U.S. patent application number 13/795831 was filed with the patent office on 2013-07-25 for foamable composition.
This patent application is currently assigned to FOAMIX LTD.. The applicant listed for this patent is Foamix Ltd.. Invention is credited to Meir Eini, Doron Friedman, Dov Tamarkin.
Application Number | 20130189196 13/795831 |
Document ID | / |
Family ID | 29765086 |
Filed Date | 2013-07-25 |
United States Patent
Application |
20130189196 |
Kind Code |
A1 |
Tamarkin; Dov ; et
al. |
July 25, 2013 |
Foamable Composition
Abstract
A foamable composition, includes (1) about 6% to about 70% by
weight of at least one organic carrier; (2) about 0.1% to about 5%
by weight of at least one surface-active agent; (3) about 0.01% to
about 5% by weight of at least one film forming agent; (4) water;
and (5) about 3% to about 25% by weight of the total composition of
at least one liquefied or compressed gas propellant. The
composition is substantially alcohol free and is used in treating,
alleviating or preventing a disorder.
Inventors: |
Tamarkin; Dov; (Macabim,
IL) ; Friedman; Doron; (Karmei Yosef, IL) ;
Eini; Meir; (Ness Ziona, IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Foamix Ltd.; |
Rohovot |
|
IL |
|
|
Assignee: |
FOAMIX LTD.
Rohovot
IL
|
Family ID: |
29765086 |
Appl. No.: |
13/795831 |
Filed: |
March 12, 2013 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
11337747 |
Jan 23, 2006 |
|
|
|
13795831 |
|
|
|
|
10911367 |
Aug 4, 2004 |
|
|
|
11337747 |
|
|
|
|
10922358 |
Aug 20, 2004 |
7700076 |
|
|
11337747 |
|
|
|
|
60492385 |
Aug 4, 2003 |
|
|
|
60497648 |
Aug 25, 2003 |
|
|
|
Current U.S.
Class: |
424/47 ;
424/45 |
Current CPC
Class: |
A61K 8/046 20130101;
A01N 25/16 20130101; A61K 9/0014 20130101; A61K 8/8152 20130101;
A61K 9/122 20130101; A61Q 19/02 20130101; A61K 8/345 20130101; A61K
8/34 20130101; A61Q 19/007 20130101; A61Q 17/04 20130101; A61K
8/922 20130101; A61K 2800/244 20130101; A61Q 19/00 20130101; A61Q
19/08 20130101; A61K 2800/24 20130101; A61K 8/87 20130101; A61Q
17/02 20130101; A61K 8/731 20130101; A61K 2800/242 20130101; A61K
8/8158 20130101; A61K 8/42 20130101; A61K 2800/30 20130101; A61K
8/736 20130101 |
Class at
Publication: |
424/47 ;
424/45 |
International
Class: |
A61K 8/04 20060101
A61K008/04; A61Q 19/08 20060101 A61Q019/08; A61Q 19/02 20060101
A61Q019/02; A61Q 19/00 20060101 A61Q019/00; A61K 9/12 20060101
A61K009/12; A61Q 17/04 20060101 A61Q017/04 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 25, 2002 |
IL |
152486 |
Claims
1. A foamable composition comprising a carrier composition and a
propellant, the carrier composition comprising: a) about 6% to
about 70% by weight of the carrier composition of an organic
carrier selected from the group consisting of a hydrophobic organic
carrier, an emollient, a polar solvent, and mixtures of any two or
more thereof; b) about 0.1% to about 5% by weight of the carrier
composition of a surface-active agent, wherein the surface-active
agent present is a non-ionic surface-active agent or a mixture of a
non-ionic surface-active agent and an ionic surface-active agent in
a ratio of 6:1 or greater than about 6:1 by weight; c) an active
agent; and d) water; wherein the propellant comprises about 3% to
about 25% by weight of the carrier composition of a liquefied or
compressed gas propellant; and wherein upon release from a
container, the foamable composition forms a breakable foam.
2. The foamable composition of claim 1, wherein the carrier
composition further comprises about 0.01% to about 5% by weight of
the carrier composition of a polymeric additive selected from the
group consisting of a gelling agent, a bioadhesive agent, a phase
change agent, and mixtures of any two or more thereof.
3. The foamable composition of claim 1, wherein the carrier
composition further comprises about 0.01% to about 5% by weight of
the carrier composition of a film forming agent.
4. The foamable composition of claim 1, wherein the carrier
composition further comprises about 0.1% to about 5% by weight of
the carrier composition of a foam adjuvant selected from the group
consisting of a fatty alcohol, a fatty acid, and mixtures
thereof.
5. The foamable composition of claim 1, wherein the organic carrier
comprises a hydrophobic organic carrier and an emollient in a ratio
of 2:8 to 8:2 by weight.
6. The foamable composition of claim 2, wherein the active agent is
selected from the group consisting of a cosmetic active agent, an
anti-infective, an antibiotic, an antibacterial agent, a
disinfectant, an antifungal agent, an antiviral agent, an
antiparasitic agent, an anti-inflammatory agent, an anti-allergic
agent, a steroid, a steroidal anti-inflammatory agent, a
nonsteroidal anti-inflammatory drug, an immunosuppressive agent, an
immunomodulator, an immunoregulating agent, a hormone, a
keratolytically active agent, an alpha hydroxyl acid, a
beta-hydroxy acid, 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,
an anesthetic, a protein, a peptide, a neuropeptide, a allergen, an
immunogenic substance, a haptene, an oxidizing agent, an
antioxidant, a dicarboxylic acid, an antiproliferative agent, an
anticancer agent, a photodynamic therapy agent, a sunscreen agent,
an anti-wrinkle agent, a radical scavenger, a metal oxide, an anti
wrinkle agent, 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 of any two or more thereof.
7. The foamable composition of claim 1, wherein the surface-active
agent is selected from the group consisting of a polysorbate, a
polyoxyethylene fatty acid ester, a polyoxyethylene alkyl ether, a
sucrose ester, a partial ester of sorbitol, a partial ester of
sorbitol anhydride, sodium methyl cocoyl taurate, sodium methyl
oleoyl taurate, sodium lauryl sulfate, triethanolamine lauryl
sulfate, a betaine, a mono-, di- or tri-ester of sucrose with fatty
acids, a monoglyceride, a diglyceride, polyoxyethylene (20)
sorbitan monostearate, polyoxyethylene (20) sorbitan monooleate,
polyoxyethylene (8) Stearate, polyoxyethylene (20) stearate,
polyoxyethylene (100) stearate, a polyoxyethylene cetyl ether,
polyoxyethylene (2) cetyl ether, polyoxyethylene (10) cetyl ether,
sorbitan monolaurate, isoceteth-20, cocamidopropyl betaine,
polyoxyethylene 40 stearate, and mixtures of any two or more
thereof.
8. The foamable composition of claim 1, wherein the surface-active
agent is a non ionic surface-active agent.
9. The foamable composition of claim 8, wherein the surface-active
agent comprises at least one non-ionic surface-active agent having
an HLB of less than 9 and at least one non-ionic surface-active
agent having HLB of equal or more than 9.
10. The foamable composition of claim 1, wherein the breakable foam
has a specific gravity of less than about 0.12 g/mL.
11. The foamable composition of claim 1, wherein the breakable foam
does not immediately collapse upon exposure to body
temperature.
12. The foamable composition of claim 1, wherein the propellant is
selected from the group consisting of butane, propane, isobutane,
and mixtures of any two or more thereof.
