U.S. patent application number 15/368231 was filed with the patent office on 2017-06-22 for foamable composition combining a polar solvent and a hydrophobic carrier.
This patent application is currently assigned to Foamix Pharmaceuticals Ltd.. The applicant listed for this patent is Foamix Pharmaceuticals Ltd.. Invention is credited to Alex BESONOV, Meir EINI, Doron FRIEDMAN, Dov TAMARKIN.
Application Number | 20170172857 15/368231 |
Document ID | / |
Family ID | 46325768 |
Filed Date | 2017-06-22 |
United States Patent
Application |
20170172857 |
Kind Code |
A1 |
TAMARKIN; Dov ; et
al. |
June 22, 2017 |
FOAMABLE COMPOSITION COMBINING A POLAR SOLVENT AND A HYDROPHOBIC
CARRIER
Abstract
The present invention relates to a foamable vehicle or cosmetic
or pharmaceutical composition, comprising: (1) an organic carrier,
at a concentration of 10% to 70% by weight, wherein said organic
carrier concurrently comprises: (i) at least one hydrophobic
organic carrier, and (ii) at least one polar solvent; (2) at least
one surface-active agent; (3) water; and (4) at least one liquefied
or compressed gas propellant at a concentration of 3% to 25% by
weight of the total composition. The present invention further
provides a method of treating, alleviating or preventing a disorder
of mammalian subject, comprising administering the above-mentioned
compositions to an afflicted target site.
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 |
|
|
Assignee: |
Foamix Pharmaceuticals Ltd.
|
Family ID: |
46325768 |
Appl. No.: |
15/368231 |
Filed: |
December 2, 2016 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
12350854 |
Jan 8, 2009 |
9622947 |
|
|
15368231 |
|
|
|
|
11488989 |
Jul 19, 2006 |
|
|
|
12350854 |
|
|
|
|
10835505 |
Apr 28, 2004 |
7820145 |
|
|
11488989 |
|
|
|
|
10911367 |
Aug 4, 2004 |
|
|
|
11488989 |
|
|
|
|
10922358 |
Aug 20, 2004 |
7700076 |
|
|
11488989 |
|
|
|
|
11124676 |
May 9, 2005 |
|
|
|
11488989 |
|
|
|
|
10532618 |
Dec 22, 2005 |
|
|
|
PCT/IB03/05527 |
Oct 24, 2003 |
|
|
|
11124676 |
|
|
|
|
60492385 |
Aug 4, 2003 |
|
|
|
60530015 |
Dec 16, 2003 |
|
|
|
60492385 |
Aug 4, 2003 |
|
|
|
60497648 |
Aug 25, 2003 |
|
|
|
60429546 |
Nov 29, 2002 |
|
|
|
60700702 |
Jul 19, 2005 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 8/37 20130101; A61K
8/8176 20130101; A61K 9/107 20130101; A61K 9/122 20130101; A61K
35/04 20130101; A61Q 19/08 20130101; A61Q 19/00 20130101; A61Q
19/02 20130101; A61K 8/31 20130101; A61K 8/046 20130101; A61K 47/06
20130101; A61K 9/0014 20130101; A61K 47/10 20130101; A61K 8/375
20130101; A61K 8/4973 20130101; A61K 47/38 20130101; A01N 25/16
20130101; A61K 47/14 20130101; A61K 8/965 20130101; A61K 8/731
20130101; A61K 47/32 20130101; A61K 47/22 20130101; A61K 8/062
20130101 |
International
Class: |
A61K 8/04 20060101
A61K008/04; A61K 8/37 20060101 A61K008/37; A61K 8/49 20060101
A61K008/49; A61K 8/81 20060101 A61K008/81; A61K 8/96 20060101
A61K008/96; A61K 9/12 20060101 A61K009/12; A61K 35/04 20060101
A61K035/04; A61K 47/06 20060101 A61K047/06; A61K 47/14 20060101
A61K047/14; A61K 47/22 20060101 A61K047/22; A61Q 19/00 20060101
A61Q019/00; A61K 47/32 20060101 A61K047/32; A61K 47/38 20060101
A61K047/38; A61K 8/73 20060101 A61K008/73; A61K 8/31 20060101
A61K008/31 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 25, 2002 |
IL |
152486 |
Claims
1-52. (canceled)
53. A foamable pharmaceutical composition comprising: (a) an
emulsion comprising: (i) an organic carrier at a concentration of
10% to 70% by weight of the composition, wherein the organic
carrier comprises: a hydrophobic solvent comprising caprylic/capric
triglyceride, isopropyl myristate, and/or mineral oil; and a polar
solvent comprising dimethyl isosorbide and/or a short chain
alcohol; (ii) a surfactant; (iii) a foam adjuvant at a
concentration of about 0.01% to about 5% by weight of the
composition; (iv) a polymeric agent at a concentration of about
0.01% to about 5% by weight of the composition; and (v) water; (b)
a liquefied or compressed gas propellant at a concentration of
about 3% to about 25% by weight of the composition; and wherein the
composition is provided in an aerosol container and upon release
from the container, the composition forms a breakable foam.
54. The composition of claim 53, wherein the short chain alcohol
comprises ethanol.
55. The composition of claim 54, wherein the polar solvent
comprises ethanol at a concentration of about 15% to about 20% by
weight of the composition.
56. The composition of claim 53, wherein the polar solvent
comprises dimethyl isosorbide at a concentration of about 20% by
weight of the composition.
57. The composition of claim 53, wherein the hydrophobic solvent is
at a concentration of about 5% to about 30% by weight of the
composition.
58. The composition of claim 53, wherein the emulsion further
comprises an emollient.
59. The composition of claim 53, wherein the emulsion further
comprises a preservative.
60. The composition of claim 53, wherein the surfactant is at a
concentration of about 0.1% to about 5% by weight of the
composition.
61. The composition of claim 53, wherein the surfactant comprises a
non-ionic surfactant and an ionic surfactant, and wherein the ratio
of the non-ionic surfactant to the ionic surfactant is greater than
6:1.
62. The composition of claim 53, wherein the surfactant is selected
from the group consisting of glyceryl monostearate, sorbitan
stearate, polysorbate 80, PEG-40 stearate, and a mixture of two or
more thereof.
63. The composition of claim 53, wherein the foam adjuvant is at a
concentration of about 0.01% to about 1% by weight of the
composition.
64. The composition of claim 53, wherein the foam adjuvant
comprises a fatty alcohol having 15 or more carbons in its carbon
chain; a fatty acid having 16 or more carbons in its carbon chain;
a fatty alcohol derived from beeswax; a mixture of alcohols, a
majority of which has at least 20 carbon atoms in their carbon
chain; a fatty alcohol having a double bond; a fatty acid having a
double bond; a branched fatty alcohol; a branched fatty acid; a
fatty acid substituted with a hydroxyl group; and a mixture of two
or more thereof.
65. The composition of claim 64, wherein the fatty alcohol having
16 or more carbons in its carbon chain comprises stearyl
alcohol.
66. The composition of claim 53, wherein the polymeric agent is
selected from a bioadhesive agent, a gelling agent, a film forming
agent, and a phase change agent.
67. The composition of claim 53, wherein the polymeric agent is
selected from the group consisting of a locust bean gum, sodium
caseinate, an egg albumin, a gelatin agar, a carrageenin gum,
sodium alginate, a xanthan gum, a quince seed extract, a tragacanth
gum, a guar gum, a starch, a chemically modified starch, a
cellulose ether, an alkyl cellulose, a hydroxyalkyl cellulose, a
hydroxyethyl cellulose, a hydroxypropyl cellulose, a methyl
cellulose, a carboxymethyl cellulose, a
methylhydroxyethylcellulose, a methylhydroxypropylcellulose, a
hydroxypropyl methylcellulose, a
hydroxyethylcarboxymethylcellulose, a
carboxymethylhydroxyethylcellulose, a hydroxypropyl guar gum, a
soluble starch, a carboxyvinyl polymer, a polyvinylpyrrolidone, a
polyvinyl alcohol, a polyacrylic acid polymer, a polymethacrylic
acid polymer, a polyvinyl acetate polymer, a polyvinyl chloride
polymer, a polyvinylidene chloride polymer, an acrylic acid/ethyl
acrylate copolymer, a carboxyvinyl polymer, a silicone dioxide, a
poly(acrylic)acid, a poly(methylvinyl ether/maleic anhydride)
copolymer, a chitosan, an alginic acid, a hyaluronic acid, a
pectin, a karaya gum, a cyclodextrin, a chemically modified
cyclodextrin, hydroxypropyl-3-cyclodextrin, a
poly(N-isopropylamide), a poloxamer, and a mixture of any two or
more thereof.
68. The composition of claim 53, wherein the liquefied or
compressed gas propellant comprises propane and/or butane.
69. The composition of claim 53, wherein: (a) the emulsion
comprises: (i) a hydrophobic solvent comprising caprylic/capric
triglyceride at a concentration of about 30% by weight of the
composition; (ii) a polar solvent comprising dimethyl isosorbide at
a concentration of about 20% by weight of the composition; (iii) a
surfactant comprising glyceryl monostearate and sorbitant stearate
at a combined concentration of about 4% by weight of the
composition; (iv) a foam adjuvant comprising stearyl alcohol at a
concentration of about 1% by weight of the composition; (v) a
polymeric agent comprising xanthan gum and hydroxypropyl
methylcellulose at a combined concentration of about 0.3% by weight
of the composition; and (vi) water; (b) a liquefied or compressed
gas propellant comprising propane and butane at a concentration of
about 8% by weight of the composition.
70. The composition of claim 53, wherein: (a) the emulsion
comprises: (i) a hydrophobic solvent comprising mineral oil and
isopropyl myristate at a combined concentration of about 9.24% by
weight of the composition; (ii) a polar solvent comprising ethanol
at a concentration of about 15% by weight of the composition; (iii)
a surfactant comprising glyceryl monostearate, polysorbate 80, and
PEG-40 stearate at a combined concentration of about 3.37% by
weight of the composition; (iv) a foam adjuvant comprising stearyl
alcohol at a concentration of about 0.77% by weight of the
composition; (v) a polymeric agent comprising xanthan gum and
hydroxypropyl methylcellulose at a combined concentration of about
0.46% by weight of the composition; and (vi) water; (b) a liquefied
or compressed gas propellant comprising propane and butane at a
concentration of about 8% by weight of the composition.
