U.S. patent application number 15/464657 was filed with the patent office on 2017-12-07 for foamable vehicle and pharmaceutical compositions thereof.
The applicant listed for this patent is Foamix Pharmaceuticals Ltd.. Invention is credited to Alex Besonov, Meir Eini, Doron Friedman, Dov Tamarkin.
Application Number | 20170348418 15/464657 |
Document ID | / |
Family ID | 46324440 |
Filed Date | 2017-12-07 |
United States Patent
Application |
20170348418 |
Kind Code |
A1 |
Tamarkin; Dov ; et
al. |
December 7, 2017 |
Foamable Vehicle and Pharmaceutical Compositions Thereof
Abstract
A hygroscopic pharmaceutical composition includes at least one
hygroscopic substance at a concentration sufficient to provide an
Aw value of at least 0.9 and an antiinfective agent. A foamble
pharmaceutical carrier includes about 50% to about 98% of a polar
solvent selected from the group consisting of a polyol and PEG; 0%
to about 48% of a secondary polar solvent; about 0.2% to about 5%
by weight of a surface-active agent; about 0.01% to about 5% by
weight of at least one polymeric agent; and a liquefied or
compressed gas propellant at a concentration of about 3% to about
25% by weight of the total composition.
Inventors: |
Tamarkin; Dov; (Maccabim,
IL) ; Friedman; Doron; (Karmei Yosef, IL) ;
Eini; Meir; (Ness Ziona, IL) ; Besonov; Alex;
(Rehovot, IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Foamix Pharmaceuticals Ltd. |
Rehovot |
|
IL |
|
|
Family ID: |
46324440 |
Appl. No.: |
15/464657 |
Filed: |
March 21, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13793893 |
Mar 11, 2013 |
9636405 |
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15464657 |
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13708284 |
Dec 7, 2012 |
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13793893 |
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12767511 |
Apr 26, 2010 |
8362091 |
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13708284 |
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11430599 |
May 9, 2006 |
7704518 |
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12767511 |
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10835505 |
Apr 28, 2004 |
7820145 |
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11430599 |
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60679020 |
May 9, 2005 |
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60784793 |
Mar 21, 2006 |
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60530015 |
Dec 16, 2003 |
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60492385 |
Aug 4, 2003 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 8/046 20130101;
A61P 17/04 20180101; A61P 31/10 20180101; A61P 31/12 20180101; A61K
9/0034 20130101; A61Q 19/00 20130101; A61K 9/0014 20130101; A61K
47/38 20130101; A61P 17/02 20180101; A61K 47/10 20130101; A01N
53/00 20130101; A01N 25/16 20130101; A61P 35/00 20180101; A61K
47/14 20130101; A01N 25/16 20130101; A61K 9/12 20130101; A61P 31/04
20180101; A61P 23/02 20180101; A61K 9/122 20130101; A61P 33/00
20180101; Y10S 514/945 20130101; A61P 17/12 20180101; A61P 17/06
20180101 |
International
Class: |
A61K 47/10 20060101
A61K047/10; A61Q 19/00 20060101 A61Q019/00; A61K 8/04 20060101
A61K008/04; A61K 47/14 20060101 A61K047/14; A01N 25/16 20060101
A01N025/16; A61K 9/00 20060101 A61K009/00; A61K 9/12 20060101
A61K009/12; A61K 47/38 20060101 A61K047/38 |
Claims
1.-21. (canceled)
22. A hygroscopic composition comprising: a diol; a water gelling
agent in an amount ranging from about 0.1% to about 5% by weight;
and an antibiotic agent in an amount ranging from about 0.1% to
about 5% by weight, wherein the composition is suitable for topical
administration, and wherein the hygroscopic composition has an Aw
value of less than about 0.9.
23. The hygroscopic composition of claim 22, wherein the diol
comprises propylene glycol.
24. The hygroscopic composition of claim 22, wherein the antibiotic
agent comprises a tetracycline antibiotic or a derivative, ester,
salt, or a mixture thereof
25. The hygroscopic composition of claim 24, wherein the
tetracycline antibiotic agent comprises minocycline or a
derivative, ester, salt, or a mixture thereof.
26. The hygroscopic composition of claim 25, wherein the
minocycline is minocycline hydrochloride.
27. The hygroscopic composition of claim 24, further comprising an
antibiotic metal.
28. The hygroscopic composition of claim 24, further comprising an
active herbal extract.
29. The hygroscopic composition of claim 28, wherein the active
herbal extract is from eucalyptus.
30. The hygroscopic composition of claim 24, wherein the water
gelling agent comprises hydroxypropyl cellulose.
31. The hygroscopic composition of claim 24, further comprising one
or more additional components.
32. The hygroscopic composition of claim 31, wherein the one or
more additional components comprises at least one preservative.
33. The hygroscopic composition of claim 32, wherein the
preservative comprises a bisulfite.
34. The hygroscopic composition of claim 31, wherein the one or
more additional components comprises a skin penetration
enhancer.
35. The hygroscopic composition of claim 31, wherein the one or
more additional components comprises a fragrance.
36. The hygroscopic composition of claim 31, wherein the one or
more additional components comprises a protectant.
37. The hygroscopic composition according to claim 24, further
comprising an essential oil.
38. The hygroscopic composition of claim 24, further comprising a
surface active agent in an amount ranging from about 0.2% to about
5% by weight.
39. The hygroscopic composition of claim 24, further comprising a
liquefied or compressed gas propellant in an aerosol container in
an amount ranging from about 3% to about 25% by weight of the total
composition, wherein upon release from the container, a foam
suitable for topical administration is formed.
40. The hygroscopic composition of claim 24, further comprising
less than about 5% ethanol.
41. The hygroscopic composition according to claim 24, wherein: the
diol is propylene glycol; the water gelling agent is hydroxypropyl
cellulose; and the tetracycline antibiotic is minocycline
hydrochloride.
42. The hygroscopic composition according to claim 41, further
comprising: at least one preservative; a skin penetration enhancer;
a fragrance; and a protectant.
43. The hygroscopic composition according to claim 41, further
comprising: at least one preservative; a skin penetration enhancer;
a fragrance; and a metal.
44. The hygroscopic composition according to claim 41, further
comprising: at least one preservative; a fragrance; and a
metal.
45. The hygroscopic composition of claim 24, wherein the Aw value
ranges from about 0.8 to about 0.9.
46. The hygroscopic composition according to claim 24, wherein the
Aw value ranges from about 0.7 to about 0.8.
47. The hygroscopic composition according to claim 24, wherein the
Aw value is less than about 0.7.
48. A hygroscopic composition comprising: a diol; a water gelling
agent in an amount ranging from about 0.1% to about 5% by weight;
and an antibiotic agent in an amount ranging from about 0.1% to
about 5% by weight, wherein the composition is suitable for topical
administration, wherein the composition does not contain a
surface-active agent, and wherein the hygroscopic composition
comprises less than about 2% water.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 13/708,284, filed on Dec. 7, 2012, which is a
continuation of U.S. patent application Ser. No. 12/767,511, filed
on Apr. 26, 2010, which is a continuation of and claims the benefit
of priority under 35 U.S.C. .sctn.120 to U.S. patent application
Ser. No. 11/430,599, filed on May 9, 2006, now U.S. Pat. No.
7,704,518, which claims the benefit under 35 U.S.C. .sctn.119(e) of
U.S. Provisional Patent Application No. 60/679,020, filed on May 9,
2005, and of U.S. Provisional Patent Application No. 60/784,793,
filed on Mar. 21, 2006, and which is a continuation-in-part
application of co-pending U.S. patent application Ser. No.
10/835,505, filed on Apr. 28, 2004, now U.S. Pat. No. 7,820,145,
which claims the benefit of priority under 35 U.S.C. .sctn.119(e)
to U.S. Patent Application Ser. No. 60/530,015, filed on Dec. 16,
2003, and U.S. Patent Application Ser. No. 60/492,385, filed on
Aug. 4, 2003, all of which are hereby incorporated in their
entirety by reference.
BACKGROUND OF THE INVENTION
[0002] This invention relates to foamable pharmaceutical and
cosmetic compositions.
[0003] External topical administration is an important route for
the administration of drugs in disease treatment. 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 hydrophobic media, namely ointment.
However, ointments often form an impermeable barrier, so that
metabolic products and excreta from the wounds to which they are
applied are not easily removed or drained away. Furthermore, it is
difficult for the active drug dissolved in the carrier to pass
through the white petrolatum barrier layer into the wound tissue,
so the efficacy of the drug is reduced. In addition, ointments and
creams often do not create an environment for promoting respiration
of the wound tissue and it is not favorable to the normal
respiration of the skin. An additional disadvantage of petroleum
jelly-based products relates to the greasy feeling left following
their topical application onto the skin, mucosal membranes and
wounds.
[0004] Foams and, in particular, foams that are substantially based
on non-aqueous solvents are complicated systems which do not form
under all circumstances. US Pat. Appl. No. 20050031547 relates to
stable oleaginous cosmetic or therapeutic foam compositions
containing certain active agents, having unique therapeutic
properties and methods of treatment using such compositions. The
foamable carrier includes at least one solvent selected from a
hydrophobic solvent, a silicone oil, an emollient, a co-solvent,
and mixtures thereof, wherein the solvent is present at a
concentration of about 70% to about 96.5% by weight of the total
composition, at least a non-ionic surface-active agent at a
concentration of about 0.1% to less than about 0%/o by weight of
the total composition; at least one gelling agent at a
concentration of about 0.1% to about 5% by weight of the total
composition; a therapeutically effective amount of at least one
active agent; and at least one liquefied or compressed gas
propellant, at a concentration of about 3% to about 25% by weight
of the total composition.
[0005] WO 00/09082 teaches an anhydrous cleansing composition for
topical application to human skin, comprising an ionic surfactant,
glycerine, propylene glycol and water insoluble benefit agents.
According to the examples of WO 00/09082, the concentration of the
ionic surfactant is in the range of 18-22%.
[0006] U.S. Pat. No. 6,765,001 comprises a composition, method of
enhancing potency and method of delivering corticosteroids in a
vehicle comprising two or more penetration enhancers selected from
the group consisting of diisopropyl adipate, dimethyl isosorbide,
propylene glycol, 1,2,6-hexapetriol, and benzyl alcohol; and one or
more of the group consisting of solvents and emulsifiers.
[0007] WO91/11991 teaches an essentially non-aqueous and non-oily
foamable composition, that can be used for rectal administration of
pharmaceuticals, comprising a liquid polar polyol or polyol
mixture, a pharmaceutically active ingredient and at least one foam
stabilizing and emulsifying surfactant. However, this foam
composition is associated with disadvantages and the purposes of
the present invention are not attained (see comparative example
below).
[0008] There remains an unmet need for improved, easy to use,
stable and non-irritating anti-infective foam formulations,
intended for treatment of dermal and mucosal tissues. Particularly,
there remains an unmet need for improved, easy to use, stable and
non-irritating anti-infective foam formulations, with unique
therapeutic properties.
SUMMARY OF THE INVENTION
[0009] In one aspect, the invention provides a hygroscopic
pharmaceutical composition including at least one hygroscopic
substance at a sufficient concentration to provide an Aw value of
the hygroscopic pharmaceutical composition of less than 0.9 and an
anti-infective agent; or the Aw value is in the range of about 0.8
and about 0.9; (2) about 0.7 and about 0.8; and (3) less than about
0.7
[0010] In one or more embodiments, the hygroscopic pharmaceutical
composition further includes at least one component, selected from
the group consisting of about 0.01% to about 5% by weight of at
least one polymeric agent selected from a bioadhesive agent, a
gelling agent, a film forming agent and a phase change agent; and
about 0.2% to about 5% by weight of a surface-active agent.
[0011] In one or more embodiments, the hygroscopic substance is
selected from the group consisting of polyethylene glycols (PEGs),
surfactants comprising PEG, polyols, monosaccharides,
disaccharides, oligosaccharides and sugar alcohols in an amount to
provide hygroscopic properties, and honey.
[0012] In another aspect, the invention provides a foamble
pharmaceutical carrier including about 50% to about 98% of a polar
solvent selected from the group consisting of (1) a polyol and (2)
a polyethylene glycol (PEG); 0% to about 48% of a secondary polar
solvent; about 0.2% to about 5% by weight of a surface-active
agent; about 0.01% to about 5% by weight of at least one polymeric
agent; and a liquefied or compressed gas propellant at a
concentration of about 3% to about 25% by weight of the total
composition.
[0013] In one or more embodiments, the compositions further
comprise up to 10% of water.
[0014] In one or more embodiments, the composition is substantially
non-aqueous and/or substantially alcohol-free.
[0015] In one or more embodiments, the composition further
comprises a therapeutically effective concentration of one or more
active agents.
[0016] In one or more embodiments, the polyol is selected from the
group consisting of a diol, a triol and a saccharide, and the triol
may be selected from the group consisting of glycerin,
butane-1,2,3-triol, butane-1,2,4-triol and hexane-1,2,6-triol, or
the diol is selected from the group consisting of propylene glycol,
butanediol, butenediol, butynediol, pentanediol, hexanediol,
octanediol, neopentyl glycol, 2-methyl-1,3-propanediol, diethylene
glycol, triethylene glycol, tetraethylene glycol, dipropylene
glycol and dibutylene glycol.
