono- and diesters. [0201] Polyethylene Glycol
Glycerol Fatty Acid Esters, such as PEG-7 Glyceryl Cocoate, PEG-7
Glyceryl Cocoate, PEG-20 Almond Glycerides, PEG-12 glyceryl
laurate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-40
glyceryl laurate, PEG-20 glyceryl oleate, and PEG-30 glyceryl
oleate. [0202] Alcohol-Oil Transesterification Products such as
PEG-5 hydrogenated castor oil, PEG-6 almond oil, PEG-6
caprylic/capric glycerides, PEG-6 peanut oil, PEG-6 corn oil, PEG-6
apricot kernel oil, PEG-6 triolein, PEG-7 hydrogenated castor oil,
PEG-8 caprylic/capric glycerides, PEG-8 corn oil, PEG-9
hydrogenated castor oil, PEG-20 corn glycerides, PEG-20 almond
glycerides, PEG-25 hydrogenated castor oil, PEG-25 trioleate,
PEG-35 castor oil, PEG-40 hydrogenated castor oil, PEG-60 corn
glycerides, PEG-60 almond oil, PEG-40 palm kernel oil, PEG-50
castor oil, PEG-50 hydrogenated castor oil. Also included as oils
in this categoty of surfactants are oil-soluble vitamins, such as
vitamins A, D, E, K, ect. Thus, derivatives of these vitamins, such
as tocopheryl PEG-100 succinate, are also suitable surfactants.
[0203] Polyglycerized Fatty Acids, such as polyglyceryl oleate,
polyglyceryl-2 dioleate, and polyglyceryl-10 trioleate
(hydrophobic); and polyglyceryl-10 laurate, polyglyceryl-10 oleate,
and polyglyceryl-10 mono, dioleate (hydrophilic). Polyglyceryl
polyricinoleates are also preferred hydrophilic and hydrophobic
surfactants. [0204] Propylene glycol fatty acid esters, such as
propylene glycol monolaurate, propylene glycol ricinoleate,
propylene glycol monooleate, propylene glycol dicaprylate/dicaprate
and propylene glycol dioctanoate. [0205] Mono- and diglycerides,
such as glyceryl monooleate, glyceryl ricinoleate, glyceryl
laurate, glyceryl dilaurate, glyceryl dioleate, glyceryl
mono/dioleate, glyceryl caprylate/caprate, caprylic acid
mono/diglycerides, and mono- and diacetylated monoglycerides.
[0206] Sterol and sterol derivatives, such as PEG-24 cholesterol
ether. [0207] Sugar esters (mono-, di- and tri-esters of sucrose
with fatty acids), such as sucrose monopalmitate and sucrose
monolaurate. [0208] Polyethylene glycol alkyl phenols
[0209] The following table provides by examples the HLB values of
various non-ionic surfactants, sorted by HLB from lowest
(hydrophobic) to highest (hydrophilic).
TABLE-US-00002 Glycol Distearate HLB = 1 PEG-7 Olivate HLB = 11
Sorbitan Trioleate HLB = 1.8 Cetearyl Glucoside HLB = 11 Propylene
Glycol Isostearate HLB = 2.5 PEG-8 Oleate HLB = 11.6 Glycol
Stearate HLB = 2.9 Polyglyceryl-3 Methyglucose Distearate Sorbitan
Sesquioleate HLB = 3.7 HLB = 12 Glyceryl Stearate HLB = 3.8
Oleth-10 HLB = 12.4 Lecithin HLB = 4 Oleth-10/Polyoxyl 10 Oleyl
Ether NF Sorbitan Oleate HLB = 4.3 HLB = 12.4 Sorbitan Monostearate
NF HLB = 4.7 Ceteth-10 HLB = 12.9 Sorbitan Stearate HLB = 4.7 PEG-8
Laurate HLB = 13 Sorbitan Isostearate HLB = 4.7 Cocamide MEA HLB =
13.5 Steareth-2 HLB = 4.9 Polysorbate 60 HLB = 14.9 Oleth-2 HLB =
4.9 Polysorbate 80 HLB = 15 Glyceryl Laurate HLB = 5.2
Isosteareth-20 HLB = 15 Ceteth-2 HLB = 5.3 PEG-60 Almond Glycerides
HLB = 15 PEG-30 Dipolyhydroxystearate HLB = 5.5 Polysorbate 80 HLB
= 15 Glyceryl Stearate SE HLB = 5.8 PEG-20 Methyl Glucose
Sesquistearate PEG-4 Dilaurate HLB = 6 HLB = 15 Methyl Glucose
Sesquistearate HLB = 6.6 Ceteareth-20 HLB = 15.2 Sorbitan Laurate
HLB = 8.6 Oleth-20 HLB = 15.3 PEG-40 Sorbitan Peroleate HLB = 9
Steareth-20 HLB = 15.3 Laureth-4 HLB = 9.7 Steareth-21 HLB = 15.5
PEG-7 Glyceryl Cocoate HLB = 10 Ceteth-20 HLB = 15.7 PEG-20 Almond
Glycerides HLB = 10 Isoceteth-20 HLB = 15.7 PEG-25 Hydrogenated
Castor Oil Polysorbate 20 HLB = 16.7 HLB = 10.8 Laureth-23 HLB =
16.9 Stearamide MEA HLB = 11 PEG-100 Stearate HLB = 18.8
Polysorbate 85 HLB = 11 Steareth-100 HLB = 18.8 PEG-80 Sorbitan
Laurate HLB = 19.1
[0210] In one or more embodiments of the composition comprises
water and a single stabilizing member, which is at least one
surface active agent. In such embodiments the at least one surface
active agent is non ionic and can comprise a solid (for example
ceteth -20) or liquid surfactant (for example Tween 80) with a HLB
between about 9 and about 16. As can be seen from the results in
Example 8 in which a non ionic surfactant alone with a HLB between
about 9-16 provides a better foam quality and stability than a non
ionic surfactant alone with a HLB value lower than about 9 or
higher than about 16. However, in order to improve stability and
collapse time the aqueous formulations comprise a second
stabilizing member, which can be an appropriate polymeric agent
(such as hydroxypropyl methylcellulose) and or an appropriate foam
adjuvant (such as cetostearyl alcohol, stearyl alcohol, stearic
acid and isostearic acid) or a polymeric agent, which has
surfactant properties such as a poloxamer. In certain embodiments a
combination of at least two stabilizing members is a synergistic
combination, such as observed in Example 9. Also by providing two
or more stabilizing members it can allow a wider range of agents
and or a broader range of HLB. In one or more other embodiments the
formulation comprises a hydrophobic or lipophilic component and the
formulation prior to addition of the propellant is an emulsion. In
such embodiments the surface active agent has a role in stabilizing
the emulsion and a role in generating a stable breakable foam.
Furthermore a system has to be selected such that upon addition of
the propellant the emulsion is not destabilized. The emulsion can
be an oil in water emulsion or if an appropriate surfactant is used
such as the following non limiting examples of glyceryl stearate,
sorbitan stearate, polyglyceryl oleate or other surfactants with an
HLB value lower than about 9, a water in oil emulsion may be
formed.
[0211] In one or more embodiments the composition is a waterless
composition and a single stabilizing member. The stabilizing member
can be at least one polymeric agent, at least one foam adjuvant or
at least one surface active agent. In such embodiments the at least
one surface active agent is non ionic and can comprise a solid
surface active agent, which is a solid ambient temperature. In one
preferred embodiment the surfactant generally comprises a linear
molecule with a more polar head, for example sorbitan monostearate
and or glyceryl monostearate. It has been observed, for example,
that when a surfactant with a non linear unsaturated fatty acid
chain is used, such as sorbitan monoleate, only a bubbly liquid is
achieved (See Example 3).This incidentally is in contrast to the
position with an aqueous system where for example Tween 80 has been
used successfully although it has an oleate moiety. In another
preferred embodiment, in the context of a waterless composition,
the surfactant has a low HLB value, being between about 2 and about
9. In certain embodiments, the HLB of the solid surface active
agent is between about 2 and about 5. It has been surprisingly
discovered that a solid surface active agent, having low HLB
provides a foam with better quality and stability than a liquid
and/or a high HLB surfactant. It has been further surprisingly
discovered that a solid surface active agent, having low HLB
evolves a breakable foam of quality, even without any additional
foam stabilizing agents (such as a polymer or a foam adjuvant).
[0212] In one or more embodiments the surface active agent is a
combination of two or more surface active agents. Such a
combination may be in certain cases more effective than a single
surfactant and provides a more stable emulsion or improved foam
quality. For example and by way of non-limiting explanation it has
been found that by choosing two surfactants, one hydrophobic and
the other hydrophilic the combination can produce a more stable
emulsion than a single surfactant. In certain embodiments the
combination is a synergistic combination. In one or more
embodiments the difference in the HLB of two surfactants is about
at least 2, or is about at least 3, or is about at least 4.
[0213] In one or more embodiments the surfactant can be, a
surfactant system comprising of a surfactant and a co surfactant, a
waxy emulsifier, a liquid crystal emulsifier, an emulsifier which
is solid or semi solid at room temperature and pressure, or
combinations of two or more agents in an appropriate proportion as
will be appreciated a person skilled in the art. Where a solid or
semi solid emulsifier combination is used it can also comprise a
solid or semi solid emulsifier and a liquid emulsifier.
[0214] In one or more embodiments the surface-active agent includes
at least one non-ionic surfactant. Ionic surfactants are known to
be irritants. Therefore, non-ionic surfactants are preferred in
applications including sensitive tissue such as found in most
mucosal tissues, especially when they are infected or inflamed. We
have surprisingly found that non-ionic surfactants alone can
provide formulations and foams of good or excellent quality in the
carriers and compositions disclosed herein.
[0215] Yet, in certain embodiments, the foamable composition
includes a mixture of at least one non-ionic surfactant and at
least one ionic surfactant, selected from the group of anionic,
cationic, zwitterionic, amphoteric and ampholytic surfactants, in a
ratio in the range of about 100:1 to 6:1. In one or more
embodiments, the non-ionic to ionic surfactant ratio is greater
than about 6:1, or greater than about 8:1; or greater than about
14:1, or greater than about 16:1, or greater than about 20:1. In
further embodiments, surface active agent comprises a combination
of a non-ionic surfactant and an ionic surfactant, at a ratio of
between 1:1 and 20:1.
[0216] In selecting a suitable surfactant or combination thereof it
should be borne in mind that the upper amount of surfactant that
can be used may be limited by the shakability of the composition.
In general terms, as the amount of non liquid surfactant is
increased the shakability of the formulation reduces until a
limitation point is reached where the formulation becomes non
shakable and unsuitable. Thus in an embodiment any effective amount
of surfactant may be used provided the formulation remains
shakable. In other certain exceptional embodiments the upper limit
may be determined by flowability such as in circumstances where the
composition is marginally or apparently non shakable. Thus in an
embodiment any effective amount of surfactant may be used provided
the formulation remains flowable.
[0217] In certain embodiments the amount of surfactant or
combination of surfactants is between about 0.05% to about 20%;
between about 0.05% to about 15%; or between about 0.05% to about
10%. In a preferred embodiment the concentration of surface active
agent is between about 0.2% and about 8%. In a more preferred
embodiment the concentration of surface active agent is between
about 1% and about 6%. In certain embodiments by comprising a
second or a second and a third stabilizing member it is possible to
minimize the amount of surfactant used in the formulation, for
example such that the surface active agent is between about 0.5%
and about 3%.
[0218] If the composition as formulated is a substantially non
shakable composition it is nevertheless possible as an exception in
the scope disclosed herein for the formulation to be flowable to a
sufficient degree to be able to flow through an actuator valve and
be released and still expand to form a good quality foam. This
surprising and unusual exception may be due one or more of a number
of factors such as the high viscosity, the softness, the lack of
crystals, the pseudoplastic or semi pseudo plastic nature of the
composition and the dissolution of the propellant into the
formulation.
Foam Adjuvant
[0219] In one or more embodiments the foamable vehicle further
includes a foam adjuvant. More particularly the foam adjuvant is
preferably a fatty acid or a fatty alcohol. Foam adjuvants, as
defined herein are also useful in facilitating improved
spreadability and absorption of the composition.
[0220] In one or more embodiments the foam adjuvant includes fatty
alcohols having 15 or more carbons in their carbon chain, such as
cetyl alcohol and stearyl alcohol (or mixtures thereof). Other
examples of fatty alcohols are arachidyl alcohol (C20), behenyl
alcohol (C22), 1-triacontanol (C30), as well as alcohols with
longer carbon chains (up to C50).
[0221] In one or more embodiments the foam adjuvant includes fatty
acids having 16 or more carbons in their carbon chain, such as
hexadecanoic acid (C16) stearic acid (C18), arachidic acid (C20),
behenic acid (C22), octacosanoic acid (C28), as well as fatty acids
with longer carbon chains (up to C50), or mixtures thereof. As for
fatty alcohols, the amount of fatty acids required to support the
foam system is inversely related to the length of its carbon
chain.
[0222] In one or more embodiments, a combination of a fatty acid
and a fatty alcohol is employed.
[0223] Optionally, the carbon atom chain of the fatty alcohol or
the fatty acid may have at least one double bond. A further class
of foam adjuvant includes a branched fatty alcohol or fatty acid.
The carbon chain of the fatty acid or fatty alcohol also can be
substituted with a hydroxyl group, such as 12-hydroxy stearic
acid.
[0224] An important property of the fatty alcohols and fatty acids
used in context of the composition disclosed herein is related to
their therapeutic properties per se. Long chain saturated and mono
unsaturated fatty alcohols, e.g., stearyl alcohol, erucyl alcohol,
arachidyl alcohol and behenyl alcohol (docosanol) have been
reported to possess antiviral, antiinfective, antiproliferative and
anti-inflammatory properties (see, U.S. Pat. No. 4,874,794). Longer
chain fatty alcohols, e.g., tetracosanol, hexacosanol,
heptacosanol, octacosanol, triacontanol, etc., are also known for
their metabolism modifying properties and tissue energizing
properties. Long chain fatty acids have also been reported to
possess anti-infective characteristics.
[0225] In one or more embodiments, a combination of a foam adjuvant
and a polymeric agent is employed. In certain embodiments the
combination is synergistic, for example as observed in Example 5
Part B, where stearyl alcohol and hydoxypropyl methylcellulose were
noted to have a synergistic effect.
[0226] In one or more embodiments, a combination of a foam adjuvant
and a surface active agent is employed.
[0227] In one or more embodiments, a combination of a foam adjuvant
and a polymeric agent is employed.
[0228] In one or more embodiments, a combination of a foam
adjuvant, a polymeric agent and a surface active agent is
employed.
Polymeric Agent
[0229] In one or more embodiments, the composition disclosed herein
contains a polymeric agent selected from the group consisting of a
bioadhesive agent, a gelling agent, a film forming agent and a
phase change agent. A polymeric agent enhances the creation of foam
having fine bubble structure, which does not readily collapse upon
release from the pressurized aerosol can. The polymeric agent
serves to stabilize the foam composition and to control drug
residence in the target organ. In certain embodiments the polymer
can have surfactant like properties and contribute to the
stabilization of emulsion formulations, such as poloxamer or
pemulen.