71. The composition of claim 53, wherein: (a) the emulsion
comprises: (i) a hydrophobic solvent comprising mineral oil and
isopropyl myristate at a combined concentration of about 8.64% by
weight of the composition; (ii) a polar solvent comprising ethanol
at a concentration of about 20% by weight of the composition; (iii)
a surfactant comprising glyceryl monostearate, polysorbate 80, and
PEG-40 stearate at a combined concentration of about 3.24% by
weight of the composition; (iv) a foam adjuvant comprising stearyl
alcohol at a concentration of about 0.72% by weight of the
composition; (v) a polymeric agent comprising xanthan gum and
hydroxypropyl methylcellulose at a combined concentration of about
0.44% by weight of the composition; and (vi) water; (b) a liquefied
or compressed gas propellant comprising propane and butane at a
concentration of about 8% by weight of the composition.
72. The composition of claim 53, wherein the breakable foam has a
density of about 0.04 g/mL to about 0.12 g/mL.
73. The composition of claim 53, wherein the weight ratio between
the polar solvent and the hydrophobic solvent is between about 1:4
and about 4:1.
74. The composition of claim 53, wherein the emulsion further
comprises an active agent.
75. A method of treating, alleviating, or preventing a disorder,
comprising topically administrating a breakable foam produced from
the composition of claim 74.
76. The method of claim 75, wherein the disorder is a
steroid-responsive inflammation, a viral infection, a fungal
infection, a bacterial infection, a parasite infestation, a pigment
disorder, a dermatosis, psoriasis, atopic dermatitis, herpes,
seborrhea, dandruff, acne, rosacea, osteoarthritis, a joint pain,
or eczema.
77. The method of claim 75, wherein the active agent is
hydrocortisone acetate, betamethasone valerate, clobetasol
proprionate, acyclovir, ciclopirox, clindomycine, azelaic acid,
metronidazole, diclofenac, or tachrolimus.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit under 35 U.S.C.
.sctn.120 of U.S. patent application Ser. No. 11/488,989, filed on
Jul. 19, 2006, entitled "Foamable Composition Combining a Polar
Solvent and a Hydrophobic Carrier", which claims benefit of
priority under 35 U.S.C. .sctn.119(e) of U.S. Provisional Patent
Application No. 60/700,702, filed on Jul. 19, 2005, entitled
"Foamable Composition Combining a Polar Solvent and a Hydrophobic
Carrier," both of which are herein incorporated by reference in
their entirety.
[0002] This application is a continuation-in-part application of
co-pending U.S. application Ser. No. 11/124,676, filed on May 9,
2005, entitled "Vasoactive Kit and Compositions and Uses Thereof,"
which is a continuation-in-part application of co-pending
International Patent Application No. 1603/005527, designating the
United States and filed on Oct. 24, 2003, which claims the benefit
of priority under 35 U.S.C. .sctn.119(e) to U.S. Patent Application
Ser. No. 60/429,546, filed on Nov. 29, 2002, both entitled
"Cosmetic and Pharmaceutical Foam," and which claims the benefit of
priority under 35 USC.sctn.119(a) to Israeli Patent Application No.
152486, filed Oct. 25, 2002, all of which are hereby incorporated
in their entirety by reference.
[0003] This application is also a continuation-in-part application
of co-pending U.S. patent application Ser. No. 10/911,367, filed on
Aug. 4, 2004, which claims the benefit of priority under 35 U.S.C.
.sctn.119(e) to U.S. Patent Application Ser. No. 60/492,385, filed
on Aug. 4, 2003, both entitled "Foam Carrier Containing Amphiphilic
Copolymer Gelling Agent" and both hereby incorporated in their
entirety by reference.
[0004] This application is also a continuation-in-part application
of co-pending U.S. patent application Ser. No. 10/835,505, filed on
Apr. 28, 2004, 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 entitled "Oleaginous Pharmaceutical and
Cosmetic Foam" and all hereby incorporated in their entirety by
reference.
[0005] This application is also a continuation-in-part application
of co-pending U.S. patent application Ser. No. 10/922,358, filed
Aug. 20, 2004, entitled "Penetrating Pharmaceutical Foam," which
claims the benefit of priority under 35 U.S.C. .sctn.119(e) to U.S.
Patent Application Ser. No. 60/497,648, filed on Aug. 25, 2003,
both of which are incorporated by reference.
BACKGROUND OF THE INVENTION
[0006] This invention relates to foamable pharmaceutical and
cosmetic compositions.
[0007] Foams and, in particular, foam emulsions are complicated
systems which do not form under all circumstances. Changes in foam
emulsion composition, such as by the addition of active ingredients
may destabilize the foam. There is therefore a need for a foam
composition which provides desirable properties to the skin and can
remain stable whilst accommodating a variety of active
ingredients.
[0008] U.S. Pat. No. 6,126,920 ("the '920 Patent") discloses
treatment of various skin diseases, and in particular, scalp
psoriasis, using a foamable pharmaceutical composition containing a
corticosteroid active substance, an aliphatic alcohol, water, a
fatty alcohol, a surface-active agent, a propellant and a buffering
agent. The foamable composition contains 40-90% w/w composition of
an aliphatic alcohol. The '920 Patent is typical of many
compositions that use aliphatic alcohols in the foam composition.
The alcohol promotes fast drying and thereby attempts to address
the sticky feeling left by many topical formulations after
application; however, alcohols, and in particular the methyl, ethyl
and isopropyl alcohols preferred in the '920 Patent, are defatting
agents and may cause skin to become dry and cracked. U.S. Pat.
Application Pub. No. US2004/0151671 provides pharmaceutical
compositions in a pressurized container, comprising a quick
breaking alcoholic foaming agent. U.S. Pat. No. 5,783,202 provides
a pediculicidal mousse composition containing a pediculicidal agent
containing (a) from about 0.1 to about 10% w/w of a pediculicidal
agent (b) about 70 to about 97% w/w of a foaming agent, which is
preferably a quick breaking alcoholic foaming agent; and (c) from
about 3 to about 20% w/w of an aerosol propellant. U.S. Pat. No.
6,730,288 teaches a pharmaceutical foam composition including (a)
an active ingredient; (b) an occlusive agent; (c) an aqueous
solvent; and (d) an organic cosolvent; wherein the active
ingredient is insoluble in water and insoluble in both water and
the occlusive agent; and wherein there is enough occlusive agent to
form an occlusive layer on the skin.
[0009] A few dermatological foam products are available on the
market.
[0010] OIux.TM. Foam, produced by Connetics, Inc., contains
clobetasol propionate. Each gram of OIux.TM. Foam contains 0.5 mg
clobetasol propionate, USP, in a thermolabile foam, which consists
of ethanol (60%), purified water, propylene glycol, cetyl alcohol,
stearyl alcohol, polysorbate 60, citric acid, and potassium
citrate. It is dispensed from an aluminum can pressurized with a
hydrocarbon propellant (propane/butane). Luxiq.TM. corticostroid
foam medication contains 1.2 mg betamethasone valerate per gram, in
a vehicle, comprising ethanol (60.4%), purified water, propylene
glycol, cetyl alcohol, stearyl alcohol, polysorbate 60, citric
acid, and potassium citrate, and pressurized with a hydrocarbon
propellant. Alcohol is known to impair the integrity of the skin
barrier, dry the skin and cause skin irritation. The incidence skin
irritation (burning, itching and stinging) as detailed the package
inserts of the above mentioned products is very high (54%),
probably due to the high alcohol content. Moreover, the respective
incidence of skin irritation caused by the vehicle of these foams
is 75%.
[0011] Thus, while alcohol is useful in solubilizing an active
agent and enabling effective dermal penetration of an active agent
is desirable, the development of a safe foam vehicle, which will
overcome the evident skin drying and irritation caused by alcohol,
is warranted.
[0012] Furthermore, foam compositions that possess a lesser degree
of thermal sensitivity, thus being more useful for the treatment of
large skin areas are desired.
SUMMARY OF THE INVENTION
[0013] The present invention relates to a foamable vehicle or
cosmetic or pharmaceutical composition comprising:
(1) an organic carrier, at a concentration of about 10% to about
70% by weight, wherein said organic carrier concurrently
comprises:
[0014] (i) at least one hydrophobic organic carrier and
[0015] (ii) at least one polar solvent
(2) at least one surface-active agent; (3) water; and (4) at least
one liquefied or compressed gas propellant at a concentration of
about 3% to about 25% by weight of the total composition.
[0016] The present invention further relates to said composition
comprising an active agent.
[0017] In some embodiments, the foamable cosmetic or pharmaceutical
composition is non-flammable, wherein said gas propellant contains
hydrofluorocarbon.
[0018] The present invention further provides a method of treating,
alleviating or preventing a disorder of mammalian subject,
comprising administering a therapeutically effective amount of the
above-mentioned compositions to an afflicted target site.
[0019] The present invention further provides use of a
therapeutically effective amount of the above-mentioned
compositions in the manufacture of a medicament.
[0020] The present invention further provides a therapeutically
effective amount of the above-mentioned compositions for use in the
manufacture of a medicament.
DETAILED DESCRIPTION OF THE INVENTION
[0021] The present invention provides a safe and effective foamable
cosmetic or pharmaceutical vehicle or composition. The vehicle or
composition contains a polar solvent, which can optionally be a
short-chain alcohol, which possesses (as such) skin drying and skin
irritation properties; however, the composition also contains a
hydrophobic carrier, which counteracts these undesirable effects
and overcomes these drawbacks.
[0022] In one or more embodiments, the foamable cosmetic or
pharmaceutical vehicle includes:
(1) an organic carrier, at a concentration of about 10% to about
70% by weight, wherein said organic carrier concurrently
comprises:
[0023] (i) at least one hydrophobic organic carrier and
[0024] (ii) at least one polar solvent
(2) at least one surface-active agent; (3) water; and (4) at least
one liquefied or compressed gas propellant at a concentration of
about 3% to about 25% by weight of the total composition.
[0025] In one or more embodiments the foamable cosmetic or
pharmaceutical vehicle includes:
(1) an organic carrier, at a concentration of about 10% to about
70% by weight, wherein said organic carrier concurrently
comprises
[0026] (i) at least one hydrophobic organic carrier, and
[0027] (ii) at least one polar solvent;
(2) about 0.1% to about 5% by weight of at least one surface-active
agent;
(3) Water; and
[0028] (4) at least one liquefied or compressed gas propellant at a
concentration of about 3% to about 25% by weight of the total
composition.
[0029] In one or more embodiments a foamable cosmetic or
pharmaceutical vehicle is provided wherein the ratio of the
hydrophobic organic carrier and the polar solvent are selected to
provide a selected pharmacological or safety property;
[0030] In one or more embodiments a foamable cosmetic or
pharmaceutical vehicle is provided also incorporating a polymeric
agent.