[0017] In one or more embodiments, the polyol consists of at least
one diol and at least one triol, and wherein the ratio between the
diol and triol is between 9:1 and 1:1.
[0018] In one or more embodiments, the composition includes a
mixture of at least one polyol and at least one PEG, and the PEG
may be selected from the group consisting of PEG 200, PEG 300, PEG
400, PEG 600, PEG 1000, PEG 4000, PEG 6000 and PEG 8000, or the
composition contains one or more PEGs in a concentration to provide
viscosity of less than 12,000 CPs.
[0019] In one or more embodiments, the composition includes a
secondary polar solvent selected from the group consisting of
dimethyl isosorbide, tetrahydrofurfuryl alcohol polyethyleneglycol,
ether, DMSO, a pyrrolidone, N-Methyl-2-pyrrolidone,
1-Methyl-2-pyrrolidinone, ethyl proxitol, dimethylacetamide, a
PEG-type surfactant, an alpha hydroxy acid, lactic acid and
glycolic acid, or the secondary polar solvent is dimethyl
isosorbide.
[0020] In one or more embodiments, the composition includes (1) at
least one polar solvent selected from a diol, a triol and PEG, and
(2) at least one secondary polar solvent, and for example, the
polar solvent comprises a mixture of at least one polyol and at
least one PEG, and for example, the polyol comprises a mixture of
at least two polyols.
[0021] In one or more embodiments, the ratio between the polyol
and/or PEG and the secondary polar solvent is between 9:1 and
1:1.
[0022] In another aspect of the invention, a method of treating a
disorder of mammalian subject includes administering a foamable
therapeutic composition to a target area, the composition
comprising a therapeutically effective concentration of an active
agent, about 50% to about 98% of a polar solvent selected from the
group consisting of (1) a polyol; and (2) a polyethylene glycol; 0%
to about 48% of a secondary polar solvent; about 0.2% to about 5%
by weight of a surface-active agent; about 0.01% to about 5% by
weight of at least one polymeric agent; and a liquefied or
compressed gas propellant at a concentration of about 3% to about
25% by weight of the total composition.
[0023] In one or more embodiments, 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.
BRIEF DESCRIPTION OF THE DRAWINGS
[0024] Various objects, features, and advantages of the present
invention can be more fully appreciated with reference to the
following detailed description of the invention when considered in
connection with the following drawings, in which like reference
numerals identify like elements. The following drawings are for the
purpose of illustration only and are not intended to be limiting of
the invention, the scope of which is set forth in the claims that
follow.
[0025] FIG. 1A-D illustrates the in vitro effect of effect of
Composition A, consisting of 2% terbinafine, 95.3% gr. polyethylene
glycol, 0.5% hydroxypropyl cellulose and 2.2% steareth-2, in
comparison with Composition B (an oil in water emulsion containing
2% terbinafine) and Composition C a commercial 1% bifonazole cream,
in the treatment of three fungal strains (microsporum canis,
trichophyton mentagrophytes and trichophyton rubrum) and one yeast
(candida albicans).
DETAILED DESCRIPTION OF THE INVENTION
[0026] The present invention relates to a composition for use as
foamable vehicle composition.
[0027] According to one or more embodiments of the present
invention, the foamable carrier, includes: [0028] a. about 50% to
about 98% of a polar solvent selected from the group consisting of
(1) a polyol; and (2) a polyethylene glycol; [0029] b. 0% to about
48% of a secondary polar solvent; [0030] c. about 0.2% to about 5%
by weight of a surface-active agent; [0031] d. about 0.01% to about
5% by weight of at least one polymeric agent; and [0032] e. a
liquefied or compressed gas propellant at a concentration of about
3% to about 25% by weight of the total composition. All % values
are provided on a weight (w/w) basis.
[0033] Water, up to 25% of the composition, and more preferably up
to 10%, and optional ingredients are added to complete the total
mass to 100%. In certain cases, the composition contains two active
agents that require different pH environments in order to remain
stable. For example, corticosteroids are typically stable at acidic
pH (they have a maximum stability at a pH of about 4-6) and vitamin
D analogues are typically stable at basic pH (they have a maximum
stability at pH values above about 8). In other cases, the active
agent degrades in the presence of water, and therefore, in such
cases the present of water in the composition is not desirable.
Thus, in certain preferred embodiments, the composition is
substantially non-aqueous. The term "substantially non-aqueous" is
intended to indicate that the composition has a water content below
about 5%, preferably below about 2%, such as below about 1.5%.
[0034] Upon release from an aerosol container, the foamable carrier
forms an expanded foam suitable for the treatment of an infected
surface and for topical administration to the skin, a body surface,
a body cavity or a mucosal surface.
[0035] The identification of a "polar solvent", as used herein, is
not intended to characterize the solubilization capabilities of the
solvent for any specific active agent or any other component of the
foamable composition. Rather, such information is provided to aid
in the identification of materials suitable for use as a part in
the foamable compositions described herein.
Polyol
[0036] In an embodiment of the present invention, the polar solvent
is a polyol. A polyol is an organic substance that contains at
least two hydroxy groups in its molecular structure.
[0037] In one or more embodiments, the foamable carrier contains at
least one diol (a compound that contains two hydroxy groups in its
molecular structure). Examples of diols include propylene glycol
(e.g., 1,2-propylene glycol and 1,3-propylene glycol), butanediol
(e.g., 1,2-butanediol, 1,3-butanediol, 2,3-butanediol and
1,4-butanediol), butanediol (e.g., 1,3-butanediol and
1,4-butenediol), butynediol, pentanediol (e.g., pentane-1,2-diol,
pentane-1,3-diol, pentane-1,4-diol, pentane-1,5-diol,
pentane-2,3-diol and pentane-2,4-diol), hexanediol (e.g.,
hexane-1,6-diol hexane-2,3-diol and hexane-2,56-diol), octanediol
(e.g., 1,8-octanediol), neopentyl glycol, 2-methyl-1,3-propanediol,
diethylene glycol, triethylene glycol, tetraethylene glycol,
dipropylene glycol and dibutylene glycol.
[0038] In one or more embodiments, the foamable carrier contains at
least one triol (a compound that contains three hydroxy groups in
its molecular structure), such as glycerin, butane-1,2,3-triol,
butane-1,2,4-triol and hexane-1,2,6-triol.
[0039] In one or more embodiments, the polyol is a mixture of
polyols. In one or more embodiments, the mixture of polyols
contains at least one diol and at least one triol. According to
certain embodiments the ratio between the diol and triol is between
9:1 and 1:1.
[0040] In one or more embodiments, part of mixture of polyols is a
saccharide. Exemplary saccharides include, but are not limited to
monosaccharide, disaccharides, oligosaccharides and sugar
alcohols.
[0041] A monosaccharide is a simple sugar that cannot be hydrolysed
to smaller units. Empirical formula is (CH2O)n and range in size
from trioses (n=3) to heptoses (n=7). Exemplary monosaccharide
compounds are ribose, glucose, fructose and galactose.
[0042] Disaccharides are made up of two monosaccharides joined
together, such as sucrose, maltose and lactose.
[0043] A sugar alcohol (also known as a polyol, polyhydric alcohol,
or polyalcohol) is a hydrogenated form of saccharide, whose
carbonyl group (aldehyde or ketone, reducing sugar) has been
reduced to a primary or secondary hydroxyl group. They are commonly
used for replacing sucrose in foodstuffs, often in combination with
high intensity artificial sweeteners to counter the low sweetness.
Some exemplary sugar alcohols, which are suitable for use according
to the present invention are mannitol, sorbitol, xylitol, maltitol,
lactitol. (Maltitol and lactitol are not completely hydrogenated
compounds--they are a monosaccharide combined with a polyhydric
alcohol). Mixtures of polyols, including (1) at least one polyol
selected from a diol and a triol; and (2) a saccharide are
contemplated within the scope of the present invention.
Polyethylene Glycol
[0044] In an embodiment of the present invention, the polar solvent
consists of a polymerized ethylene glycol, namely polyethylene
glycol, which is also termed "PEG". Exemplary PEGs are provided in
the following table.
TABLE-US-00001 Composition Av. Molecular weight Appearance Melting
point (.degree. C.) PEG 200 190~210 Oily liquid PEG 300 285~315
Oily liquid PEG 400 380~420 Oily liquid PEG 600 570~630 Oily liquid
17~22 PEG 1000 950~1050 Solid 35~40 PEG 4000 3800~4400 Solid 53~58
PEG 6000 5600~6400 Solid 55~60 PEG 8000 7500~8500 Solid 58~65
[0045] Thus, in an embodiment of the present invention, the PEG is
selected from the group consisting of PEG 200, PEG 300, PEG 400,
PEG 600, PEG 1000, PEG 4000, PEG 6000 and PEG 8000. The foamable
carrier according to the present invention can contain a single PEG
or a mixture of two or more PEGs. PEGs having molecular weight of
more that about 1000 possess gelling properties; i.e., they
increase the viscosity of a composition. Therefore, by combining
PEGs with different molecular weights/melting points, one can
attain varying levels of flowability as desirable for the treatment
of a given target site. The concentration of the PEG should be in a
level that results in viscosity, prior to filling of the
composition into aerosol canisters, of less than 12,000 CPs, and
more preferably, less than 10,000 CPs.
Secondary Polar Solvent
[0046] Optionally, a secondary polar solvent is added to the
foamable composition of the present invention. The secondary polar
solvent is selected from a variety of organic solvents that are
typically miscible on both water and oil. Examples of polar solvent
that can be contained in the foamable carrier of the present
invention include dimethyl isosorbide, tetrahydrofurfuryl alcohol
polyethyleneglycol ether (glycofurol), DMSO, pyrrolidones, (such as
N-Methyl-2-pyrrolidone and 1-Methyl-2-pyrrolidinone), ethyl
proxitol, dimethylacetamide (DMAc), PEG-type surfactants and alpha
hydroxy acids, such as lactic acid and glycolic acid.
Solubilization and Penetration Enhancement
[0047] In many cases, polyols, PEGs and polar solvents possess a
high solubilizing power and thus, they can enable increased
concentrations of a pharmaceutical active agent. Polyols, PEGs and
polar solvents are also known for their skin penetration
enhancement properties. These properties enable high drug
bioavailability in the target area of treatment, resulting in an
enhanced therapeutic effect. Occasionally, combinations of a
polyol, PEGs and a secondary polar solvent, exhibit an increased
permeability across the skin, as suggested, for example, in Eur J
Pharm Biopharm. 1998 November; 46(3):265-71.
[0048] Thus, in one or more embodiments, the foamable carrier
contains (1) at least one polar solvent, selected from a polyol
(selected from a diol and a triol) and PEG; and (2) at least one
secondary polar solvent.
[0049] In one or more embodiments, the foamable carrier contains
(1) a mixture of at least two polyols; and (2) at least one
secondary polar solvent. In additional embodiments, the foamable
carrier contains a mixture of at least one polyol and at least one
PEG; yet in other embodiments the foamable carrier contains (1) a
mixture of at least one polyol and at least one PEG and (2) at
least one secondary polar solvent.
[0050] According to certain embodiments the ratio between the
polyol and/or PEG and the secondary polar solvent is between 9:1
and 1:1.
[0051] In certain embodiments, the polyol is selected from the
group consisting of propylene glycol, hexylene glycol and glycerin
(and mixtures thereof); and the secondary polar solvent is selected
from the group consisting of dimethyl isosorbide, diethylene glycol
monoethyl ether, a liquid polyethylene glycol and glycofurol.
[0052] In certain embodiments, the foamable carrier contains (1) at
least one polyol; and (2) dimethyl isosorbide.
[0053] Short chain alcohols, such as ethanol and propanol are known
as polar solvents, however, according to one or more embodiments,
the composition of the present invention 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 polar solvents due to their
skin-irritating effect.
[0054] Thus, in certain embodiments, 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%. However, in other embodiments,
a short chain alcohol can be included in the composition, as long
as the ratio between the short chain alcohol and the polyol is less
than 1:4 by weight.
Polymeric Agent
[0055] The composition of the present invention contains a
polymeric agent. It has been documented that the presence of a
polymeric agent is necessary for 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. Preferably, the polymeric agent is soluble or readily
dispersible in the polyol; or in the mixture of a polyol and an
additional polar solvent.
[0056] Non-limiting examples of polymeric agents that are soluble
or readily dispersible in propylene glycol are
Hydroxypropylcellulose and 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.
[0057] Other polymeric agents are suitable for use according to the
present invention provided that they are soluble or readily
dispersible in the polyol; or in the mixture of a polyol and an
additional polar solvent, on a case by case basis.
[0058] 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.
[0059] 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.
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 while they are considered herein as "secondary polar
solvents", as detailed herein, they are also considered polymeric
agents.
[0060] Mixtures of the above polymeric agents are contemplated.