[0230] Exemplary polymeric agents include, in a non-limiting
manner, naturally-occurring polymeric materials, such as locust
bean gum, sodium alginate, sodium caseinate, egg albumin, gelatin
agar, carrageenin gum, sodium alginate, xanthan gum, quince seed
extract, tragacanth gum, guar gum, cationic guars, hydroxypropyl
guar gum, starch, amine-bearing polymers such as chitosan; acidic
polymers obtainable from natural sources, such as alginic acid and
hyaluronic acid; chemically modified starches and the like,
carboxyvinyl polymers, polyvinylpyrrolidone, polyvinyl alcohol,
polyacrylic acid polymers, polymethacrylic acid polymers, polyvinyl
acetate polymers, polyvinyl chloride polymers, polyvinylidene
chloride polymers and the like.
[0231] Additional exemplary polymeric agents include semi-synthetic
polymeric materials such as cellulose ethers, such as
methylcellulose, hydroxypropyl cellulose, hydroxypropyl
methylcellulose, hydroxyethyl cellulose, hydroxy propylmethyl
cellulose, methylhydroxyethylcellulose,
methylhydroxypropylcellulose, hydroxyethylcarboxymethylcellulose,
carboxymethyl cellulose, carboxymethylcellulose
carboxymethylhydroxyethylcellulose, and cationic celluloses,
carbomer (homopolymer of acrylic acid is crosslinked with an allyl
ether pentaerythritol, an allyl ether of sucrose, or an allyl ether
of propylene, such as Carbopol.RTM. 934, Carbopol.RTM. 940,
Carbopo.RTM. 941, Carbopol.RTM. 980 and Carbopol.RTM. 981.
Poloxamers (synthetic block copolymer of ethylene oxide and
propylene) such as Poloxamer 124, Poloxamer 188, Poloxamer 237,
Poloxamer 338 and Poloxamer 407. Other useful Poloxamers are: 181,
182, 183, 184, 185, 212, 215, 217, 231, 234, 235, 238, 331, 333,
334, 335, 401, 402, and 403. Polyethylene glycol, having molecular
weight of 1000 or more (e.g., PEG 1,000, PEG 4,000, PEG 6,000 and
PEG 10,000) also have gelling capacity and they are also considered
polymeric agents.
[0232] In one or more embodiments the polymer is hydoxypropyl
methyl cellulose, for example where the formulation is waterless
and a single stabilizing member is utilized, the polymeric agent
comprises hydroxypropyl methyl cellulose.
[0233] Mixtures of the above polymeric agents are contemplated.
[0234] In one or more embodiments the polymer is used in
combination with another stabilizing member, which can be a
surfactant and or a foam adjuvant.
[0235] The concentration of the polymeric agent should be selected
so that the composition, after filling into aerosol canisters and
pressurized with propellant, is flowable, and can be shaken in the
canister. In one or more embodiments, the concentration of the
polymeric agent is selected such that the viscosity of the
composition, prior to filling of the composition into aerosol
canisters, is less than about 30,000 CP, and more preferably, less
than about15,000 CP. In one or more embodiments, the viscosity of
the composition, prior to filling of the composition into aerosol
canisters, is less than about 10,000 CP, or less than about 5,000
CP, or less than about 3,000 CP.
Combination of a Foam Adjuvant and a Polymeric Agent
[0236] Interestingly, when a foam adjuvant (e.g., stearyl alcohol)
alone or a polymeric agent (e.g., hydroxypropyl methylcellulose)
alone is used with DMSO, a foam of good quality is obtained, but it
quickly collapses upon exposure to 36.degree. C. (collapse time 10
and 30 sec respectively), as shown in formulations D21 and D07.
However, surprisingly, when these two components are combined with
DMSO, they act synergistically to produce a good quality foam with
a collapse time of 120 seconds as shown in formulation D22 (See
Example 5 Part B).
Optional Organic Carriers
[0237] Optionally, the foamable composition further includes at
least one organic carrier selected from the group consisting of a
hydrophobic organic carrier, a petrolatum, an organic protic polar
solvent, and mixtures thereof, at a concentration of about 2% to
about 50% by weight.
Hydrophobic Solvent/Emollient
[0238] One or more hydrophobic solvents are optionally included in
the composition, in order to add to the sensory properties of the
composition and/or in order to impart skin conditioning properties.
In an embodiment, the hydrophobic solvent is an emollient, i.e., a
substance that softens and soothes the skin. Emollients are used to
correct dryness and scaling of the skin. The hydrophobic solvent
and/or the emollient can be selected from the group consisting of
mineral oil, alkyl esters of fatty acids such as isopropyl
palmitate, isopropyl isostearate, diisopropyl adipate, diisopropyl
dimerate, octyl palmitate, cetyl lactate, cetyl ricinoleate,
tocopheryl acetate, acetylated lanolin alcohol, cetyl acetate,
phenyl trimethicone, glyceryl oleate, tocopheryl linoleate, wheat
germ glycerides, arachidyl propionate, myristyl lactate, decyl
oleate, ricinoleate, isopropyl lanolate, pentaerythrityl
tetrastearate, neopentylglycol dicaprylate/dicaprate, isononyl
isononanoate, isotridecyl isononanoate, myristyl myristate,
triisocetyl citrate, octyl dodecanol, maleated soybean oil,
unsaturated or polyunsaturated oils, such as olive oil, corn oil,
soybean oil, canola oil, cottonseed oil, coconut oil, sesame oil,
sunflower oil, borage seed oil, syzigium aromaticum oil, hempseed
oil, herring oil, cod-liver oil, salmon oil, flaxseed oil, wheat
germ oil, evening primrose oils; essential oils; and silicone oils,
such as dimethicone, cyclomethicone, polyalkyl siloxane, polyaryl
siloxane, polyalkylaryl siloxane, a polyether siloxane copolymer
and a poly(dimethylsiloxane)-(diphenyl-siloxane) copolymer. In
certain embodiments the carrier is a petrolatum.
[0239] While the aprotic polar solvent and water are generally
miscible, when a hydrophobic carrier is included to the
composition, it is necessary to create an emulsion between the
water/aprotic polar solvent mixture and the hydrophobic carrier.
Even when the composition is waterless, the hydrophobic carrier is
typically insoluble in the aprotic solvent, and therefore it is
necessary to create an emulsion between the aprotic polar solvent
and the hydrophobic carrier.
Protic Polar Solvent
[0240] A "protic polar solvent" is an organic solvent that has a
hydrogen atom bound to an oxygen as in a hydroxyl group or a
nitrogen as in an amine group. They are typically soluble in both
water and oil.
[0241] In one or more embodiments, the formulation can comprise a
protic polar solvent.
[0242] In one or more embodiments, the protic polar solvent is a
polyol. Polyols are organic substances that contain at least two
hydroxy groups in their molecular structure.
[0243] In one or more embodiments, the protic polar solvent
contains an diol (a compound that contains two hydroxy groups in
its molecular structure), such as propylene glycol (e.g.,
1,2-propylene glycol and 1,3-propylene glycol), butanediol (e.g.,
1,4-butaneediol), butanediol (e.g., 1,3-butaneediol and
1,4-butenediol), butynediol, pentanediol (e.g., 1,5-pentanediol),
hexanediol (e.g., 1,6-hexanediol), octanediol (e.g.,
1,8-octanediol), neopentyl glycol, 2-methyl-1,3-propanediol,
diethylene glycol, triethylene glycol, tetraethylene glycol,
dipropylene glycol and dibutylene glycol.
[0244] In one or more embodiments, the polar solvent contains a
triol (a compound that contains three hydroxy groups in its
molecular structure), such as glycerin and 1,2,6-Hexanetriol.
[0245] Additional examples of protic polar solvents include
polyols, such as glycerol (glycerin), propylene glycol, hexylene
glycol, diethylene glycol, propylene glycol n-alkanols, terpenes,
di-terpenes, tri-terpenes, terpen-ols, limonene, terpene-ol,
1-menthol, dioxolane, ethylene glycol, other glycols, alkanols,
such as dialkylamino acetates, and admixtures thereof. dimethyl
isosorbide, ethyl proxitol, dimethylacetamide (DMAc) and alpha
hydroxy acids, such as lactic acid and glycolic acid.
[0246] According to still other embodiments, the polar solvent is a
polyethylene glycol (PEG) or PEG derivative that is liquid at
ambient temperature, including PEG200 (MW (molecular weight) about
190-210 kD), PEG300 (MW about 285-315 kD), PEG400 (MW about 380-420
kD), PEG600 (MW about 570-630 kD) and higher MW PEGs such as PEG
4000, PEG 6000 and PEG 10000 and mixtures thereof.
[0247] Lower molecular weight alcohols can sometimes be more potent
as a solvent, for example by extracting lipids from the skin layers
more effectively, which characteristic can adversely affect the
skin structure and cause dryness and irritation. So where a lower
molecular weight alcohol is used in a formulation other ingredients
are ideally selected to ameliorate or prevent such side
effects.
[0248] Many polar solvents, for example propylene glycol and
glycerin, possess the beneficial property of a heumectant.
[0249] In one or more embodiments, the polar solvent is a
humectant.
Additional Components
[0250] In an embodiment, a composition disclosed herein includes
one or more additional components. Such additional components
include but are not limited to anti oxidants anti perspirants,
anti-static agents, buffering agents, bulking agents, chelating
agents, cleansers, colorants, conditioners, deodorants, diluents,
dyes, emollients, fragrances, hair conditioners, herbal extracts,
humectants, keratolytic agents, pearlescent aids, perfuming agents,
permeation enhancers, pH-adjusting agents, preservatives,
protectants, skin penetration enhancers, softeners, solubilizers,
sunscreens, sun blocking agents, sunless tanning agents, viscosity
modifiers, flavanoids and vitamins. As is known to one skilled in
the art, in some instances a specific additional component may have
more than one activity, function or effect.
Propellants
[0251] The composition of the present invention requires the
addition of a propellant in order to generate a foam. In one or
more embodiments the propellant makes up between about 3% and about
45% or between about 3% and about 35% of the foamable composition,
preferably between about 5% and about 25% of the composition. In
preparing the formulations the ingredients other than propellant
are combined to 100% and the propellant is added thereafter so that
the ratio of formulation to propellant can range from 100:3 to
100:45 or from 100:3 to 100:35 or preferably 100:5 to 100:25. In
the case of bag in can where the propellant is separate from the
composition any amount can be used that is sufficient to drive the
contents of the bag out of the canister. In certain embodiments the
propellant in the bag can be the same as and in certain other
embodiments be different from the propellant in the
composition.
[0252] Suitable propellants include volatile hydrocarbons such as
butane, propane, isobutene or mixtures thereof. In one or more
embodiments a hydrocarbon mixture AP-70 is used. Hydrofluorocarbon
(HFC) propellants are also suitable as propellants in the context
disclosed herein. Exemplary HFC propellants include 1,1,1,2
tetrafluorethane (Dymel 134), and 1,1,1,2,3,3,3 heptafluoropropane
(Dymel 227). Dimethyl ether is also useful. In one or more
embodiments use of compressed gases (e.g., air, carbon dioxide,
nitrous oxide, and nitrogen) is also possible. Chloro fluorocarbon
propellants on the other hand are no longer considered suitable for
use in cosmetic, pharmaceutical and other formulations due to inter
alia the potential environmental damage that they can do.
[0253] In one or more embodiments a combination of at least two
propellants, selected from HFC, hydrocarbon propellants, dimethyl
ether and compressed gases is contemplated.
[0254] In one or more embodiments the propellant can also be used
to expel formulation using a bag in can system or a can in can
system as will be appreciated by someone skilled in the art. In
certain embodiments the part of the propellant system is in the
formulation and part separate from the formulation. In this way it
is possible to reduce the amount of surfactant in the formulation
but still provide good expulsion from the canister, where the
foamable formulation is expelled quickly but without jetting or
noise.
Alcohol Free
[0255] According to one or more embodiments, the foamable
composition is substantially alcohol-free, i.e., free of short
chain alcohols. Short chain alcohols, having up to 5 carbon atoms
in their carbon chain skeleton and one hydroxyl group, such as
ethanol, propanol, isopropanol, butanol, iso-butanol, t-butanol and
pentanol, are considered less desirable solvents or polar solvents
due to their skin-irritating effect. Thus, the composition is
substantially alcohol-free and includes less than about 5% final
concentration of lower alcohols, preferably less than about 2%,
more preferably less than about 1%.
Alcoholic
[0256] According to one or more certain other embodiments, the
foamable composition includes a short chain alcohol. In a preferred
embodiment the short chain alcohol is ethanol. In one embodiment
the composition is waterless. In another embodiment it is aqueous
or water containing and in a further embodiment it is substantially
non-aqueous. In various embodiments the amount of short chain
alcohol is about or above about 5%, about or above about 10%; about
or above about 15% about or above about 20%. In one or more
embodiments the range of short chain alcohol is between about 5% to
about 25%. In certain embodiments when short chain alcohol is
present the formulation is breakable and not thermolabile or
substantially not thermolabile. By substantially not thermolabile
is meant that the foam upon expulsion onto a warm body surface at
about 35-37.degree. C. does not collapse rapidly within about 30
seconds. In one or more alternative embodiments the formulation is
thermolabile.
[0257] In one or more alternative embodiments the formulation
comprises high amounts of short chain alcohol. In certain
embodiments the amount of short chain alcohol is about or above
about 25%, is about or above about 30%, is about or above about
35%, is about or above about 40%; is about or above about 45%, is
about or above about 50%; is about or above about 55% or is about
or above about 60%.
[0258] In one or more embodiments there is provided a composition
comprising an aprotic polar solvent and a protic polar solvent, in
which the protic polar solvent can be a short chain alcohol. Such a
combination may conceivably contribute to directed skin delivery of
active agents.
Aprotic-Aqueous Fomulations
[0259] In certain cases, the active agent is soluble in the
presence of water, and therefore, in such cases the presence of
water in the composition can be desirable. In certain preferred
embodiments, the composition comprises only a small amount of
water. In other embodiments water is a substantial component. In
one or more embodiments the range of water can be from about 0.1%
to about 5%, or from about 5% to about 15%, or from about 15% to
about 25%, or from about 25% to about 35%, or from about 35% to
about 45%, or from about 45% to about 55%, or from about 55% to
about 65%, or from about 55% to about 65%, or from about 65% to
about 75%, or from about 75% to about 85% or from about 5% to about
85%, or from about 10% to about 75%. In one or more embodiments the
formulation can be aprotic-hydroalcoholic.
Waterless Formulations
[0260] In certain cases, the active agent degrades in the presence
of water, and therefore, in such cases the presence of water in the
composition is not desirable. Thus, in certain preferred
embodiments, the composition is substantially non-aqueous. The term
"substantially non-aqueous" or "substantially waterless" is
intended to indicate that the composition has water content below
about 5%, preferably below about 2%, such as below about 1.5%. In
certain other preferred embodiments the composition is non aqueous
or waterless.