[0031] In one or more embodiments the polymeric agent is selected
from a bioadhesive agent, a gelling agent, a film forming agent and
a phase change agent and can be from about 0.01% to about 5% by
weight
[0032] In one or more embodiments, a pharmaceutical or cosmetic
foamable product is provided, wherein a pharmaceutical or a
cosmetic active agent is incorporated in a foamable vehicle, which
contains a polar solvent and a hydrophobic organic carrier.
[0033] Thus, in one or more embodiments, the pharmaceutical or
cosmetic foamable product comprises:
(1) an effective concentration of at least one pharmaceutical or
cosmetic active agent; (2) an organic carrier, at a concentration
of about 10% to about 70% by weight, wherein said organic carrier
concurrently comprises
[0034] (i) at least one hydrophobic organic carrier
[0035] (ii) at least one polar solvent;
(3) about 0.1% to about 5% by weight of at least one surface-active
agent; and (4) at least one liquefied or compressed gas propellant
at a concentration of about 3% to about 25% by weight of the total
composition.
[0036] In one or more embodiments of the pharmaceutical or cosmetic
foamable product is non-flammable.
[0037] Water and optional ingredients are added to complete the
total mass to 100%.
[0038] All % values are provided on a weight (w/w) basis.
Polar Solvent
[0039] A "polar solvent" is an organic solvent, typically soluble
in both water and oil. Certain polar solvents posess the beneficial
property of a heumectant, being a substance, which helps retain
moisture, for example propylene glycol and glycerin.
[0040] In one or more embodiments, the polar solvent is a
heumectant.
[0041] According to one or more embodiments, the polar solvent
comprises a short chain alcohol. 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. In one or more embodiments the
concentration of the short chain alcohols is from about 5% to about
70%, preferably from about 10% to about 60%.
[0042] In one or more embodiments, the polar solvent is a polyol.
Polyols are organic substances that contain at least two hydroxy
groups in their molecular structure.
[0043] In one or more embodiments, the polar solvent contains an
diol (a compound that contains two hydroxy groups in its molecular
structure), such as propylene glycol (e.g., 1,2-propylene glycol
and 1,3-propylene glycol), butanediol (e.g., 1,4-butanediol),
butanediol (e.g., 1,3-butanediol and 1,4-butenediol), butynediol,
pentanediol (e.g., 1,5-pentanediol), hexanediol (e.g.,
1,6-hexanediol), octanediol (e.g., 1,8-octanediol), neopentyl
glycol, 2-methyl-1,3-propanediol, diethylene glycol, triethylene
glycol, tetraethylene glycol, dipropylene glycol and dibutylene
glycol.
[0044] In one or more embodiments, the polar solvent contains a
triol (a compound that contains three hydroxy groups in its
molecular structure), such as glycerin and 1,2,6-Hexanetriol.
[0045] Other non-limiting examples of polar solvents include
pyrrolidones, (such as N-methyl-2-pyrrolidone and
1-methyl-2-pyrrolidinone), dimethyl isosorbide, 1,2,6-hexapetriol,
dimethyl sulfoxide (DMSO), ethyl proxitol, dimethylacetamide (DMAc)
and alpha hydroxy acids, such as lactic acid and glycolic acid.
[0046] According to still other embodiments, the polar solvent is a
polyethylene glycol (PEG) or PEG derivative that is liquid at
ambient temperature, including PEG200 (MW (molecular weight) about
190-210 kD), PEG300 (MW about 285-315 kD), PEG400 (MW about 380-420
kD), PEG600 (MW about 570-630 kD) and higher MW PEGs such as PEG
4000, PEG 6000 and PEG 10000 and mixtures thereof.
[0047] Polar solvents are known to enhance the penetration of
active agent into the skin and through the skin, and therefore,
their inclusion in the composition of the present invention is
desirable, despite their undesirable skin drying and irritation
potential. There is at one level a commonality between the
different polar solvents and their penetration enhancement
properties. However, lower molecular weight alcohols can sometimes
be more potent as a solvent, for example by extracting lipids from
the skin layers more effectively, which characteristic can
adversely affect the skin structure and cause dryness and
irritation. Therefore the selection of the hydrophobic carrier to
counteract these negative effects may be of more importance when
using the lower moleculular weight alcohols.
Hydrophobic Solvent
[0048] A "hydrophobic organic carrier" 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.
[0049] The identification of a hydrophobic organic carrier or
"hydrophobic solvent", as used throughout this specification
synonymously, 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 hydrophobic carrier in the foamable
compositions described herein.
[0050] In one or more embodiments, the hydrophobic organic carrier
is a high-melting point hydrocarbon, such as, petrolatum.
[0051] In one or more other embodiments the use of high melting
point hydrocarbons, such as petrolatum in concentrations of more
than 10%, are not desirable since they have a waxy feeling when
applied to the skin; yet, in certain additional embodiments, when
an extensive refatting effect is required, then petrolatum in
concentrations of more than 10%, for example between about 10% and
about 50% is included in the composition of the present
invention.
[0052] According to one or more embodiments, hydrophobic solvents
are liquid oils originating from vegetable, marine or animal
sources. Suitable liquid oil includes saturated, unsaturated or
polyunsaturated oils. By way of example, the unsaturated oil may be
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 or
mixtures thereof, in any proportion.
[0053] Suitable hydrophobic solvents also include polyunsaturated
oils containing poly-unsaturated fatty acids. In one or more
embodiments, the unsaturated fatty acids are selected from the
group of omega-3 and omega-6 fatty acids. Examples of such
polyunsaturated fatty acids are linoleic and linolenic acid,
gamma-linoleic acid (GLA), eicosapentaenoic acid (EPA) and
docosahexaenoic acid (DHA). Such unsaturated fatty acids are known
for their skin-conditioning effect, which contribute to the
therapeutic benefit of the present foamable composition. Thus, the
hydrophobic solvent can include at least 6% of an oil selected from
omega-3 oil, omega-6 oil, and mixtures thereof.
[0054] In the context of the present invention, oils that possess
therapeutically beneficial properties are termed as
"therapeutically active oil."
[0055] Another class of hydrophobic solvents is the essential oils,
which are also considered therapeutically active oils, and which
contain active biologically occurring molecules and, upon topical
application, exert a therapeutic effect. Non-limiting examples of
essential oils include rosehip oil, which contain retinoids and is
known to reduce acne and post-acne scars, and tea tree oil, which
possess antibacterial, antifungal and antiviral properties. Other
examples of essential oils are oils of anise, basil, bergemont,
camphor, cardamom, carrot, canola, cassia, catnip, cedarwood,
citronella, clove, cypress, eucalyptus, frankincense, garlic,
ginger, grapefruit, hyssop, jasmine, jojova, lavender, lavandin,
lemon, lime, mandarin, marjoram, myrrh, neroli, nutmeg, orange,
peppermint, petitgrain, rosemary, sage, spearmint, star anise,
tangerine, thyme vanilla, verbena and white clover.
[0056] Another class of therapeutically active oils includes liquid
hydrophobic plant-derived oils, which are known to possess
therapeutic benefits when applied topically.
[0057] Silicone oils also may be used and are desirable due to
their known skin protective and occlusive properties. Suitable
silicone oils include non-volatile silicones, such as polyalkyl
siloxanes, polyaryl siloxanes, polyalkylaryl siloxanes and
polyether siloxane copolymers, polydimethylsiloxanes (dimethicones)
and poly(dimethylsiloxane)-(diphenyl-siloxane) copolymers. Silicone
oils are also considered therapeutically active oil, due to their
barrier retaining and protective properties.
[0058] A further class of hydrophobic carriers includes hydrophobic
liquids, selected from the family of organic liquids described as
"emollients." Emollients possess a softening or soothing effect,
especially when applied to body areas, such as the skin and mucosal
surfaces. Examples of suitable emollients include isopropyl
myristate, isopropyl palmitate, isopropyl isostearate, diisopropyl
adipate, diisopropyl dimerate, maleated soybean oil, octyl
palmitate, cetyl lactate, cetyl ricinoleate, tocopheryl acetate,
cetyl acetate, 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, octyl
dodecanol, sucrose esters of fatty acids and octyl
hydroxystearate.
[0059] The foamable composition of the present invention can be an
emulsion, or microemulsion, including an aqueous phase and an
organic carrier phase.
[0060] One non-limiting benefit of combining a polar solvent and a
hydrophobic carrier is apparent in the resulting conservation of
skin barrier properties.
[0061] Another non-limiting benefit of combining a polar solvent
and a hydrophobic carrier is further apparent in the reduction of
skin irritation.
[0062] Another non-limiting benefit of the vehicle or composition
of the present invention is to provide increased penetration of the
active or beneficial agent whilst replenishing the skin for example
by moisturizing or adding fats or oils.
[0063] The ratio between the polar solvent and the hydrophobic
carrier is determined according to the desirable pharmacologic and
safety properties of the product. Typically, the polar solvent to
hydrophobic carrier ranges between about 1:4 and about 4:1, for
example, about 1:4, about 1:2, about 3:4, about 1:1, about 5:4,
about 4:2, about 2:1, about 3:1 and about 4:1. When high
solubilization and/or enhanced dermal or transdermal delivery of a
drug is desirable, the polar solvent to hydrophobic carrier is
selected within the range of about 1:1 and about 4:1, for example,
about 1:1, about 5:4. about 6:4, about 7:4, about 2:1, about 3:1
and about 4:1 Yet, in other case, when the need of enhanced skin
protection and skin barrier build-up is more pronounced, the polar
solvent to hydrophobic carrier is selected within the range of
about 2:8 and about 1:1, for example, about 1:4, about 1:2, about
3:4 and about 1:1.
[0064] The following table, Table 1 exemplifies, in a non-limiting
manner, pairs of polar solvent and the hydrophobic carrier, as
provided in the present invention. The examples of the previous
paragraph are incorporated herin by reference.