[0061] The concentration of the polymeric agent should be selected
so that the composition, after filling into aerosol canisters, 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 12,000 CPs, and
more preferably, less than 10,000 CPs.
Surface-Active Agent
[0062] The composition of the present invention further contains a
surface-active agent. Surface-active agents (also termed
"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. Lipophilic emulsifiers form water-in-oil
(w/o) emulsions; hydrophilic surfactants form oil-in-water (o/w)
emulsions. 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).
[0063] According to one or more embodiments the composition
contains a single surface active agent having an HLB value between
about 7 and 12, or more than one surface active agent and the
weighted average of their HLB values is between about 7 and about
12.
[0064] Preferably, the composition of the present invention
contains a non-ionic surfactant. Nonlimiting examples of possible
non-ionic surfactants include polysorbates, such as polyoxyethylene
(20) sorbitan monostearate (Tween 60) and poly(oxyethylene) (20)
sorbitan monooleate (Tween 80); poly(oxyethylene) (POE) fatty acid
esters, such as Myrj 45, Myrj 49, Myrj 52 and Myrj 59;
poly(oxyethylene) alkylyl ethers, such as poly(oxyethylene) cetyl
ether, poly(oxyethylene) palmityl ether, polyethylene oxide
hexadecyl ether, polyethylene glycol cetyl ether, brij 38, brij 52,
brij 56 and brij W1; sucrose esters, partial esters of sorbitol and
its anhydrides, such as sorbitan monolaurate and sorbitan
monolaurate; mono or diglycerides, isoceteth-20, and mono-, di- and
tri-esters of sucrose with fatty acids (sucrose esters).
[0065] Non-limiting examples of non-ionic surfactants that have HLB
of about 7 to about 12 include PEG 100 stearate (HLB=11), Laureth 4
(HLB=9.7) and cetomacrogol ether (e.g., polyethylene glycol 1000
monocetyl ether).
[0066] Yet, in additional embodiments, the composition contains a
single surface active agent or a combination of surface active
agents having an HLB values between about 9 and about 14; and in
other embodiments, the composition contains one or more surface
active agents, having an HLB value between about 2 and about 9.
[0067] In certain cases, the surface active agent is selected from
the group of cationic, zwitterionic, amphoteric and ampholytic
surfactants, such as sodium methyl cocoyl taurate, sodium methyl
oleoyl taurate, sodium lauryl sulfate, triethanolamine lauryl
sulfate and betaines.
[0068] In one or more embodiments of the present invention, 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 provide foams of excellent quality, i.e. a score
of "E" according to the grading scale discussed herein below.
[0069] Thus, in a preferred embodiment, the surface active agent,
the composition contains a non-ionic surfactant, or a mixture of
non-ionic surfactants as the sole surface active agent. Yet, in
additional embodiments, the foamable composition includes a mixture
of at least one non-ionic surfactant and at least one ionic
surfactant in a ratio in the range of about 100:1 to 6:1. 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. The concentration of the surface active agent
is between about 0.1% and about 5%.
Hydrophobic Solvent
[0070] Optionally, the foamable carrier further contains at least
one hydrophobic solvent. The identification of a "hydrophobic
solvent", as used herein, is not intended to characterize the
solubilization capabilities of the solvent for any specific active
agent or any other component of the foamable composition. Rather,
such information is provided to aid in the identification of
materials suitable for use as a part in the foamable compositions
described herein.
[0071] A "hydrophobic solvent" as used herein refers to a material
having solubility in distilled water at ambient temperature of less
than about 1 gm per 100 mL, more preferable less than about 0.5 gm
per 100 mL, and most preferably less than about 0.1 gm per 100
mL.
[0072] In one or more embodiments, the hydrophobic organic carrier
is an oil, such as mineral oil, isopropyl palmitate, isopropyl
isostearate, diisopropyl adipate, diisopropyl dimerate, maleated
soybean oil, 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, propylene glycol ricinoleate, isopropyl lanolate,
pentaerythrityl tetrastearate, neopentylglycol
dicaprylate/dicaprate, isononyl isononanoate, isotridecyl
isononanoate, myristyl myristate, triisocetyl citrate, octyl
dodecanol, 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
siloxanes, polyaryl siloxanes, polyalkylaryl siloxanes and
polyether siloxane copolymers, polydimethylsiloxanes (dimethicones)
and poly(dimethylsiloxane)-(diphenyl-siloxane) copolymers.
Foam Adjuvant
[0073] Optionally, a foam adjuvant is included in the foamable
carriers of the present invention to increase the foaming capacity
of surfactants and/or to stabilize the foam. In one or more
embodiments of the present invention, the foam adjuvant agent
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). Fatty alcohols,
derived from beeswax and including a mixture of alcohols, a
majority of which has at least 20 carbon atoms in their carbon
chain, are especially well suited as foam adjuvant agents. The
amount of the fatty alcohol required to support the foam system is
inversely related to the length of its carbon chains. Foam
adjuvants, as defined herein are also useful in facilitating
improved spreadability and absorption of the composition.
[0074] In one or more embodiments of the present invention, the
foam adjuvant agent 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.
[0075] 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 agent 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.
Additional Components
[0076] In an embodiment of the present invention, a composition of
the present invention includes one or more additional components.
Such additional components include but are not limited to anti
perspirants, anti-static agents, buffering agents, bulking agents,
chelating agents, cleansers, colorants, conditioners, deodorants,
diluents, dyes, emollients, fragrances, hair conditioners,
humectants, 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 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.
[0077] In an embodiment of the present invention, the additional
component is a pH adjusting agent or a buffering agent. Suitable
buffering agents include but are not limited to acetic acid, adipic
acid, calcium hydroxide, citric acid, glycine, hydrochloric acid,
lactic acid, magnesium aluminometasilicates, phosphoric acid,
sodium carbonate, sodium citrate, sodium hydroxide, sorbic acid,
succinic acid, tartaric acid, and derivatives, salts and mixtures
thereof.
[0078] In an embodiment of the present invention, the additional
component is an emollient. Suitable emollients include but are not
limited to mineral oil, lanolin oil, coconut oil, cocoa butter,
olive oil, aloe vera extract, jojoba oil, castor oil, fatty acids,
fatty alcohols, diisopropyl adipate, hydroxybenzoate esters,
benzoic acid esters of C9 to C15 alcohols, isononyl iso-nonanoate,
silicone oils, polyethers, C12 to C15 alkyl benzoates, oleic acid,
stearic fatty acid, cetyl alcohols, hexadecyl alcohol, dimethyl
polysiloxane, polyoxypropylene cetyl ether, polyoxypropylene butyl
ether, and derivatives, esters, salts and mixtures thereof.
[0079] In an embodiment of the present invention, the additional
component is a humectant. Suitable humectants include but are not
limited to guanidine, urea, glycolic acid, glycolate salts,
ammonium glycolate, quaternary alkyl ammonium glycolate, lactic
acid, lactate salts, ammonium lactate, quaternary alkyl ammonium
lactate, aloe vera, aloe vera gel, allantoin, urazole, alkoxylated
glucose, hyaluronic acid, lactamide monoethanolamine, acetamide
monoethanolamine and derivatives, esters, salts and mixtures
thereof.
[0080] In an embodiment of the present invention, the additional
component is a preservative. Suitable preservatives include but are
not limited to C12 to C15 alkyl benzoates, alkyl
p-hydroxybenzoates, aloe vera extract, ascorbic acid, benzalkonium
chloride, benzoic acid, benzoic acid esters of C9 to C15 alcohols,
butylated hydroxytoluene, castor oil, cetyl alcohols, chlorocresol,
citric acid, cocoa butter, coconut oil, diazolidinyl urea,
diisopropyl adipate, dimethyl polysiloxane, DMDM hydantoin,
ethanol, fatty acids, fatty alcohols, hexadecyl alcohol,
hydroxybenzoate esters, iodopropynyl butylcarbamate, isononyl
iso-nonanoate, jojoba oil, lanolin oil, methylparaben, mineral oil,
oleic acid, olive oil, polyethers, polyoxypropylene butyl ether,
polyoxypropylene cetyl ether, potassium sorbate, silicone oils,
sodium propionate, sodium benzoate, sodium bisulfite, sorbic acid,
stearic fatty acid, vitamin E, vitamin E acetate and derivatives,
esters, salts and mixtures thereof.
[0081] In an embodiment of the present invention, the additional
component is a skin penetration enhancer. Suitable skin penetration
enhancers include but are not limited to acetone, acyl lactylates,
acyl peptides, acylsarcosinates, alkanolamine salts of fatty acids,
alkyl benzene sulphonates, alkyl ether sulphates, alkyl sulphates,
anionic surface-active agents, benzyl benzoate, benzyl salicylate,
butan-1,4-diol, butyl benzoate, butyl laurate, butyl myristate,
butyl stearate, cationic surface-active agents, citric acid,
cocoamidopropylbetaine, decyl methyl sulfoxide, decyl oleate,
dibutyl azelate, dibutyl phthalate, dibenzyl sebacate, dibutyl
sebacate, dibutyl suberate, dibutyl succinate, dicapryl adipate,
didecyl phthalate, diethylene glycol, diethyl sebacate,
diethyl-m-toluamide, di(2-hydroxypropyl) ether, diisopropyl
adipate, diisopropyl sebacate, N,N-dimethyl acetamide, dimethyl
azelate, N,N-dimethyl formamide, 1,5-dimethyl-2-pyrrolidone,
dimethyl sebacate, dimethyl sulphoxide, dioctyl adipate, dioctyl
azelate, dioctyl sebacate, 1,4 dioxane,
1-dodecylazacyloheptan-2-one, dodecyl dimethyl amine oxides, ethyl
caprate, ethyl caproate, ethyl caprylate, 2-ethyl-hexyl
pelargonate, ethyl-2-hydroxypropanoate, ethyl laurate, ethyl
myristate, 1-ethyl-2-pyrrolidone, ethyl salicylate, hexyl laurate,
2-hydroxyoctanoic acid, 2-hydroxypropanoic acid, 2-hydroxypropionic
acid, isethionates, isopropyl isostearate, isopropyl palmitate,
guar hydroxypropyltrimonium chloride, hexan-2,5-diol, khellin,
lamepons, lauryl alcohol, maypons, metal salts of fatty acids,
methyl nicotinate, 2-methyl propan-2-ol, 1-methyl-2-pyrrolidone,
5-methyl-2-pyrrolidone, methyl taurides, miranol, nonionic
surface-active agents, octyl alcohol, octylphenoxy
polyethoxyethanol, oleic ethanolamide, pleyl alcohol,
pentan-2,4-diol, phenoxyethanol, phosphatidyl choline, phosphine
oxides, polyalkoxylated ether glycollates, poly(diallylpiperidinium
chloride), poly(dipropyldiallylammonium chloride), polyglycerol
esters, polyoxyethylene lauryl ether, polyoxy:polyoxyethylene
stearate, polyoxypropylene 15 stearyl ether, poly(vinyl pyridinium
chloride), propan-1-ol, propan-2-ol, propylene glycol
dipelargonate, pyroglutamic acids, 2-pyrrolidone, pyruvic acids,
Quaternium 5, Quaternium 18, Quaternium 19, Quaternium 23,
Quaternium 31, Quaternium 40, Quaternium 57, quartenary amine
salts, quaternised poly (dimethylaminoethylmethacryl-ate),
quaternised poly (vinyl alcohol), sapamin hydrochloride, sodium
cocaminopropionate, sodium dioctyl sulphonsuccinate, sodium
laurate, sodium lauryl ether sulphate, sodium lauryl sulphate,
sugar esters, sulphosuccinate, tetrahydrofuran, tetrahydrofurfural
alcohol, transcutol, triethanolamine dodecyl benzene sulphonate,
triethanolamine oleate, urea, water and derivatives, esters, salts
and mixtures thereof.
Propellants
[0082] Examples of suitable propellants include volatile
hydrocarbons such as butane, propane, isobutane and fluorocarbon
gases, or mixtures thereof.
[0083] In certain embodiments, fluorohydrocarbon propellants, other
than chloro-fluoro carbons (CMCs) which are non-ozone-depleting
propellants, are particularly useful in the production of a
non-flammable foamable composition.
[0084] Such propellants include, but are not limited to
hydrofluorocarbon (HFC) propellants, that contain no chlorine
atoms, and as such, falls completely outside concerns about
stratospheric ozone destruction by chlorofluorocarbons or other
chlorinated hydrocarbons. Exemplary non-flammable propellants
according to this aspect of the invention include propellants made
by DuPont under the registered trademark Dymel, such as 1,1,1,2
tetrafluorethane (Dymel 134), and 1,1,1,2,3,3,3 heptafluoropropane
(Dymel 227), 1,1, difluoro ethane (Dymel 152) and 1,1,1,3,3,3
hexafluoropropane. HFCs possess Ozone Depletion Potential of 0.00
and thus, they are allowed for use as propellant in aerosol
products.
[0085] The propellant makes up about 5-25 wt % of the foamable
composition. Aerosol propellants are used to generate and
administer the foamable composition as a foam. The total
composition including propellant, foamable compositions and
optional ingredients is referred to as the foamable
composition.