[0261] By non aqueous or waterless is meant that the composition
contains no or substantially no, free or unassociated or absorbed
water. It will be understood by a person of the art that the
waterless solvents and substances miscible with them disclosed
herein can be hydrophilic and can contain water in an associated or
entrapped or absorbed form and may absorb water from the atmosphere
and the ability to do so is its hygroscopic water capacity. It is
intended that essentially non-aqueous formulations are included
within its scope such that the formulations may have present a
small amount of water. In some embodiments the composition
ingredients are pretreated to reduce, remove or eliminate any
residual or associated or absorbed water.
Modulating Agent
[0262] In one or more embodiments the formulation includes a
modulating agent, The term modulating agent is used to describe an
agent which can improve the stability of or stabilize a foamable
carrier or composition and or an active agent by modulating the
effect of a substance or residue present in the carrier or
composition.
[0263] In one or more embodiments the substance or residue may for
example be acidic, basic or a buffer system and potentially alter
an artificial pH in a waterless or substantially non-aqueous
environment or it may be one or more metal ions which may act as a
potential catalyst in a waterless or substantially non aqueous
environment. In various certain embodiments it may be an ionization
agent or an anti oxidization agent or a flavanoid or mixtures
thereof that are effective in a waterless or substantially non
aqueous environment. The modulating agent may in one or more
embodiments act to modulate the ionic or polar characteristics and
any acid-base balance of a waterless or substantially non-aqueous
carrier, composition, foamable carrier or foamable composition or
resultant foam disclosed herein.
[0264] In one or more other embodiments the modulating agent is
used to describe an agent which can affect pH in an aqueous
solution. The agent can be any of the known buffering systems used
in pharmaceutical or cosmetic formulations as would be appreciated
by a man of the art. It can also be an organic acid, a carboxylic
acid, a fatty acid an amino acid, an aromatic acid, an alpha or
beta hydroxyl acid an organic base or a nitrogen containing
compound.
[0265] In certain embodiments the substance or residue may be one
or more metal ions which may act as a potential catalyst in a
aqueous environment. In various certain embodiments it may be an
ionization agent or an anti oxidization agent or a flavanoid or
mixtures thereof that are effective in an aqueous environment. The
modulating agent may in one or more embodiments act to modulate the
ionic or polar characteristics and any acid-base balance of an
aqueous carrier, composition, foamable carrier or foamable
composition or resultant foam disclosed herein.
[0266] In certain embodiments the formulation is an emulsion. The
emulsion may be formed prior to the addition of propellant or upon
the introduction of propellant. The emulsion may be a waterless
emulsion or it may be an aqueous emulsion (oil in water or oil in
water). In various certain embodiments the substance or residue may
for example be acidic or basic and potentially alter pH in an
emulsion environment or it may be one or more metal ions which may
act as a potential catalyst in an emulsion environment. In various
certain embodiments it may be an ionization agent or an anti
oxidization agent or a flavanoid or mixtures thereof that are
effective in an emulsion environment. The modulating agent may in
one or more embodiments act to modulate the ionic or polar
characteristics and any acid-base balance of an emulsion carrier,
composition, foamable carrier or foamable composition or resultant
foam disclosed herein.
[0267] In one or more further embodiments the modulating agent is a
chelating or sequestering or complexing agent that is sufficiently
soluble or functional in the solvent to enable it to "mop up" or
"lock" metal ions. In one or more embodiments a preferred non
limiting example is EDTA.
[0268] In other embodiments the modulating agent is a buffer, as
defined by Van Slyke [Van Slyke, J. Biol. Chem. 52, 525 (1922)], as
"a substance which by its presence in solution increases the amount
of acid or alkali that must be added to cause unit change in
pH."
[0269] Modulating agents may be added to the compositions of the
subject invention, preferably from about 0.1% to about 10%, more
preferably from about 1% to about 5%, of the composition. Where the
active agent itself is the modulating agent alone or in combination
with another modulating agent it will be added at an effective dose
which may be outside these ranges. For example azelaic acid may be
at about 15% of the composition.
[0270] It is important to maintain skin surface pH in order to
prevent susceptibility to bacterial skin infections or skin damage
and disease. Thus, adding a modulating agent, which contributes to
the stabilization of skin pH at the desirable level, is
advantageous.
[0271] In the same fashion, adding an acidic modulating agent to a
foamable composition, which is intended for vaginal application is
advantageous, since better protection against vaginal infection is
attained with pH lower than about 4.5.
[0272] Non-limiting examples of antioxidants/radical scavengers are
ascorbic acid and derivatives, tocopherol or derivatives thereof
(succinate, or sorbate or acetate or other esters), propyl galate,
butylated hydroxy toluene and butyl hydroxy anisol. Non-limiting
examples of positive ionization agents are benzyl conium chloride,
and cetyl pyridium chloride. Non-limiting examples of negative
ionization agents are sodium lauryl sulfate, sodium lauryl
lactylate and phospholipids.
[0273] A non-limiting list of flavanoid compounds is: benzquercin,
diosmin, ethoxazorutoside, flavodate, sodium hesperidin,
leucocianido, monoxerutin, oxerutin, quercetin, rutoside,
rosmarinic acid.
[0274] In one or more embodiments the modulating agent is mixture
or combination of two or more modulating agents.
Composition and Foam Physical Characteristics and Advantages
[0275] A pharmaceutical or cosmetic composition manufactured using
the foamable carrier is very easy to use. When applied onto the
afflicted body surface of mammals, i.e., humans or animals, it is
in a foam state, allowing free application without spillage. Upon
further application of a mechanical force, e.g., by rubbing the
composition onto the body surface, it freely spreads on the surface
and is rapidly absorbed.
[0276] In one or more embodiments the foamable composition has an
acceptable shelf-life of at least six months or at least one year,
or preferably, at least two years at ambient temperature.
[0277] The foamable compositions according to the present invention
are stable chemically and physically. For example as seen in
Example14 following accelerated stability studies, the foam met the
specified stability and assay criteria. The high quality foams
disclosed herein can demonstrate desirable texture; can form fine
bubble structures that do not break immediately upon contact with a
surface, and can spread easily on the treated area and can absorb
quickly.
[0278] The composition should also preferably be free flowing, to
allow it to flow through the aperture of the container, e.g., and
aerosol container, and create an acceptable foam.
Foam Quality
[0279] Foam quality can be graded as follows:
[0280] Grade E (excellent): very rich and creamy in appearance,
does not show any bubble structure or shows a very fine (small)
bubble structure; does not rapidly become dull; upon spreading on
the skin, the foam retains the creaminess property and does not
appear watery.
[0281] Grade G (good): rich and creamy in appearance, very small
bubble size, "dulls" more rapidly than an excellent foam, retains
creaminess upon spreading on the skin, and does not become
watery.
[0282] Grade FG (fairly good): a moderate amount of creaminess
noticeable, bubble structure is noticeable; upon spreading on the
skin the product dulls rapidly and becomes somewhat lower in
apparent viscosity.
[0283] Grade F (fair): very little creaminess noticeable, larger
bubble structure than a "fairly good" foam, upon spreading on the
skin it becomes thin in appearance and watery.
[0284] Grade P (poor): no creaminess noticeable, large bubble
structure, and when spread on the skin it becomes very thin and
watery in appearance.
[0285] Grade VP (very poor): dry foam, large very dull bubbles,
difficult to spread on the skin.
[0286] Topically administrable foams are typically of quality grade
E or G, when released from the aerosol container. Smaller bubbles
are indicative of more stable foam, which does not collapse
spontaneously immediately upon discharge from the container. The
finer foam structure looks and feels smoother, thus increasing its
usability and appeal.
Breakability
[0287] A further aspect of the foam is breakability. The balance
between stability and breakability of the foam coming out of the
container is very delicate: on one hand the foam should not be
"quick breaking", i.e., it should be stable upon release from the
pressurized container and not break as a result of exposure to skin
temperature; and on the other hand, it should be "breakable", i.e.,
it should spread easily, break down and absorb into the skin or
membrane upon application of mild shear force. The foam is
thermally stable, yet breaks under shear force. Shear-force
breakability of the foam is clearly advantageous over thermally
induced breakability. Thermally sensitive foams immediately or
quickly collapse upon exposure to skin temperature and, therefore,
cannot be usefully applied on the hand and afterwards delivered to
the afflicted area since transfer would have to be effected
immediately.
[0288] Breakable foam is a specialized low density type of foam
that is stable on release at least in the short time span of about
minutes, but can break readily upon the application of shear force
such as gentle rubbing to spread easily over a target surface.
Unlike other types of foams, breakable foam is not thermolabile,
nor does it display late or long-delayed expansion over
minutes.
Foam Density
[0289] Another property of the foam is density (specific gravity),
as measured upon release from the aerosol can. Typically, foams
have specific gravity of about 0.20 g/mL or less, such as less than
about 0.20 g/mL; or less than about 0.12 g/mL; or less than about
0.10 g/mL; or less than about 0.08 g/mL, depending on their
composition and on the propellant concentration.
Shakability
[0290] `Shakability` means that the composition contains some or
sufficient flow to allow the composition to be mixed or remixed on
shaking. That is, it has fluid or semi fluid properties.
Shakability is described further in the section on Tests.
Collapse Time
[0291] The collapse time of foam represents its tendency to be
temperature-sensitive and its ability to be at least short term
stable so as to allow a user sufficient time to comfortably handle
and apply the foam to a target area without being rushed and or
concerned that it may rapidly collapse, liquefy and or disappear.
Collapse time is examined by dispensing a given quantity of foam
and photographing sequentially its appearance with time during
incubation at 36.degree. C. Thus, it is useful for selecting foam
products, which are "breakable" but not "quick breaking", which
maintain structural stability at skin temperature for at least a
reasonable period of time. In one or more embodiments it can be
about more than a minute, about more than two minutes, about more
than 3 minutes, about more than 4 minutes, about more than 5
minutes or longer. In one or more limited embodiments it can be
shorter than one minute, for example about more than 50 seconds,
about more than 40 seconds and occasionally about more than 30
seconds. In a preferred embodiment it can be more than about one
minute and in a more preferred embodiment it can be more than about
3 minutes. Collapse time can also provide an indication of the rate
of drainage in the foam formulation of the fluid around the bubbles
under the influence of gravity. Short collapse times indicate fast
or rapid drainage, whilst long collapse times indicate slow
drainage.
Pharmaceutical Composition
[0292] The foamable composition is an ideal vehicle for active
pharmaceutical ingredients and active cosmetic ingredients. In the
context active pharmaceutical ingredients and active cosmetic
ingredients are collectively termed "active agent" or "active
agents". In one or more embodiments the composition comprises a
therapeutically effective concentration of at least one active
agent. In one or more embodiments the composition comprises at
least two therapeutic agents. In certain embodiments the aprotic
formulation facilitates the combination of active agents otherwise
unstable in water, which for example are unstable at different
pH's.
[0293] Suitable active agents include but are not limited to an
active herbal extract, an acaricides, an age spot and keratose
removing agent, an allergen, an alpha hydroxyl acid, an analgesic
agent, an antiacne agent, an antiallergic agent, an antiaging
agent, an antibacterial agent, an antibiotic, an antiburn agent, an
anticancer agent, an antidandruff agent, an antidepressant, an
antidermatitis agent, an antiedemic anent, an antifungal agent, an
antihistamine, an antihelminth agent, an antihyperkeratolyte agent,
an anti-infective agent, an antiinflammatory agent, an
antiirritant, an antilipemic agent, an antimicrobial agent, an
antimycotic agent, an antioxidant, an antiparasitic agent, an
antiproliferative agent, an antipruritic agent, an antipsoriatic
agent, an antirosacea agent, an antiseborrheic agent, an antiseptic
agent, an antiswelling agent, an antiviral agent, an anti-wart
agent, an anti-wrinkle agent, an antiyeast agents, an astringent, a
beta-hydroxy acid, benzoyl peroxide, a topical cardiovascular
agent, a chemotherapeutic agent, a corticosteroid, an immunogenic
substance, a dicarboxylic acid, a disinfectant, a fungicide, a hair
growth regulator, a haptene, a hormone, a hydroxy acid, an
immunosuppressant, an immunoregulating agent, an immunomodulator,
an insecticide, an insect repellent, a keratolytic agent, a lactam,
a local anesthetic agent, a lubricating agent, a masking agent, a
metals, a metal oxide, a mitocide, a neuropeptide, a non-steroidal
anti-inflammatory agent, an oxidizing agent, a pediculicide, a
peptide, a protein, a photodynamic therapy agent, a radical
scavenger, a refatting agent, a retinoid, a sanative, a scabicide,
a self tanning agent, a skin protective agent, a skin whitening
agent, a steroid, a steroid hormone, a vasoconstrictor, a
vasodilator,a vitamin, a vitamin A, a vitamin A derivative, a
vitamin B, a vitamin B derivative, a vitamin C, a vitamin C
derivative, a vitamin D, a vitamin D derivative, a vitamin D
analog, a vitamin F, a vitamin F derivative, a vitamin K, a vitamin
K derivative, a wound healing agent and a wart remover. As is known
to one skilled in the art, in some instances a specific active
agent may have more than one activity, function or effect.
Encapsulation of an Active Agent
[0294] In one or more embodiments, the active agent is encapsulated
in particles, microparticles, nanoparticles, microcapsules,
microsphres, nanocapsules, nanospheres, liposomes, niosomes,
polymer matrix, silica-gel, graphite, nanocrystals or microsponges.
Such particles can have various functions, such as (1) protection
of the drug from degradation; (2) modification of the drug release
rate from the composition; (3) control of skin penetration profile;
and (4) mitigation of adverse effects, due to the controlled
release of the active agent from the encapsulation particles.
Solubility of an Active Agent
[0295] In an embodiment, the active agent is not fully soluble in
water or, is not fully soluble in the presence of a hydrophobic
solvent in the formulation, or is not fully soluble in the oil
phase of the emulsion. In one or more embodiments the active agent
is soluble in the composition or a phase thereof. In one or more
embodiments the active agent is insoluble in water and wherein the
active agent is solubilized the in the composition. In an
embodiment, the aprotic polar solvent is present in the composition
in an amount sufficient to solubilize the active agent in the
composition. In one or more embodiments, aprotic polar solvent acts
to improve the solubility of an active agent. In certain preferred
embodiments, the active agent to be solubilized is selected from
the group consisting of a non-steroidal anti-inflammatory agent, a
local anesthetic agent, a steroid, an immunomodulators, a
keratolytically active agent, an anti-acne agent, an anti-rosacea
agent, an antiinfective agent and an anti-psoriasis agent. In a
preferred embodiment the active agent to be solubilized is
diclofenac. In one or more embodiments a protic solvent acts to
improve solubility of an active agent. In one or more embodiments
the delivery of the active agent is improved by the aprotic solvent
and or protic solvent.
[0296] In one or more embodiments the active agent is intended for
transdermal delivery. In certain embodiments the aprotic polar
solvent in included in the composition in a concentration which is
sufficient to increase the rate of absorption of such active agent
through organic tissues including skin and nails.
Exemplary Groups of Active Agents
NSAID
[0297] In an embodiment, the active agent is a non-steroidal
anti-inflammatory agent. In the context a nonsteroidal
antiinflammatory agent (also termed herein "NSAID") is a
pharmaceutically active compound, other than a corticosteroid,
which affects the immune system in a fashion that results in a
reduction, inhibition, prevention, amelioration or prevention of an
inflammatory process and/or the symptoms of inflammation and or the
production pro-inflammatory cytokines and other pro-inflammatory
mediators, thereby treating or preventing a disease that involves
inflammation.