TABLE-US-00001 Exemplary Polar Solvent/ Exemplary Polar Hydrophobic
Hydrophobic Solvent Carrier Carrier Ratio Comment A short chain A
hydrophobic Between about To provide enhanced alcohol, selected
carrier, selected 1:4 and about delivery of an active from ethanol,
from mineral oil, 4:1. agent, while conserving propanol,
petrolatum, isopropyl skin barrier isopropanol, myristate,
isopropyl To provide enhanced butanol palmytate, a skin barrier
build-up, triglyceride and which facilitates the silicone oil
recovery of damaged skin. A short chain Ester of fatty acid Between
about To provide enhanced alcohol, selected 1:4 and about delivery
of an active from ethanol, 4:1. agent, while conserving propanol,
skin barrier isopropanol, To provide enhanced butanol skin barrier
build-up, which facilitates the recovery of damaged skin. A short
chain Combination of at Between about To provide enhanced alcohol,
selected least one triglyceride 1:4 and about delivery of an active
from ethanol, and at least one 4:1. agent, while conserving
propanol, ester of a fatty acid skin barrier isopropanol, To
provide enhanced butanol skin barrier build-up, which facilitates
the recovery of damaged skin. A polyethylene A hydrophobic Between
about To provide enhanced glycol PEG carrier, selected 1:1 and
about delivery of an active from mineral oil, 4:1 agent, while
conserving petrolatum, isopropyl skin barrier myristate, isopropyl
palmytate, a triglyceride and silicone oil Dimethyl A hydrophobic
Between about To provide enhanced isosorbide carrier, selected 1:1
and about delivery of an active from mineral oil, 4:1 agent, while
conserving petrolatum, isopropyl skin barrier myristate, isopropyl
To provide enhanced palmytate, a skin barrier build-up,
triglyceride and which facilitates the silicone oil recovery of
damaged skin. Dimethyl A triglyceride Between about To provide
increased isosorbide 4:1 and about solubility of a drug, 1:4,
enhanced delivery and skin barrier build-up Dimethyl
Capric-caprylic Between about To provide increased isosorbide
triglyceride 1:4 and about solubility of a drug, 1:1 enhanced
delivery and skin barrier build-up Dimethyl Ester of fatty acid
Between about To provide increased isosorbide 1:4 and about
solubility of a drug, 1:1 enhanced delivery and skin barrier
build-up Dimethyl Combination of at Between about To provide
increased isosorbide least one triglyceride 1:4 and about
solubility of a drug, and at least one 1:1 enhanced delivery and
ester of a fatty acid skin barrier build-up A diol selected A
hydrophobic Between about To provide enhanced from the group of
carrier, selected 4:1 and about skin barrier build-up propylene
glycol, from mineral oil, 1:4 butanediol, petrolatum, isopropyl
hexanediol, myristate, isopropyl octanediol, palmytate, a
propanediol, triglyceride and diethylene glycol, silicone oil
triethylene glycol, tetraethylene glycol, dipropylene glycol and
dibutylene glycol. A triol (a A hydrophobic Between about To
provide enhanced compound that carrier, selected 4:1 and about skin
barrier build-up contains three from mineral oil, 1:4 hydroxy
groups in petrolatum, isopropyl its molecular myristate, isopropyl
structure), such as palmytate, a glycerin and 1,2,6- triglyceride
Hexanetriol. An alpha hydroxy A hydrophobic Between about To
provide enhanced acids, such as carrier, selected 4:1 and about
skin barrier build-up lactic acid and from mineral oil, 1:4
glycolic acid petrolatum, isopropyl myristate, isopropyl palmytate,
a triglyceride DMSO A hydrophobic Between about To provide enhanced
carrier, selected 4:1 and about skin barrier build-up from mineral
oil, 1:4, petrolatum, isopropyl myristate, isopropyl palmytate, a
triglyceride A pyrrolidone, A hydrophobic Between about To provide
enhanced such as N-methyl- carrier, selected 4:1 and about skin
barrier build-up 2-pyrrolidone and from mineral oil, 1:4
1-methyl-2- petrolatum, isopropyl pyrrolidinone myristate,
isopropyl palmytate, a triglyceride A combination of A hydrophobic
Between about To provide enhanced at least two polar carrier,
selected 1:4 and about delivery of an active solvents from mineral
oil, 4:1. agent, while conserving petrolatum, isopropyl skin
barrier myristate, isopropyl To provide enhanced palmytate, a skin
barrier build-up, triglyceride and which facilitates the silicone
oil recovery of damaged skin. A combination of Ester of fatty acid
Between about To provide increased at least two polar 1:4 and about
solubility of a drug, solvents 1:1 enhanced delivery and skin
barrier build-up A combination of Combination of at Between about
To provide increased at least two polar least one triglyceride 1:4
and about solubility of a drug, solvents and at least one 1:1
enhanced delivery and ester of a fatty acid skin barrier
build-up
[0065] In one or more embodiments, the polar solvent consists of a
single polar solvent. Yet, in additional embodiments, the polar
solvent consists of a combination of two or more polar
solvents.
[0066] In one or more embodiments, the hydrophobic carrier consists
of a single polar solvent. Yet, in additional embodiments, the
hydrophobic carrier consists of a combination of two or more
hydrophobic carriers.
[0067] In order to derive a composition which is readily foamable
upon release from a pressurized container, additional components
are required, as provided hereinbelow.
Surface Active Agent
[0068] 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. 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).
The surface-active agent according to the present invention has an
HLB value, suitable for stabilizing an emulsion comprising the
aqueous phase and the organic carrier of the composition.
[0069] According to one or more embodiments of the present
invention, the surface-active agent has a hydrophilic lipophilic
balance (HLB) between about 9 and about 14, which is the required
HLB (the HLB required to stabilize an O/W emulsion of a given oil)
of most oils and hydrophobic solvents. Thus, in one or more
embodiments, the composition contains a single surface active agent
having an HLB value between about 9 and about 14 (e.g., about 9,
about 10, about 11, about 12, about 13 and about 14), and in one or
more embodiments, the composition contains more than one surface
active agent and the weighted average of their HLB values is
between about 9 and about 14 (e.g. about 9, about 10, about 11,
about 12, about 13 and about 14). Yet, in other embodiments, when a
water-in-oil emulsion is desirable, the composition contains one or
more surface-active agents, having an HLB value between about 2 and
about 9 (e.g., about 2, about 3, about 4, about 5, about 6, about
7, about 8 and about 9).
[0070] The surface-active agent is selected from anionic, cationic,
nonionic, zwitterionic, amphoteric and ampholytic surfactants, as
well as mixtures of these surfactants. Such surfactants are well
known to those skilled in the therapeutic and cosmetic formulation
art. Non-limiting examples of possible 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, sodium methyl cocoyl taurate, sodium methyl oleoyl
taurate, sodium lauryl sulfate, triethanolamine lauryl sulfate and
betaines.
[0071] In one or more embodiments of the present invention, the
surface-active agent includes a 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.
[0072] In one or more embodiments, the surface-active agent
includes a mixture of a non-ionic surfactant and an ionic
surfactant in a ratio in the range of about 100:1 to about 6:1. In
one or more embodiments, the non-ionic to ionic surfactant ratio is
greater than about 6:1, or greater than about 8:1; or greater than
about 14:1, or greater than about 16:1, or greater than about
20:1.
[0073] In one or more embodiments of the present invention, a
combination of a non-ionic surfactant and an ionic surfactant (such
as sodium lauryl sulphate and cocamidopropylbetaine) is employed,
at a ratio of between 1:1 and 20:1, for example, about 1:1, about
4:1, about 8:1, about 12:1, about 16:1 and about 20:1 or at a ratio
of 4:1 to 10:1, for example, about 4:1, about 6:1, about 8:1 and
about 10:1. The resultant foam has a low specific gravity, e.g.,
less than 0.1 g/ml.
[0074] Thus, in an exemplary embodiment, a combination of an
non-ionic surfactant having HLB of less than about 9 and an
non-ionic surfactant having HLB of equal or more than about 9 is
employed, at a ratio of between about 1:8 and about 8:1, or at a
ratio of about 4:1 to about 1:4, wherein the HLB of the combination
of emulsifiers is between about 9 and about 14.
[0075] In one or more embodiments of the present invention, the
surface-active agent includes mono-, di- and tri-esters of sucrose
with fatty acids (sucrose esters), prepared from sucrose and esters
of fatty acids or by extraction from sucro-glycerides. Suitable
sucrose esters include those having high monoester content, which
have higher HLB values.
[0076] The total surface-active agent is in the range of about 0.1
to about 5% of the composition, and is occasionally less than about
2% or less than about 1%.
Polymeric Agent
[0077] In one or more embodiments, the foamable composition
contains a polymeric agent. The polymeric agent serves to stabilize
the foam composition and to control drug residence in the target
organ. Exemplary polymeric agents are classified below in a
non-limiting manner. In certain cases, a given polymer can belong
to more than one of the classes provided below.
[0078] In one or more embodiments, the composition of the present
invention includes a gelling agent. A gelling agent controls the
residence of a therapeutic composition in the target site of
treatment by increasing the viscosity of the composition, thereby
limiting the rate of its clearance from the site. Many gelling
agents are known in the art to possess mucoadhesive properties.
[0079] The gelling agent can be a natural gelling agent, a
synthetic gelling agent and an inorganic gelling agent. Exemplary
gelling agents that can be used in accordance with one or more
embodiments of the present invention include, for example,
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, starch, chemically modified starches and
the like, semi-synthetic polymeric materials such as cellulose
ethers (e.g. hydroxyethyl cellulose, hydroxypropyl cellulose,
methyl cellulose, carboxymethyl cellulose,
methylhydroxyethylcellulose, methylhydroxypropylcellulose,
hydroxypropylmethyl cellulose, hydroxyethylcarboxymethylcellulose,
carboxymethylcellulose and carboxymethylhydroxyethylcellulose),
guar gum, hydroxypropyl guar gum, soluble starch, cationic
celluloses, cationic guars, and the like, and synthetic polymeric
materials, such as carboxyvinyl polymers, polyvinylpyrrolidone,
polyvinyl alcohol, polyacrylic acid polymers, polymethacrylic acid
polymers, polyvinyl acetate polymers, polyvinyl chloride polymers,
polyvinylidene chloride polymers and the like. Mixtures of the
above compounds are also contemplated.
[0080] Further exemplary gelling agents include the acrylic
acid/ethyl acrylate copolymers and the carboxyvinyl polymers.
Non-limiting examples include Carbopol.RTM. 934, Carbopol.RTM. 940,
Carbopol.RTM. 950, Carbopol.RTM. 980, Carbopol.RTM. 951 and
Carbopol.RTM. 981.
[0081] Yet, in other embodiments, the gelling agent includes
inorganic gelling agents, such as silicone dioxide (fumed
silica).
[0082] Mucoadhesive/bioadhesion has been defined as the attachment
of synthetic or biological macromolecules to a biological tissue.