13. The foamable composition of claim 2, wherein the polymeric
additive comprises a gelling agent selected from the group
consisting of locust bean gum, sodium alginate, sodium caseinate,
egg albumin, gelatin agar, carrageenin gum, xanthan gum, quince
seed extract, tragacanth gum, guar gum, starch, chemically modified
starches, cellulose ethers, hydroxyethyl cellulose, methyl
cellulose, carboxymethyl cellulose, hydroxy propylmethyl cellulose,
hydroxypropyl guar gum, soluble starch, cationic celluloses,
cationic guars, carboxyvinyl polymers, polyvinylpyrrolidone,
polyvinyl alcohol, polyacrylic acid polymers, polymethacrylic acid
polymers, polyvinyl acetate polymers, polyvinyl chloride polymers,
polyvinylidene chloride polymers, acrylic acid/ethyl acrylate
copolymers, crosslinked copolymers of acrylic acid and C10-C30
alkyl acrylate, carboxyvinyl polymers, carbopols, and mixtures of
any two or more thereof.
14. The foamable composition of claim 1 wherein the organic carrier
comprises two or more of: a) a hydrophobic organic carrier
comprising an oil; b) an emollient selected from the group
consisting of hexylene glycol, propylene glycol, isostearic acid
derivatives, isopropyl palmitate, isopropyl isostearate, isopropyl
myristate, ethyl acetate, butyl acetate, methyl propionate,
capric/caprylic triglycerides, octyl myristate, dodecyl-myristate,
diisopropyl adipate, diisopropyl dimerate, maleated soybean oil,
octyl palmitate, cetyl lactate, cetyl ricinoleate, tocopheryl
acetate, acetylated lanolin alcohol, cetyl acetate, phenyl
trimethicone, glyceryl oleate, tocopheryl linoleate, wheat germ
glycerides, arachidyl propionate, myristyl lactate, decyl oleate,
propylene glycol ricinoleate, isopropyl lanolate, pentaerythrityl
tetrastearate, neopentylglycol dicaprylate/dicaprate, isononyl
isononanoate, isotridecyl isononanoate, myristyl myristate,
triisocetyl citrate, octyl dodecanol, sucrose esters of fatty
acids, octyl hydroxystearate, and mixtures of any two or more
thereof; iii. a polar solvent selected from the group consisting of
a polyol, glycerol, propylene glycol, hexylene glycol, diethylene
glycol, a propylene glycol n-alkanols, a terpene, a di-terpene, a
tri-terpene, a terpen-ol, limonene, menthol, dioxolane, ethylene
glycol, a glycol, a sulfoxide, dimethylsulfoxide,
dimethylformanide, methyl dodecyl sulfoxide, dimethylacetamide,
monooleate of ethoxylated glycerides,
1-dodecylazacycloheptan-2-one, 2-(n-nonyl)-1,3-dioxolane, a
polyethylene glycol, PEG 200, PEG 300, PEG 400, PEG 600, PEG 4000,
PEG 6000, PEG 10000, and mixtures of any two or more thereof.
15. The foamable composition of claim 1, wherein the carrier
comprises a microemulsion.
16. The foamable composition of claim 14, wherein the emollient
comprises diisopropyl adipate.
17. The foamable composition of claim 14, wherein the oil comprises
mineral oil.
18. The foamable composition of claim 8, wherein the surface-active
agent comprises a polyoxyethylene alkyl ether.
19. The foamable composition of claim 6, wherein the retinoid
comprises tazarotene.
20. The foamable composition of claim 1, wherein the carrier is
free of short-chain monohydric alcohols having up to 5 carbon atoms
in their carbon chain.
21. The foamable composition of claim 1, wherein the water is
present in the foamable composition at 25-95% by weight of the
carrier composition.
22. A foamable composition comprising a carrier composition and a
propellant, the carrier composition comprising: a) a hydrating
combination comprising: i. about 6% to about 70% by weight of the
carrier composition of an organic carrier comprising a hydrophobic
organic carrier, an emollient, and a polar solvent; and ii. about
0.01% to about 5% by weight of the carrier composition of a film
forming agent and/or a polymeric agent; b) about 0.1% to about 5%
by weight of the carrier composition of a surface-active agent,
wherein the surface-active agent is a non-ionic surface-active
agent or a mixture of a non-ionic surface-active agent and an ionic
surface-active agent in a ratio of 6:1 or greater than about 6:1 by
weight, and; c) an active agent; and d) water; wherein the
propellant comprises about 3% to about 25% by weight of the carrier
composition of a liquefied or compressed gas propellant, and
wherein upon release from a container, the foamable composition
forms a breakable foam which when applied to skin can elevate skin
hydration by about 20% to about 45%.
23. The foamable composition of claim 22, wherein the hydrophobic
organic carrier and the emollient are in a ratio of 2:8 to 8:2 by
weight.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation application of U.S.
application Ser. No. 11/337,747, filed Jan. 23, 2006, which is 1) a
continuation-in-part application of International Patent
Application No. IB03/005527, 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, and claims
the benefit of priority under 35 U.S.C. .sctn.119(a) to Israeli
Patent Application No. 152486, filed Oct. 25, 2002; 2) a
continuation-in-part application of 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; and 3) a
continuation-in-part application of U.S. patent application Ser.
No. 10/922,358, filed Aug. 20, 2004, 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, and claims the benefit
of priority under 35 U.S.C. .sctn.119(a) to Israeli Patent
Application No. 152486, filed Oct. 25, 2002, all of which are
incorporated by reference in their entirety.
BACKGROUND OF THE INVENTION
[0002] This invention relates to alcohol-free foamable
pharmaceutical and cosmetic compositions that possesses a
film-forming property.
[0003] 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.
[0004] U.S. Pat. No. 6,126,920 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. U.S. Pat. No. 6,126,920 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.
[0005] US Published Application No. 2004/0151671 provides
pharmaceutical compositions in a pressurized container, comprising
a quick breaking alcoholic foaming agent.
[0006] 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.
[0007] 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.
[0008] WO 2004/071479 describes a composition in a pressurized
container for forming a hydroalcoholic foam, comprising at least
one active agent, a water insoluble film forming polymer, a
hydroalcoholic foaming agent and an aerosol propellant.
BRIEF DESCRIPTION OF THE INVENTION
[0009] The present invention provides a film-forming foamable
cosmetic or pharmaceutical vehicle, and cosmetic and/or
pharmaceutical compositions thereof.
[0010] In one or more embodiments, the foamable cosmetic or
pharmaceutical vehicle includes:
[0011] (1) about 6% to about 70% by weight of an organic
carrier;
[0012] (2) about 0.1% to about 5% by weight of a surface-active
agent;
[0013] (3) about 0.01% to about 5% by weight of a film forming
agent; and
[0014] (4) about 3% to about 25% by weight of the total composition
of a liquefied or compressed gas propellant.
[0015] Water and optional ingredients are added to complete the
total mass to 100%.
[0016] 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 an hydrophobic organic carrier
[0017] Thus, in one or more embodiments, the pharmaceutical or
cosmetic foamable product includes:
[0018] (1) an effective concentration of a pharmaceutical or
cosmetic active agent;
[0019] (2) an organic carrier, at a concentration of about 6% to
about 70% by weight;
[0020] (3) about 0.1% to about 5% by weight of a surface-active
agent; and
[0021] (4) a liquefied or compressed gas propellant at a
concentration of about 3% to about 25% by weight of the total
composition.
[0022] Water and optional ingredients are added to complete the
total mass to 100%.
[0023] All % values are provided on a weight (w/w) basis.