[0298] In one or more embodiments, the NSAID is an inhibitor of the
cyclooxygenase (COX) enzyme. Two forms of cyclooxygenase are known
today: the constitutive cyclooxygenase (COX-1); and the inducible
cyclooxygenase (COX-2), which is pro-inflammatory. Thus, in one or
more embodiments, the NSAID is selected from the group consisting
of a COX-1 inhibitor, a COX-2 inhibitor or a non-selective NSAID,
which simultaneously inhibits both COX-1 and COX-2.
[0299] In one or more embodiments, the NSAID is salicylic acid a
salicylic acid derivatives. Exemplary salicylic acid derivative
include, in a non limiting fashion, aspirin, sodium salicylate,
choline magnesium trislicylate, salsalate, diflunisal,
salicylsalicylic acid, sulfasalazine, olsalazine, esters of
salicylic acid with a carboxylic acid, esters of salicylic acid
with a dicarboxylic acid, esters of salicylic acid with a fatty
acid, esters of salicylic acid with a hydroxyl fatty acid, esters
of salicylic acid with an essential fatty acid, esters of salicylic
acid with a polycarboxylic acid, and any compound wherein salicylic
acid is linked to an organic moiety through a covalent bond.
[0300] In one or more embodiments, the NSAID is para-aminophenol
(e.g., acetaminophen) and salts and derivatives thereof.
[0301] In one or more embodiments, the NSAID is an indole or an
indole-acetic acid derivative (e.g., indomethacin, sulindac,
etodolac) and salts and derivatives thereof.
[0302] In one or more embodiments, the NSAID is an aryl acetic
acids (e.g., tolmetin, diclofenac, ketorolac) and salts and
derivatives thereof.
[0303] In one or more embodiments, the NSAID is an arylpropionic
acid and salts and derivatives thereof. Exemplary arylpropionic
acid derivative include, in a non limiting fashion, are ibuprofen,
naproxen, flubiprofen, ketoprofen, fenoprofen, oxaprozin.
[0304] In one or more embodiments, the NSAID is anthranilic acids
or an anthranilic acid derivative, also termed "fenamates" (e.g.,
mefenamic acid, meclofenamic acid) and salts and derivatives
thereof.
[0305] In one or more embodiments, the NSAID is selected from the
group of enolic acids, enolic acid salts, enolic acid esters,
amides, anhydrides and salts and derivatives thereof. Non-limiting
examples of enolic acid derivatives include oxicams (piroxicam,
tenoxicam) and pyrazolidinediones (phenylbutazone,
oxyphenthratrazone)
[0306] Yet, in additional embodiments, the NSAID is an alkanone
(e.g., nabumetone).
[0307] Selective COX-2 Inhibitors include, in an exemplary manner
diaryl-substituted furanones (e.g., Rofecoxib); diaryl-substituted
pyrazoles (e.g., Celecoxib); indole acetic acids (e.g., Etodolac);
and sulfonanilides (e.g., Nimesulide) and salts and derivatives
thereof.
[0308] In an embodiment, the aprotic polar solvent is present in
the composition in an amount sufficient to solubilize the NSAID, as
exemplified herein by the solubilization of diclofenac.
Local Anesthetic Agents
[0309] In an embodiment, the active agent is a local anesthetic
agent. Without limiting the scope of the invention, the anesthetic
agent can be selected from the group consisting of benzocaine,
lidocaine, bupivacaine, chlorprocaine, dibucaine, etidocaine,
mepivacaine, tetracaine, dyclonine, hexylcaine, procaine, cocaine,
ketamine, pramoxine, phenol, any pharmaceutically acceptable salts
thereof and mixtures of such anesthetic agents. Any mixture of
synergistically beneficial anesthetic agents is contemplated. In an
embodiment, the aprotic polar solvent is present in the composition
in an amount sufficient to solubilize the anesthetic agent.
Steroids
[0310] In an embodiment, the active agent is a steroid. In certain
embodiments the steroid is a corticosteroid, including but not
limited to, bydrocortisone, hydroxyltriamcinolone, alpha-methyl
dexamethasone, dexamethasone-phosphate, beclomethsone dipropionate,
clobetasol valemate, desonide, desoxymethasone,
desoxycorticosterone acetate, dexamethasone, dichlorisone,
diflorasone diacetate, diflucortolone valerate, fluadrenolone,
fluclorolone acetonide, fludrocortisone, flumethasone pivalate,
fluosinolone acetonide, fluocinonide, flucortine butylester,
fluocortolone, fluprednidene (fluprednylidene) acetate,
flurandrenolone, halcinonide, hydrocortisone acetate,
hydrocortisone butyrate, methylprednisolone, triamcinolone
acetonide, cortisone, cortodoxone, flucetonide, fludrocortisone,
difluorosone diacetate, fluradrenolone acetonide, medrysone,
amcinafel, amcinafide, betamethasone and the balance of its esters,
chloroprednisone, chlorprednisone acetate, clocortelone,
clescinolone, dichlorisone, difluprednate, flucloronide,
flunisolide, fluoromethalone, fluperolone, fluprednisolone,
hydrocortisone valerate, hydrocortisone cyclopentylpropionate,
hydrocortmate, mepreddisone, paramethasone, prednisolone,
prednisone, beclomethasone dipropionate, triamcinolone, as well as
analogs, derivatives, salts, ions and complexes thereof.
[0311] In certain embodiments, the steroid is a hormone or a
vitamin, as exemplified by pregnane, cholestane, ergostane,
aldosterone, androsterone, calcidiol, calciol, calcitriol,
calcipotriol, clomegestone, cholesterol, corticosterone, cortisol,
cortisone, dihydrotestosterone, ergosterol, estradiol, estriol,
estrone, ethinylestradiol, fusidic acid, lanosterol, prednisolone,
prednisone, progesterone, spironolactone, timobesone and
testosterone, as well as analogs, derivatives, salts, ions and
complexes thereof.
[0312] In an embodiment, the aprotic polar solvent is present in
the composition in an amount sufficient to solubilize the
steroid.
Keratolytically Active Agents
[0313] A keratolytic agent may be included as an active agent of a
foamable composition. The term "keratolytically active agent" as
used herein includes a compound that loosens and removes the
stratum corneum of the skin, or alters the structure of the keratin
layers of skin. Keratolytically active agents are used in the
treatment of dermatological disorders that involve dry skin,
hyperkeratinization (such as psoriasis), skin itching (such as
xerosis), acne and rosacea.
[0314] Suitable keratolytically active agents include phenol and
substituted phenolic compounds. Such compounds are known to
dissolve and loosen the intracellular matrix of the
hyperkeratinized tissue. As such, they are used in the treatment of
dermatological disorders. Dihydroxybenzene and derivatives thereof
have been recognized as potent keratolytic agents. Resorcinol
(m-dihydroxybenzene) and derivatives thereof are used in anti-acne
preparations. In addition to hydroquinone (p-dihydroxybenzene)
having anti-pigmentation properties, hydroquinone is also known to
be keratolytic. These compounds also exhibit antiseptic properties.
Cresols also possess bactericidal and keratolytic properties.
[0315] Vitamin A and vitamin A derivatives, also termed herein
"retinoids", such as retinoic acid, isoretinoic acid, retinol and
retinal are another class of keratolytically active agents.
[0316] Another group of keratolytically active agents include
alpha-hydroxy acids, such as lactic acid and glycolic acid and
their respective salts and derivatives; and beta-hydroxy acids,
such as salicylic acid (o-hydroxybenzoic acid) and salicylic acid
salts and pharmaceutically acceptable derivatives.
[0317] Another class of keratolytically active agents includes urea
and urea derivatives.
Immunomodulators
[0318] In an embodiment, the active agent is an immunomodulator.
Immunomodulators are chemically or biologically-derived agents that
modify the immune response or the functioning of the immune system.
Immunomodulators suitable for use according to the present
invention include, among other options, cyclic peptides, such as
cyclosporine, tacrolimus, tresperimus, pimecrolimus, sirolimus,
verolimus, laflunimus, laquinimod and imiquimod, as well as
analogs, derivatives, salts, ions and complexes thereof. Such
compounds, delivered in the foam, are especially advantageous in
skin disorders such as psoriasis, eczema and atopic dermatitis,
where the large skin areas are to be treated. In an embodiment, the
aprotic polar solvent is present in the composition in an amount
sufficient to solubilize the immunomodulator.
Retinoids
[0319] In an embodiment, the active agent is a retinoid. Retinoids
suitable for use according to the present invention include, among
other options, retinol, retinal, retinoic acid, isotretinoin,
tazarotene, adapalene, 13-cis-retinoic acid, acitretin all-trans
beta carotene, alpha carotene, lycopene, 9-cis-beta-carotene,
lutein and zeaxanthin, as well as analogs, derivatives, salts, ions
and complexes thereof.
Anti-Acne and Anti-Rosacea Active Agents
[0320] In an embodiment, the active agent is an anti-acne or an
anti-rosacea agent. The anti-acne agent can be selected from the
group consisting of resorcinol, sulfur, salicylic acid and
salicylates, alpha-hydroxy acids, nonsteroidal anti-inflammatory
agents, benzoyl peroxide, retinoic acid, isoretinoic acid and other
retinoid compounds, adapalene, tazarotene, azelaic acid and azelaic
acid derivatives, antibiotic agents, such as erythromycin and
clyndamycin, coal tar, zinc salts and complexes, and combinations
thereof, in a therapeutically effective concentration.
Antipsoriasis Agents
[0321] In an embodiment, the active agent is an anti-psoriasis
agent. Such anti-psoriasis agent can be selected, among other
options, from the group of keratolytically-active agents, salicylic
acid, coal tar, anthralin, corticosteroids, vitamin D and
derivatives and analogs thereof, including vitamin D3 analogs such
as calcitriol, calcipotriol; retinoids, such as tazarotene and
photodymamic therapy agents.
Antiinfective Agents
[0322] In an embodiment, the active agent is an anti-infective
agent. Such anti-infective agent can be selected from the group of
an antibiotic agent, an antibacterial agent, an antifungal agent,
an agent that controls yeast, an antiviral agent and an
antiparasitic agent. Exemplary antiinfective agents are exemplified
by beta-lactam antibiotic, an aminoglycoside, an ansa-type
antibiotic, an anthraquinone, an azole, metronidazole, an
antibiotic glycopeptide, a macrolide, erythromycin, clindamycin, an
antibiotic nucleoside, an antibiotic peptide, polymyxin B, an
antibiotic polyene, an antibiotic polyether, an antibiotic
quinolone, an antibiotic steroid, fucidic acid, mupirocin,
chloramphenicol, a sulfonamide, tetracycline, an antibiotic metal,
silver, copper, zinc, mercury, tin, lead, bismuth, cadmium,
chromium, an oxidizing agent, iodine, iodate, a periodate, a
hypochlorite, a permanganate, a substance that release free
radicals and/or active oxygen, a cationic antimicrobial agent, a
quaternary ammonium compound, a biguanide, chlorohexidine, a
triguanide, a bisbiguanide, a polymeric biguanide and a naturally
occurring antibiotic compound, as well as analogs, derivatives,
salts, ions and complexes thereof.
Aprotic Polar Solvents with Therapeutic Properties
[0323] In certain embodiments, the aprotic polar solvent possesses
therapeutic properties on its own and therefore, it can be regarded
as "active agent". For example, DMSO acts as a topical analgesic,
it reduces pain and it also reduces inflammation by several
mechanisms. It is an antioxidant--a scavenger of the free radicals
that gather at the site of injury.
[0324] Because aprotic polar solvents, such as DMSO increases the
rate of absorption of some compounds through organic tissues
including skin and nails, formulations comprising such aprotic
polar solvents can be used as a drug delivery system.
Fields of Applications
[0325] The foamable carrier is suitable for treating any inflicted
surface. In one or more embodiments, foamable carrier is suitable
for administration to the skin, a body surface, a mucosal surface
and a body cavity, e.g., the cavity and/or the mucosa of the nose,
mouth, eye, ear, respiratory system, vagina or rectum (severally
and interchangeably termed herein "target site").
[0326] By selecting a suitable active agent, or a combination of
two or more active agents, the foamable composition is useful in
treating an animal or a human patient having any one of a variety
of dermatological disorders, including dermatological pain,
dermatological inflammation, acne, acne vulgaris, inflammatory
acne, non-inflammatory acne, acne fulminans, nodular papulopustular
acne, acne conglobata, dermatitis, bacterial skin infections,
fungal skin infections, viral skin infections, parasitic skin
infections, skin neoplasia, skin neoplasms, pruritis, cellulitis,
acute lymphangitis, lymphadenitis, erysipelas, cutaneous abscesses,
necrotizing subcutaneous infections, scalded skin syndrome,
folliculitis, furuncles, hidradenitis suppurativa, carbuncles,
paronychial infections, rashes, erythrasma, impetigo, ecthyma,
yeast skin infections, warts, molluscum contagiosum, trauma or
injury to the skin, post-operative or post-surgical skin
conditions, scabies, pediculosis, creeping eruption, eczemas,
psoriasis, pityriasis rosea, lichen planus, pityriasis rubra
pilaris, edematous, erythema multiforme, erythema nodosum,
granuloma annulare, epidermal necrolysis, sunburn,
photosensitivity, pemphigus, bullous pemphigoid, dermatitis
herpetiformis, keratosis pilaris, callouses, corns, ichthyosis,
skin ulcers, ischemic necrosis, miliaria, hyperhidrosis, moles,
Kaposi's sarcoma, melanoma, malignant melanoma, basal cell
carcinoma, squamous cell carcinoma, poison ivy, poison oak, contact
dermatitis, atopic dermatitis, rosacea, purpura, moniliasis,
candidiasis, baldness, alopecia, Behcet's syndrome, cholesteatoma,
Dercum disease, ectodermal dysplasia, gustatory sweating, nail
patella syndrome, lupus, hives, hair loss, Hailey-Hailey disease,
chemical or thermal skin burns, scleroderma, aging skin, wrinkles,
sun spots, necrotizing fasciitis, necrotizing moistens, gangrene,
scarring, and vitiligo.
[0327] Likewise, the foamable composition is suitable for treating
a disorder of a body cavity or mucosal surface, e.g., the mucosa of
the nose, mouth, eye, ear, respiratory system, vagina or rectum.
Non limiting examples of such conditions include chlamydia
infection, gonorrhea infection, hepatitis B, herpes, HIV/AIDS,
human papillomavirus (HPV), genital warts, bacterial vaginosis,
candidiasis, chancroid, granuloma Inguinale, lymphogranuloma
venereum, mucopurulent cervicitis (MPC), molluscum contagiosum,
nongonococcal urethritis (NGU), trichomoniasis, vulvar disorders,
vulvodynia, vulvar pain, yeast infection, vulvar dystrophy, vulvar
intraepithelial neoplasia (VIN), contact dermatitis, pelvic
inflammation, endometritis, salpingitis, oophoritis, genital
cancer, cancer of the cervix, cancer of the vulva, cancer of the
vagina, vaginal dryness, dyspareunia, anal and rectal disease, anal
abscess/fistula, anal cancer, anal fissure, anal warts, Crohn's
disease, hemorrhoids, anal itch, pruritus ani, fecal incontinence,
constipation, polyps of the colon and rectum.