Mucoadhesive agents are a class of polymeric biomaterials that
exhibit the basic characteristic of a hydrogel, i.e. swell by
absorbing water and interacting by means of adhesion with the
mucous that covers epithelia. Compositions of the present invention
may contain a mucoadhesive macromolecule or polymer in an amount
sufficient to confer bioadhesive properties. The bioadhesive
macromolecule enhances the delivery of biologically active agents
on or through the target surface. The mucoadhesive macromolecule
may be selected from acidic synthetic polymers, preferably having
an acidic group per four repeating or monomeric subunit moieties,
such as poly(acrylic)- and/or poly(methacrylic) acid (e.g.,
Carbopol.RTM., Carbomer.RTM.), poly(methylvinyl ether/maleic
anhydride) copolymer, and their mixtures and copolymers; acidic
synthetically modified natural polymers, such as
carboxymethylcellulose (CMC); neutral synthetically modified
natural polymers, such as (hydroxypropyl)methylcellulose; basic
amine-bearing polymers such as chitosan; acidic polymers obtainable
from natural sources, such as alginic acid, hyaluronic acid,
pectin, gum tragacanth, and karaya gum; and neutral synthetic
polymers, such as polyvinyl alcohol or their mixtures. An
additional group of mucoadhesive polymers includes natural and
chemically modified cyclodextrin, especially
hydroxypropyl-.beta.-cyclodextrin. Such polymers may be present as
free acids, bases, or salts, usually in a final concentration of
about 0.01% to about 0.5% by weight. Many mucoadhesive agents are
known in the art to also possess gelling properties.
[0083] In one or more embodiments, the polymeric agent contains a
film-forming component. The film-forming component may include a
water-insoluble alkyl cellulose or hydroxyalkyl cellulose.
Exemplary alkyl cellulose or hydroxyalkyl cellulose polymers
include ethyl cellulose, propyl cellulose, butyl cellulose,
cellulose acetate, hydroxypropyl cellulose, hydroxybutyl cellulose,
and ethylhydroxyethyl cellulose, alone or in combination. In
addition, a plasticizer or a cross-linking agent may be used to
modify the polymer's characteristics. For example, esters such as
dibutyl or diethyl phthalate, amides such as diethyldiphenyl urea,
vegetable oils, fatty acids and alcohols such as oleic and myristyl
acid may be used in combination with the cellulose derivative.
[0084] In one or more embodiments, the polymeric agent includes a
phase change polymer, which alters the composition behavior from
fluid-like prior to administration to solid-like upon contact with
the target mucosal surface. Such phase change results from external
stimuli, such as changes in temperature or pH and exposure to
specific ions (e.g., Ca.sup.2+). Non-limiting examples of phase
change polymers include poly(N-isopropylamide) and Poloxamer
407.RTM..
[0085] The polymeric agent is present in an amount in the range of
about 0.01% to about 5.0% by weight of the foam composition. In one
or more embodiments, it is typically less than about 1 wt % of the
foamable composition.
[0086] Preferably, a therapeutically effective foam adjuvant is
included in the foamable compositions 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.
[0087] 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.
[0088] In one or more embodiments, a combination of a fatty acid
and a fatty ester is employed.
[0089] Optionally, the carbon atom chain of the fatty alcohol or
the fatty acid may have a 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.
[0090] A property of the fatty alcohols and fatty acids used in
context of the composition of the present invention is related to
their therapeutic properties per se. Long chain saturated and mono
unsaturated fatty alcohols, e.g., stearyl alcohol, erucyl alcohol,
arachidyl alcohol and behenyl alcohol (docosanol) have been
reported to possess antiviral, antiinfective, antiproliferative and
antiinflammatory properties (see, U.S. Pat. No. 4,874,794). Longer
chain fatty alcohols, e.g., tetracosanol, hexacosanol,
heptacosanol, octacosanol, triacontanol, etc., are also known for
their metabolism modifying properties and tissue energizing
properties. Long chain fatty acids have also been reported to
possess anti-infective characteristics.
[0091] In one or more embodiments, the active agent is encapsulated
in particles, microparticles, nanoparticles, microcapsules,
spheres, microspheres, nanocapsules, nanospheres, liposomes,
niosomes, polymer matrix, nanocrystals or microsponges.
[0092] The composition of the present invention may further
optionally include a variety of formulation excipients, which are
added in order to fine-tune the consistency of the formulation,
protect the formulation components from degradation and oxidation
and modify their consistency. Such excipients may be selected, for
example, from stabilizing agents, antioxidants, humectants,
preservatives, colorant and odorant agents and other formulation
components, used in the art of formulation.
[0093] 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 carrier. The propellant makes up about
3% to about 25% (w/w) of the foamable carrier or composition.
Examples of suitable propellants include volatile hydrocarbons such
as butane, propane, isobutane or mixtures thereof, and fluorocarbon
gases.
Non-Flammable Stable Foam Compositions
[0094] Alcohol and organic solvents render foams inflammable. It
has been surprisingly discovered that fluorohydrocarbon
propellants, other than chloro-fluoro carbons (CMOs), which are
non-ozone-depleting propellants, are particularly useful in the
production of a non-flammable foamable composition. A test
according to European Standard prEN 14851, titled "Aerosol
containers--Aerosol foam flammability test" revealed that
compositions containing an organic carrier that contains a
hydrophobic organic carrier and/or a polar solvent, which are
detected as inflammable when a hydrocarbon propellant is used,
become non-flammable, while the propellant is an HFC
propellant.
[0095] Such propellants include, but are not limited to,
hydrofluorocarbon (HFC) propellants, which contain no chlorine
atoms, and as such, fall 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). HFCs possess Ozone Depletion Potential of 0.00 and
thus, they are allowed for use as propellant in aerosol
products.
[0096] Notably, the stability of foamable emulsions including HFC
as the propellant is improved in comparison with the same
composition made with a hydrocarbon propellant.
Active Agents
[0097] It is to be understood that the active agents useful herein
can in some instances provide more than one benefit or operate via
more than one mode of action. Therefore, classifications herein are
made for the sake of convenience and are not intended to limit the
active agent to that particular application or applications
listed.
[0098] The composition of the present invention comprises an active
agent that provides therapeutic or cosmetic activity.
[0099] Non-limiting examples of active agents include an
anti-infective, an antibiotic, an antibacterial agent, an
antifungal agent, an antiviral agent, an antiparasitic agent, a
steroidal anti-inflammatory agent, a nonsteroidal anti-inflammatory
agent, an immunosuppressive agent, an immunomodulator, an
immunoregulating agent, a hormonal agent, a steroid, a vasoactive
agent, a vasoconstrictor, a vasodilator, vitamin A, a vitamin A
derivative, a retinoid, vitamin B, a vitamin B derivative, vitamin
C, a vitamin C derivative, vitamin D, a vitamin D derivative,
vitamin E, a vitamin E derivative, vitamin F, a vitamin F
derivative, vitamin K, a vitamin K derivative, a wound healing
agent, a burn healing agent, a disinfectant, an anesthetic, an
antiallergic agent, an alpha hydroxyl acid, lactic acid, glycolic
acid, a beta-hydroxy acid, a protein, a peptide, a neuropeptide, an
allergen, an immunogenic substance, a haptene, an oxidizing agent,
an antioxidant, a dicarboxylic acid, azelaic acid, sebacic acid,
adipic acid, fumaric acid, an insecticide, an antiproliferative
agent, an anticancer agent, a photodynamic therapy agent, an
anti-wrinkle agent, a radical scavenger, a metal oxide (e.g.,
titanium dioxide, zinc oxide, zirconium oxide, iron oxide),
silicone oxide, talc, an anti-acne agent, a skin whitening agent, a
self tanning agent, an anti-cellulite agent, a skin protective
agent, a masking agent, an anti-wart agent, a refatting agent, a
lubricating agent and mixtures thereof at any proportion. The
concentration of the active agent can be adapted to exert a
therapeutic effect on a disease when applied to an afflicted area.
Various different therapeutic effects of the herbs and their
extracts are, for example, illustrated in the above-mentioned
references.
[0100] In one or more embodiments the active agent may be an
extract or tincture of one or more beneficial agents that have
beneficial properties, for example, when applied to the skin, a
body surface, a body cavity or a mucosal surface. The extract can
be, for example, alcoholic, hydroalcoholic, propelyne glycol,
glycerine, dry, press, cold, hot, liquid carbon dioxide, oil or
other process known in the art. The extract or tincture may
comprise of substances of animal, plant, (such as herb, fruit,
vegetable) mineral or other origin. Nonlimiting examples are
proteins, polypepeptides, sugars, hyularonic acid, and coal tar.
Herbal extracts may be from any known therapeutic herb, as listed
for example in Herbal Medicines, London: Pharmaceutical Press
Electronic Version 2006 or in the American Herbal Association
electronic publication Herbal gram or in German Commission E., such
as, angelica, calendula, celery, coltsfoot, comfrey, dandelion,
jamaica dogwood, kava, marshmallow, prickly ash, northern prickly
ash, southern senna, valerian, agrimony, aloe vera, alfalfa,
artichoke, avens, bayberry, bloodroot, blue flag, bogbean, boldo,
boneset, broom, buchu, burdock, burnet, calamus, calendula,
cascara, centaury, cereus, chamomile, german chamomile, roman
chamomile, cinnamon, clivers, cohosh, black, cohosh, blue, cola,
corn silk, couchgrass, cowslip, damiana, devil's claw, drosera,
echinacea, elder, elecampane, euphorbia, eyebright, figwort,
frangula, fucus, fumitory, garlic, golden seal, gravel root, ground
ivy, guaiacum, hawthorn, holy thistle, hops, horehound black,
horehound white, horse chestnut hydrangea, ispaghula, juniper,
lady's lipper, liferoot, lime flower, liquorice, lobelia, mate,
meadowsweet, mistletoe, motherwort, myrrh, nettle, parsley, parsley
piert, passionflower, pennyroyal, pilewort, plantain, pleurisy
root, pokeroot, poplar, pulsatilla, queen's delight, raspberry, red
clover, rosemary, sage, sarsaparilla, sassafras, scullcap, senega,
shepherd's purse, skunk cabbage, slippery elm, squill, St. john's
wort, stone root, tansy, thyme, uva-ursi, vervain, wild carrot,
wild lettuce, willow, witch hazel, yarrow and yellow dock.
[0101] When the extract is dissolved in a polar solvent, such as a
short chain alcohol (e.g., ethanol and isopropyl alcohol),
propelyne glycol and glycerin, then the polar solvent of the
extract can also comprise part or all of the "polar solvent"
component of the foamable composition, as specified throughout this
specification and likewise the polar solvent of the foamable
composition can also comprise as part or all of the "polar solvent"
component of the extract.
[0102] In one or more embodiments, the active agent is an
anti-infective agent, selected from an antibiotic agent, an
antibacterial agent, an anti-fungal agent, an anti-viral agent and
an anti-parasite agent.