Hygroscopic Property of the Composition
[0086] A hydroscopic substance is a substance that absorbs water
readily from its surroundings. Microorganisms require water to grow
and reproduce, and such water requirements are best defined in
terms of water activity of the substrate. The water activity of a
solution is expressed as Aw=P/Po, where P is the water vapor
pressure of the solution and Po is the vapor pressure of pure water
at the same temperature. Addition of a hygroscopic substance to an
aqueous solution in which a microorganism is growing will have the
effect of lowering the Aw, with a consequent effect upon cell
growth. Every microorganism has a limiting Aw, below which it will
not grow, e.g., for streptococci, klebsiella spp., escherichia
coli, clostridium perfringens, and pseudomonas spp. the Aw value is
0.95. Staphylococcus aureus is most resistant and can proliferate
with an Aw as low as 0.86.
[0087] The water activity of a product can be determined from the
relative humidity of the air surrounding the sample when the air
and the sample are at equilibrium. Measurement is performed by
placing a sample in an enclosed space where this equilibrium can
take place. Once this occurs, the water activity of the sample and
the relative humidity of the air are equal. The measurement taken
at equilibrium is called an equilibrium relative humidity or ERH.
The relationship between the water activity and ERH is in
accordance with the following formula: Aw=ERH/100
[0088] Various types of water activity instruments are commercially
available. One exemplary instrument uses chilled-mirror dewpoint
technology while other instruments measure relative humidity with
sensors that change electrical resistance or capacitance.
[0089] Polyols, PEGs and other polar solvents have a great affinity
for water, and as such, they exhibit hygroscopic properties. The
concentration of the polyol, the PEG and/or other polar solvents
determines the Aw of the carrier. In one or more embodiments, the
polyols, the PEG and/or the secondary polar solvent is contained in
the composition of the present invention at a sufficient
concentration to provide an Aw value of the hygroscopic carrier of
less than 0.9. In other embodiments, the concentration of the
polyol, the PEG and/or secondary polar solvent in the composition
is selected to provide a Aw value selected from the ranges of (1)
about 0.8 and about 0.9; (2) about 0.7 and about 0.8; and (3) less
than about 0.7.
[0090] As such, a composition containing a polyol, a PEG with or
without a secondary polar solvent can be used as topical treatment
of superficial infectious conditions.
[0091] The advantage of providing a hygroscopic composition in a
pressurized packaging presentation is readily perceived. The usage
of all other presentations, such as solutions, creams, lotions,
ointments and the like involves repeated opening of the package
closure, resulting in absorption of water from the surrounding
environment and a subsequent elevation of the Aw (thus lowering the
hygroscopicity of the product, and therefore decreasing its
anti-infective potential. By contrast, a pressurized packaging does
not allow for any humidity to be absorbed by the preparation, and
therefore, the hygroscopic character of the composition cannot be
damaged.
[0092] In one or more embodiments, the hygroscopic composition of
the present invention further contains an anti-infective agent,
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. Combining the
anti-infective effect of a hygroscopic composition, which acts
through a dehydration mechanism, with an additional anti-infective
agent that acts through alternate mechanisms results in a
synergistic effect and consequently higher success rate of the
treatment.
Composition and Foam Physical Characteristics and Advantages
[0093] A pharmaceutical or cosmetic composition manufactured using
the foamable carrier of the present invention 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.
[0094] The foamable composition of the present invention is stable,
having an acceptable shelf-life of at least one year, or
preferably, at least two years at ambient temperature, as revealed
in accelerated stability tests. Organic carriers and propellants
tend to impair the stability of emulsions and to interfere with the
formation of stable foam upon release from a pressurized container.
It has been observed, however, that the foamable compositions
according to the present invention are surprisingly stable.
Following accelerated stability studies, they demonstrate desirable
texture; they form fine bubble structures that do not break
immediately upon contact with a surface, spread easily on the
treated area and absorb quickly.
[0095] The composition should also be free flowing, to allow it to
flow through the aperture of the container, e.g., and aerosol
container, and create an acceptable foam.
[0096] Foam quality can be graded as follows:
[0097] 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.
[0098] 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.
[0099] 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.
[0100] 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.
[0101] Grade P (poor): no creaminess noticeable, large bubble
structure, and when spread on the skin it becomes very thin and
watery in appearance.
[0102] Grade VP (very poor): dry foam, large very dull bubbles,
difficult to spread on the skin.
[0103] 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.
[0104] As further aspect of the foam is breakability. The breakable
foam is thermally stable, yet breaks under sheer force. Sheer-force
breakability of the foam is clearly advantageous over thermally
induced breakability. Thermally sensitive foams immediately
collapse upon exposure to skin temperature and, therefore, cannot
be applied on the hand and afterwards delivered to the afflicted
area.
[0105] The foam of the present invention has several advantages,
when compared with hydroalcoholic foam compositions, such as
described in WO 2004/071479: [0106] (1) Breakability. The foam of
the present invention is thermally stable. Unlike hydroalcoholic
foam compositions of the prior art, the foam of the present
invention is not "quick breaking", i.e., it does not readily
collapse upon exposure to body temperature environment. Sheer-force
breakability of the foam is clearly advantageous over thermally
induced breakability, since it allows comfortable application and
well directed administration to the target area. [0107] (2) Skin
drying and skin barrier function. Short chain alcohols are known to
dry the skin and impair the integrity of the skin barrier. By
contrast, including a film forming agent in the composition of the
present invention foes not cause unwanted skin barrier damage.
[0108] (3) Irritability. Due to the lack of alcohol and improvement
in skin barrier function, skin irritability is eliminated.
[0109] Another property of the foam is specific gravity, as
measured upon release from the aerosol can. Typically, foams have
specific gravity of less than 0.12 g/mL; or less than 0.10 g/mL; or
less than 0.08 g/mL, depending on their composition and on the
propellant concentration.
Pharmaceutical Composition
[0110] The foamable composition of the present invention is an
ideal vehicle for active pharmaceutical ingredients and active
cosmetic ingredients. In the context of the present invention,
active pharmaceutical ingredients and active cosmetic ingredients
are collectively termed "active agent" or "active agents". A
foamable composition, comprising an active agent has the following
advantages: [0111] 1. The foamable composition provides a preferred
solvent for active agents, particularly water-insoluble agents.
[0112] 2. The inclusion of a polyol and/or a PEG and a secondary
polar solvent in the foamable composition facilitates a co-solvent
effect, resulting increased concentrations of soluble active agent
in the dosage form, thus facilitating enhanced skin penetration of
the active agent. In many cases, increased penetration is
positively correlated with improved clinical outcome. In certain
case, attaining an increased drug penetration into the target site
of action enables a decrease of treatment frequency, for example,
from twice or three times daily to once daily. [0113] 3. Polyols
and PEGs; and combinations of a polyol and/or PEG with a secondary
polar solvent are known as skin penetration enhancers, thus,
increasing drug residence in the target area and increasing
clinical efficacy, as detailed above. [0114] 4. The fact that the
composition contains no water, or up to 25% and more preferably up
to 10% water minimizes the probability of degradation of
water-sensitive active agents. Furthermore, as exemplified herein,
a foam containing a polyol and/or PEG with no water at all can be
formed in accordance with the composition and process of the
present invention. Such compositions ensure high stability of water
sensitive active agents. [0115] 5. Combining the anti-infective
effect of a hygroscopic composition, which acts through a
dehydration mechanism, with an additional anti-infective agent,
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, that acts through
alternate mechanisms results in a synergistic effect and
consequently higher success rate of the treatment. [0116] 6. The
foamable polyol composition in contained in an impermeable
pressurized packaging presentation is impermeable and thus, the
active agent is not exposed to environmental degradation factors,
such as light and oxidating agent during storage.
[0117] Thus, in a preferred embodiment of the present invention,
the composition includes at least one active agent. [0118] a. a
therapeutically effective concentration of an active agent; and
[0119] b. about 50% to about 98% of a polar solvent, selected from
the group consisting of a polyol and a polyethylene glycol; [0120]
c. 0% to about 48% of a secondary polar solvent; [0121] d. about
0.2% to about 5% by weight of a surface-active agent; [0122] e.
about 0.01% to about 5% by weight of at least one polymeric agent;
and [0123] f. a liquefied or compressed gas propellant at a
concentration of about 3% to about 25% by weight of the total
composition.
[0124] In the context of combining a hygroscopic carrier according
to the present invention and an anti-infective active agent, a
pharmaceutical composition is provided, including: [0125] a. a
hygroscopic substance at a sufficient concentration to provide an
Aw value of the hygroscopic carrier of less than 0.9. The
concentration of the hygroscopic substance in the composition can
be designed to provide a Aw value selected from the ranges of (1)
about 0.8 and about 0.9; (2) about 0.7 and about 0.8; and (3) less
than about 0.7; [0126] b. about 0.2% to about 5% by weight of a
surface-active agent; [0127] c. about 0.01% to about 5% by weight
of at least one polymeric agent selected from a bioadhesive agent,
a gelling agent, a film forming agent and a phase change agent;
[0128] d. a therapeutically effective concentration of an
anti-infective agent; and [0129] e. a liquefied or compressed gas
propellant at a concentration of about 3% to about 25% by weight of
the total composition.
[0130] An exemplary case for the inclusion of an anti-infective
agent in a hygroscopic composition is provided herewith. It has
been surprisingly discovered that combining an antifungal agent in
a hygroscopic composition results in an anti-infective effect on
strains that are not supposed to be affected by the said antifungal
agent. For example, terbinafine is know to be highly effective
against dermatophite pathogens, but not against candida. In-vitro
studies have revealed, however that terbinafine, dissolved in a
hygroscopic carrier, effectively inhibited the spreading of candida
albicans, while a control preparation, comprising the same
concentration of terbinafine in an emulsion base was not effective.
Thus, combining an antifungal agent in a hygroscopic composition
results in an expansion of the spectrum of infective strains that
can benefit form the therapy, and furthermore, in can render an
improved effect of such a composition on mixed infections or in
infections that are not accurately diagnosed.
[0131] Consequently, in another aspect of the present invention, a
pharmaceutical composition, which possesses an improved antifungal
activity or that possesses an antifungal activity on an expanded
spectrum of pathogens, is provided, including: [0132] a. a
hygroscopic composition, comprising a hygroscopic substance at a
sufficient concentration to provide an Aw value of the hygroscopic
carrier of less than 0.9. The concentration of the hygroscopic
substance in the composition can be designed to provide a Aw value
selected from the ranges of (1) about 0.8 and about 0.9; (2) about
0.7 and about 0.8; and (3) less than about 0.7; [0133] b. an
anti-infective agent, 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.
Preferably, the anti-infective agent is an antifungal agent, and
more preferably the anti-infective agent is terbinafine.
Active Agents
[0134] Suitable active agents include but are not limited to active
herbal extracts, acaricides, age spot and keratose removing agents,
allergen, analgesics, local anesthetics, antiacne agents,
antiallergic agents, antiaging agents, antibacterials, antibiotics,
antiburn agents, anticancer agents, antidandruff agents,
antidepressants, antidermatitis agents, antiedemics,
antihistamines, antihelminths, antihyperkeratolyte agents,
antiinflammatory agents, antiirritants, antilipemics,
antimicrobials, antimycotics, antiproliferative agents,
antioxidants, anti-wrinkle agents, antipruritics, antipsoriatic
agents, antirosacea agents antiseborrheic agents, antiseptic,
antiswelling agents, antiviral agents, antiyeast agents,
astringents, topical cardiovascular agents, chemotherapeutic
agents, corticosteroids, dicarboxylic acids, disinfectants,
fungicides, hair growth regulators, hormones, hydroxy acids,
immunosuppressants, immunoregulating agents, insecticides, insect
repellents, keratolytic agents, lactams, metals, metal oxides,
mitocides, neuropeptides, non-steroidal anti-inflammatory agents,
oxidizing agents, pediculicides, photodynamic therapy agents,
retinoids, sanatives, scabicides, self tanning agents, skin
whitening agents, asoconstrictors, vasodilators, vitamins, vitamin
D derivatives, wound healing agents and wart removers. As is known
to one skilled in the art, in some instances a specific active
active agent may have more than one activity, function or
effect.
[0135] In an embodiment of the present invention, the active agent
is an active herbal extract. Suitable active herbal extracts
include but are not limited to angelica, anise oil, astragali
radix, azalea, benzyl acetate, birch tar oil, bomyl acetate,
cacumen biotae, camphor, cantharidin, capsicum, cineole, cinnamon
bark, cinnamon leaf, citronella, citroneliol, citronellyl acetate,
citronellyl formate, eucalyptus, eugenyl acetate, flos carthami,
fructus mori, garlic, geraniol, geranium, geranyl acetate,
habanera, isobutyl angelicate, lavender, ledum latifolium, ledum
palustre, lemongrass, limonene, linalool, linalyl acetate, methyl
anthranilate, methyl cinnamate, mezereum, neem, nerol, neryl
acetate, nettle root extract, oleum ricini, oregano, pinenes,
.alpha.-pinene, .beta.-pinene, radix angelicae sinesis, radix
paenoiae rubra, radix polygoni multiflori, radix rehmanniae,
rhizoma pinelliae, rhizoma zingiberis recens, sabadilla, sage,
sandalwood oil, saw palmetto extract, semen sesami nignrum,
staphysagria, tea tree oil, terpene alcohols, terpene hydrocarbons,
terpene esters, terpinene, terpineol, terpinyl acetate and
derivatives, esters, salts and mixtures thereof. In an embodiment
of the present invention, the active agent is an acaricide.