DETAILED DESCRIPTION OF THE INVENTION
[0024] The foamable composition is substantially alcohol-free,
i.e., free of short chain monohydric alcohols. Short chain
monohydric alcohols, having up to 5 carbon atoms in their carbon
chain skeleton and one hydroxyl group, such as ethanol, propanol,
isopropanol, butanol, iso-butanol, t-butanol and pentanol, are
considered less desirable solvents or polar solvents due to their
skin-irritating effect. Thus, the composition is substantially
alcohol-free and includes less than about 5% final concentration of
lower alcohols, preferably less than about 2%, more preferably less
than about 1%.
[0025] The foamable composition of the present invention can be an
emulsion, or microemulsion, including an aqueous phase and an
organic carrier phase. The organic carrier, also termed herein
interchangeably "organic solvent" or "solvent", is selected from a
hydrophobic organic carrier (also termed herein "hydrophobic
solvent"), an emollient, a polar solvent, and a mixture
thereof.
Organic Carrier
[0026] The organic carrier includes hydrophobic solvent carriers,
polar solvent carriers and emollients, and mixtures thereof. The
identification of an organic carrier (or "solvent"), as used
herein, is not intended to characterize the solubilization
capabilities of the carrier 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 an organic carrier in the foamable compositions
described herein. 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. It is liquid at ambient
temperature.
[0027] In one or more embodiments, the hydrophobic organic carrier
is an oil, such as mineral oil. Mineral oil (Chemical Abstracts
Service Registry number 8012-95-1) is a mixture of aliphatic,
naphthalenic, and aromatic liquid hydrocarbons that derive from
petroleum. It is typically liquid; its viscosity is in the range of
between about 35 CST and about 100 CST (at 40.degree. C.), and its
pour point (the lowest temperature at which an oil can be handled
without excessive amounts of wax crystals forming so preventing
flow) is below 0.degree. C.
[0028] 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.
[0029] 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. In the context of
the present invention, oils that possess therapeutically beneficial
properties are termed "therapeutically active oil".
[0030] Another class of hydrophobic solvents is the essential oils,
which are also considered therapeutically active oil, which contain
active biologically occurring molecules and, upon topical
application, exert a therapeutic effect, which is conceivably
synergistic to the beneficial effect of the steroid in the
composition.
[0031] Another class of therapeutically active oils includes liquid
hydrophobic plant-derived oils, which are known to possess
therapeutic benefits when applied topically.
[0032] 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. These
are chosen from cyclic or linear polydimethylsiloxanes containing
from about 3 to about 9, preferably from about 4 to about 5,
silicon atoms. Volatile silicones such as cyclomethicones can also
be used. Silicone oils are also considered therapeutically active
oil, due to their barrier retaining and protective properties.
[0033] In one or more embodiments, the hydrophobic carrier includes
at least 2% by weight silicone oil or at least 5% by weight.
[0034] The solvent may be a mixture of two or more of the above
hydrophobic solvents in any proportion.
[0035] A further class of organic carrier includes "emollients"
that have a softening or soothing effect, especially when applied
to body areas, such as the skin and mucosal surfaces. Emollients
are not necessarily hydrophobic. Examples of suitable emollients
include hexyleneglycol, propylene glycol, isostearic acid
derivatives, isopropyl palmitate, isopropyl isostearate,
diisopropyl adipate, diisopropyl dimerate, maleated soybean oil,
octyl palmitate, cetyl lactate, cetyl ricinoleate, tocopheryl
acetate, acetylated lanolin alcohol, cetyl acetate, phenyl
trimethicone, glyceryl oleate, tocopheryl linoleate, wheat germ
glycerides, arachidyl propionate, myristyl lactate, decyl oleate,
propylene glycol ricinoleate, isopropyl lanolate, pentaerythrityl
tetrastearate, neopentylglycol dicaprylate/dicaprate, isononyl
isononanoate, isotridecyl isononanoate, myristyl myristate,
triisocetyl citrate, octyl dodecanol, sucrose esters of fatty
acids, octyl hydroxystearate and mixtures thereof.
[0036] According to one or more embodiments of the present
invention, the hydrophobic organic carrier includes a mixture of a
hydrophobic solvent and an emollient. According to one or more
embodiments, the foamable composition is a mixture of mineral oil
and an emollient in a ratio between 2:8 and 8:2 on a weight
basis.
[0037] A "polar solvent" is an organic solvent, typically soluble
in both water and oil. Examples of polar solvents include polyols,
such as glycerol (glycerin), propylene glycol, hexylene glycol,
diethylene glycol, propylene glycol n-alkanols, terpenes,
di-terpenes, tri-terpenes, terpen-ols, limonene, terpene-ol,
1-menthol, dioxolane, ethylene glycol, other glycols, sulfoxides,
such as dimethylsulfoxide (DMSO), dimethylformanide, methyl dodecyl
sulfoxide, dimethylacetamide, monooleate of ethoxylated glycerides
(with 8 to 10 ethylene oxide units), azone
(1-dodecylazacycloheptan-2-one), 2-(n-nonyl)-1,3-dioxolane, esters,
such as isopropyl myristate/palmitate, ethyl acetate, butyl
acetate, methyl proprionate, capric/caprylic triglycerides,
octylmyristate, dodecyl-myristate; myristyl alcohol, lauryl
alcohol, lauric acid, lauryl lactate ketones; amides, such as
acetamide oleates such as triolein; various alkanoic acids such as
caprylic acid; lactam compounds, such as azone; alkanols, such as
dialkylamino acetates, and admixtures thereof.
[0038] According to one or more 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.
[0039] In one or more embodiments, a pharmaceutically or
cosmetically active agent is an organic substance which is
semi-liquid or liquid at ambient temperature. As such, a
semi-liquid or liquid pharmaceutically or cosmetically active agent
can be considered as part of the "organic carrier", as defined
herein. Non-limiting examples of semi-liquid or liquid
pharmaceutically or cosmetically active agent include, but are not
limited to permethrin, pyrethrum extract, piperonyl butoxide,
diethyl toluamide (DEET), dimethyl phthalate and vitamin E
(tocopherol). Several sunscreen agents are semi-liquid or liquid.
The semi-liquid or liquid pharmaceutically or cosmetically active
agent can be included in the foamable composition as a sole organic
carrier component, or in combination with additional organic
carriers, as detailed above. In certain case, such as the DEET
composition for insect repellency the only "organic carrier" is
DEET, which is present at a 5%-30% concentration and more
preferably at a concentration of 15-20%.
[0040] In certain embodiments, the organic carrier is a combination
of a hydrophobic carrier and a polar solvent; or a combination of
an emollient and a polar solvent; or a combination of a hydrophobic
carrier, an emollient and a polar solvent. Polar solvents may be
added to the foam composition for a variety of reasons, such as to
increase drug solubilization, promote dermal drug delivery or
provide a desired sensory feeling. However, polar solvents tend to
dry the skin and impair the integrity of the skin barrier. By
contrast, by combining a polar solvent and a hydrophobic carrier,
or an emollient or both, unwanted skin barrier damage is reduced. A
ratio of 8:1 and 1:4 between the hydrophobic carrier/emollient and
the polar solvent is preferred.
Film Forming Agent
[0041] The foamable composition of the present invention contains a
film forming agent. The film forming agent serves to stabilize the
foam composition and to control drug residence in the target organ,
thereby limiting the rate of its clearance from the site. The film
formation properties of the foamable composition help maintain
active ingredients on the site of application by imparting
resistance to abrasion or rub-off. Furthermore, in certain cases,
the film that is formed promotes the penetration of active agents
into the skin (intradermal penetration) and through the skin
(transdermal penetration), as it creates an occlusive or
semi-occlusive layer at the treatment site.