[0103] The antibacterial drug can be active against gram positive
and gram-negative bacteria, protozoa, aerobic bacteria and
unaerobic ones.
[0104] In one or more embodiments, the antibiotic agent is selected
from the classes consisting of beta-lactam antibiotics, synthetic
and semi-synthetic penicillins, aminoglycosides, ansa-type
antibiotics, anthraquinones, antibiotic azoles, antibiotic
glycopeptides, macrolides, antibiotic nucleosides, antibiotic
peptides, antibiotic polyenes, antibiotic polyethers, quinolones,
fluoroquinolnes, antibiotic steroids, cyclosporines, sulfonamides,
tetracycline, chloramphenicol, dicarboxylic acids, such as azelaic
acid, salicylates, antibiotic metals, oxidizing agents, substances
that release free radicals and/or active oxygen, cationic
antimicrobial agents, quaternary ammonium compounds, biguanides,
triguanides, bisbiguanides and analogs and polymers thereof and
naturally occurring antibiotic compounds.
[0105] Additional antibacterial agents, which are non-specific,
include strong oxidants and free radical liberating compounds, such
as hydrogen peroxide, bleaching agents (e.g., sodium, calcium or
magnesium hypochloride and the like), iodine, chlorohexidine and
benzoyl peroxide.
[0106] The antifungal agent can be an azole compound. Exemplary
azole compounds include azoles selected from the group consisting
of azoles, diazoles, triazoles, miconazole, ketoconazole,
clotrimazole, econazole, mebendazole, bifonazole, butoconazole,
fenticonazole, isoconazole, oxiconazole, sertaconazole,
sulconazole, thiabendazole, tiaconazole, fluconazole, itraconazole,
ravuconazole and posaconazole.
[0107] Additional exemplary antifungal agents include griseofulvin,
ciclopirox, amorolfine, terbinafine, Amphotericin B, potassium
iodide, flucytosine (5FC) and any combination thereof at a
therapeutically effective concentration.
[0108] In one or more embodiments, the active agent is an
anti-viral agent. Any known antiviral agent, in a therapeutically
effective concentration, can be incorporated in the foam
composition of the present invention. Exemplary antiviral agents
include, but not limited to, acyclovir, famciclovir, gancyclovir,
valganciclovir and abacavir.
[0109] In another embodiment according to the present invention,
the active agent is an anti-inflammatory or anti-allergic agent.
Anti-inflammatory agents can be selected from the group of
corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs),
antihistamines, immunosuppressant agents, immunomodulators; and any
combination thereof at a therapeutically effective
concentration.
[0110] Non-limiting examples of corticosteroids include
hydrocortisone, hydrocortisone acetate, desonide, betamethasone
valerate, clobetasone-17-butyrate, flucinonide, fluocinolone
acetonide, alcometasone dipropionate, mometasone furoate,
prednicarbate, triamcinolone acetonide, betamethasone-17-benzoate,
methylprednisolone aceponate, betamethasone dipropionate,
halcinonide, triamcinolone acetonide, halobetasol and
clobetasol-17-propionate.
[0111] A second class of anti-inflammatory agents, which is useful
in the foam of the present invention, includes the nonsteroidal
anti-inflammatory agents (NSAIDs). The variety of compounds
encompassed by this group is well known to those skilled in the
art. Specific non-steroidal anti-inflammatory agents useful in the
composition invention include, but are not limited to, oxicams,
such as piroxicam, isoxicam, tenoxicam, sudoxicam; salicylates,
such as salicylic acid, ethyl salicylate, methyl salycilate,
aspirin, disalcid, benorylate, trilisate, safapryn, solprin,
diflunisal, and fendosal; scetic acid derivatives, such as
diclofenac, fenclofenac, indomethacin, sulindac, tolmetin,
isoxepac, furofenac, tiopinac, zidometacin, acematacin, fentiazac,
zomepirac, clindanac, oxepinac, felbinac, and ketorolac; fenamates,
such as mefenamic, meclofenamic, flufenamic, niflumic, and
tolfenamic acids; propionic acid derivatives, such as ibuprofen,
naproxen, benoxaprofen, flurbiprofen, ketoprofen, fenoprofen,
fenbufen, indopropfen, pirprofen, carprofen, oxaprozin,
pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, and
tiaprofenic; and pyrazoles, such as phenylbutazone,
oxyphenbutazone, feprazone, azapropazone, and trimethazone.
[0112] Any further steroidal and nonsteroidal compounds, having the
capacity to prevent, alleviate the symptoms of, treat or cure
inflammation processes, are generally included, as possible
anti-inflammatory agents, according to the present invention.
[0113] Antiallergic active agents include antihistamine compounds,
including, in a non limiting manner, thylenediamines, such as
pyrilamine (mepyramine), antazoline and methapyrilene;
tripelennamine phenothiazines, such as promethazine, methdilazine
and trimeprazine; ethanolamines, such as diphenhydramine,
bromodiphenhydramine, carbinoxamine, clemastine, dimenhydrinate,
diphenylpyraline, doxylamine and phenyltoxamine; piperazines, such
as cyclizine, buclizine, chlorcyclizine, hydroxyzine, meclizine and
thiethylperazine; alkylamines, such as brompheniramine,
pyrrobutamin, desbrompheniramine, tripolidine,
dexchlorpherniramine, chlorpheniramine; dimethindene and
pheniramine; and piperidines, such as cyproheptadine and azatadine.
These active agents, as well as additional antihistamines can also
be incorporated in the composition of the present invention.
[0114] The composition of the present invention may also comprise
an anti-inflammatory or antiallergic agent, wherein said agent
reduces the occurrence of pro-inflammatory cytokines or inhibits
the effect of pro-inflammatory cytokines.
[0115] Immunosuppressant agents, immunoregulating agents and
immunomodulators are chemically or biologically derived agents that
modify the immune response or the functioning of the immune system
(as by the stimulation of antibody formation or the inhibition of
white blood cell activity). Immunosuppressant agents and
immunomodulators include, among other options, cyclic peptides,
such as cyclosporine, tacrolimus, tresperimus, pimecrolimus,
sirolimus (rapamycin), verolimus, laflunimus, laquinimod and
imiquimod.
[0116] In one or more embodiments, the active agent is a topical
anesthetic. Examples of topical anesthetic drugs include, but not
limited to, benzocaine, lidocaine, bupivacaine, chlorprocaine,
dibucaine, etidocaine, mepivacaine, tetracaine, dyclonine,
hexylcaine, procaine, cocaine, ketamine, pramoxine, and phenol.
Mixtures of such anesthetic agents may be synergistically
beneficial.
[0117] In one or more embodiments, the active agent is a
"keratolytically active agent." The term "keratolytically active
agent" refers herein to a compound which loosens and removes the
stratum corneum of the skin, or alters the structure of the keratin
layers of the skin.
[0118] Suitable keratolytically active agents include phenol and
substituted phenolic compounds. Such compounds are known to
dissolve and loosen the intracellular matrix of the
hyperkeratinized tissue. Dihydroxy benzene and derivatives thereof
have been recognized as potent keratolytic agents. Resorcinol
(m-dihydroxybenzene) and derivatives thereof are used in anti-acne
preparations. Hydroquinone (p-dihydroxybenzene), besides its
anti-pigmentation properties, is also keratolytic.
[0119] Vitamin A and its derivatives, such as retinoic acid,
isoretinoic acid, retinol and retinal are another preferred class
of keratolytically active agents.
[0120] Another group of keratolytically active agents include
alpha-hydroxy acids, such as lactic acid and glycolic acid and
their respective salts and derivatives; and beta-hydroxy acids,
such as Salicylic acid (o-hydroxybenzoic acid) and its salts and
pharmaceutically acceptable derivatives, which typically possess
anti-inflammatory, as well as keratolytic, activity. Yet, another
class of preferred keratolytically active agents includes urea and
its derivatives.
[0121] In one or more embodiments, the active agent is a retinoid.
Retinoids include, for example, retinol, retinal, all-trans
retinoic acid and derivatives, isomers and analogs thereof.
Etretinate, actiretin, isotretinoin, adapalene and tazarotene are
further examples of said retinoid isomers and analogs.
[0122] In one or more embodiments, the active agent is an
insecticide or an insect repellent agent.
[0123] In one or more embodiments, the active agent is an anti
cancer agent.
[0124] In one or more embodiments, the active agent is a
photodynamic therapy (PDT) agent. By way of example, such PDT
agents can be modified porphyrins, chlorins, bacteriochlorins,
phthalocyanines, naphthalocyanines, pheophorbides, purpurins,
m-THPC, mono-L-aspartyl chlorin e6, bacteriochlorins,
phthalocyanines, benzoporphyrin derivatives, as well as
photosensitizer precursors, such as aminolevulinic acid (ALA).
[0125] In one or more embodiments, the active agent is an agent
useful in the treatment of burns, wounds, cuts and ulcers. The foam
compositions of the present invention may comprise a combination of
anti-infective agents (against bacteria, fungi and/or viruses),
anti-inflammatory agents (steroidal and/or NSAIDs) and pain
relieving components.
[0126] The foam compositions of the present invention, with or
without further active ingredients, are suitable for the further
application as "cosmeceutical" preparation (cosmetic products with
therapeutic benefit), to treat "cosmetic" skin disorders, such as
aging skin, wrinkles, hyperpigmentation (melasma, chloasma,
freckles, etc.), scaly skin and other skin undesirable
properties.
[0127] Any cosmetically active agent is considered an active agent
in the context of the present invention. The CTFA Cosmetic
Ingredient Handbook describes a wide variety of non-limiting
cosmetic and pharmaceutical ingredients commonly used in the skin
care industry, which are suitable for use in the compositions of
the present invention. Examples of these ingredient classes
include: abrasives, absorbents, aesthetic components such as
fragrances, pigments, colorings/colorants, essential oils,
astringents, etc. (e.g., clove oil, menthol, camphor, eucalyptus
oil, eugenol, menthyl lactate, witch hazel distillate), anti-acne
agents, anti-caking agents, antifoaming agents, anti-microbial
agents (e.g., iodopropyl butylcarbamate), antioxidants, binders,
biological additives, buffering agents, bulking agents, chelating
agents, chemical additives, colorants, cosmetic astringents,
cosmetic biocides, denaturants, drug astringents, external
analgesics, film formers or materials, e.g., polymers, for aiding
the film-forming properties and substantivity of the composition
(e.g., copolymer of eicosene and vinyl pyrrolidone), opacifying
agents, pH adjusters, propellants, reducing agents, sequestrants,
skin bleaching and lightening agents (e.g., hydroquinone, kojic
acid, ascorbic acid, magnesium ascorbyl phosphate, ascorbyl
glucosamine), skin-conditioning agents (e.g., humectants, including
miscellaneous and occlusive), skin soothing and/or healing agents
(e.g., panthenol and derivatives (e.g., ethyl panthenol), aloe
vera, pantothenic acid and its derivatives, allantoin, bisabolol,
and dipotassium glycyrrhizinate), skin treating agents, and
vitamins and derivatives thereof.