[0328] In an embodiment the composition is useful for the treatment
of an infection. In one or more embodiments, the composition is
suitable for the treatment of an infection, selected from the group
of a bacterial infection, a fungal infection, a yeast infection, a
viral infection and a parasitic infection.
[0329] In an embodiment the composition is useful for the treatment
of wound, ulcer and burn.
[0330] In an embodiment the target site is selected from the group
consisting of the skin, a body cavity, a mucosal surface, the nose,
the mouth, the eye, the ear canal, the respiratory system, the
vagina and the rectum.
[0331] The composition is also suitable for administering a hormone
to the skin or to a mucosal membrane or to a body cavity, in order
to deliver the hormone into the tissue of the target organ, in any
disorder that responds to treatment with a hormone.
[0332] In an embodiment the target site is selected from the group
consisting of the skin, a body cavity, a mucosal surface, the nose,
the mouth, the eye, the ear canal, the respiratory system, the
vagina and the rectum. In an embodiment the disorder is selected
from the group consisting of dermatological pain, dermatological
inflammation, acne, acne vulgaris, inflammatory acne,
non-inflammatory acne, acne fulminans, nodular papulopustular acne,
acne conglobata, dermatitis, bacterial skin infections, fungal skin
infections, viral skin infections, parasitic skin infections, skin
neoplasia, skin neoplasms, pruritis, cellulitis, acute
lymphangitis, lymphadenitis, erysipelas, cutaneous abscesses,
necrotizing subcutaneous infections, scalded skin syndrome,
folliculitis, furuncles, hidradenitis suppurativa, carbuncles,
paronychial infections, rashes, erythrasma, impetigo, ecthyma,
yeast skin infections, warts, molluscum contagiosum, trauma or
injury to the skin, post-operative or post-surgical skin
conditions, scabies, pediculosis, creeping eruption, eczemas,
psoriasis, pityriasis rosea, lichen planus, pityriasis rubra
pilaris, edematous, erythema multiforme, erythema nodosum,
granuloma annulare, epidermal necrolysis, sunburn,
photosensitivity, pemphigus, bullous pemphigoid, dermatitis
herpetiformis, keratosis pilaris, callouses, corns, ichthyosis,
skin ulcers, ischemic necrosis, miliaria, hyperhidrosis, moles,
Kaposi's sarcoma, melanoma, malignant melanoma, basal cell
carcinoma, squamous cell carcinoma, poison ivy, poison oak, contact
dermatitis, atopic dermatitis, rosacea, purpura, moniliasis,
candidiasis, baldness, alopecia, Behcet's syndrome, cholesteatoma,
Dercum disease, ectodermal dysplasia, gustatory sweating, nail
patella syndrome, lupus, hives, hair loss, Hailey-Hailey disease,
chemical or thermal skin burns, scleroderma, aging skin, wrinkles,
sun spots, necrotizing fasciitis, necrotizing myositis, gangrene,
scarring, and vitiligo, chlamydia infection, gonorrhea infection,
hepatitis B, herpes, HIV/AIDS, human papillomavirus (HPV), genital
warts, bacterial vaginosis, candidiasis, chancroid, granuloma
Inguinale, lymphogranuloma venereum, mucopurulent cervicitis (MPC),
molluscum contagiosum, nongonococcal urethritis (NGU),
trichomoniasis, vulvar disorders, vulvodynia, vulvar pain, yeast
infection, vulvar dystrophy, vulvar intraepithelial neoplasia
(VIN), contact dermatitis, pelvic inflammation, endometritis,
salpingitis, oophoritis, genital cancer, cancer of the cervix,
cancer of the vulva, cancer of the vagina, vaginal dryness,
dyspareunia, anal and rectal disease, anal abscess/fistula, anal
cancer, anal fissure, anal warts, Crohn's disease, hemorrhoids,
anal itch, pruritus ani, fecal incontinence, constipation, polyps
of the colon and rectum; and wherein the active agent is suitable
for treating said disorder.
[0333] In one embodiment the disorder is an inflammation, skin
inflammation, acne, rosacea, actinic keratosis, skin cancer, a
local pain, joint pain and ostheoarthritis; the active agent is a
nonsteroidal anti-inflammatory drug, given at a therapeutically
effective concentration.
[0334] In one embodiment the disorder is psoriasis; the active
agent is a vitamin D, a vitamin D derivative, a vitamin D analog, a
vitamin D3 analog (such as calcitriol and calcipotriol) given at a
concentration between about 0.0001% and about 0.02% by weight.
[0335] In one embodiment the active agent is permethrin. In a
Preferred embodiment it is at a concentration between about 1% and
about 8% by weight.
Cosmetic Use
[0336] In one or more embodiments, the aprotic polar solvent
foamable carrier may be used for cosmetic use. For example it may
be used as part of a cosmetic formulation to prevent a cosmetic
disorder or to improve the skin. Alternatively it may be used with
cosmetic effect for example as a cosmetic remover. Unexpectedly, it
has been found that foam containing aprotic solvents displays
advantages over the prior art removers. It can be dispensed in
small quantities as a foam targeted to a surface and applied
locally with mechanical force causing the foam to break. The
aprotic solvent can then solubilize the cosmetic which can then be
and removed for example using a cloth. The foam is short term
stable and avoids the mess, spills and over use of liquid aprotic
solvents.
[0337] The following examples further exemplify the aprotic polar
solvent foamable pharmaceutical carriers, pharmaceutical
compositions thereof, cosmetic carriers, cosmetic compositions
thereof, methods for preparing the same, and uses of the
compositions. The examples are for the purposes of illustration
only and are not intended to be limiting of the invention. Many
variations may be carried out by one of ordinary skill in the art
and are contemplated within the full scope disclosed herein.
[0338] In one embodiment the foamable compositions and foams are
suitable for use in treating, ameliorating, reducing or preventing
a dermatological, cosmetic or mucosal disorder. More particularly,
they are suitable for use where such disorders would otherwise be
less responsive when treated with one agent alone.
Methods/Tests
General Manufacturing Procedures
[0339] The following procedures are used to produce the foam
samples described in the examples below, in which only the steps
relevant to each formulation are performed depending on the type
and nature of ingredients used.
[0340] A) Waterless Formulations [0341] Step 1: Gelling agents, if
present, are added to the aprotic polar solvent at room temperature
under mixing until formulation homogeneity is obtained. [0342] Step
2: The mixture/solvent is warmed to about 50-60.degree. C.,
surfactants and/or foam adjuvants, if present, are added under
agitation until complete dissolution. [0343] Step 3: Hydrophobic
and/or hydrophilic solvents, if present are heated to 50-60.degree.
C. and added under mixing until formulation homogeneity is
achieved. [0344] Step 4: The mixture is cooled down to room
temperature and temperature-sensitive agents (e.g., active agents),
humectants, preservatives, pH-buffering agents or cosmetic agents,
if present, are added under mixing until dissolution. [0345] Step
5: The formulation is packaged in aerosol canisters which are
crimped with a valve, pressurized with propellant and equipped with
an actuator suitable for foam dispensing.
[0346] B) Aqueous or Water Containing Formulations [0347] Step 1:
Water is added to the aprotic polar solvent at room temperature.
Gelling agents, if present, are added to the mixture at room
temperature under mixing until formulation homogeneity is obtained.
[0348] Step 2: The mixture/aqueous solvent is warmed to about
50-60.degree. C., surfactants and/or foam adjuvants, if present,
are added under agitation until complete dissolution. [0349] Step
3: Hydrophobic and/or hydrophilic solvents, if present, are heated
to 50-60.degree. C. and added under mixing until formulation
homogeneity is achieved (to form an emulsion). [0350] Step 4: The
mixture is cooled down to room temperature and
temperature-sensitive agents (e.g., active agents), humectants,
preservatives, pH-buffering agents or cosmetic agents, if present,
are added under mixing until dissolution. [0351] Step 5: The
formulation is packaged in aerosol canisters which are crimped with
a valve, pressurized with propellant and equipped with an actuator
suitable for foam dispensing.
[0352] Materials
TABLE-US-00003 TABLE 1 Exemplary possible ingredients suitable for
the production of foamable comnpositions disclosed herein. Chemical
Name Function Commercial Name Supplier Carbomer 934P Gelling agent
Carbomer 934P Spectrum Carbomer copolymer Type A Gelling agent
Pemulen TR-2 Noveon Ceteth 2 Surfactant Brij 52 Fluka Ceteth 20
Surfactant Lipocol C20 Lipo Cetostearyl alcohol Foam adjuvant
Speziol C16-C18 Cognis Diclofenac sodium Active agent Diclofenac
sodium Sriken Dimethyl Sulfoxide Solvent Dimethyl Sulfoxide Fluka
Ethanol absolute Solvent Ethanol J. T Baker Glycerin Humectant
Glycerin Cognis Glycerol Monostearate Surfactant Cutina GMS Cognis
Hydroxypropyl cellulose Gelling agent Klucel EF Hercules
Hydroxypropyl methylcellulose Gelling agent Methocel K100M Colorcon
Dow Light Mineral Oil Solvent Light Liquid Paraffin Gadot
Minocycline HCl Active agent Minocycline HCl Hovione Paraffin Wax
Thickener; Paraffin 51-53 Merck Stabilizer PEG-100 Stearate
Surfactant Myrj 59P Uniqemqa Petrolatum, White Solvent Sofmetic LMP
MMP Poloxamer 188 Gelling agent Lutrol F68 BASF Poloxamer 407
Gelling agent Lutrol F127 BASF Polyglyceryl Oleate Surfactant
Plurol Oleique CC497 Gattefosse Polysorbate 80 Surfactant Tween 80
Croda Propane/Isobutane/Butane Propellant AP-70 Aeropress
(55:18:27) Corporation Propylene glycol Humectant Propylene Glycol
Gadot Sorbitan Monooleate Surfactant Span 80 Spectrum Sorbitan
Monostearate Surfactant Span 60 Degussa Steareth-2 Surfactant
Sympatens AS/020G Kolb Stearic Acid Foam adjuvant Edenor ST1 Cognis
Stearyl Alcohol Foam adjuvant Speziol C18 Cognis Terbinafine HCl
Active agent Terbinafine HCl Taro Urea Humectant carbamide Gadot
Xanthan Gum Gelling agent Xanthan Gum 11K CP Kelco US
Production Under Vacuum
[0353] Optionally, the foamable carrier may be produced under
nitrogen and under vacuum. Whilst the whole process can be carried
out under an oxygen free environment, it can be sufficient to apply
a vacuum after heating and mixing all the ingredients to obtain an
emulsion or homogenous liquid. Preferably the production chamber is
equipped to apply a vacuum but if not the formulation can be for
example placed in a desiccator to remove oxygen prior to filing and
crimping.
Canisters Filling and Crimping
[0354] Each aerosol canister is filled with the pre-foam
formulation ("PEE", i.e., foamable carrier) and crimped with valve
using vacuum crimping machine. The process of applying a vacuum
will cause most of the oxygen present to be eliminated. Addition of
hydrocarbon propellant may without being bound by any theory
further help to reduce the likelihood of any remaining oxygen
reacting with the active ingredient. It may do so, without being
bound by any theory, by one or more of dissolving in the oil or
hydrophobic phase of the formulation, by dissolving to a very
limited extent in the aqueous phase, by competing with some oxygen
from the formulation, by diluting out any oxygen, by a tendency of
oxygen to occupy the dead space, and by oxygen occupying part of
the space created by the vacuum being the unfilled volume of the
canister or that remaining oxygen is rendered substantially
ineffective in the formulation.
Pressurizing
[0355] Pressurizing is carried out using a hydrocarbon gas or gas
mixture. Canisters are filled and then warmed for 30 seconds in a
warm bath at 50.degree. C. and well shaken immediately
thereafter.
Tests
[0356] By way of non-limiting example stability tests are briefly
set out below as would be appreciated by a person of the art.
Collapse Time
[0357] Collapse time (CT) is examined by dispensing a given
quantity of foam and photographing sequentially its appearance with
time during incubation at 36.degree. C. It is useful for evaluating
foam products, which maintain structural stability at skin
temperature for at least 1 minute. Foams which are structurally
stable on the skin for at least one minute are termed "short term
stable" carriers or foams.
Density
[0358] In this procedure, the foam product is dispensed into
vessels (including dishes or tubes) of a known volume and weight.
Replicate measurements of the mass of foam filling the vessels are
made and the density is calculated. The canister and contents are
allowed to reach room temperature. Shake the canister to mix the
contents and dispense and discard 5-10 mL. Then dispense foam into
a pre-weighed tube, filling it until excess is extruded.
Immediately remove (level off) excess foam at both ends and weigh
the filled tube on the weighing balance.
Viscosity
[0359] Viscosity is measured with Brookfield LVDV-II+PRO with
spindle SC4-25 at ambient temperature and 10, 5 and 1 RPM.
Viscosity is usually measured at 10 RPM. However, at about the
apparent upper limit for the spindle of .about.>50,000 CP, the
viscosity at 1 RPM may be measured, although the figures are of a
higher magnitude.
Chemical Stability
[0360] The amount of active agent present is analyzed in foam
expelled from various pressurized canisters containing foam
formulations using HPLC. Analysis is carried out at zero time and
at appropriate time intervals thereafter. The canisters are stored
in controlled temperature incubators at one or more of 5 C, at 25
C, at, 40 C and at 50 C. At appropriate time intervals canisters
are removed and the amount of active agent in the foam sample is
measured.
Bubble Size
[0361] Foams are made of gas bubbles entrapped in liquid. The
bubble size and distribution reflects in the visual texture and
smoothness of the foam. Foam bubbles size is determined by
dispensing a foam sample on a glass slide, taking a picture of the
foam surface with a digital camera equipped with a macro lens. The
diameter of about 30 bubbles is measured manually relatively to
calibration standard template. Statistical parameters such as mean
bubble diameter, standard deviation and quartiles are then
determined. Measuring diameter may also be undertaken with image
analysis software. The camera used was a Nikon D40.times. Camera
(resolution 10 MP) equipped with Sigma Macro Lens (ref: APO MACRO
150 mm F2.8 EX DG HSM). Pictures obtained are cropped to keep a
squared region of 400 pixels.times.400 pixels.
Microscopic Observation
[0362] The light microscope enables observing and measuring
particles from few millimeters down to one micron. Light microscope
is limited by the visible light wavelength and therefore is useful
to measuring size of particles above 800 nanometers and practically
from 1 micron (1,000 nanometers).
[0363] When foam is examined under a microscope for the presence of
particles, crystals or agglomerates, for example, a cover slide is
carefully placed over a small foam sample and pressure is applied
to the cover causing most of the bubbles to break. Some of the foam
bubbles can sometimes still be observed in the formulations, as can
be seen in FIG. 3. The fluid under the cover slide can then be
viewed to identify whether or not there are any particles, crystals
or agglomerates.
Shakability
[0364] Shakability represents the degree to which the user is able
to feel/hear the presence of the liquid contents when the filled
pressurized canister is shaken. Shaking is with normal mild force
without vigorous shaking or excessive force. When the user cannot
sense the motion of the contents during shaking the product may be
considered to be non-shakable. This property may be of particular
importance in cases where shaking is required for affecting proper
dispersion of the contents.