[0042] The film forming component may include at least one
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.
[0043] Exemplary commercially available film forming agent is
DERMACRYL from National Starch and Chemical Co. These hydrophobic,
high-molecular-weight, carboxylated acrylic copolymers are
compatible with a broad range of cosmetic raw materials. They can
be used in traditional O/W and W/O emulsions. Exemplary DERMACRYL
copolymers, suitable as film forming agents according to the
present invention include DERMACRYL-LT, DERMACRYL-79 and
DERMACRYL-AQF.
[0044] Another exemplary commercially available film forming agent
is Aculyn from Rohm & Haas. Aculyn is an anionic
hydrophobically modified alkali-soluble acrylic polymer emulsion
(HASE) this is lightly crosslinked with unusually high aqueous
thickening and stabilizing efficiency. Suitable acrylate copolymers
are exemplified by, but are not limited to Aculyn 22
(acrylates/steareth-20 methacrylate copolymer-Rohm & Haas)
Aculyn 25 (acrylates/laureth-25 methacrylate copolymer-Rohm &
Haas), Aculyn 28 (acrylates/beheneth-25 methacrylate copolymer-Rohm
& Haas), Aculyn 46 (PRG-150/stearyl alcohol/SMDI copolymer-Rohm
& Haas). Analogous acrylate copolymers from alternative
commercial sources are also suitable.
[0045] Additional non-limiting examples of film forming polymers
include, but are not limited to hydrophobically-modified
polysaccharides (such as Natrosol Plus from Hercules),
hydrophobically-modified ethoxylated urethanes (such as the RM
series from Rohm & Haas), Acrylates/Alkyl Acrylate
Cross-Polymer (such as Pemulen TR-1 and Pemulen TR-2), Carbopol
1382 (Acrylates/C10-30 alkyl acrylate crosspolymer-Noveon),
Natrosol CS Plus 330, 430, Polysurf 67 (cetyl hydroxyethyl
cellulose-Hercules), Stabylen 30 (acrylates/vinyl isodecanoate-3V),
Structure 2001 (acrylates/steareth-20 itaconate copolymer-National
Starch), Structure 3001 (acrylates/ceteth-20 itaconate
copolymer-National Starch), and Structure Plus
(acrylates/aminoacrylates/C10-30 alkyl PEG 20 itaconate
copolymer-National Starch), polyvinylpyrrolidone/vinylacetate
(Luviskol VA 73W from BASF), polyurethane-1 (Luvi-set PUR from BASF
or PUR 28-001A from National Starch), polyvinylcaprolactam (Luvitec
VCAP from BASF), polyvinylpyrrolidone/polyvinylcaprolactam (Luvitec
VPC from BASF),
polyvinylpyrrolidone/dimethylaminopropylmethacrylamide (Styleze
CC-10 from ISP),
polyvinylpyrrolidone/polyvinylcaprolactam/dimethylaminopropylmethacrylami-
de (Aquaflex SF-40 from ISP), isobutylene
ethylmaleimide/hydroxyethylmaleimide (Aquaflex FX-64 from ISP),
polyvinyl-pyrrolidone/dimethylaminoethylmeth-acrylate (Copolymer
845 from ISP), quaternized
polyvinyl-pyrrolidone/di-methylaminoethylmethacrylate (Gafquat 734,
Gafquat 755, or Gafquat 755N from ISP),
polyvinylpyrrolidone/polyvinylcaprolactam/dimethyl-aminoethylmethacrylate
(Gaffix VC-713 from ISP), and
poly(vinylacetate/crotonates/vinylneodecanoate) (Resyn 28-2930 from
National Starch) and
octylacrylamide/acrylate/butylamino-ethylmethacrylate (Amphomer
from National Starch).
[0046] In one or more embodiments, the film forming agent is
chitosan. Chitosan is a natural polymer obtained by the hydrolysis
of chitin, a native polymer present in shellfish. Together with
chitin, chitosan is considered the second most abundant
polysaccharide after cellulose. Chitosan forms a film by binding to
lipids, proteins and many other biologically active substances of
the skin, hair and other tissues. Importantly, in addition to its
film-forming property, chitosan has antiinfective properties. For
example, chitosan is known to inhibit the adhesion of candida
albicans to human cells and tissues.
[0047] In one or more embodiments, the film forming agent is
pullulan. Pullulan is a polysaccharide produced from a cultivated
fungus of Aureobasidium pullulans (pulluaria pullulans). Pullulan
is an alpha-glucan mainly constituted of maltrotriose as repeating
units linearly joined through alpha-1,6-glycosidic linkages, not
branched. Preferably, the pullulan used in the compositions of the
invention will exhibit a molecular weight of 200,000 to 2,000,000
Daltons. In certain embodiments, the film forming agent is a
combination of pullulan and polyvinyl alcohol, wherein the
composition contains 3 to 30% pullulan and 3 to 30 wt % polyvinyl
alcohol.
[0048] The film forming 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.
[0049] Typically, due to their polymeric nature and their tendency
to form polymeric aggregate and/or networks, film forming agents
also possess gelling properties.
[0050] In order to derive a composition which is readily foamable
upon release from a pressurized container, additional components
are required, as provided hereinbelow.
[0051] 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.
[0052] 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 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. 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.
[0053] 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 non-ionic surfactants
include polysorbates, such as polyoxyethylene (20) sorbitan
monostearate (Tween 60) and poly(oxyethylene) (20) sorbitan
monooleate (Tween 80); poly(oxyethylene) (POE) fatty acid esters,
such as Myrj 45, Myrj 49, Myrj 52 and Myrj 59; poly(oxyethylene)
alkylyl ethers, such as poly(oxyethylene) cetyl ether,
poly(oxyethylene) palmityl ether, polyethylene oxide hexadecyl
ether, polyethylene glycol cetyl ether, brij 38, brij 52, brij 56
and brij W1; sucrose esters, partial esters of sorbitol and its
anhydrides, such as sorbitan monolaurate and sorbitan monolaurate;
mono or diglycerides and isoceteth-20
[0054] Surfactants such as sodium methyl cocoyl taurate, sodium
methyl oleoyl taurate, sodium lauryl sulfate, triethanolamine
lauryl sulfate and betaines are ionic, i.e., anionic, cationic or
zwitterionic.
[0055] In one or more embodiments of the present invention, the
surface-active agent includes an non-ionic surfactant. Ionic
surfactants are known to be effective as foaming agents, however,
they are also known for their skin and mucosal irritancy.
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, which have a lesser foaming
effect provide foams of excellent quality, i.e. a foam quality
score "E" according to the grading scale discussed hereinbelow.
[0056] In one or more embodiments, the surface active agent
includes a mixture of an non-ionic surfactant and an ionic
surfactant in a ratio in the range of about 100:1 to 6:1. In one or
more embodiments, the non-ionic to ionic surfactant ratio is
greater than about 6:1, or greater than about 8:1; or greater than
about 14:1, or greater than about 16:1, or greater than about
20:1.
[0057] 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, or at a ratio of 4:1 to 10:1.
The resultant foam has a low specific gravity, e.g., less than 0.1
g/ml.
[0058] Thus, in an exemplary embodiment, a combination of an
non-ionic surfactant having HLB of less than 9 and an non-ionic
surfactant having HLB of equal or more than 9 is employed, at a
ratio of between 1:8 and 8:1, or at a ratio of 4:1 to 1:4, wherein
the HLB of the combination of emulsifiers is between about 9 and
about 14.
[0059] 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.