Suitable acaricides include but are not limited to amitraz,
flumethrin, fluvalinate and derivatives, esters, salts and mixtures
thereof.
[0136] In an embodiment of the present invention, the active agent
is an age spot and keratoses removing agent. Suitable age spot and
keratoses removing agent include but are not limited to hydroxy
acids, azelaic acid and other related dicarboxylic acids,
retinoids, kojic acid, arbutin, nicotinic, ascorbic acid,
hydroquinone and derivatives, esters, salts and mixtures thereof.
Certain nonsteroidal anti-inflammatory agents, such as diclofenac
are also useful for the treatment of keratoses.
[0137] In an embodiment of the present invention, the active agent
is an analgesic. Suitable analgesics include but are not limited to
benzocaine, butamben picrate, dibucaine, dimethisoquin, dyclonine,
lidocaine, pramoxine, tetracaine, salicylates and derivatives,
esters, salts and mixtures thereof.
[0138] In an embodiment of the present invention, the active agent
is a local anesthetic. Suitable local anesthetics include but are
not limited to benzocaine, benzyl alcohol, bupivacaine, butamben
picrate, chlorprocaine, cocaine, dibucaine, dimethisoquin,
dyclonine, etidocaine, hexylcaine, ketamine, lidocaine,
mepivacaine, phenol, pramoxine, procaine, tetracaine, salicylates
and derivatives, esters, salts and mixtures thereof.
[0139] In an embodiment of the present invention, the active agent
is an antiacne agent. Suitable antiacne agents include but are not
limited to N-acetylcysteine, adapalene, azelaic acid, benzoyl
peroxide, cholate, clindamycin, deoxycholate, erythromycin,
flavinoids, glycolic acid, meclocycline, metronidazol, mupirocin,
octopirox, phenoxy ethanol, phenoxy proponol, pyruvic acid,
resorcinol, retinoic acid, salicylic acid, scymnol sulfate,
sulfacetamide-sulfur, sulfur, tazarotene, tetracycline, tretinoin
triclosan and derivatives, esters, salts and mixtures thereof.
[0140] In an embodiment of the present invention, the active agent
is an antiaging agent. Suitable antiaging agents include but are
not limited to sulfur-containing D and L amino acids, alpha-hydroxy
acids s, beta-hydroxy acids (e.g. salicylic acid), urea, hyaluronic
acid, phytic acid, lipoic acid; lysophosphatidic acid, skin peel
agents (e.g., phenol, resorcinol and the like), vitamin B3
compounds (e.g., niacinamide, nicotinic acid and nicotinic acid
salts and esters, including non-vasodilating esters of nicotinic
acid (such as tocopheryl nicotinate), nicotinyl amino acids,
nicotinyl alcohol esters of carboxylic acids, nicotinic acid
N-oxide and niacinamide N-oxide), vitamin B5 and retinoids (e.g.,
retinol, retinal, retinoic acid, retinyl acetate, retinyl
palmitate, retinyl ascorbate) skin barrier forming agents,
melatonin and derivatives, esters, salts and mixtures thereof.
[0141] In an embodiment of the present invention, the active agent
is an antibiotic. The terms "antibiotic" as used herein shall
include, but is not limited to, any substance being destructive to
or inhibiting the growth of bacteria or any substance having the
capacity to inhibit the growth of or to destroy bacteria. In one or
more embodiments, the antibiotic agent is selected from the group
consisting of a beta-lactam antibiotic, an aminoglycoside, an
ansa-type antibiotic, an anthraquinone, an azole, an antibiotic
glycopeptide, a macrolide, an antibiotic nucleoside, an antibiotic
peptide, an antibiotic polyene, an antibiotic polyether, an
antibiotic quinolone, an antibiotic steroid, a sulfonamide, an
antibiotic metal, an oxidizing agent, 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, a triguanide, a bisbiguanide, a
polymeric biguanide, and analogs, derivatives, salts, ions and
complexes thereof.
[0142] Suitable antibiotics include but are not limited to
amanfadine hydrochloride, amanfadine sulfate, amikacin, arnikacin
sulfate, aminoglycosides, amoxicillin, ampicillin, ansamycins,
bacitracin, beta-lactams, candicidin, capreomycin, carbenicillin,
cephalexin, cephaloridine, cephalothin, cefazolin, cephapirin,
cephradine, cephaloglycin, chloramphenicols, chlorhexidine,
chlorhexidine gluconate, chlorhexidine hydrochloride, chloroxine,
chlorquinaldol, chlortetracycline, chlortetracycline hydrochloride,
ciprofloxacin, circulin, clindamycin, clindamycin hydrochloride,
clotrimazole, cloxacillin, demeclocycline, diclosxacillin,
diiodohydroxyquin, doxycycline, ethambutol, ethambutol
hydrochloride, erythromycin, erythromycin estolate, erythromycin
stearate, farnesol, floxacillin, gentamicin, gentamicin sulfate,
gramicidin, griseofulvin, haloprogin, haloquinol, hexachlorophene,
iminocyldline, iodate, iodine, iodochlorhydroxyquin, kanamycin,
kanamycin sulfate, lincomycin, lineomycin, lineomycin
hydrochloride, macrolides, meclocycline, methacycline, methacycline
hydrochloride, methenamine, methenamine hippurate, methenamine
mandelate, methicillin, metronidazole, miconazole, miconazole
hydrochloride, microcrystalline and nanocrystalline particles of
silver, copper, zinc, mercury, tin, lead, bismuth, cadmium and
chromium, minocycline, minocycline hydrochloride, mupirocin,
nafcillin, neomycin, neomycin sulfate, netilmicin, netilmicin
sulfate, nitrofurazone, norfloxacin, nystatin, octopirox,
oleandomycin, orcephalosporins, oxacillin, oxytetracycline,
oxytetracycline hydrochloride, parachlorometa xylenol, paromomycin,
paromomycin sulfate, penicillins, penicillin G, penicillin V,
pentamidine, pentamidine hydrochloride, phenethicillin, polymyxins,
quinolones, streptomycin sulfate, tetracycline, tobramycin,
tolnaftate, triclosan, trifampin, rifamycin, rolitetracycline,
spectinomycin, spiramycin, streptomycin, sulfonamide,
tetracyclines, tetracycline, tobramycin, tobramycin sulfate,
triclocarbon, triclosan, trimethoprim-sulfamethoxazole, tylosin,
vancomycin, yrothricin and derivatives, esters, salts and mixtures
thereof.
[0143] In an embodiment of the present invention, the active agent
is an antidandruff agent. Suitable antidandruffagents include but
are not limited to aminexil, benzalkonium chloride, benzethonium
chloride, 3-bromo-1-chloro-5,5-dimethyl-hydantoin, chloramine B,
chloramine T, chlorhexidine, N-chlorosuccinimide,climbazole-,
1,3-dibromo-5,5-dimethylhydantoin,
1,3-dichloro-5,5-dimethyl-hydantoin, betulinic acid, betulonic
acid, celastrol, crataegolic acid, cromakalin, cyproterone acetate,
dutasteride, finesteride, ibuprofen, ketoconozole, oleanolic acid,
phenytoin, picrotone olamine, salicylic acid, selenium sulphides,
triclosan, triiodothyronine, ursolic acid, zinc gluconate, zinc
omadine, zinc pyrithione and derivatives, esters, salts and
mixtures thereof.
[0144] In an embodiment of the present invention, the active agent
is an antihistamine. Suitable antihistamines include but are not
limited to chlorcyclizine, diphenhydramine, mepyramine,
methapyrilene, tripelennamine and derivatives, esters, salts and
mixtures thereof.
[0145] In an embodiment of the present invention, the active agent
is an antimycotic Also termed antifungal agent. The terms
"antimycotic" and "antifungal" as used herein include, but is not
limited to, any substance being destructive to or inhibiting the
growth of fungi and yeast or any substance having the capacity to
inhibit the growth of or to destroy fungi and/or yeast.
[0146] In one or more embodiments, the antifungal agent is an agent
that is useful in the treatment of a superficial fungal infection
of the skin, dermatophytosis, microsporum, trichophyton and
epidermophyton infections, candidiasis, oral candidiasis (thrush),
candidiasis of the skin and genital mucous membrane, candida
paronychia, which inflicts the nail and nail bed and genital and
vaginal candida, which inflict genitalia and the vagina.
[0147] Suitable antimycotics include but are not limited to
allylamines, amorolfine, amphotericin B, azole compounds,
bifonazole, butoconazole, chloroxine, clotrimazole, ciclopirox
olamine, clotrimazole, econazole, elubiol, fenticonazole,
fluconazole, flucytosine (5FC), griseofulvin, itraconazole,
ketoconazole, mafenide acetate, miconazole, naftifine, natamycin,
tolnaftate, nystatin, polyenes, oxiconazole, sulbentine,
sulconazole, terbinafine, terconazole, tioconazole, undecylenic
acid and derivatives, esters, salts and mixtures thereof.
[0148] In an embodiment of the present invention, the active agent
is an antipruritic. Suitable antipruritics include but are not
limited to menthol, methdilazine, trimeprazine, urea and
derivatives, esters, salts and mixtures thereof.
[0149] In an embodiment of the present invention, the active agent
is an additional antipsoriatic agent. Suitable additional
antipsoriatic agents include but are not limited to
6-aminonicotinamide, 6-aminonicotinic acid, 2-aminopyrazinamide,
anthralin, 6-carbamoylnicotinamide, 6-chloronicotinamide,
2-carbamoylpyrazinamide, corticosteroids,
6-dimethylaminonicotinamide, dithranol, 6-formylaminonicotinamide,
6-hydroxy nicotinic acid, 6-substituted nicotinamides,
6-substituted nicotinic acid, 2-substituted pyrazinamide,
tazarotene, thionicotinamide, trichothecene mycotoxins and
derivatives, esters, salts and mixtures thereof.
[0150] In an embodiment of the present invention, the active agent
is an antirosacca agent. Suitable antirosacea agents include but
are not limited to azelaic acid, metronidazole, sulfacetamide and
derivatives, esters, salts and mixtures thereof. Certain
nonsteroidal anti-inflammatory agents, such as salicylic acid,
salycilates, piroxicam and diclofenac are also useful for the
treatment of Rosacea.
[0151] In an embodiment of the present invention, the active agent
is an antiseborrheic agent. Suitable antiseborrheic agents include
but are not limited to glycolic acid, salicylic acid, selenium
sulfide, zinc pyrithione, a dicarboxylic acid, such as azelaic acid
and derivatives, esters, salts and mixtures thereof.
[0152] In an embodiment of the present invention, the active agent
is an antiviral agent. Suitable antiviral agents include but are
not limited to acyclovir, gancyclovir, ribavirin, amantadine,
rimantadine nucleoside-analog reverse transcriptase inhibitors,
such as zidovudine, didanosine, zalcitabine, tavudine, lamivudine
and vidarabine, non-nucleoside reverse transcriptase inhibitors,
such as nevirapine and delavirdine, protease inhibitors, such as
saquinavir, ritonavir, indinavir and nelfinavir, and interferons
and derivatives, esters, salts and mixtures thereof.
[0153] In an embodiment of the present invention, the active agent
is a chemotherapeutic agent. Suitable chemotherapeutic agents
include but are not limited to daunorubicin, doxorubicin,
idarubicin, amrubicin, pirarubicin, epirubicin, mitoxantrone,
etoposide, teniposide, vinblastine, vincristine, mitomycin C, 5-FU,
paclitaxel, docetaxel, actinomycin D, colchicine, topotecan,
irinotecan, gemcitabine cyclosporin, verapamil, valspodor,
probenecid, MK571, GF120918, LY335979, biricodar, terfenadine,
quinidine, pervilleine A, XR9576 and derivatives, esters, salts and
mixtures thereof.