Shakability Scoring:
TABLE-US-00004 [0365] Good shakability (conforms to required
quality specification) 2 Moderate shakability (conforms to required
quality specification) 1 Not shakable (fails to meet required
quality specification) but 0 may still be flowable and allow foam
formation of quality Is substantially not able to pass through
valve Block
EXAMPLES
[0366] The invention is described with reference to the following
examples. This invention is not limited to these examples and
experiments. Many variations will suggest themselves and are within
the full intended scope.
Section A--Waterless Aprotic Foamable Vehicles
Example 1--Waterless Composition Containing Dimethyl Sulfoxide
("DMSO") Alone
TABLE-US-00005 [0367] % w/w Formulation D01 Ingredients Dimethyl
Sulfoxide (DMSO) 100.0 Total 100.0 Propellant AP-70 10.0 Foam
Properties Foam Quality Poor Collapse Time (sec) 0
[0368] Comments: Formulation D01 did not give a foam, but a bubbly
liquid. DMSO alone does not have self-foaming or foam-boosting
properties. The results may also suggest a defoaming effect or role
of aprotic solvents.
Example 2--Waterless Compositions containing Dimethyl Sulfoxide and
Various Polymeric (Gelling) Agents
Part A
TABLE-US-00006 [0369] % w/w Formulations D02 D03 D04 D05 D06
Ingredients Dimethyl Sulfoxide 99.0 98.0 98.0 95.0 98.0 Xanthan Gum
1.0 -- -- -- -- Hydroxypropyl cellulose -- 2.0 -- -- -- Pemulen
TR-2 -- -- 2.0 -- -- Poloxamer 188 -- -- -- 5.0 -- Carbomer 934P --
-- -- -- 2.0 Total 100.0 100.0 100.0 100.0 100.0 Propellant AP-70
10.0 10.0 10.0 10.0 10.0 Foam Properties Foam Quality Poor Fair
Fair Fair Fair Collapse Time (sec) 0 5 30 5 0
[0370] Comments: Various different gelling agents were mixed with
DMSO. With the exception of xanthan gum, all the other polymers
dissolved in DMSO to form liquid gels prior to the addition of
propellant. Xanthan did not dissolve and remained as a powder.
Compositions D02 to D06, merely produced either bubbly liquids or
very watery foams that rapidly collapse and not of quality. The
results may also indicate a defoaming effect or role of aprotic
solvents.
Part B
TABLE-US-00007 [0371] % w/w Formulations D07 D08 Ingredients
Dimethyl Sulfoxide 99.5 99.0 Hydroxypropyl 0.5 1.0 methylcellulose
K100M Total 100.0 100.0 Propellant AP-70 10.0 10.0 Foam Properties
Foam Quality Good Good Collapse Time (sec) 30 45
[0372] Comments: Surprisingly, the addition of hydroxypropyl
methylcellulose to DMSO improves the foam quality and gave good
quality foams. In contrast hydroxypropyl cellulose without the
methyl group even with 4 times the concentration does not produce a
foam of quality with DMSO. Moreover, and increase in the
hydroxypropyl methylcellulose concentration from 0.5% to 1%
improved the foam collapse time from 30 sec to 45 sec. There is
however still is a need for a longer collapse time to improve ease
of application on the skin. In one or more embodiments the
polymeric or gelling agent is hydroxypropyl methylcellulose.
Part C
TABLE-US-00008 [0373] % w/w Formulations D22B D22C Ingredients
Dimethyl Sulfoxide 95.0 99.0 Hydroxypropyl -- 0.5 methylcellulose
K100M Parrafin 51-53 5.0 5.0 Total 100.0 100.0 Propellant AP-70
10.0 10.0 Foam Properties Foam Quality Poor Poor Collapse Time
(sec) Immediate Immediate
[0374] Comments: Whilst it was shown above in Part B that the
addition of hydroxypropyl methylcellulose to DMSO can improve foam
quality and generate good quality foam it can been seen here that
in the presence of paraffin wax hydroxypropyl methylcellulose was
ineffective and poor foam was produced.
Example 3--Waterless Compositions containing Dimethyl Sulfoxide and
Surface Active Agents
TABLE-US-00009 [0375] Physical % w/w Formulations HLB state D09 D10
D11 D12 D13 D14 D15 D16 Ingredients Dimethyl -- Liquid 97.0 97.0
97.0 97.0 97.0 97.0 97.0 94.0 Sulfoxide Tween 80 15.0 Liquid 3.0 --
-- -- -- -- -- -- Ceteth 20 15.7 Solid -- 3.0 -- -- -- -- -- 3.0
Polyglyceryl 6.0 Liquid -- -- 3.0 -- -- -- -- -- Oleate Sorbitan
4.3 Liquid -- -- -- 3.0 -- -- -- -- Monooleate Ceteth 2 5.3 Solid
-- -- -- -- 3.0 -- -- 3.0 Sorbitan 4.7 Solid -- -- -- -- -- 3.0 --
-- Monostearate Glycerol 3.8 Solid -- -- -- -- -- -- 3.0 --
Monostearate Total -- -- 100 100 100 100 100 100 100 100 Propellant
AP-70 -- Gas 10.0 10.0 10.0 10.0 10.0 10.0 10.0 10.0 Foam
Properties Foam Quality -- -- Poor Fair Poor Poor Good Good
Excellent Good Collapse Time (sec) -- -- 0 5 0 0 10 >180 >180
10
[0376] Comments: Various different non-ionic surfactants (surface
active agents) were dissolved into DMSO. As shown in formulations
D09 to D12, the addition of several surfactants of various HLB
values and physical states (solid vs. liquid) merely produced
either bubbly liquids or very watery foams that rapidly collapse
and not of quality. Formulations D13 and D16 gave good quality
foams, but they quickly collapsed and turned into bubbly liquids.
Combining linear surfactants one with a high HLB and one with a low
HLB (see D16) did not appear to result in any improvement.
Therefore, it is not obvious how to create good quality breakable
foams with random addition of surfactants.
[0377] However, very surprisingly, the addition of sorbitan
monostearate or glycerol monostearate to DMSO dramatically improved
the foam quality and good to excellent quality breakable foams were
produced, which did not collapse after 180 sec of incubation at
36.degree. C. Upon application to a target site and a simple rub of
the foams with the hand, these quality foams broke, spread evenly
over the skin and were readily absorbed into the skin. For
waterless formulations a solid surfactant with a low HLB is
preferred.
[0378] It can be noted that sorbitan monostearate and glycerol
monostearate share some common properties: both of them are solids
at room temperature; have a linear fatty acid chain; a polar head
(glycerol/sorbitan) and have an HLB value smaller that 5.0. Each
one of these properties taken alone is not sufficient to create a
good quality breakable foam, as described in formulations D09 to
D12 and D16. But without being bound by any theory it is thought
that when the properties of solid at room temperature, low HLB,
linear hydrophobic chain with a polar head are combined, they act
synergistically to create good to excellent quality breakable foams
as shown in formulations D14 and D15. In one or more embodiments
the surface active agent is a solid with a low HLB. In further
embodiments the surface active agent may include a linear
hydrophobic chain and a polar head.
Example 4--Waterless Foamable Compositions Containing Dimethyl
Sulfoxide, Surface Active Agents and Examples of Different Active
Agents
TABLE-US-00010 [0379] % w/w Formulations D17 D18 D19 Ingredients
Dimethyl Sulfoxide 92.0 96.0 96.0 Glycerol Monostearate 3.0 3.0 3.0
Diclofenac 5.0 -- -- Minocycline HCl -- 1.0 -- Terbinafine -- --
1.0 Total 100.0 100.0 100.0 Propellant AP-70 10.0 10.0 10.0 Foam
Properties Foam Quality Good Good Good Collapse Time (sec) >180
>180 >180 Presence of drug crystals None* None* None* *Whilst
the API was dissolved some very few surfactant crystals were noted.
In one or more embodiments crystals are eliminated or substantially
eliminated. By way of non limiting example a co-solvent or a
co-surfactant may be added to dissolve the crystals or the amount
of agent may be reduced to an optimal level where the crystals
dissolve.
[0380] Comments: Several active pharmaceutical agents ("API") were
dissolved into stock formulation D15 described above, containing
DMSO and glycerol monostearate. As shown in formulations D17 to
D19, the addition of various drugs gave good quality breakable
foams which did not collapse after 180 sec of incubation at
36.degree. C. Moreover, microscopic observation of foam samples
revealed the API's were dissolved in these formulations. It follows
that the API bioavailability should be improved if dissolved since
the DMSO can then aid penetration
Example 5--Waterless Compositions containing Dimethyl Sulfoxide and
Combinations of Foam Adjuvants, Polymeric With and Without Surface
Active Agents
[0381] Part A--With Surface Active Agents
TABLE-US-00011 % w/w Formulations D26 D23 D24 D25 D15 D55
Ingredients Dimethyl 94.0 94.0 93.5 96.5 97 Sulfoxide Dimethyl --
-- -- -- -- 97 Formamide Stearyl Alcohol 3.0 3.0 3.0 -- -- --
Glycerol -- 3.0 3.0 3.0 3.0 3.0 Monostearate Tween 80 3.0 -- -- --
-- -- Hydroxypropyl -- -- 0.5 0.5 -- -- methylcellulose K100M Total
100.0 100.0 100.0 100.0 100.0 100.0 Propellant AP-70 10.0 10.0 10.0
10.0 10.0 10.0 Foam Properties Foam Quality Good Good Good Good
Excellent Poor Collapse Time 10 >180 >180 >180 >180 0
(sec)
[0382] Comments: A foam adjuvant (stearyl alcohol) was dissolved
into DMSO and used with a surfactant Tween. Although the
formulation produced a good quality foam it collapsed almost
immediately. As shown in Formulation D26, the random combination of
a foam adjuvant and a surfactant does not achieve satisfactory
results in terms of foam quality and stability, showing the need
for an appropriate selection of the foam stabilizing components as
taught in this disclosure. Replacing Tween with glycerol
monostearate produced quality foam with a collapse time of more
than three minutes. In the presence of glycerol monostearate the
addition of a foam adjuvant or a gelling agent produced no
significant change in the measured parameters. Thus, formulations
D23, D24 and D25 describe combinations of two or more stabilizing
components appropriately selected from the group consisting of a
surfactant; a foam adjuvant and a gelling agent that gave good
quality breakable foams that did not collapse after 180 sec at
36.degree. C.
[0383] There are advantages to combine one or both of foam
adjuvants and gelling agents with surfactants, as this can inter
alia bring; a higher formulation viscosity and structure which is
suitable for formulations which are to contain a suspension of
non-dissolved active agents and thus provide a more homogeneous API
suspension; an improved foaming; a more stable emulsion; greater
stability when the propellant is added into the formulation,
although adding an inappropriate combination or too high viscosity
can lead to destabilization on addition of propellant such that
successful combinations and the amounts are non obvious in order to
achieve a foam of quality and a stable foamable formulation.
Moreover, achieving a specific type of foam and foam properties is
certainly non obvious. Nevertheless, in one or more embodiments the
combination of foam adjuvants and gelling agents with surfactants
may enable a decrease in the surfactant concentration without any
degradation of the foam properties. Such a decrease in surfactant
concentration can be desirable in topical applications, as lower
levels can avoid or minimize potential irritation, particularly if
the formulations are to be used on sensitive targets such as wounds
or body cavities. Moreover, such combinations have been
unexpectedly observed to produce surprising synergetic effects.
[0384] Formulation D55 containing Dimethylformamide in contrast to
what was surprisingly observed with DMSO fails to give a foam of
acceptable quality, showing that not all aprotic polar solvents are
suitable to be used at high concentrations in combination with
glyceryl monostearate.
[0385] Part B--Without Surface Active Agents
TABLE-US-00012 % w/w Formulations D20 D21 D07 D22 Ingredients
Dimethyl Sulfoxide 97.0 97.0 99.5 96.5 Stearyl Alcohol -- 3.0 --
3.0 Stearic Acid 3.0 -- -- -- Hydroxypropyl -- -- 0.5 0.5
methylcellulose K100M Total 100.0 100.0 100.0 100.0 Propellant
AP-70 10.0 10.0 10.0 10.0 Foam Properties Foam Quality Poor Good
Good Good Collapse Time (sec) 0 10 30 120
[0386] A foam adjuvant was dissolved in DMSO instead of a
surfactant. As seen from formulations D20 and D21, the addition of
stearic acid to DMSO gave a bubbly liquid whereas the addition of
stearyl alcohol gave a good quality foam but that collapsed almost
immediately after 10 sec.
[0387] Interestingly, both stearyl alcohol and hydroxypropyl
methylcellulose when used separately with DMSO give good quality
foams that quickly collapse, after 10 and 30 sec respectively, as
seen in formulations D21 and D07. But very surprisingly, when these
two components are combined with DMSO, they act synergistically to
produce a good quality foam with a substantially improved collapse
time of 120 seconds as seen in formulation D22.
[0388] In one or more embodiments there is provided a
surfactant-free foam formulation comprising DMSO, and fatty
alcohols and polymeric agents. In one or more alternative
embodiments there is provided a surfactant-free foam formulation
comprising DMSO, and fatty alcohols essentially free of polymeric
agents. In one or more other embodiments there is provided a
surfactant-free foam formulation comprising DMSO and polymeric
agents essentially free of fatty alcohols.
Example 6--Comparison of Waterless Foamable Vehicle Compositions
Containing DMSO and Urea/Ethanol/Lipophilic Compound with a Control
Formulation Containing Water and a Classic Emulsion Foam
Formulation
Part A--DMSO Formulations
TABLE-US-00013 [0389] % w/w % w/w % w/w % w/w Formulation D27 D50
D52 D51 Ingredients Dimethyl Sulfoxide 45.0 45.0 45.0 45.0 Glycerin
(humectant) 15.0 15.0 15.0 15.0 Propylene glycol 15.0 15.0 15.0
15.0 (humectant) Ethanol 20.0 -- -- -- Urea -- 20.0 -- --
Petrolatum -- -- 20.0 -- Water -- -- -- 20.0 Cetostearyl alcohol
1.5 1.5 1.5 1.5 Steareth-2 2.0 2.0 2.0 2.0 Hydroxypropyl 1.5 1.5
1.5 1.5 cellulose EF Total 100.0 100.0 100.0 100.0 Propellant AP-70
8.0 8.0 8.0 8.0 Foam properties Foam Quality Good to Good Good Good
Excellent Shakability Good Good Good Good Density NM 0.034 0.097
0.063 Collapse NM >180 180 >180 Any after taste NM No Very
Slight Yes Any Breath odour NM No Very Slight Yes NM = Not
Measured
[0390] Comments: Formulations D27 is an example of a waterless foam
of good to excellent quality containing 45% DMSO, Ethanol,
humectants, a foam adjuvant, a low HLB solid surfactant and a
gelling agent. It can be noted that the addition of about 20% of
ethanol did not appear to affect the foam stability or quality.
[0391] A preliminary study was run with formulations D50, D51 and
D52 to determine whether any formulations can prevent the known
side effect of or after taste and breath odor after use of DMSO.