[0060] 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%.
[0061] Optionally, gelling agents can be included in the
composition of the present invention, in addition to the film
forming agent. Gelling agents or other polymeric additive may be
present in a range of about 0.01 wt % to about 5 wt %. Exemplary
gelling agents that can be optionally used include, but are not
limited to, 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, starch, chemically modified starches and
the like, semi-synthetic polymeric materials such as cellulose
ethers (e.g. hydroxyethyl cellulose, methyl cellulose,
carboxymethyl cellulose, hydroxy propylmethyl cellulose),
polyvinylpyrrolidone, polyvinylalcohol, 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
contemplated.
[0062] Further exemplary gelling agents include the acrylic
acid/ethyl acrylate copolymers and the carboxyvinyl polymers, which
consist essentially of a colloidal water-soluble polyalkenyl
polyether crosslinked polymer of acrylic acid crosslinked with a
crosslinking agent such as polyallyl sucrose or polyallyl
pentaerythritol. Examples include Carbopol.RTM. 934, Carbopol.RTM.
940, Carbopol.RTM. 950, Carbopol.RTM. 980, Carbopol.RTM. 951 and
Carbopol.RTM. 981.
[0063] In one or more embodiments, the gelling agent is 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..
[0064] Yet, in other embodiments, the gelling agent includes
inorganic gelling agents, such as silicone dioxide (fumed
silica).
[0065] A further class of gelling agents includes
mucoadhesive/bioadhesive polymers in an amount sufficient to confer
bioadhesive properties. The bioadhesive polymers can 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.
[0066] Mixtures of gelling agents are contemplated.
[0067] Optionally, a 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. Foam
adjuvants may be present in a range of about 0.1 wt % to about 5 wt
%. 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 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.
[0068] 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.
[0069] In one or more embodiments, a combination of a fatty acid
and a fatty alcohol is employed. The fatty acids and fatty alcohol
may be present in equal amounts, or the proportions may range from
4:1 and 1:4 fatty acid to fatty alcohol
[0070] The carbon atom chain of the fatty alcohol or the fatty acid
may optionally have one or more double bonds. 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.
[0071] 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.
Active Agent
[0072] In one or more embodiments, the foamable carrier of the
present invention contains a safe an effective concentration of a
pharmaceutical or a cosmetic therapeutic agent (collectively termed
herein as "active agent"). The active agent is present in an amount
to be effective for its intended purpose. The actual amount may
vary widely. For example, in some embodiments, only a few weight
percent or even a fraction of a weight percent of active agent is
sufficient. In other embodiments, e.g., sun screens and insect
repellant, the active agent may constitute a significant component
of the foamable composition.
[0073] 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.
[0074] The composition of the present invention comprises an active
agent that provides therapeutic or cosmetic activity.
[0075] Non-limiting examples of families of active agents include
an anti-infective, an antibiotic, an antibacterial agent, a
disinfectant, an antifungal agent, an antiviral agent, an
antiparasitic agent, an anti-inflammatory agent, an anti-allergic
agent, a steroid, a steroidal anti-inflammatory agent, a
nonsteroidal anti-inflammatory drug, an immunosuppressive agent, an
immunomodulator, an immunoregulating agent, a hormone, a
keratolytically active agent, an alpha hydroxyl acid, a
beta-hydroxy acid, 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,
an anesthetic, a protein, a peptide, a neuropeptide, a allergen, an
immunogenic substance, a haptene, an oxidizing agent, an
antioxidant, a dicarboxylic acid, an antiproliferative agent, an
anticancer agent, a photodynamic therapy agent, a sunscreen agent,
an anti-wrinkle agent, a radical scavenger, a metal oxide, silicone
oxide, talc, an anti wrinkle agent, 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.
[0076] 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.
[0077] An antibiotic or an antibacterial drug can be active against
gram positive and gram-negative bacteria, protozoa, aerobic
bacteria and unaerobic ones.
[0078] 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.
[0079] Additional antibiotic/antibacterial agents, which is
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.
[0080] The antifungal agent can be an azole compound. Exemplary
azole compounds include azole is an imidazole or triazole 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.
[0081] Additional exemplary antifungal agents include griseofulvin,
ciclopirox, amorolfine, terbinafine, Amphotericin B, potassium
iodide, flucytosine (5FC) and any combination thereof at a
therapeutically effective concentration.
[0082] 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 are not
limited to acyclovir, famciclovir, gancyclovir, valganciclovir and
abacavir.
[0083] According to 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
consisting of corticosteroids (also broadly termed herein
"steroids"), non-steroidal anti-inflammatory drugs (NSAIDs),
anti-histamines, immunosuppressive agents, immunomodulators,
immunoregulating agents, and any combination thereof at a
therapeutically effective concentration.
[0084] Non-limiting examples of corticosteroids include
hydrocortisone, hydrocortisone acetate, desonide, Betamethasone,
betamethasone valerate, betamethasone dipropionate,
betamethasone-17-benzoate, clobetasone-17-butyrate, flucinonide,
fluocinolone acetonide, alcometasone dipropionate, mometasone
furoate, prednicarbate, triamcinolone acetonide, methylprednisolone
aceponate, halcinonide, triamcinolone acetonide, halobetasol and
clobetasol-17-propionate.
[0085] 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.
[0086] Any further steroidal and nonsteroidal compounds, having the
capacity to prevent, alleviate the symptoms of, treat or cure
inflammation processes, are generally included, as
anti-inflammatory agents, according to the present invention.
[0087] 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.
[0088] 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.
[0089] 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.
[0090] Hormones include steroid and non-steroid hormones. Steroid
hormones can be selected from the group consisting of an androgen,
an estrogen and a progestogen.
[0091] Exemplary androgens include testosterone, testosterone
cipionate, testosterone decanoate, testosterone enantate,
testosterone isocaproate, testosterone phenylpropionate,
testosterone propionate, testosterone undecylate,
5a-dihydrotestosterone, dehydroepiandrosterone (also termed
prasterone and DHEA), androstenedione, androstanediol,
androsterone, androstenolone, prasterone enantate, prasterone
sodium sulfate, ormeloxifene, mesterolone, fluoxymesterone,
methyltestosterone, gestrinone, delmadinone, delmadinone acetate,
chlormadinone, chlormadinone acetate, danazol and testolactone.
Exemplary estrogens include estradiol, estradiol benzoate,
estradiol cipionate, estradiol dipropionate, estradiol enantate,
estradiol hexahydrobenzoate, estradiol phenylpropionate, estradiol
valerate, polyestradiol phosphate, estriol, estriol sodium
succinate, estriol succinate, polyestriol phosphate, quinestradol,
ethinylestradiol, estrapronicate, mestranol, estrapronicate and
equilin. Exemplary progestogens include progesterone,
norethisterone, norethisterone acetate, norethisterone enantate,
medroxyprogesterone acetate, delmadinone acetate, flugestone
acetate, dydrogesterone, desogestrel, norgestrel, levonorgestrel,
dydrogesterone, gestodene, chlormadinone acetate, dienogest,
drospirenone, lynestrenol, tybolone, cyproterone acetate, megestrol
acetate, nomegestrol acetate;
[0092] 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 skin.
[0093] 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.
[0094] Vitamin A and its derivatives, such as retinoic acid,
isoretinoic acid, retinol and retinal are another preferred class
of keratolytically active agents.
[0095] Another group of keratolytically active agents include
alpha-hydroxy acids, such as lactic acid, glycolic acid, citric
acid and malic 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.
[0096] 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.