[0154] In an embodiment of the present invention, the active agent
is a corticosteroid. Suitable corticosteroids include but are not
limited to alclometasone dipropionate, amcinafel, amcinafide,
amcinonide, beclomethasone, beclomethasone dipropionate,
betamethsone, betamethasone benzoate, betamethasone
dexamethasone-phosphate, dipropionate, betamethasone valerate,
budesonide, chloroprednisone, chlorprednisone acetate,
clescinolone, clobetasol, clobetasol propionate, clobetasol
valerate, clobetasone, clobetasone butyrate, clocortelone,
cortisone, cortodoxone, craposone butyrate, desonide,
desoxymethasone, dexamethasone, desoxycorticosterone acetate,
dichlorisone, diflorasone diacetate, diflucortolone valerate,
diflurosone diacetate, diflurprednate, fluadrenolone, flucetonide,
flucloronide, fluclorolone acetonide, flucortine butylesters,
fludroxycortide, fludrocortisone, flumethasone, flumethasone
pivalate, flumethasone pivalate, flunisolide, fluocinolone,
fluocinolone acetonide, fluocinonide, fluocortin butyl,
fluocortolone, fluorometholone, fluosinolone acetonide,
fluperolone, fluprednidene acetate, fluprednisolone hydrocortamate,
fluradrenolone, fluradrenolone acetonide, flurandrenolone,
fluticasone, halcinonide, halobetasol, hydrocortisone,
hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone
cyclopentylpropionate, hydrocortisone valerate,
hydroxyltriamcinolone, medrysone, meprednisone, .alpha.-methyl
dexamethasone, methylprednisolone, methylprednisolone acetate,
mometasone furoate, paramethasone, prednisolone, prednisone,
pregnenolone, progesterone, spironolactone, triamcinolone,
triamcinolone acetonide and derivatives, esters, salts and mixtures
thereof.
[0155] In an embodiment of the present invention, the active agent
is a hair growth regulator. Suitable hair growth regulators include
but are not limited to N-acetylgalactosamine, N-acetylglucosamine,
N-acetylmannosamine, acitretin, aminexil, ascomycin, asiatic acid,
azelaic acid, benzalkonium chloride, benzethonium chloride,
benzydamine, benzyl nicotinate, benzoyl peroxide, benzyl peroxide,
betulinic acid, betulonic acid, calcium pantothenate, celastrol,
cepharanthine, chlorpheniramine maleate, clinacycin hydrochloride,
crataegolic acid, cromakalin, cyproterone acetate, diazoxide,
diphenhydramine hydrochloride, dutasteride, estradiol,
ethyl-2-hydroxypropanoate, finasteride,
D-fucono-1,5-lactone,furoate, L-galactono-1,4-lactone,
D-galactosamine, D-glucaro-1,4-lactone, D-glucosamine-3-sulphatc,
hinokitiol, hydrocortisone, 2-hydroxypropionic acid, isotretinoin,
itraconazole, ketoconazole, latanoprost, 2-methyl propan-2-ol,
minocyclin, minoxidil, mipirocin, mometasone, oleanolic acid,
panthenol, 1,10-phenanthroline, phenytoin, prednisolone,
progesterone, propan-2-ol, pseudoterins, resorcinol, selenium
sulfide, tazarotene, triclocarbon, triclosan, triiodothyronine,
ursolic acid, zinc pyrithione and derivatives, esters, salts and
mixtures thereof.
[0156] In an embodiment of the present invention, the active agent
is a hormone. Suitable hormones include but are not limited to
methyltestosterone, androsterone, androsterone acetate,
androsterone propionate, androsterone benzoate, androsteronediol,
androsteronediol-3-acetate, androsteronediol-17-acetate,
androsteronediol 3-17-diacetate, androsteronediol-17-benzoate,
androsteronedione, androstenedione, androstenediol,
dehydroepiandrosterone, sodium dehydroepiandrosterone sulfate,
dromostanolone, dromostanolone propionate, ethylestrenol,
fluoxymesterone, nandrolone phenpropionate, nandrolone decanoate,
nandrolone furylpropionate, nandrolone cyclohexane-propionate,
nandrolone benzoate, nandrolone cyclohexanecarboxylate,
androsteronediol-3-acetate-1-7-benzoate, oxandrolone, oxymetholone,
stanozolol, testosterone, testosterone decanoate,
4-dihydrotestosterone, 5a-dihydrotestosterone, testolactone,
17a-methyl-19-nortestosterone, desogestrel, dydrogesterone,
ethynodiol diacetate, medroxyprogesterone, levonorgestrel,
medroxyprogesterone acetate, hydroxyprogesterone caproate,
norethindrone, norethindrone acetate, norethynodrel, allylestrenol,
19-nortestosterone, lynoestrenol, quingestanol acetate,
medrogestone, norgestrienone, dimethisterone, ethisterone,
cyproterone acetate, chlormadinone acetate, megestrol acetate,
norgestimate, norgestrel, desogrestrel, trimegestone, gestodene,
nomegestrol acetate, progesterone, 5a-pregnan-3b,20a-diol sulfate,
5a-pregnan-3b,20b-diol sulfate, 5a-pregnan-3b-ol-20-one,
16,5a-pregnen-3b-ol-20-one, 4-pregnen-20b-ol-3-one-20-sulfate,
acetoxypregnenolone, anagestone acetate, cyproterone,
dihydrogesterone, flurogestone acetate, gestadene,
hydroxyprogesterone acetate, hydroxymethylprogesterone,
hydroxymethyl progesterone acetate, 3-ketodesogestrel, megestrol,
melengestrol acetate, norethisterone, progestins and derivatives,
esters, salts and mixtures thereof.
[0157] In an embodiment of the present invention, the active agent
is a hydroxyacid. Suitable hydroxy acids include but are not
limited to agaricic acid, aleuritic acid, allaric acid, altraric
acid, arabiraric acid, ascorbic acid, atrolactic acid, benzilic
acid, citramalic acid, citric acid, dihydroxytartaric acid,
erythraric acid, galactaric acid, galacturonic acid, glucaric acid,
glucuronic acid, glyceric acid, glycolic acid, gularic acid,
gulonic acid, hydroxypyruvic acid, idaric acid, isocitric acid,
lactic acid, lyxaric acid, malic acid, mandelic acid, mannaric
acid, methyllactic acid, mucic acid, phenyllactic acid, pyruvic
acid, quinic acid, ribaric acid, ribonic acid, saccharic acid,
talaric acid, tartaric acid, tartronic acid, threaric acid, tropic
acid, uronic acids, xylaric acid and derivatives, esters, salts and
mixtures thereof.
[0158] In an embodiment of the present invention, the active agent
is a keratolytic agent. The term "keratolytic agent" is used herein
to mean a compound which loosens and removes the stratum corneum of
the skin, or alters the structure of the keratin layers of skin.
Keratolytic agents are used in the treatment of many dermatological
disorders, which involve dry skin, hyperkeratiinization (such as
prsoriasis), skin itching (such as xerosis), acne and rosacea.
Suitable keratolytic agents include but are not limited to
N-acetylcysteine, azelaic acid, cresols, dihydroxy benzene
compounds, such as resorcinol and hydroquinone, alpha-hydroxy
acids, such as lactic acid and glycolic acid, phenol, pyruvic acid,
resorcinol, sulfur, salicylic acid, retinoic acid, isoretinoic
acid, retinol, retinal, urea and derivatives, esters, salts and
mixtures thereof.
[0159] In an embodiment of the present invention, the active agent
is a lactam. Suitable lactams include but are not limited to
L-galactono-1,4-lactam, L-arabino-1,5-lactam, D-fucono-1,5-lactam,
D-glucaro-1,4-lactam, D-glucurono-6,3-lactam,
2,5-tri-O-acetyl-D-glucurono-6,3-lactam,
2-acetamido-2-deoxyglucono-1,5-1-actam,
2-acetamido-2-deoxygalactono-1,5-lactam,
D-glucaro-1,4:6,3-dilactam-, L-idaro-1,5-lactam,
2,3,5,tri-O-acetyl-D-glucaro-1,4-lactam,
2,5-di-O-acetyl-D-glucaro-1,4:6,3-dilactam, D-glucaro-1,5-lactam
methyl ester, 2-propionoamide-2-deoxyglucaro-1,5-lactam and
derivatives, esters, salts and mixtures thereof.
[0160] In an embodiment of the present invention, the active agent
is a non-steroidal anti-inflammatory agent. Suitable non-steroidal
anti-inflammatory agent include but are not limited to azelaic
acid, oxicams, piroxicam, isoxicam, tenoxicam, sudoxicam,
CP-14,304, salicylates, aspirin, disalcid, benorylate, trilisate,
safapryn, solprin, diflunisal, fendosal, acetic acid derivatives,
diclofenac, fenclofenac, indomethacin, sulindac, tolmetin,
isoxepac, furofenac, tiopinac, zidometacin, acematacin, fentiazac,
zomepirac, clindanac, oxepinac, felbinac, ketorolac, fenamates,
mefenamic, meclofenamic, flufenamic, niflumic, tolfenamic acids,
propionic acid derivatives, ibuprofen, naproxen, benoxaprofen,
flurbiprofen, ketoprofen, fenoprofen, fenbufen, indopropfen,
pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen,
tioxaprofen, suprofen, alminoprofen, tiaprofen, pyrazoles,
phenylbutazone, oxyphenbutazone, feprazone, azapropazone,
trimethazone and derivatives, esters, salts and mixtures
thereof.
[0161] In an embodiment of the present invention, the active agent
is insecticide. The term "insecticide, is used herein to mean a
compound which kills, inhibits the growth of, impeded the
proliferation of or repels insects. Insecticides include, for
example, agents that can kill lice, flees, ticks, mites, scabies
and mousquitos, as well as agents that repel such insects. Suitable
insecticides include but are not limited to DDT, lindane,
malathion, permethrin, allethrin, biopermethrin, transpermethrin,
phenothrin, diethyl-m-toluamide, dimethyl phthalate, piperonyl
butoxide, pyrethroids and derivatives, esters, salts and mixtures
thereof.
[0162] In an embodiment of the present invention, the active agent
is a vasodilator. Suitable vasodilators include but are not limited
to agents that modulate the activity of the enzyme nitric oxide
synthase, nicotinic acid, ethyl nicotinate, amyl nitrite, amyl
nitrate, ethyl nitrite, butyl nitrite, isobutyl nitrite, glyceryl
trinitrate, octyl nitrite, sodium nitrite, sodium nitroprusside,
clonitrate, erythrityl tetranitrate, isosorbide mononitrate,
isosorbide dinitrate, mannitol hexanitrate, pentaerythritol
tetranitrate, penetrinitol, triethanolamine trinitrate, trolnitrate
phosphate (triethanolamine trinitrate diphosphate),
propatylnitrate, nitrite esters of sugars, nitrite esters of
polyols, nitrate esters of sugars, nitrate esters of polyols,
nicorandil, apresoline, diazoxide, hydralazine,
hydrochlorothiazide, minoxidil, pentaerythritol, tolazoline,
scoparone, a beta-adrenergic blocker, an alpha-adrenoceptor
blocker, a prostaglandin, sildenafil, dipyridamole, catecholamine,
isoproternol, furosemide, prostaglandin, prostacyclin, enalaprilat,
morphine, acepromazine, prazosin (.alpha.-blocker), enalapril,
Captopril, amlodipine, minoxidil, tadalafil, vardenafil,
phenylephrin, etilefein, caffeine, capsaicin, an extract capsicum,
achillea millefolium (Yarrow), allium sativum (garlic), amoracia
rusticana (horseradish), berberis vulgaris (barberry), cimicifuga
racemosa (black cohosh), coleus forskholii (coleus), coptis
(goldenthread), crataegus (hawthorn), eleutherococcus senticosus
(siberian ginseng), ginkgo biloba(ginkgo), melissa offiicnalis
(lemon balm), olca europaea (olive leaf), panax ginseng (Chinese
ginseng), petroselinum crispum (parsley), scutellaria baicalensis
(baical skullcap), tilia europaea (linden flower), trigonella
foenum-graecum (fenugreek), urtica dioica (nettles), valeriana
officinalis (valerian), viburnum (cramp, bark, black haw), veratrum
viride (American hellebore), verbena officinalis (vervain),
xanthoxylum americanum (prickly ash), zingiber officinale (ginger),
rauwolfia serpentina (Indian snakeroot), viscum album, wild yarn,
sasparilla, licorice, damiana, yucca, saw palmetto, gotu kola
(centella asiatica), yohimbine and salts, hazel nut, brazil nut and
walnut, and derivatives, esters, salts and mixtures thereof.
[0163] In an embodiment of the present invention, the active agent
is a vasoconstrictor. Suitable vasodilators include but are not
limited to ephedrine, epinephrine, phenylephrine, angiotensin,
vasopressin; an extract ephedra sinica (ma huang), polygonum
bistorta (bistort root), hamamelis virginiana (witch hazel),
hydrastis canadensis (goldenseal), lycopus virginicus (bugleweed),
aspidosperma quebracho (quebracho blanco), cytisus scoparius
(scotch broom) and cypressand and derivatives, esters, salts and
mixtures thereof.
[0164] In an embodiment of the present invention, the active agent
is a retinoid. Suitable retinoids include but are not limited to
retinol, retinal, retinoic acid, all-trans retinoic acid,
isotretinoin, tazarotene, adapalene, 13-cis-retinoic acid,
acitretin all-trans beta carotene, alpha carotene, lycopene,
9-cis-beta-carotene, lutein and zeaxanthin.