These DMSO side effects were observed to be suppressed when urea is
added to the formulation (see D50), are unexpectedly greatly
reduced in case of petrolatum (see D52), but are still present when
water is added to the formulation (see D51). Thus, in one or more
embodiments, there are provided DMSO formulations that are useful
in reducing after taste and breath odor side effects.
[0392] Comments: All the formulations D50, D51, D52, produced good
to excellent quality foam with low density and good collapse time.
To determine which formulations would be compatible and suitable
for use with human skin and their hydration effect, if any, double
blind corneometer studies were carried out to determine the
skin-hydration effect of the formulations.
Part B--Manufacturing Procedure
[0393] Formulation D50: [0394] 1) Add Hydroxypropyl cellulose EF to
water at room temperature while mixing to "Gel". [0395] 2) Heat to
50-60.degree. C. and add Cetostearyl alcohol and Steareth-2 while
mixing to dissolution. [0396] 3) Add slowly Glycerin anhydrous and
Propylene glycol while mixing to homogeneity. [0397] 4) Cool to RT
and add slowly Urea while mixing to homogeneity. [0398] 5) Complete
water if necessary to 100%
Formulation D51:
[0398] [0399] 1) 2) 3) and 5) as above; 4) Cool to room temperature
and add slowly water while mixing to homogeneity.
Formulation D52:
[0399] [0400] 1) 2) 3) and 5) as above; 4) Cool to room temperature
and add slowly Petrolatum while mixing to homogeneity.
Formulation D27:
[0400] [0401] 1) 2) 3) and 5) as above; 4) Cool to room temperature
and add slowly Ethanol while mixing to homogeneity.
Part C--Corneometer Study
[0402] Comparison of Formulations D50, D51, D52 with DMSO and a
Classic Emollient tested for skin hydration.
TABLE-US-00014 Classic Emollient % w/w Isopropyl myristate 6.00
Glycerol monostearate 0.50 PEG-40 stearate 3.00 Stearyl alcohol
1.00 Xanthan gum 0.30 Methocel K100M 0.30 Polysorbate 80 1.00 Water
81.30 Preservative 0.60 Total 100.00 Propellant AP70 8.00
[0403] Skin hydration is measured using a Corneometer.RTM. CM 825
instrument. (Courage+Khazaka, Koln, Germany). The measuring
principle of the Corneometer.RTM. CM 825 is based on capacitance
measurement of dielectric medium. Any change in the dielectric
constant due to skin surface hydration alters the capacitance of a
measuring capacitor. It is capable of detecting even slight changes
in the skin hydration level.
[0404] Study Flow chart is shown below:
TABLE-US-00015 STUDY ACTIVITY Baseline* 4 hours Inclusion/exclusion
criteria X Application of the test preparations X Assessment of
skin hydration X Assessment of tolerability X parameters and
Adverse Events
[0405] Skin hydration level is assessed at baseline with the
Corneometer.RTM. CM 825. The formulations are applied in designated
chambers under occlusion for 4 hours which are then removed and the
skin cleaned. Hydration is then measured.
[0406] Study protocol: The study was performed in a temperature
controlled room (20-24.degree. C.). Subjects washed their arms with
water (no soap) and dried their arms with dry paper towel.
Formulations were applied using test chambers. The location of each
chamber within the stripe was marked once applied (maximum of 6
stripes on each arm). Each stripe contained only one formulation.
One stripe served as a control, non treated area. Formulations,
control products and control non treated areas were randomly
assigned to the treatment sites according to a randomization list,
provided by the study statistician. The application array was
unknown to the study operator and subjects. An amount of
approximately 4 mg (40 ul) of each of the study formulations was
applied on the treatment sites as described by the randomization
list. Skin hydration level was assessed at baseline T=0 (minimum 15
minutes following rinse), using the Corneometer.RTM. CM 825, and
tested based on study design.
[0407] Healthy subjects were applied with single dose of
formulations D50, D51, and D52 as shown in Part A above and the
emollient formulation herein. As shown in FIG. 1 and FIG. 2, quite
unexpectedly the formulations with DMSO have a substantial
moisturizing effect when compared with the control and with the
Classic Emollient. No significant difference can be seen from the
addition of Urea, Petrolatum and Water to the DMSO based
formulations. It can be appreciated that the moisturizing effect
does not come from urea, petrolatum or water since the effect is
closely similar in all three cases. This is completely surprising
since DMSO is known for its quick penetration. Also very
surprisingly, is the discovery that waterless DMSO formulations D50
and D52 have a substantial moisturizing effect despite the lack of
water and additionally they can ameliorate against after taste and
breath odor side effects. Thus, in one or more embodiments there
are provided DMSO formulations that are useful in improving skin
hydration.
Part D--Aprotic-Alcoholic Formulations with 0% 20% and 40% Ethanol
and Foam Properties
TABLE-US-00016 % w/w % w/w % w/w Formulation D50 D27 D101
Ingredients Dimethyl Sulfoxide 45.00 45.00 45.00 Glycerin
(humectant) 15.00 15.00 -- Propylene glycol (humectant) 15.00 15.00
6.50 Ethanol 0.00 20.00 40.00 Urea 20.00 -- -- Cetostearyl alcohol
1.50 1.50 3.00 Steareth-2 2.00 2.00 4.00 Hydroxypropyl cellulose EF
1.50 1.50 1.50 Total 100.00 100.00 100.00 Propellant AP-70 8.00
8.00 8.00 Foam properties Foam Quality Good Good to Poor Excellent
Shakability Good Good Good Collapse Time at 36.degree. C. (sec)
>180 NM* Immediate *NM: Not Measured
[0408] Comments: Formulations D27, D50 and D101 were prepared
according to the General Manufacturing Procedures described in the
Method/Test section. As can be seen from the above Table
Formulations D27 D50,which are waterless formulations containing up
to 20% ethanol provide good to excellent quality breakable foams.
However, when the ethanol content reaches 40% of the formulation, a
clear defoaming effect is observed and no quality foam was
produced, unlike as in formulation D101. The aprotic alcoholic
defoaming effect was observed in the presence of surfactant so it
follows that in the absence of surfactant the defoaming effect may
be of the same order or more pronounced. So in one or more
embodiments the level of short chain alcohols, such as, ethanol, is
about or less than about 35%, is about or less than about 30%; is
about or less than about 25%, is about or is less than about 20%,
is about or is less than about 15%, is about or is less than about
10%, is about or is less than about 5%.
Example 7--Waterless Foamable Vehicle Compositions Containing DMSO
and a Hydrophobic Solvent
TABLE-US-00017 [0409] % w/w Formulations D28 D29 D30 Ingredients
Dimethyl Sulfoxide 77.0 73.5 69.0 Stearyl Alcohol -- 3.0 5.0
Glycerol Monostearate 3.0 3.0 5.0 Hydroxypropyl -- 0.5 1.0
methylcellulose K100M Light Mineral Oil 20.0 20.0 20.0 Total 100.0
100.0 100.0 Propellant AP-70 10.0 10.0 10.0 Foam Properties Foam
Quality Fairly Good Good Good Collapse Time (sec) 90 150
>180
[0410] Comments: A hydrophobic solvent was added into a mixture of
DMSO and glyceryl monostearate. As shown in formulation D28, the
addition of mineral oil to DMSO gave a fairly good quality foam
that collapsed after 90 sec. In comparison with example D15
(containing DMSO and glyceryl monostearate only), it can be seen
that the addition of a hydrophobic solvent has a defoaming
effect.
[0411] Formulations D29 and D30 show that, when sufficient amounts
of a foam adjuvant and a gelling agent are further added to the
components of formulation D28, good quality breakable foam that did
not collapse after 180 sec can be produced. Thus, in the presence
of a hydrophobic solvent the inclusion of additional foam
stabilizers to the surfactant substantially improves collapse
time.
[0412] FIG. 3 depicts a microscopic observation of formulation D30
where droplets can been seen, showing that mineral oil and dimethyl
sulfoxide form an emulsion in the presence of a surface active
agent. Dimethyl sulfoxide is immiscible with hydrophobic solvents.
Thus, it will form a waterless emulsion with hydrophobic solvents
with surfactant. Having a hydrophobic solvent present can add to
the sensory feeling and help to maintain skin moisture and oil.
Although DMSO can aid penetration of other ingredients into the
skin and mucosal membrane because DMSO is not miscible per se with
hydrophobic solvents it leads to another useful property and
advantage; namely that for topical and mucosal body cavity use,
where the formulations are to be repeatedly applied and left on the
skin or within the body cavity DMSO should not lead to stripping of
the skin or mucosal membrane of oils.
Section B--Aqueous or Water Containing Aprotic Formulations
Example 8--Compositions Containing 45% Dimethyl Sulfoxide, Water
and Surface Active Agents
TABLE-US-00018 [0413] Physical % w/w Formulations HLB state D32 D33
D34 D35 D36 Ingredients Dimethyl -- Liquid 45.0 45.0 45.0 45.0 75.0
Sulfoxide Water -- Liquid 52.0 52.0 52.0 52.0 20.0 Tween 80 15.0
Liquid 3.0 -- -- -- -- Ceteth 20 15.7 Solid -- 3.0 -- -- -- PEG-100
18.8 Solid -- -- -- -- 5.0 Stearate Sorbitan 4.3 Liquid -- -- 3.0
-- -- Monooleate Glycerol 3.8 Solid -- -- -- 3.0 -- Monostearate
Total -- -- 100.0 100.0 100.0 100.0 100.0 Propellant AP-70 -- Gas
10.0 10.0 10.0 10.0 8.0 Foam Properties Foam Quality -- --
Excellent Excellent Fairly Fair Fairly Good Good Collapse Time
(sec) -- -- 90 75 45 20 not measured
[0414] Comments: Various different surfactants were dissolved into
a mixture of DMSO and water. As shown in formulation D34 and D35,
the addition of solid or liquid surfactants of HLB value smaller
than 5 does not give satisfying foams, but either bubbly liquids or
very watery foams that rapidly collapse. This is in contrast to
what was observed with waterless formulations where low HLB solid
surfactants with a linear fatty acid and a more polar head were
preferred. Glycerol monostearate which produces excellent waterless
quality foams with DMSO is rendered ineffective here by the
addition of water. Further, as seen in formulation D36, the
addition of PEG-100 Stearate, a solid surfactant with a high HLB
value of 18.8 produced a very watery foam. Thus, making quality
foams containing both water and dimethyl sulfoxide is not obvious
considering was has been learned above in the production of
waterless DMSO foams.
[0415] However, surprisingly, the addition of liquid or solid
surfactants of HLB value close to 15 such as Tween 80 and Ceteth 20
to the water/DMSO mixture dramatically improves the foam quality.
Moreover, this was achieved without the addition of polymer to
stabilize the foam. As shown in formulations D32 and D33, excellent
quality breakable foams were produced, that did not collapse after
75 to 90 seconds of incubation at 36.degree. C. Upon application to
a target site and a simple rub of the foams with the hand, the
foams broke, spread evenly over the skin and were readily absorbed
into the skin. Without being bound by any theory it may be that the
range of surfactants which can be applied successfully in aqueous
or water containing DMSO formulations is much wider than available
for waterless formulations.
Example 9--Compositions Containing from 25% to 75% DMSO
Part A--Formulation Containing Ssurfactants
TABLE-US-00019 [0416] % w/w Formulations D36 D38 D37 D39
Ingredients Dimethyl Sulfoxide 75.0 75.0 25.0 75.0 Water 20.0 20.0
70.0 20.0 Poloxamer 188 -- 5.0 3.0 3.0 PEG-100 Stearate 5.0 -- 2.0
2.0 Total 100.0 100.0 100.0 100.0 Propellant AP-70 8.0 8.0 8.0 8.0
-- Foam Properties Foam Quality Fairly Good Fairly Good Good
Good
[0417] Comments: Formulations D36 and D38 each of which contained
only one foam stabilizing component (PEG-100 Stearate and Poloxamer
respectively) provided only fairly good foam quality. However,
formulations D37 and D39, which contain at least two foam
stabilizing components (Cetostearyl alcohol+Poloxamer 407+Methocel
K100M; or Poloxamer 188+PEG 100-Stearate) provided good to
excellent foam quality. It is interesting to note that PEG-100
Stearate alone and Poloxamer alone fail to produce foams of good
quality even at 5% by weight (see formulations D36 and D38).
However, when these two components are combined, they surprisingly
act synergistically to provide stable and breakable foams of good
quality. Thus in one or more embodiments the aprotic foamable
compositions comprise a synergistic combination of surface active
agent and a polamer with surface active agent like properties, such
as PEG 100 Stearate and Poloxamer.
Part B--Formulations Without Surfactant
TABLE-US-00020 [0418] % w/w Formulation D103 Ingredients Dimethyl
Sulfoxide 76.60 Water 20.00 Stearyl alcohol 3.00 Methocel K100M
0.40 Total 100.00 Propellant AP-70 8.00 Foam properties Foam
Quality Good Shakability Good Collapse Time at 36.degree. C. (sec)
90
[0419] Comments: Formulation D103 was prepared according to the
General Manufacturing Procedures described in the Method/Test
section. This formulation is an example of an aqueous vehicle
containing very high amounts of DMSO, some water, a fatty alcohol,
a polymeric agent but no surfactant. Surprisingly, and despite the
absence of surfactant and the high aprotic solvent level, a
breakable foam of good quality was obtained which did not collapse
for 90 seconds at 36.degree. C.
[0420] In one or more embodiments, there is provided a
surfactant-free foam formulation comprising DMSO, water, fatty
alcohols and polymeric agents which provides a breakable foam of
good quality. In one or more alternative embodiments there is
provided a a surfactant-free foam formulation comprising DMSO,
water, and fatty alcohols essentially free of polymeric agents. In
one or more other embodiments there is provided a surfactant-free
foam formulation comprising DMSO, water, and polymeric agents
essentially free of fatty alcohols.
Example 10--Compositions Containing from 19% to 45% DMSO With and
Without Diclofenac as an Active Agent ("API")
Part A--With and Without API
TABLE-US-00021 [0421] % w/w D40 D42 Formulations (Placebo) D40 D41
(Placebo) D42 D43 Ingredients DMSO 45.00 45.00 45.50 45.50 45.50
45.50 Water 30.50 29.00 17.90 18.10 19.60 17.90 Glycerin 7.00 7.00
10.70 10.80 10.80 10.70 Propylene glycol 5.00 5.00 10.70 10.80
10.80 10.70 Ethanol 10.00 10.00 11.20 11.30 11.30 11.20 Cetostearyl
alcohol 1.00 1.00 1.00 0.80 0.80 1.10 Poloxamer 407 1.00 1.00 1.00
-- -- -- Hydroxypropyl 0.50 0.50 0.50 0.40 0.40 0.50
methylcellulose K100M PEG 100-Stearate -- -- -- 0.80 0.80 0.90
Diclofenac - sodium -- 1.50 1.50 -- 1.50 1.50 Total 100.00 100.00
100.00 100.00 100.00 100.00 Propellant AP-70 8.00 8.00 8.00 8.00
8.00 8.00 Foam Properties Foam Quality Excellent Excellent Good to
Good Good Good to Excellent Excellent Collapse Time (sec) >180
>180 >180 >180 >180 >180 Presence of drug Placebo No
No Placebo No No crystals
[0422] Comments: Formulations D40 to D43 are examples of foam
vehicles with and without an active agent, containing 45% of DMSO,
water, humectants, gelling agents, a foam adjuvant and/or
surfactants. Formulations which contain at least two foam
stabilizing components provided breakable foams of good to
excellent quality that did not collapse after 180 sec at 36.degree.