[0097] In one or more embodiments, the active agent is a
dicarboxylic acid. Exemplary pharmaceutically and cosmetically
active dicarboxylice acids include azelaic acid, sebacic acid,
adipic acid, fumaric acid and salts, isomers and analogs
thereof.
[0098] In one or more embodiments, the active agent is a topical
anesthetic. Examples of topical anesthetic drugs include
benzocaine, lidocaine, bupivacaine, chlorprocaine, dibucaine,
etidocaine, mepivacaine, tetracaine, dyclonine, hexylcaine,
procaine, cocaine, ketamine, pramoxine, benzyl alcohol and phenol.
Mixtures of such anesthetic agents may be synergistically
beneficial.
[0099] In one or more embodiments, the active agent is an
insecticide or an insect repellent agent. By way of example,
insecticide can be selected selected from the group consisting of
permethrin, hexachlorobenzene, carbamate, naturally occuring
pyrethroids, permethrin, allethrin, malathion, piperonyl butoxide
and any combination thereof at a therapeutically effective
concentration. There are several types of insect repellents to use
when protecting people and animals from flying or biting insects,
spiders, ticks and mites. By way of example, these may include DEET
(N,N-diethyl-m-toluamide), dimethyl phthalate, piperonyl butoxide
and permethrin. The application of insecticides or insect repellent
agents in foam is very convenient. Foam spreads easily, even over
large and/or hairy areas. The film forming agent present in the
foam composition helps retain the insecticide or insect repellent
on the treated area for an extended period of time.
[0100] In one or more embodiments the active agent is a sunscreen
agent. As used herein, sunscreen agents include both chemical and
physical sunblocks. Suitable sunscreen agents may be organic or
inorganic.
[0101] A wide variety of conventional organic sunscreen actives are
suitable for use herein. Specific suitable sunscreen actives
include, for example: p-aminobenzoic acid, its salts and its
derivatives (ethyl, isobutyl, glyceryl esters;
p-dimethylaminobenzoic acid); anthranilates (i.e.,
o-amino-benzoates; methyl, menthyl, phenyl, benzyl, phenylethyl,
linalyl, terpinyl, and cyclohexenyl esters); salicylates (amyl,
phenyl, octyl, benzyl, menthyl, glyceryl, and di-pro-pyleneglycol
esters); cinnamic acid derivatives (menthyl and benzyl esters,
a-phenyl cinnamonitrile; butyl cinnamoyl pyruvate);
dihydroxycinnamic acid derivatives (umbelliferone,
methylumbelliferone, methylaceto-umbelliferone);
trihydroxy-cinnamic acid derivatives (esculetin, methylesculetin,
daphnetin, and the glucosides, esculin and daphnin); hydrocarbons
(diphenylbutadiene, stilbene); dibenzalacetone and
benzalacetophenone; naphtholsulfonates (sodium salts of
2-naphthol-3,6-disulfonic and of 2-naphthol-6,8-disulfonic acids);
di-hydroxynaphthoic acid and its salts; o- and
p-hydroxybiphenyldisulfonates; coumarin derivatives (7-hydroxy,
7-methyl, 3-phenyl); diazoles (2-acetyl-3-bromoindazole, phenyl
benzoxazole, methyl naphthoxazole, various aryl benzothiazoles);
quinine salts (bisulfate, sulfate, chloride, oleate, and tannate);
quinoline derivatives (8-hydroxyquinoline salts,
2-phenylquinoline); hydroxy- or methoxy-substituted benzophenones;
uric and violuric acids; tannic acid and its derivatives (e.g.,
hexaethylether); (butyl carbotol) (6-propyl piperonyl) ether;
hydroquinone; benzophenones (oxybenzene, sulisobenzone,
dioxybenzone, benzoresorcinol, 2,2',4,4'-tetrahydroxybenzophenone,
2,2'-dihydroxy-4,4'-dimethoxybenzophenone, octabenzone;
4-isopropyldibenzoylmethane; butylmethoxydibenzoylmethane;
etocrylene; octocrylene; [3-(4'-methylbenzylidene bornan-2-one),
terephthalylidene dicamphor sulfonic acid and
4-isopropyl-di-benzoylmethane.
[0102] A safe and effective amount of the organic sunscreen active
is used, typically from about 1% to about 20%, more typically from
about 2% to about 10% of the composition. Exact amounts will vary
depending upon the sunscreen or sunscreens chosen and the desired
Sun Protection Factor (SPF).
[0103] Inorganic sunscreens useful herein include the following
metallic oxides; titanium dioxide having an average primary
particle size of from about 15 nm to about 100 nm, zinc oxide
having an average primary particle size of from about 15 nm to
about 150 nm, zirconium oxide having an average primary particle
size of from about 15 nm to about 150 nm, iron oxide having an
average primary particle size of from about 15 nm to about 500 nm,
and mixtures thereof. When used herein, the inorganic sunscreens
are present in the amount of from about 0.1% to about 20%,
preferably from about 0.5% to about 10%, more preferably from about
1% to about 5%, of the composition.
[0104] In one or more embodiments, the active agent is an anti
cancer agent, i.e., an agent that has an effect in preventing,
treating or alleviating the symptoms of cancer. Preferred anti
cancer agents are agents that are capable of treating skin
malignant tumors, such as basal cell carcinoma, squamous sell
carcinoma, melanoma and Kaposi's sarcoma, as well as pre-cancerous
conditions, such as actinic keratosis. In certain cases, topical
cytotoxic and antiproliferative drugs are used to prevent, treat or
alleviate the symptoms of such cancers.
[0105] In one or more embodiments, the active agent is a
photodynamic therapy (PDT) agent. By way of example, such PDT
agents can be selected from the group comprising 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).
[0106] 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. Upon application, the foam spreads easily,
covering the surface of the affected area, and without causing
pain, and retains the activew agent(s) at the surface for an
extended period of time, due to the beneficial effect of the film
forming agent.
[0107] 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.
[0108] The term "cosmetic active agent" means the principle
component or components that act to perform the primary function or
functions of the cosmetic composition. Any cosmetic 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 active agents 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, clove oil, menthol, camphor, eucalyptus oil, eugenol,
menthyl lactate, witch hazel distillate, anti-acne agents,
anti-microbial agents (e.g., iodopropyl butylcarbamate),
antioxidants, biological additives, cosmetic astringents, cosmetic
biocides, 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), and vitamins and derivatives
thereof.
[0109] 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.
[0110] In one or more embodiments, the active agent is an
anti-oxidants 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.
[0111] In one or more embodiments, the active agent is a
self-tanning active agent, such as dihydroxyacetone.
[0112] 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; pigments.
[0113] It is further pointed out that unsaturated polyunsaturated
fatty acids and 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), as well as their respective glyceride
esters (also termed herein "unsaturated oils" and "poly-unsaturated
oils", respectively), 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 certain embodiments, 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 oils and
poly-unsaturated oils.
[0114] In one or more embodiments, a pharmaceutically or
cosmetically active agent is an organic substance which is
semi-liquid or liquid at ambient temperature. As such, a
semi-liquid or liquid pharmaceutically or cosmetically active agent
can be concurrently considered as an "active agent" and as an
"organic carrier", as defined herein. Non-limiting examples of
semi-liquid or liquid pharmaceutically or cosmetically active agent
include, but are not limited to permethrin, diethyl toluamide
(DEET), dimethyl phthalate, and vitamin E (tocoferol). The
semi-liquid or liquid pharmaceutically or cosmetically active agent
can be included in the foamable composition as a sole organic
carrier, or in combination with additional organic carriers, as
detailed above.