[0128] In one or more embodiments, the active agent is an agent
useful in the treatment of acne, wrinkles and scars. Examples of
useful anti-acne actives include resorcinol, sulfur, salicylic acid
and salicylates, alpha-hydroxy acids, nonsteroidal
anti-inflammatory agents, benzoyl peroxide, retinoic acid,
isoretinoic acid and other retinoid compounds, adapalene,
tazarotene, azelaic acid and azelaic acid derivatives, antibiotic
agents, such as erythromycin and clyndamycin, zinc salts and
complexes, and combinations thereof, in a therapeutically effective
concentration. Exemplary anti-wrinkle/anti-atrophy active agents
suitable for use in the compositions of the present invention
include sulfur-containing D and L amino acids and their derivatives
and salts, particularly the N-acetyl derivatives; thiols; hydroxy
acids (e.g., alpha-hydroxy acids such as lactic acid and glycolic
acid and their derivatives and salts; or beta-hydroxy acids such as
salicylic acid and salicylic acid salts and derivatives), 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). In the case of dry, scaly skin
(xerosis) and ichthyosis such agents can alleviate the symptoms by
temporary relief of itching associated with these conditions.
[0129] In one or more embodiments, the active agent is an
anti-oxidant or a radical scavenger. Anti-oxidants/radical
scavengers such as ascorbic acid (vitamin C) and its salts,
ascorbyl esters of fatty acids, ascorbic acid derivatives (e.g.,
magnesium ascorbyl phosphate, sodium ascorbyl phosphate, ascorbyl
sorbate), tocopherol (vitamin E), tocopherol sorbate, tocopherol
acetate, other esters of tocopherol, butylated hydroxy benzoic
acids and their salts,
6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid, gallic acid
and its alkyl esters, especially propyl gallate, uric acid and its
salts and alkyl esters, sorbic acid and its salts, lipoic acid,
amines (e.g., N,N-diethylhydroxylamine, amino-guanidine),
sulfhydryl compounds (e.g., glutathione), dihydroxy fumaric acid
and its salts, lycine pidolate, arginine pilolate,
nordihydroguaiaretic acid, bioflavonoids, curcumin, lysine,
methionine, proline, superoxide dismutase, silymarin, tea extracts,
grape skin/seed extracts, melanin, and rosemary extracts may be
used.
[0130] It is further pointed out that polyunsaturated fatty acids,
containing omega-3 and omega-6 fatty acids (e.g., linoleic and
linolenic acid, gamma-linoleic acid (GLA), eicosapentaenoic acid
(EPA) and docosahexaenoic acid (DHA)) are beneficial in the
treatment of psoriasis and other skin inflammation conditions.
Likewise, emollients and silicone oils exert moisture-retaining and
skin protective effects on the skin. Thus, in a preferred
embodiment, a skin protective foam is provided, wherein the
hydrophobic carrier comprises in full or in part, an organic liquid
selected from the group consisting of emollients, silicone oil and
oils rich in unsaturated fatty acids.
[0131] In one or more embodiments, the active agent is a
self-tanning active Agent, such as dihydroxyacetone.
[0132] According to another embodiment, the active agent comprises
solid matter or particulate matter, i.e., material that is not
soluble in the liquid carrier composition of the foamable
composition. For definition purposes, solid matter shall mean
material that is not soluble in the foamable composition more than
10% of the concentration intended to be included in said foamable
composition. By way of example, the following classes of solid
matter substances are presented: metallic oxides, such as titanium
dioxide, zinc oxide, zirconium oxide, iron oxide; silicon
containing materials such as silicone oxide and talc; carbon, for
example in the form of amorphous carbon or graphite; insoluble
oxidizing agents, such as benzoyl peroxide, calcium and magnesium
hypochlorite; metallic Silver; cosmetic scrub materials, including,
for example meals of strawberry seeds, raspberry seeds, apricot
seeds, sweet almond, cranberry seeds; and pigments.
[0133] According to certain embodiments, the active agent is
selected from the group of solvent, surface active agent, foam
adjuvant and gelling agent, which are, on a case-by-case basis,
known to possess a therapeutic benefit.
[0134] In one or more embodiments at least one or at least two
active agents are included in the composition.
[0135] Composition and Foam Physical Characteristics and
Advantages
[0136] 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.
[0137] The foamable composition can be in the state of (1)
solutions; (2) a readily dispersable suspension; or (3) an
emulsion. It is stable, having an acceptable shelf life of a year,
or at least two years at ambient temperature, as revealed in
accelerated stability tests. Polar solvents, hydrophobic carriers
and propellants, which are a mixture of low molecular weight
hydrocarbons, tend to impair the stability of emulsions and to
interfere with the formation of a 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.
[0138] 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. Compositions containing
semi-solid hydrophobic solvents, e.g., white petrolatum, as the
main ingredients of the oil phase of the emulsion, exhibit high
viscosity and poor flowability and are inappropriate candidates for
a foamable composition.
[0139] Foam quality can be graded as follows:
[0140] 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.
[0141] 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.
[0142] 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.
[0143] 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.
[0144] Grade P (poor): no creaminess noticeable, large bubble
structure, and when spread on the skin it becomes very thin and
watery in appearance.
[0145] Grade VP (very poor): dry foam, large very dull bubbles,
difficult to spread on the skin.
[0146] 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.
[0147] As a 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.
[0148] The foam of the present invention has several advantages,
when compared with hydroalcoholic foam compositions, such as
described in U.S. Pat. Nos. 6,126,920 and 5,783,202: [0149] (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. [0150] (2) Skin drying and skin barrier function.
Polar solvents known to dry the skin and impair the integrity of
the skin barrier. By contrast, combining a polar solvent and a
hydrophobic carrier, as described herein, unwanted skin barrier
damage is reduced, as demonstrated in tran-epidermal water loss
measurements. [0151] (3) Irritability. Due to the improvement in
skin barrier function, skin irritability is corrected.
[0152] In terms of usability, the foamable composition is most
advantageous, as revealed by clinical trials:
[0153] (i) Ease of application. [0154] When foam is released it
expands and allows easy spreading on the target area. This
advantage is particularly meaningful in regards to the treatment of
large skin surfaces. [0155] Upon application, the foam readily
spreads and absorbs into the skin.
[0156] (ii) The Foam is Drip-Free [0157] The foam is not liquid and
therefore does not leak when applied. [0158] This allows precise
application, without the product being spread on clothes or other
parts of the body.
[0159] 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 0.12 g/mL; or
less than 0.08 g/mL, depending on their composition and on the
propellant concentration.
[0160] For the purpose of the specification the external limits of
the various ranges given are approximate as will be appreciated by
those skilled in the art. Therefore, for the purpose of
interpreting the outer limits of the range the limits shall be
deemed to include up to a 20% leeway outside the range, preferably
a 10% leeway.
[0161] Fields of Applications
[0162] According to one or more embodiments of the present
invention, the foamable carrier and the foamable pharmaceutical or
cosmetic composition of the present invention are intended for
administration to an animal or a human subject. In one or more
embodiments, the composition is intended to treat the skin, a body
surface, a body cavity or a mucosal surface, e.g., the mucosa of
the nose, mouth, eye, ear, respiratory system, vagina or
rectum.
[0163] By including an appropriate active agent in the compositions
of the present invention, the composition are useful in treating a
patient having any one of a variety of dermatological disorders,
which include inflammation as one or their etiological factors
(also termed "dermatoses"), such as classified in a non-limiting
exemplary manner according to the following groups:
[0164] Dermatitis including contact dermatitis, atopic dermatitis,
seborrheic dermatitis, nummular dermatitis, chronic dermatitis of
the hands and feet, generalized exfoliative dermatitis, stasis
dermatitis; lichen simplex chronicus; diaper rash;
[0165] Bacterial infections including cellulitis, acute
lymphangitis, lymphadenitis, erysipelas, cutaneous abscesses,
necrotizing subcutaneous infections, staphylococcal scalded skin
syndrome, folliculitis, furuncles, hidradenitis suppurativa,
carbuncles, paronychial infections, and erythrasma;
[0166] Fungal Infections including dermatophyte infections, yeast
Infections; parasitic Infections including scabies, pediculosis,
creeping eruption;
[0167] Viral Infections;
[0168] Disorders of hair follicles and sebaceous glands including
acne, rosacea, perioral dermatitis, hypertrichosis (hirsutism),
alopecia, including male pattern baldness, alopecia areata,
alopecia universalis and alopecia totalis; pseudofolliculitis
barbae, keratinous cyst;
[0169] Scaling papular diseases including psoriasis, pityriasis
rosea, lichen planus, pityriasis rubra pilaris;
[0170] Benign tumors including moles, dysplastic nevi, skin tags,
lipomas, angiomas, pyogenic granuloma, seborrheic keratoses,
dermatofibroma, keratoacanthoma, keloid;
[0171] Malignant tumors including basal cell carcinoma, squamous
cell carcinoma, malignant melanoma, paget's disease of the nipples,
kaposi's sarcoma;
[0172] Reactions to sunlight, including sunburn, chronic effects of
sunlight, photosensitivity;
[0173] Bullous diseases including pemphigus, bullous pemphigoid,
dermatitis herpetiformis, linear immunoglobulin A disease;
[0174] Pigmentation disorders including hypopigmentation such as
vitiligo, albinism and postinflammatory hypopigmentation and
hyperpigmentation such as melasma (chloasma), drug-induced
hyperpigmentation, postinflammatory hyperpigmentation;
[0175] Disorders of cornification including ichthyosis, keratosis
pilaris, calluses and corns, actinic keratosis;
[0176] Pressure sores, open wounds, chronic wounds, open ulcers and
burns; Disorders of sweating; and
[0177] Inflammatory reactions including drug eruptions, toxic
epidermal necrolysis, erythema multiforme, erythema nodosum, and
granuloma annulare.