[0165] In an embodiment of the present invention, the active agent
is a vitamin D analog. Suitable retinoids include but are not
limited to calcipotriene, cholecalciferol,
25-hydroxycholecalciferol, 1.alpha.,25-dihydroxycholecalciferol,
ergocalciferol, 1.alpha.,25-dihydroxyergocalciferol,
22,23-dihydroergocalciferol, 1,24,25-trihydroxycholecalciferol,
previtamin D.sub.3, tachysterol.sub.3 (also termed tacalciol),
isovitamin D.sub.3, dihydrotachysterol.sub.3, (1S)-hydroxycalciol,
(24R)-hydroxycalcidiol, 25-fluorocalciol, ercalcidiol, ertacalciol,
(5E)-isocalciol, 22,23-dihydroercalciol, (24S)-methylcalciol,
(5E)-(10S)-10,19-dihydroercalciol, (24S)-ethylcalciol and
(22E)-(24R)-ethyl-22,23-didehydrocalciol. In a preferred
embodiment, the vitamin D analog is calcipotriene, which is useful
in the treatment of psoriasis.
[0166] In an embodiment of the present invention, the active agent
is selected from the group consisting of an immunosuppressants and
immunoregulating agents. Suitable immunosuppressants and
immunoregulating agents include but are not limited to cyclic
peptides, such as cyclosporine, tacrolimus, tresperimus,
pimecrolimus, sirolimus (rapamycin), verolimus, laflunimus,
laquinimod, imiquimod derivatives, esters, salts and mixtures
thereof. In one or more embodiments, the immunomodulator is a
calcineurin Inhibitor.
[0167] In an embodiment of the present invention, the active agent
is a wart remover. Suitable wart removers include but are not
limited to imiquimod, podophyllotoxin and derivatives, esters,
salts and mixtures thereof.
[0168] In an embodiment of the present invention, the active agent
is a photodynamic therapy (PDT) agent. Suitable PDT agents include
but are not limited to modified porphyrins, chlorins,
bacteriochlorins, phthalocyanines, naphthalocyanines,
pheophorbides, purpurins, m-THPC, mono-L-aspartyl chlorin e6,
bacteriochlorins, phthalocyanines, benzoporphyrin derivatives, as
well as photosensitiser precursors, such as aminolevulinic acid and
derivatives, esters, salts and mixtures thereof.
[0169] In an embodiment of the present invention, the active agent
is an antioxidant or a radical scavenger. Suitable antioxidants and
radical scavengers agents include but are not limited to ascorbic
acid, ascorbyl esters of fatty acids, magnesium ascorbyl phosphate,
sodium ascorbyl phosphate, ascorbyl sorbate, tocopherol, tocopheryl
sorbate, tocopheryl acetate, butylated hydroxy benzoic acid,
6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid, gallic
acid, propyl gallate, uric acid, sorbic acid, lipoic acid,
diethylhydroxylamine, amino-guanidine, glutathione, dihydroxy
fumaric acid, lycine pidolate, arginine pilolate,
nordihydroguaiaretic acid, bioflavonoids, curcumin, lysine,
methionine, proline, superoxide dismutase, silymarin, tea extracts,
grape skin/seed extracts, melanin, and polyunsaturated oils,
containing omega-3 and omega-6 fatty acids (e.g., linoleic and
linolenic acid, gamma-linoleic acid, eicosapentaenoic acid and
docosahexaenoic acid and derivatives, esters, salts and mixtures
thereof.
[0170] In an embodiment of the present invention, the active agent
is a self-tanning agent, such as dihydroxyacetone.
[0171] In an embodiment of the present invention, the active agent
is an agent, capable of treating hyperhidrosis. Suitable
hyperhidrosis agents include but are not limited to anticholinergic
drugs, boric acid, tannic acid, resorcinol, potassium permanganate,
formaldehyde, glutaraldehyde, methenamine, a Lewis acid, aluminum
chloride, aluminum chlorohydrates, zirconium chlorohydrates,
aluminum-zirconium-Glycine (AZG) complex, aluminum hydroxybromide,
a glycopyrrolate compound, a 5-alpha-reductase inhibitor,
finasteride, epristeride, flutamide, spironolactone, saw palmetto
extract, cholestan-3-one, a mono- and dicarboxylic acid having 4 to
18 carbon atoms, botulinum toxin, a 5-HT2C receptor antagonist, a
5-HT2C receptor antagonist, ketanserin, ritanserin, mianserin,
mesulergine, cyproheptadine, fluoxetine, mirtazapine, olanzapine
and ziprasidone.
[0172] In an embodiment of the present invention, the active agent
is a sunscreen agent. Suitable sunscreen agents include but are not
limited to titanium dioxide, zinc oxide, zirconium oxide, iron
oxide, p-aminobenzoic acid and its derivatives (ethyl, isobutyl,
glyceryl esters; p-dimethylaminobenzoic acid); anthranilic acid
derivatives (i.e., o-amino-benzoates, methyl, menthyl, phenyl,
benzyl, phenylethyl, linalyl, terpinyl, and cyclohexenyl esters);
salicylates (amyl, phenyl, octyl, benzyl, menthyl, glyceryl, and
di-pro-pyleneglycol esters); cinnamic acid derivatives (menthyl and
benzyl esters, a-phenyl cinnamonitrile; butyl cinnamoyl pyruvate);
dihydroxycinnamic acid derivatives (umbelliferone,
methylumbelliferone, methylaceto-umbelliferone);
trihydroxy-cinnamic acid derivatives (esculetin, methylesculetin,
daphnetin, and the glucosides, esculin and daphnin); hydrocarbons
(diphenylbutadiene, stilbene); dibenzalacetone and
benzalacetophenone; naphtholsulfonates (sodium salts of
2-naphthol-3,6-disulfonic and of 2-naphthol-6,8-disulfonic acids);
di-hydroxynaphthoic acid, o- and p-hydroxybiphenyldisulfonates,
coumarin derivatives (7-hydroxy, 7-methyl, 3-phenyl), diazoles
(2-acetyl-3-bromoindazole, phenyl benzoxazole, methyl
naphthoxazole, quinine salts (bisulfate, sulfate, chloride, oleate,
and tannate); quinoline derivatives (8-hydroxyquinoline salts,
2-phenylquinoline); hydroxy- or methoxy-substituted benzophenones;
uric and violuric acids; tannic acid and its derivatives (e.g.,
hexaethylether); (butyl carbotol) (6-propyl piperonyl) ether;
hydroquinone; benzophenones (oxybenzene, sulisobenzone,
dioxybenzone, benzoresorcinol, 2,2',4,4'-tetrahydroxybenzophenone,
2,2'-dihydroxy-4,4'-dimethoxybenzophenone, octabenzone;
4-isopropyldibenzoylmethane; butylmethoxydibenzoylmethane;
etocrylene; octocrylene; [3-(4'-methylbenzylidene bornan-2-one),
terephthalylidene dicamphor sulfonic acid and
4-isopropyl-di-benzoylmethane.
[0173] In an embodiment of the present invention, the active agent
is a figure-forming agent and an agent, capable of treating
cellulite. Suitable such agents include but are not limited to
baldderwack extract, butcher's, broom, cayenne, dandelion, red
clover, ginkgo biloba, horse chestnut, witch hazel and borage oil,
caffeic acid, nicotinic acid, theophiline and pentoxyphilline and
salts and derivatives thereof.
[0174] Several disorders of the skin, body cavity or mucosal
surface (e.g., the mucosa or the cavity of the nose, mouth, eye,
ear, vagina or rectum) involve a combination of etiological
factors. For example, fungal and bacterial infections and that are
inflamed and have symptoms of redness and/or itching warrant
therapy that combines an anti-infective agent and an
anti-inflammatory agent. Thus, in several cases, combining at least
two active agents that treat different etiological factors results
in a synergistic effect and consequently higher success rate of the
treatment.
[0175] In certain cases, the composition contains two active
agents, where each of the active agents require a different pH
environment in order to remain stable. For example, corticosteroids
are typically stable at acidic pH values (they have a maximum
stability at a pH of about 4-6) and of vitamin D analogues are
typically stable at basic pH values (they have a maximum stability
at pH values above about 8). In order to circumvent the problem of
instability it is preferred that the composition is substantially
non-aqueous. The term "substantially non-aqueous" is intended to
indicate that the composition has a water content below about 5%,
preferably below about 2%, such as below about 1.5%.
Fields of Applications
[0176] The foamable carrier of the present invention is suitable
for treating any infected surface. In one or more embodiments,
foamable carrier is suitable for administration to the skin, a body
surface, a body cavity or mucosal surface, 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").
[0177] By selecting a suitable active agent, or a combination of at
least two active agents, the foamable composition of the present
invention 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, grannuloma annulare, epidermal
necrolysis, sunburn, photosensitivity, pemphigus, bullous
pemphigoid, dermatitis herpetifbrmis, 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, necrtizing
myositis, gangrene, scarring, and vitiligo.
[0178] Likewise, the foamable composition of the present invention
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,
lymphogranloma 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.
[0179] In an embodiment of the present invention, 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.
[0180] In an embodiment of the present invention, the composition
is useful for the treatment of wound, ulcer and burn. This use is
particularly important since the composition of the present
invention creates a thin, semi-occlusive layer, which coats the
damaged tissue, while allowing exudates to be released from the
tissue.
[0181] The composition of the present invention 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.
[0182] In light of the hygroscopic nature of the composition, it is
further suitable for the treatment and prevention of post-surgical
adhesions. Adhesions are scars that form abnormal connections
between tissue surfaces. Post-surgical adhesion formation is a
natural consequence of surgery, resulting when tissue repairs
itself following incision, cauterization, suturing, or other means
of trauma. When comprising appropriate protective agents, the foam
is suitable for the treatment or prevention of post surgical
adhesions. The use of foam is particularly advantageous because
foam can expand in the body cavity and penetrate into hidden areas
that cannot be reached by any other alternative means of
administration.
[0183] 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 of the appended claims.
Example 1--Foamable Carriers Containing Polyols
TABLE-US-00002 [0184] TECH TECH TECH PG-014 PG-015 PG-016
Ingredient % W/W % W/W % W/W Propylene glycol (PG) 82.00 92.00
60.00 Laureth-4 2.00 2.00 2.00 Glyceryl stearate and PEG-100 4.00
4.00 3.00 stearate (Simulsol 165) PEG 4000 10.00 Glycerin anhydrous
33.00 Hydroxypropylcellulose 2.00 2.00 2.00 (Klucel EF) Total
100.00 100.00 100.00 Foam quality Good Good Good Shakability
Shakable Shakable Shakable
[0185] Notes: [0186] The compositions are substantially non-aqueous
[0187] Composition TECH PG-015 contains the minimum number of
components that constitute a foamable composition, which upon
release from an aerosol pressurized container affords foam of Good
or Excellent quality. It contains a diol (PG), a polymeric agent
(Klucel EF), and a non-ionic surface active agent (PEG-100 stearate
and Laureth 4) [0188] Composition TECH PG-014 demonstrates that the
addition of 10% PEG (secondary polar solvent) maintains Good foam
quality. [0189] Composition TECH PG-016 demonstrates that a mixture
of two polyols (PG and glycerin maintains Good foam quality. This
composition possesses high skin hydration effect. [0190] The
liquefied or gas propellant can be added at a concentration of
about 3% to about 25%.
Example 2--Foamable Carriers Containing Polyols
TABLE-US-00003 [0191] TECH TECH TECH PG-021 PG-024 PG-025
Ingredient % W/W % W/W % W/W Propylene glycol (PG) 91.00 58.00
43.00 Stearyl alcohol 2.00 1.00 1.00 Laureth-4 2.00 2.00 2.00
Glyceryl stearate and PEG-100 3.00 3.00 3.00 stearate (Simulsol
165) Glycerin 33.00 33.00 Hydroxypropylcellulose (Klucel EF) 2.00
3.00 3.00 Dimethyl isosorbide (DMI) 15.00 Total 100.00 100.00
100.00 Foam quality Excellent Excellent Excellent Shakability
Shakable Shakable Shakable
[0192] The following procedure was employed when the compositions
of Example 2 were produced.
Step 1: Preparation of Phase A
[0193] 1. Heat Propylene glycol and stearyl alcohol to
80-85.degree. C. [0194] 2. Add Klucel while mixing. [0195] 3. Cool
to 70-75.degree. C. Addall other ingredients while mixing.
Agitation continues until solution uniformity is reached [0196] 4.
Cool solution to 30.degree. C. with moderate mixing.
Step 2: Canisters Filling and Crimping
[0196] [0197] 1. Each aerosol canister 35.times.70 mm is filled
with 30.+-.5% g of the composition [0198] 2. Each canister was
closed with an aerosol valve, using a vacuum crimping machine.
Step 3: Pressurizing
[0199] Propellant (mix of propane, butane and isobutane) was added
to each of the canisters
[0200] Notes: [0201] Composition TECH PG-021, 24 and 25
demonstrates that the addition of 1-2% stearyl alcohol (foam
adjuvant) facilitates the formation of foam with Excellent quality.
Substituting Stearyl alcohol with stearic acid results in an
excellent foam too. [0202] Composition TECH PG-025 demonstrates
that the addition of 15% DMI (foam adjuvant) facilitates the
formation of foam with Excellent quality. This composition
possesses high skin penetration enhancing properties. [0203] The
liquefied or gas propellant can be added at a concentration of
about 3% to about 25%.