[0115] According to certain embodiment, the active agent is
selected from the group consisting of a solvent, a surface active
agent, a foam adjuvant and a gelling agent, which are, on a case by
case basis known to possess a therapeutic benefit.
[0116] Combinations of more than one active agent are contemplated.
Thus, in certain embodiments, the composition contains at least two
active agents. In further embodiments each of the at least two
active agents exerts itsr therapeutic effect through at different
mode of action, thus providing synergy and consequent synergistic
therapeutic results.
[0117] 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.
Optional Formulation Excipients
[0118] 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.
"Alcohol Free"
[0119] Unlike the composition disclosed in WO 2004/071479, which
contains a high concentration of a monohydric aliphatic alcohol,
the composition of the present invention does not contain such
amount alcohols. For the purpose of the present application, the
term "alcohol free" shall mean that the composition contains no
more than an incidental amount of an aliphatic alcohol, e.g. less
than about 7.5% of any aliphatic alcohol, having one to six carbon
atoms in their carbon backbone, or no more than 7.5% of any mixture
of such aliphatic alcohols. Alcohols at these low levels are not
considered to have a negative effect on skin or mucous membranes.
In one or more embodiments, the foamable compositions do not
contain any alcohol.
Propellants
[0120] Examples of suitable propellants include volatile
hydrocarbons such as butane, propane, isobutane and fluorocarbon
gases, or mixtures thereof.
[0121] In certain embodiments, fluorohydrocarbon propellants, other
than chloro-fluoro carbons (CMCs) which are non-ozone-depleting
propellants, are particularly useful in the production of a
non-flammable foamable composition.
[0122] Such propellants include, but are not limited to
hydrofluorocarbon (HFC) propellants, which contain no chlorine
atoms, and as such, falls completely outside concerns about
stratospheric ozone destruction by chlorofluorocarbons or other
chlorinated hydrocarbons. Exemplary non-flammable propellants
according to this aspect of the invention include propellants made
by DuPont under the registered trademark Dymel, such as 1,1,1,2
tetrafluorethane (Dymel 134), and 1,1,1,2,3,3,3 heptafluoropropane
(Dymel 227), 1,1, difluoro ethane (Dymel 152) and 1,1,1,3,3,3
hexafluoropropane. HFCs possess Ozone Depletion Potential of 0.00
and thus, they are allowed for use as propellant in aerosol
products.
[0123] The propellant makes up about 5-25 wt % of the foamable
composition. Aerosol propellants are used to generate and
administer the foamable composition as a foam. The total
composition including propellant, foamable compositions and
optional ingredients is referred to as the foamable
composition.
Composition and Foam Physical Characteristics and Advantages
[0124] 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.
[0125] The foamable composition of the present invention is stable,
having an acceptable shelf-life of an year, or at least two years
at ambient temperature, as revealed in accelerated stability tests.
Organic carriers and propellants tend to impair the stability of
emulsions and to interfere with the formation of 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.
[0126] 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.
[0127] Foam quality can be graded as follows:
[0128] 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.
[0129] 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.
[0130] 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.
[0131] 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.
[0132] Grade P (poor): no creaminess noticeable, large bubble
structure, and when spread on the skin it becomes very thin and
watery in appearance.
[0133] Grade VP (very poor): dry foam, large very dull bubbles,
difficult to spread on the skin.
[0134] 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.
[0135] As further aspect of the foam is breakability. The breakable
foam is thermally stable, yet breaks under sheer force. Sheer-force
breakability of the foam is clearly advantageous over thermally
induced breakability. Thermally sensitive foams immediately
collapse upon exposure to skin temperature and, therefore, cannot
be applied on the hand and afterwards delivered to the afflicted
area.
[0136] The foam of the present invention has several advantages,
when compared with hydroalcoholic foam compositions, such as
described in WO 2004/071479: [0137] (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. [0138] (2) Skin
drying and skin barrier function. short chain alcohols are known to
dry the skin and impair the integrity of the skin barrier. By
contrast, including a film forming agent in the composition of the
present invention foes not cause unwanted skin barrier damage.
[0139] (3) Irritability. Due to the lack of alcohol and improvement
in skin barrier function, skin irritability is eliminated.
[0140] In terms of usability, the foamable composition is most
advantageous, as revealed by clinical trials: [0141] (i) Ease of
application. [0142] 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.
[0143] Upon application, the foam readily spreads and absorbs into
the skin. [0144] (ii) The Foam is Drip-Free [0145] The foam is not
liquid and therefore does not leak when applied. [0146] This allows
precise application, without the product being spread on clothes or
other parts of the body.
[0147] 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.
Fields of Applications
[0148] According to one or more embodiments of the present
invention, the foamable carrier and the foamable pharmaceutical or
cosmetic composition of the present invention is 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.
[0149] 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:
[0150] 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;
[0151] Bacterial infections including cellulitis, acute
lymphangitis, lymphadenitis, erysipelas, cutaneous abscesses,
necrotizing subcutaneous infections, staphylococcal scalded skin
syndrome, folliculitis, furuncles, hidradenitis suppurativa,
carbuncles, paronychial infections, erythrasma;
[0152] Fungal Infections including dermatophyte infections, yeast
Infections; parasitic Infections including scabies, pediculosis,
creeping eruption;
[0153] Viral Infections;
[0154] 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;
[0155] Scaling papular diseases including psoriasis, pityriasis
rosea, lichen planus, pityriasis rubra pilaris;
[0156] Benign tumors including moles, dysplastic nevi, skin tags,
lipomas, angiomas, pyogenic granuloma, seborrheic keratoses,
dermatofibroma, keratoacanthoma, keloid;
[0157] Malignant tumors including basal cell carcinoma, squamous
cell carcinoma, malignant melanoma, Paget's disease of the nipples,
Kaposi's sarcoma;
[0158] Reactions to sunlight, including sunburn, chronic effects of
sunlight, photosensitivity;
[0159] Bullous diseases including pemphigus, bullous pemphigoid,
dermatitis herpetiformis, linear immunoglobulin A disease;
[0160] Pigmentation disorders including hypopigmentation such as
vitiligo, albinism and postinflammatory hypopigmentation and
hyperpigmentation such as melasma (chloasma), drug-induced
hyperpigmentation, postinflammatory hyperpigmentation;
[0161] Disorders of cornification including ichthyosis, keratosis
pilaris, calluses and corns, actinic keratosis;
[0162] Pressure sores, open wounds, chronic wounds, open ulcers and
burns;
[0163] Disorders of sweating; and
[0164] Inflammatory reactions including drug eruptions, toxic
epidermal necrolysis; erythema multiforme, erythema nodosum,
granuloma annulare.
[0165] Upon application of the foam, incorporating an active agent,
the foam spreads easily, covering the surface of the affected area,
and without causing pain. It retains the active agent(s) at the
surface for an extended period of time, due to the beneficial
effect of the film forming agent.
[0166] 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 thoracic cavity, the
abdominal cavity, the ventral 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.
[0167] 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.
[0168] 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.
[0169] The following examples exemplify the therapeutic kits and
pharmacological compositions and methods described herein. The
examples are for the purposes of illustration only and are not
intended to be limiting of the invention.
[0170] The following examples exemplify the therapeutic
compositions and pharmacological compositions and methods described
herein. The examples are for the purposes of illustration only and
are not intended to be limiting of the invention.