C.
[0423] It can be noted that the addition of about 10% of ethanol
did not appear to affect the foam stability or quality. It can also
be noted that the addition of an active agent did not appear to
affect foam quality and stability, and that all these compositions
fully dissolve diclofenac sodium. Accordingly, the penetration of
the dissolved API should be facilitated by the aprotic solvent DMSO
to provide good bioavailability.
Part B--DMSO Carrier Formulation Without Polymer
TABLE-US-00022 [0424] w/w % Formulations D100 Ingredients DMSO
45.00 Water 20.00 Ethanol 10.00 Glycerin 10.00 Propylene Glycol
10.00 Cetostearyl alcohol 1.25 Polysorbate 80 1.25 Ceteth-2 1.25
PEG-100 Stearate 1.25 Total 100.00 Propellant AP-70 10.00 Foam
Properties Foam Quality Excellent Shakability Good Collapse Time
(sec) >180
[0425] Comments: Formulation D100 was prepared according to the
General Manufacturing Procedures described in the Method/Test
section. This formulation is an example of a foam vehicle without
polymer containing 45% of DMSO, water, humectant, a foam adjuvant
and surfactants that can generate excellent quality foam that did
not collapse after 180 sec at 36.degree. C. The presence of about
10% of ethanol did not appear to affect the foam quality or the
collapse time.
Part C
[0426] A sample of formulation D40 above was tested for additional
physical parameters and the results are provided below:
TABLE-US-00023 Viscosity of the pre-foam formulation (cPs) 146
Density of the foam (g/ml) 0.066 Foam pH (diluted 1:5 with water)
6.01 Mean Bubble Size (micrometers) 69
[0427] Comments: Formulation D44 is an example of a foam vehicle
containing 19% of DMSO, 50% of water, a hydrophobic solvent, a
gelling agent, a foam adjuvant and a surfactant. It can be seen
that formulations containing a protic polar solvent, an aprotic
polar solvent, an apolar solvent and a suitable combination of foam
stabilizing agents, can provide breakable foams of good to
excellent quality that do not collapse after 180 sec.
Part D--Emulsion with Hydrophobic Solvent
TABLE-US-00024 w/w % w/w % w/w % D44 D53 D54 Formulations (Placebo)
(Placebo) (Placebo) Ingredients DMSO 19.00 45.00 45.00 Water 50.00
29.00 35.00 Light Mineral Oil 20.00 15.00 15.00 Stearyl Alcohol
5.00 5.00 -- Hydroxypropyl 1.00 1.00 -- methylcellulose K100M
Glycerol monostearate 5.00 5.00 5.00 Total 100.00 100.00 100.00
Propellant AP-70 10.00 10.00 10.00 Foam Properties Foam Quality
Good Good Good Collapse Time (sec) >180 >180 >180 Foam
Density -- 0.166 0.213
[0428] Comments: All the formulations provide quality foams with
satisfactory collapse times. Surprisingly, there is no apparent
change in quality or collapse on removal of the foam adjuvant and
polymer but the density is unexpectedly less when they are present.
Without being bound to any theory, it may be that foam adjuvants
and/or polymeric agents can enable a better propellant dissolution
within the pressurized formulation, and so an improved expansion
upon foam dispensing.
Part E--Without Surfactant
[0429] See Example 9, Part B from which it was unexpectedly
observed that a surfactant-free foam formulation comprising DMSO,
water, fatty alcohols and polymeric agents provides a breakable
foam of good quality.
Part F--Manufacture:
[0430] Formulation D53: [0431] 1) Mix DMSO and water, Add Methocel
K100M at room temperature and mix until gel formation. [0432] 2)
Heat to 50-60.degree. C., add stearyl alcohol and glycerol
monostearate and mix until dissolution. [0433] 3) Add slowly light
mineral oil and mix until homogeneity is obtained. [0434] 4) Cool
to room temperature and complete water if necessary to 100% [0435]
Formulation D54: [0436] 1) Mix DMSO and Water. [0437] 2) Heat to
50-60.degree. C. and add glycerol monostearate while mixing to
dissolution. [0438] 3) & 4) As above.
Example 11--Foamable Vehicle Compositions Containing 45% of Aprotic
Solvent
Part A--Various Other Examples of Aprotic Solvents
TABLE-US-00025 [0439] % w/w Formulations D45 D46 D47 Ingredients
Acetone 45.00 -- -- Acetonitrile -- 45.00 -- DMF -- -- 45.00 Water
30.50 30.50 30.50 Glycerin 7.00 7.00 7.00 Propylene glycol 5.00
5.00 5.00 Ethanol 10.00 10.00 10.00 Cetostearyl alcohol 1.00 1.00
1.00 Poloxamer 407 1.00 1.00 1.00 Hydroxypropyl 0.50 0.50 0.50
methylcellulose K100M Total 100.00 100.00 100.00 Propellant AP-70
8.00 8.00 8.00 Foam Properties Foam Quality Good Good Excellent
Colapse Time (sec) >180 120 >180
[0440] Comments: Formulations D45 to D47 are examples of foam
vehicles containing 45% of a polar aprotic sovent, ethanol, water,
humectants, gelling agents and a foam adjuvant. The polar aprotic
sovents used comprise acetone, acetonitrile and dimethyl formamide.
The three formulations provided breakable foams of good to
excellent quality that did not collapse after 120 to 180 sec at
36.degree. C., showing that the present invention includes a range
of polar aprotic solvents. It can be noted that the addition of
about 10% of ethanol did not appear to affect the foam stability or
quality.
Part B--Aprotic-Hydroalcoholic Formulations with 10%; 11.3% and 40%
Alcohol
TABLE-US-00026 % w/w % w/w % w/w D40 D42 D102 Formulations
(Placebo) (Placebo) (Placebo) DMSO 45.00 45.50 30.00 Water 30.50
18.10 15.00 Glycerin 7.00 10.80 -- Propylene glycol 5.00 10.80 6.50
Ethanol 10.00 11.30 40.00 Cetostearyl alcohol 1.00 0.80 3.00
Poloxamer 407 1.00 -- -- Hydroxypropyl 0.50 0.40 -- methylcellulose
K100M PEG 100-Stearate -- 0.80 -- Steareth-2 -- -- 4.00
Hydroxypropyl -- -- 1.50 cellulose EF Total 100.00 100.00 100.00
Propellant AP-70 8.00 8.00 8.00 Foam Properties Foam Quality
Excellent Good Excellent Colapse Time (sec) >180 >180 60
[0441] Comments: Formulations D40, D42 and D102 were prepared
according to the General Manufacturing Procedures described in the
Method/Test section. All these aprotic-aqueous formulations
produced a foam of quality. Formulation D102 is an example of
aqueous foam containing 30% DMSO, a humectant, a fatty alcohol, a
polymer and a surfactant, with a high ethanol content of 40% which
surprisingly generated a foam of excellent quality. Due to the high
ethanol content of D102, the collapse time is shorter than in
formulations D40 and D42, but remains essentially satisfactory. In
complete contrast, as can be seen in Example 6 Part D, a similar
non-aqueous formulation with 40% alcohol did not produce a foam.
Thus, it follows that Aprotic--hydroalcoholic formulations are more
resilient than their non-aqueous counterparts and that the presence
of a relatively small amount of water aids in the quality and or
stabilization of the resultant foam.
Section C--Usability Testing
Example 12--Comparative Tolerability and Acceptability Study of a
Waterless Foam DMSO Composition vs. Aqueous Foam DMSO
Composition
[0442] A panel of three testers was asked to apply on their hand an
aqueous DMSO foam preparation and a waterless DMSO foam
preparation. The waterless formulation was D15 (see Example 3
above) and the aqueous formulation was D33 (see Example 8
above).
[0443] Each was asked to describe their feelings about the ease of
application, skin feeling and penetrability of each of the
products.
[0444] Both formulations were described as having a good appearance
and an excellent ease of application and penetration speed into the
skin upon slight rubbing. Testers added that the aqueous
formulation has a very slight greasy feeling on skin, and the
waterless formulation has a slight greasy feeling on skin. In both
cases, the greasy feeling disappeared after 10 to 20 seconds.
Testers did not report any after-taste or bad breath after
application. It may be a further unexpected advantage of DMSO foams
that such side effects are absent or ameliorated due to the low
density of the foam--allowing small amounts to be spread over a
target area--and or due to the composition of formulation.
Section D--Packaging Compatibility
Part A--Background
[0445] Aprotic solvents, such as, DMSO have outstanding solvent
properties, being able to dissolve a wide range of organic and
inorganic compounds, including plastics, resins and alloys used in
fabrication of canisters and valve parts. Therefore, packaging
components for holding and delivering such solvents canreadily
corrode and/or deteriorate especially when high concentrations are
present in the compositions, as disclosed in the present foam
formulations.
[0446] Aerosol packaging is primarily composed of a coated
canister, a valve, an actuator and optionally a dip-tube. The
components being in prolonged contact with the formulations are
mainly the canister internal coating and valve parts (cup and
housing). In the following study the compatibility of various
packaging components with highly concentrated DMSO solution was
assessed in the absence of propellant.
Part B--Procedure
[0447] The tested packaging components are incubated in contact
with a solution of DMSO in water (50:50 w/w) during up to six
months at 50.degree. C. At the desired time-points, the packaging
components are removed from the incubators, canisters are opened
and a visual observation is performed to determine the presence
deterioration, corrosion, peeling, scratches, etc that may result
from the prolonged contact with the DMSO solution.
Part C--Compatibility Results
[0448] An aluminum canister with a polyimide amide (PAM) internal
coating was filled with a solution of DMSO in water (50:50 w/w),
crimped with an epoxy coated valve having a dip-tube and incubated
at 50.degree. C.
TABLE-US-00027 Incubation Canister conditions coating Valve cup
Valve housing Dip-tube 1 M 50.degree. C. no change no change slight
change in color no change 2 M 50.degree. C. no change no change
color became pale no change yellow 3 M 50.degree. C. no change no
change color became pale no change yellow 6 M 50.degree. C. no
change no change color became yellow no change
[0449] Surprisingly, no canister deterioration was observed, even
after 6 months at 50.degree. C. No corrosion or deterioration was
observed in the valve cup and in the dip-tube. Only a minor change
in color of the valve housing was observed, which is acceptable and
not considered as deterioration.
[0450] However, a canister with an internal coating made of phenol
epoxy and containing formulation D22 showed signs of corrosion
after 6 months at room temperature. The valve cup and housing
though was of epoxy type and did not show any sign of corrosion.
There was no diptube in this canister. So over time during storage
canisters, for example, with phenol epoxy coatings can display
corrosion and deterioration.
[0451] In one or more embodiments, there is provided a kit
comprising an aerosol canister, a valve, an actuator, optionally a
dip-tube, and a DMSO foam formulation, wherein the packaging
components are compatible with a formulation containing DMSO, and
wherein essentially no corrosion or deterioration is observed. In
one or more embodiments the canisters are essentially free of
corrosion and or deterioration for 1 month, or 2 months or for 3
months or for 6 months or for 12 months or for 18 months or for 24
months at room temperature. In one or more further embodiments the
canisters are essentially free of corrosion and or deterioration
for 1 month, or for 2 months, or for 3 months, or for 6 months, or
for 12 months, or for 18 months, or for 24 months at 40.degree. C.
In one or more further embodiments the canisters are essentially
free of corrosion and or deterioration for 1 month, or 2 months or
for 3 months, or for 6 months, or for 12 months, or for 18 months,
or for 24 months at 50.degree. C. In one or more other embodiments
any corrosion and or deterioration observed was not of
significance. In one or more embodiments any corrosion and or
deterioration observed in the canisters was not of significance for
1 month, or for 2 months, or for 3 months, or for 6 months, or for
12 months, or for 18 months, or for 24 months at room temperature.
In one or more further embodiments any corrosion and or
deterioration observed in the canisters was not of significance for
1 month, or for 2 months, or for 3 months, or for 6 months, or for
12 months, or for 18 months, or for 24 months at 40.degree. C. In
one or more further embodiments any corrosion and or deterioration
observed in the canisters was not of significance for 1 month, or
for 2 months, or for 3 months, or for 6 months, or for 12 months,
or for 18 months, or for 24 months at 50.degree. C. Part D--Can in
Can
[0452] Background: A bag in can can be used in three basic ways
with propellant, namely, a) with the propellant not in the bag and
being separate from the formulation in the bag; b) with propellant
present in the formulation in the bag only; c) with propellant both
in the bag and outside of the bag. In case a) without surfactant
the formulation is likely to exit as a gel or fluid. In cases b)
and c) the formulation can foam. The propellant outside the bag is
to expel the contents of the bag. The propellant within the
formulation in the bag is to generate foam. When the formulation is
primarily expelled by propellant outside the bag then the amount of
propellant in the formulation can influence foam properties, such
as, density.
[0453] An aluminum can-in-can canister with a phenol epoxy internal
coating was filled with a solution of DMSO in water (50:50 w/w),
crimped with an epoxy coated valve without dip-tube and incubated
for one month at 50.degree. C.
[0454] After opening of the canister, no corrosion or deterioration
was observed neither on the canister internal coating, nor on the
different valve parts.
[0455] In one or more embodiments, there is provided a kit
comprising a can-in-can aerosol canister, a valve, an actuator,
optionally a dip-tube, and a DMSO foam formulation, wherein the
packaging components are compatible with a formulation containing
DMSO, and wherein no corrosion or deterioration is observed. In one
or more embodiments the canisters are essentially free of corrosion
and or deterioration for 1 month, or 2 months or for 3 months or
for 6 months or for 12 months or for 18 months or for 24 months at
room temperature. In one or more further embodiments the canisters
are essentially free of corrosion and or deterioration for 1 month,
or for 2 months, or for 3 months, or for 6 months, or for 12
months, or for 18 months, or for 24 months at 40.degree. C. In one
or more further embodiments the canisters are essentially free of
corrosion and or deterioration for 1 month, or 2 months or for 3
months, or for 6 months, or for 12 months, or for 18 months, or for
24 months at 50.degree. C. In one or more other embodiments any
corrosion and or deterioration observed was not of significance. In
one or more embodiments any corrosion and or deterioration observed
in the canisters was not of significance for 1 month, or for 2
months, or for 3 months, or for 6 months, or for 12 months, or for
18 months, or for 24 months at room temperature. In one or more
further embodiments any corrosion and or deterioration observed in
the canisters was not of significance for 1 month, or for 2 months,
or for 3 months, or for 6 months, or for 12 months, or for 18
months, or for 24 months at 40.degree. C. In one or more further
embodiments any corrosion and or deterioration observed in the
canisters was not of significance for 1 month, or for 2 months, or
for 3 months, or for 6 months, or for 12 months, or for 18 months,
or for 24 months at 50.degree. C.
* * * * *