Example 3--Foamable Carriers Containing Polyols
TABLE-US-00004 [0204] TECH TECH TECH PG-026 PG-027 PG-028
Ingredient % W/W % W/W % W/W Stearyl alcohol 2.00 1.00 1.00
Propylene glycol (PG) 76.00 46.00 78.00 Laureth-4 2.00 2.00 2.00
Glyceryl stearate (and) PEG-100 1.50 stearate (Simulsol 165)
Glycerin anhydrous 33.00 Hydroxypropylcellulose (Klucel EF) 2.00
1.50 1.50 Dimethyl isosorbide (DMI) 15.00 15.00 15.00 Glyceryl
stearate 1.00 1.00 Ceteareth-6 (and) stearyl alcohol 2.00 1.50
(Macrogol cetostearyl ether) Total 100.00 100.00 100.00 Foam
quality Excellent Excellent Excellent
[0205] Notes: [0206] Composition TECH PG-027 demonstrates that a
mixture of two polyols (PG and glycerin, plus DMI (secondary polar
solvent) maintains Excellent foam quality. This composition
possesses high skin hydration effect. It further possesses high
skin penetration enhancing properties. [0207] The liquefied or gas
propellant can be added at a concentration of about 3% to about
25%.
Example 4--Additional Foamable Carriers Containing Polyols, Having
Excellent Foam Structure
TABLE-US-00005 [0208] TECH-PG TECH-PG TECH-PG TECH-PG TECH-PG 029
030 031 032 033 Ingredient % w/w % w/w % w/w % w/w % w/w Propylene
Glycol 91.0 58.0 43.0 46.0 78.0 Stearyl Alcohol 2.0 1.0 1.0 1.0 1.0
Glycerin -- 33.0 33.0 33.0 -- Klucel EF 2.0 3.0 3.0 1.5 1.5
Laureth-4 2.0 2.0 2.0 2.0 2.0 Simulsol 165 3.0 3.0 3.0 1.5 --
Dimethyl Isosorbide -- -- 15.0 15.0 15.0 Macrogol Cetostearyl Ether
-- -- -- -- 1.5 Glyceryl Stearate -- -- -- -- 1.0
Example 5--Foamable Polyols Compositions, Containing Steroid
Drugs
[0209] The following steroids were included in formulations were
included in formulations TECH-PG 30,31 and 33: bethamethasone
valerate 0.12%, clobetasol propionate 0.05%, bethamethasone
dipropionate 0.05%, fluocinolone acetonide 0.025%, hydrocortison
acetate 0.5% and hydrocortison butyrate 0.1%. All samples were
stored at 50.degree. C. for 4 weeks, in order to assess their
stability. The following table provides the results of this
short-term stability study, which indicated high compatibility
between the polyol composition and the steroid drugs, which are
known to be temperature-sensitive.
TABLE-US-00006 % Degradation after 4 weeks at 50.degree. C. TECH-PG
032 TECH-PG 033 Bethamethasone Valerate 0.12% 1.8% 1.7% Clobetasol
Propionate 0.05% 4.2% 5.0% Bethamethasone Dipropionate 0.05% 0 0
Fluocinolone Acetonide 0.025% 1.3% 1.7% Hydrocortison Acetate 0.5%
1.6% 2.1% Hydrocortison Butyrate 0.1% 2.6% 2.8
Example 6--Foamable Polyol Pharmaceutical Composition Comprising a
Combination of Betamethasone Dipropionate and Calcipotriol
TABLE-US-00007 [0210] FXCLB1 FXCLB2 Ingredient % W/W % W/W
Propylene glycol 90.945 77.945 Stearyl alcohol 2.00 1.00 Klucel EF
2.00 1.50 Laureth-4 2.00 2.00 Simulsol 165 3.00 Macrogol
Cetostearyl Ether 1.50 Glyceryl Stearate 1.00 Dimethyl isosorbide
15.00 Calcipotriol 0.005 0.005 Betamethasone Dipropionate 0.05
0.05
[0211] Notes: [0212] Composition FXCLB1 and FXCLB2 contain two
active agents (a corticosteroid and a vitamin D derivative, which
are known of exert a synergistic therapeutic effect in psoriasis.
These compositions contribute to enhanced skin penetration of the
active agents. [0213] The liquefied or gas propellant can be added
at a concentration of about 3% to about 25%.
Example 7--Foamable Polyol Pharmaceutical Composition Comprising
Acyclovir
TABLE-US-00008 [0214] Ingredient % W/W Acyclovir 5.00 Propylene
Glycol 43.70 Stearyl Alcohol 0.95 Glycerin 31.35 Hydroxypropyl
cellulose 1.43 Laureth-4 1.90 Glyceryl Monostearate/PEG 100
Stearate 1.43 Dimethyl Isosorbide 14.25
[0215] Notes: [0216] The composition contains acyclovir, which is
not fully soluble in the polyol and DMI mixture. However, due to
the unique composition, the acyclovir does not readily precipitate
and does not undergo caking. Furthermore, thanks to the low
viscosity of the composition, upon shaking the active agent readily
re-disperses in the composition, resulting in full formulation
uniformity. [0217] The combination of polyols and dimethyl
isosorbide contributes to enhanced skin bioavailability of the
active agent. [0218] The liquefied or gas propellant can be added
at a concentration of about 3% to about 25%.
Example 8--Foamable Compositions Containing Polyethylene Glycol
TABLE-US-00009 [0219] % w/w % w/w % w/w % w/w % w/w % w/w % w/w
PEG400 87.50 91.50 87.50 89.50 87.50 87.50 87.50 Klucel MX
(hydroxypropyl cellulose) 0.50 0 0.50 0 0.50 0 0.50 Klucel LF
(hydroxypropyl cellulose) 0 0.50 0 0.50 0 0.50 0 Lipocol C2 (POE
(2) cetyl ether) 2.00 2.00 0 0 0 0 0 Myrj 52 0 0 2.00 2.00 0 0 0
Steareth-2 0 0 0 0 2.00 2.00 0 Dermofeel G10L (Polyglyceryl-10 0 0
0 0 0 0 2.00 Laurate) Propellant 10 6 10 8 10 10 10 Density 0.060
0.063 0.063 0.055 0.052 0.050 0.075
[0220] Notes: [0221] The liquefied or gas propellant can be added
at a concentration of about 3% to about 25%. [0222] The foams of
this example have a non-ionic surface active agent at a
concentration of 2%. Total amounts of surface active agent foam
adjuvant and polymeric agent is in the range of 2.5%. [0223] The
compositions are useful as carriers of various active therapeutic
active agents.
Example 9--Foamable Hygroscopic Compositions, Containing
Mupirocin
[0224] The following table exemplifies the use of PEG as a
hygroscopic substance, which also serves as an effective solvent
for Mupirocin, which is practically insoluble in mineral oil and
other commonly used ointment solvents. Note that Mupirocin is
incompatible with most solvents and thus, a foam comprising PEG as
the sole solvent is highly valuable.
TABLE-US-00010 % w/w % w/w % w/w Mupirocin 2.00 2.00 2.00 PEG400
89.50 89.50 89.50 Hydroxypropyl cellulose 0.50 0.50 0.50 Steareth-2
2.00 1.00 0 Polyglyceryl-10 2.00 Laurate Propellant
(Propane/butane)* 6.0 6.0 6.0 Density 0.060 0.060 0.062
[0225] Notes: [0226] The liquefied or gas propellant can be added
at a concentration of about 3% to about 25%. [0227] The foams of
this example have a non-ionic surface active agent at a
concentration of 2%. Total amounts of surface active agent foam
adjuvant and polymeric agent is in the range of 2.5% (w/w).
Example 10--Foamable Hygroscopic Compositions, Containing
Terbinafine
[0228] The following table exemplifies the use of PEG as a
hygroscopic substance, which also serves as an effective solvent
for terbinafine, which is hard to dissolve in common formulation
excipients.
TABLE-US-00011 % w/w % w/w % w/w Terbinafine 2.00 2.00 6.00 PEG400
89.50 89.50 89.50 Hydroxypropyl cellulose 0.50 0.50 0.50 Steareth-2
2.00 1.00 0 Polyglyceryl-10 2.00 Laurate Propellant
(Propane/butane)* 6.0 6.0 6.0 Density 0.060 0.060 0.062
Example 11--Comparative In-Vitro Activity of a Hygroscopic
Composition Containing Terbinafine
[0229] A comparative in-vitro study was set to evaluate the effect
of Composition A, consisting of 2% terbinafine, 95.3% gr.
polyethylene glycol, 0.5% hydroxypropyl cellulose and 2.2%
steareth-2, in comparison with Composition B (an oil in water
emulsion containing 2% terbinafine) and Composition C a commercial
1% bifonazole cream.
[0230] Three fungal strains (microsporum canis, trichophyton
mentagrophytes and trichophyton rubrum) and one yeast (candida
albicans) were seeded in the center of a Petri dish, and then, were
surrounded by a film containing each of the compositions, using a
swab, soaked with each of the compositions. The proliferation and
spreading of the microorganisms was followed up for 14 day by
visual and photographic observations.
[0231] As shown in FIG. 1, Composition A inhibited the
proliferation and spreading of all the fungal and yeast strains
effectively. By contrast, both Compositions B and C failed to
inhibit the growth of candida. Composition C was also ineffective
in the inhibition of microsporum canis and Trichophyton rubrum.
Example 12--Foamable Hygroscopic Composition Containing Dimethyl
Isosorbide
TABLE-US-00012 [0232] % w/w % w/w % w/w % w/w Oleyl alcohol 2.50 --
-- -- IPM 5.00 5.00 5.00 -- Caprylic/Capric Triglyceride 5.00 5.00
5.00 46.00 (MCT oil) Epikuron P100 -- -- -- 10.00 PPG-15 stearyl
ether -- -- -- 2.00 Sorbitane stearate 8.00 8.00 8.00 2.00 Glyceril
monostearate -- 1.00 1.00 1.00 Stearyl alcohol -- 5.00 5.00 --
Cetostearyl alcohol 8.00 -- -- -- Klucel MF -- 0.50 -- -- PVP K-90
-- -- -- 0.50 Sisterna SP50 5.00 8.00 8.00 -- Propylene glycol 2.50
-- -- -- DMI 55.50 59.00 59.50 20.00 Water pure -- -- -- 10.00
Phenonip 0.50 0.50 0.50 0.50 Propellant 8.00 8.00 8.00 8.00
Example 13--Hygroscopic Antifungal Compositions
TABLE-US-00013 [0233] Ointment Type Lacquer Type % w/w % w/w % w/w
% w/w % w/w % w/w PEG 400 92.00 92.00 93.00 -- 54.00 46.00 PEG 4000
6.00 -- -- -- -- -- PEG 6000 -- 6.00 6.00 -- 10.00 8.00 Ethyl
acetate/ -- -- -- 30.00 30.00 30.00 Isopropanol Urea -- -- -- -- --
10.00 Terbinafine 2.00 2.00 -- 2.00 4.00 -- Ciclopirox -- -- 1.00
-- -- 4.00
[0234] The lacquer type compositions are suitable for the treatment
of infected cornified tissues, and particularly the nail.
Example 14--Comparison Between Polyethylene-Based Foamable
Compositions with and without Gelling Agent
[0235] The compositions of the test articles are provided in the
following table. All foams were dispensed on a warm surface
(38.degree. C.), and the time to full collapse of the foam was
measured. As shown in the table, it has been strikingly
demonstrated that foam compositions without a gelling agent exhibit
a 100% breakdown within 30 seconds, while foams containing gelling
agent remained, with and without surfactant, were stable for
several minutes. This is relevant from the usability point of view,
since a foam that is unstable at skin temperature cannot be applied
to large areas affectively.
TABLE-US-00014 Formulation with Formulations without gelling agent
gelling agent PG33 PG34 PG35 PG36 TEC49 PG29 % w/w % w/w % w/w %
w/w % w/w % w/w PEG 400 87.25 93.00 91.00 92.00 90.50 93.50 Klucel
GF -- -- -- -- 0.50 0.50 (gelling agent) Ceteareth-15 -- -- 2.00
1.00 -- -- Emulsiying 1.80 -- -- -- -- -- Wax NF Steareth-10 --
0.40 -- 0.50 -- -- PEG-40 1.35 -- -- -- -- -- stearate Steareth-2
-- 0.60 1.00 0.50 1.00 Span 60 2.70 -- -- -- -- -- Polysorbate 60
0.90 -- -- -- -- -- Propellant 6.00 6.00 6.00 6.00 8.00 6.00
Collapse time <30 <30 <30 <30 240 >300 (Seconds;
38.degree. C.)
Example 15--Foamable Hygroscopic Composition Containing
Polyethylene Glycol with No Surfactant
TABLE-US-00015 [0236] % w/w PEG 400 93.50 Klucel GF 0.50 Propellant
(Butane/propane) 6.00 Foam quality E Density 0.09
* * * * *