[0178] The same advantage is expected when the composition is
topically applied to a body cavity or mucosal surfaces, including,
but not limited to the cranial cavity, the thoratic cavity, the
abdominal cavity, the venteral cavity, the vagina, the rectum and
penile cavities, the urinary tract, the nasal cavity, the mouth,
the eye, the ear the peritoneum, the large and small bowel, the
caecum, bladder, and stomach, the cavity between the uterus and the
fallopian tubes, the ovaries and other body areas, which may accept
topically-applied products. The composition of the present
invention is suitable to treat conditions of a body cavity and a
mucosal membrane, such as post-surgical adhesions, 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] According to one or more embodiments of the present
invention, the compositions are also useful in the therapy of
non-dermatological disorders by providing transdermal or
trans-mucosal delivery of an active agent that is effective against
non-dermatological disorders.
[0180] In one or more embodiments, the disorder is a health
abnormality that responds to treatment with a hormone. A typical
example of such abnormality is sexual dysfunction in men and women
whereby androgen therapy is successfully used to restore sexual
function. Other non-limiting examples of disorders/medical
indications that are in the scope of treatment with a hormone
according to the present invention are androgen deficiency,
estrogen deficiency, growth disorders, hypogonadism, cancer,
vasomotor symptoms, menopausal disorders, vulvar and vaginal
atrophy, urethritis, hypoestrogenism, osteoarthritis, osteoporosis,
uterine bleeding, Hirsutism, Virilization, ovarian tumors,
hypothalamic pituitary unit diseases, testicular tumors, prostate
cancer, hypopituitarism, Klinefelter's syndrome, testicular
feminisation, orchitectomy, vasomotor symptoms (such as "hot
flashes") associated with the menopause, metabolic abnormalities
and mood disturbances.
[0181] The following examples further exemplify the, foamable
carrier, the pharmaceutical and cosmetic compositions of the
present invention, methods for preparing the same, and therapeutic
uses of the compositions. The examples are for the purposes of
illustration only and are not intended to be limiting of the
invention. Many variations may be carried out by one of ordinary
skill in the art and are contemplated within the full scope of the
present invention.
[0182] A general procedure for preparing foamable compositions is
set out in WO 2004/037225 which is incorporated herin by reference.
Moreover, with respect to using one or more polar solvents, the
polor solvent is added to the aqueous phase mixture in the course
of preparation.
Example 1--Foamable Carrier, Containing Polar Solvent (Dimethyl
Isosorbide) and Hydrophobic Carrier (Caprylic/Capric
Triglyceride)
TABLE-US-00002 [0183] Foam A Foam B Foam C % w/w % w/w % w/w
Caprylic/capric 30.0 19.0 40.0 triglyceride (Hydrophobic carrier)
Dimethyl isosorbide 20.0 20.0 20.0 (Polar solvent) Glyceryl oleate
1.0 2.0 1.0 (Surfactant) PPG-15 stearyl ether 5.0 15.0 5.0
(Surfactant) Lecithin (Surfactant) 20.0 20.0 10.0 Sorbitan stearate
-- -- 5.0 (Surfactant) Sucrose stearate 5.0 5.0 -- (Surfactant) PVP
K-90 0.5 0.5 0.5 (Polymeric agent) Preservative 0.5 0.5 0.5
Propane/Butane 8.00 8.00 8.00 (Propellant) Purified water to100.00
to100.00 to100.00 Foam properties Foam quality Excellent Excellent
Excellent Density 0.06 0.08 0.06 Formulation type Dispersion
Homogeneity Homogenious Homogenious Homogenious upon mild upon mild
upon mild shaking shaking shaking
Example 2--Foamable Carrier, Containing Polar Solvent (Dimethyl
Isosorbide and Propylene Glycol) and Hydrophobic Carrier
(Caprylic/Capric Triglyceride and Isopropyl Myristate)
TABLE-US-00003 [0184] Foam D Foam E Foam F % w/w % w/w % w/w
Caprylic/capric 5.00 5.00 5.00 triglyceride (Hydrophobic carrier)
Isopropyl myristate 5.00 5.00 5.00 (Hydrophobic carrier) Dimethyl
isosorbide 55.50 62.00 59.00 (Polar solvent) Propylene glycol 2.50
-- -- (Polar solvent) Glyceryl monostearate -- 1.00 1.00
(Surfactant) Sorbitan monostearate 8.00 5.00 8.00 (Surfactant)
Sucrose stearate 5.00 5.00 8.00 (Surfactant) Hydroxypropyl- -- 0.50
-- cellulose (Polymeric agent) Cetostearyl alcohol 8.00 8.00 --
(Foam adjuvant) Stearyl alcohol -- -- 5.00 (Foam adjuvant) Oleyl
alcohol 2.50 -- -- (Foam adjuvant) Preservative 0.5 0.5 0.5
Propane/Butane 8.00 8.00 8.00 (Propellant) Purified water to100.00
to100.00 to100.00 Foam properties Foam quality Excellent Excellent
Good Density 0.13 0.23 0.21 Formulation type Solution Solution
Solution Homogeneity Homogeneous Homogeneous Homogeneous upon mild
upon mild upon mild shaking shaking shaking
Example 3--Foamable Carrier, in the Form of Emulsion, Containing
Polar Solvent (Diethyl Isosorbide) and Hydrophobic Carrier
(Caprylic/Capric Triglyceride)
TABLE-US-00004 [0185] Foam G % w/w Caprylic/capric triglyceride
(Hydrophobic carrier) 30.00 Dimethyl isosorbide (Polar solvent)
20.00 Glyceryl monostearate (Surfactant) 2.00 PPG-15 stearyl ether
3.00 Sorbitan stearate (Surfactant) 2.00 Xanthan gum (Polymeric
agent) 0.15 Hydroxypropyl methylcellulose (Polymeric agent) 0.15
Stearyl alcohol (Foam adjuvant) 1.00 Preservative 0.5
Propane/Butane (Propellant) 8.00 Purified water to100.00 Foam
properties Foam quality Excellent Density 0.12 Formulation type
Emulsion Emulsion stability (centrifuge) Stable
Example 4--Foamable Carrier, in the Form of Emulsion, Containing
Polar Solvent (Ethanol) and Hydrophobic Carrier (Caprylic/Capric
Triglyceride)
TABLE-US-00005 [0186] Foam H Foam I % w/w % w/w Mineral oil
(Hydrophobic carrier) 4.62 4.32 Isopropyl myristate (Hydrophobic
carrier) 4.62 4.32 Ethanol (Polar solvent) 15.00 20.00 Glyceryl
monostearate (Surfactant) 0.39 0.36 Polysorbate 80 (Surfactant)
0.77 0.72 PEG-40 stearate (Surfactant) 2.31 2.16 Xanthan gum
(Polymeric agent) 0.23 0.22 Hydroxypropyl methylcellulose
(Polymeric agent) 0.23 0.22 Stearyl alcohol (Foam adjuvant) 0.77
0.72 Preservative 0.50 0.50 Propane/Butane (Propellant) 8.00 8.00
Purified water to100.00 to100.00 Foam properties Foam quality
Excellent Excellent Density 0.04 0.04 Formulation type Emulsion
Emulsion Emulsion stability (centrifuge) Stable Stable
Example 5--Non-Flammable Foamable Carriers
TABLE-US-00006 [0187] Foam J % w/w Caprylic/capric triglyceride
(Hydrophobic carrier) 5.00 Isopropyl myristate (Hydrophobic
carrier) 5.00 Dimethyl isosorbide (Polar solvent) 59.00 Propylene
glycol (Polar solvent) -- Glyceryl monostearate (Surfactant) 1.00
Sorbitan monostearate (Surfactant) 8.00 Sucrose stearate
(Surfactant) 8.00 Hydroxypropylcellulose (Polymeric agent) --
Cetostearyl alcohol (Foam adjuvant) -- Stearyl alcohol (Foam
adjuvant) 5.00 Oleyl alcohol (Foam adjuvant) -- Preservative 0.5
1,1,1,2 tetrafluorethane (Dymel 134) 8.00 Purified water to100.00
Foam K % w/w Mineral oil (Hydrophobic carrier) 4.32 Isopropyl
myristate (Hydrophobic carrier) 4.32 Ethanol (Polar solvent) 20.00
Glyceryl monostearate (Surfactant) 0.36 Polysorbate 80 (Surfactant)
0.72 PEG-40 stearate (Surfactant) 2.16 Xanthan gum (Polymeric
agent) 0.22 Hydroxypropyl methylcellulose (Polymeric agent) 0.22
Stearyl alcohol (Foam adjuvant) 0.72 Preservative 0.50 1,1,1,2
tetrafluorethane (Dymel 134) 8.00 Purified water to100.00
Example 6--Inflammability Test
[0188] The following compositions were tested for inflammability
according to European Standard prEN 14851: (1) Foam F; (2) Foam I;
(3) Foam J; and (4) Foam K.
[0189] Procedure: Approximately 5 g of foam, mousse gel or paste is
sprayed from the aerosol container on to a watchglass. An ignition
source (a lighter) was placed at the base of the watchglass and any
ignition and sustained combustion of the foam, mousse, gel or paste
was observed. The test was carried out in a draught-free
environment capable of ventilation, with the temperature controlled
at 20.degree. C..+-.5.degree. C. and relative humidity in the range
of 30% to 80%. According to the standard, appearance of a stable
flame which is at least 4 cm high and which is maintained for at
least 2 seconds defines a product as "inflammable".
Results:
[0190] Foam F and Foam I were found "inflammable".
[0191] Foam J and Foam K were found "non-flammable".
Example 7
[0192] Exemplary concentrations of active agents in foamable
compositions are set out in Table 2. Each active agent is added
into, for example, any of the carriers listed in any of Examples 1
to 5 above in a therapeutically effective concentration and amount.
The methodology of addition is well known to those of the art. The
composition is adjusted in each case so that it is made up to 100%
w/w as appropriate by purified water.
TABLE-US-00007 TABLE 2 Exemplary Concentrations of Examples of
Active Agents Concen- Class tration Exemplary Use Hydrocortisone
acetate 1% Steroid responsive inflammation Betamethasone valerate
0.1% and psoriasis or atopic dermatitis Clobetasol proprionate
0.05% Acyclovir 5% Viral infection, herpes Ciclopirox 1% Fungal
infection, seborrhea, dandruff, Clindomycin 2% Bacterial infection,
acne, rosacea, Azelaic acid 15% Acne, rosacea, pigmentation
disorder and various dermatoses Metronidazol 0.25%-2% Rosacea,
bacterial infections and parasite infestations Diclofenac 1%
Osteoarthritus, joint pain Tachrolimus 0.2% Atopic dermatitis,
eczema and inflammation
[0193] The above examples represent different drug classes and it
is to be understood that other drugs belonging to each of the
classes represented above may be included and used in the
compositions of the present invention in a safe and effective
amount.
* * * * *