EXAMPLE 1
Insect Repellent Composition Containing a Film Forming Polymer
TABLE-US-00001 [0171] Ingredient % w/w Diethyltoluamide 25.00
Glycerine 5.00 PEG 400 5.00 Stearic acid 4.00 Span 60 4.00 Tween 60
2.00 Dermacryl 79 (film forming agent) 0.7 Isosearic Acid 0.50
Triethanolamine 0.46 Phenonip (preservative) 0.25 Pemulen TR2 (film
forming agent) 0.06 Propellant (propane and butane) 6.00 Water
47.03 100.00
EXAMPLE 2
Insect Repellency Test in Humans
[0172] The efficacy of the foamable composition of Example 1 as
repellent against Aedes aegypti mosquitoes was tested under
laboratory conditions, in comparison with the same composition
without the film forming polymer Dermacryl and Pemulen.
[0173] The mosquitoes used in this work were laboratory-reared,
sugar-fed, 3- to 5-days-old adult Aedes aegypti. Before the test,
the mosquitoes were starved for 24 h .The test was carried out from
8.30 to 16.30.
[0174] The test was conducted in a room maintained at
23.+-.2.degree. C. Human volunteers were used, whereby one of the
repellents was applied to one bare forearm and hand and another
formulation to the other forearm and hand. Then, every hour for
during the test period, each volunteer put each treated arm into a
mosquito cage, containing about 150-200 starved Aedes aegypti adult
mosquitoes for 10 minutes. The number of mosquitoes landing on each
of the arms was counted during each 10-minute exposure (8 replicas)
for a total period of 8-hours. The number of bites for each
10-minute exposure period was also recorded.
[0175] For each of the volunteers, the number of landed mosquitoes
and bites on the bare untreated forearm of eight human volunteers
during 10 min in mosquito (Aedes aegypti) cages each hour for 8
hours is presented in the following table:
TABLE-US-00002 DEET Foam without Dermacryl DEET Foam with Dermacryl
Volunteer # 1 Volunteer # 2 Volunteer # 1 Volunteer # 2 Number of
No. Number No. Number No. Number of No. Exposure landed of of
landed of of landed of landed of (Hours) mosquitoes Mean bites
mosquitoes Mean bites mosquitoes Mean bites mosquitoes Mean bites 0
0 0 0 1 0.25 0 0 0 0 0 0.25 0 0 0 0 0 0.37 0 0 0 1 2 0.5 0 0 1 0 0
0 0 1 1 0 1 1 1 1 0 0 0 1 1 0 0 0 0.12 0 0 0 0 0 0 0 0 0 1 0 0.12 0
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 0 0 0 1 0.12 0 0 0 0
0 0.12 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 3
2 0 0 0 0.37 0 0 0 0 0 0.12 0 0 0 0 0 0.37 0 0 0 0 0 0 0 0 0 0 1 0
0 1 0 0 2 1 0 0 0 0 0 4 1 1 0 1 0.75 0 0 0 0 0 0 0 1 1 0 1 0.5 0 0
1 1 0 0.25 0 0 1 1 1 0 0 0 0 1 0 0 0 0 0 0 0 5 3 2 0 0 1 0 0 0 1 0
0.25 0 2 1 1 0 0.75 0 0 0 0 0 0 0 1 1 0 1 1 0 0 0 0 0 1 1 0 0 0 0 6
2 1 1 2 1 0 0 0 0 0 0.37 0 2 2 2 3 1.37 0 0 1 0 0 0.12 0 1 0 0 1 1
1 1 0 1 1 0 0 0 0 0 0 7 3 3 3 3 3 6 1 0 0 0 0.25 0 1 0 1 2 1.37 1 1
0 0 0 0.12 0 3 2 3 4 1 0 0 0 3 2 1 1 0 0 0 0 8 3 5 5 4 4.12 17 0 0
0 1 0.62 0 3 3 3 0 1.62 3 0 0 0 1 0.37 0 4 5 4 3 0 0 2 2 02 2 0 0 0
0 2
[0176] As seen in the above table, the DEET Foam with Dermacryl was
superior to the same composition with no Dermacryl. It was
protective for a longer period of time and the total number of
bites was far less when the DEET Foam with Dermacryl was used.
EXAMPLE 3
Foamable Composition Containing Aculyn and Pemulen for Treating
Atopic Dermatitis
TABLE-US-00003 [0177] Ingredient % w/w Mineral Oil 3.00 Shea Butter
2.00 Avocado Oil 4.00 C12-C15 Alkyl Benzoate 4.00 Cyclomethicone
(Dow Corning 245) 0.50 Stearyl Dimethicone (Dow Corning 2502) 2.00
Stearic Acid 0.80 Polyoxyl 2 Stearyl Ether (Brij72) 0.75
Polyoxyethylene 21 Stearyl Ether (Brij721) 1.50 Behenyl Alcohol
0.40 Acrylates/C10-30 Alkylacrilate Crosspolymer 0.10 (Pemulen TR2,
film forming agent) Bis PEG/PPG-18Methyl Ether Dimethyl Silane 1.00
(Dow Corning 2501, film forming agent) Propylene Glycol 3.00
Glycerin 5.00 PEG150/Stearyl Alcohol/SMDI Copolymer 1.00 (Aculyn46)
Aloe Vera extract 0.30 Triethanolamine (TEA) 0.15 Water 60.10
Disodium EDTA 0.10 Sodium Hyaluronate (1%) 0.50 Licorice Extract
0.50 Alpha Bisabolol 0.30 Tocopheryl Acetate 0.50 Allantoin 0.50
Propane/Butane/Isobutane 8.00 Total 100.00
[0178] The composition of Example 3 contains two film forming
agents and a series of active agents that are known to affect skin
inflammation, including avocado oil, cyclomethicone, dimethicone,
aloe vera extract, sodium hyaluronate, licorice extract, alpha
bisabolol, tocopheryl acetate and allantoin. Conceivably, at least
two of these active agents are required to attain effective
treatment.
EXAMPLE 4
A Human Study, to Test the Skin Hydration Effect of a Foamble
Composition Containing Aculyn and Pemulene for Treating Atopic
Dermatitis
[0179] Several skin disorders are characterized, among other
etiological factors, by severe skin dryness, as exemplified by
psoriasis, atopic dermatitis, xerosis and ichthyosis. Atopic
dermatitis is a chronic disease that affects the skin. In atopic
dermatitis, the skin becomes extremely itchy. Scratching leads to
redness, swelling, cracking, excreting clear fluid, and finally,
crusting and scaling. In most cases, there are periods when the
disease is worse (called exacerbations or flares) followed by
periods when the skin improves or clears up entirely (called
remissions). As some children with atopic dermatitis grow older,
their skin disease improves or disappears altogether, although
their skin often remains dry and easily irritated. In others,
atopic dermatitis continues to be a significant problem in
adulthood.
[0180] It is commonly accepted that emollients are a standard of
care, steroid sparing and useful for both prevention and
maintenance therapy as stated in a recent Guidelines of Care for
Atopic Dermatitis by the American Academy of Dermatology.
[0181] The objective of the present study was to assess the skin
hydration properties of the composition of Example 3, in comparison
with the commercially available medicated cream, namely Atopiclair
that does not contain film-forming agents.
[0182] Six human volunteers were treated once with the composition
of Example 3 on one forearm and with Atopiclair on the other
forearm. A untreated site remained as control site. Skin hydration
values were determined at each designated treatment site, using the
Corneometer CM825 instrument (Courage+Khazaka, Koln, Germany) at
constant room conditions (24.degree. C. and 40% humidity).
[0183] The following table present skin hydration values, as
measured by Corneometer for the composition of Example 3,
Atopiclair and no-treatment, at Baseline and 1, 3 and 6 hours after
treatment, as well as the percent change of skin hydration from
Baseline and p Values (vs. Baseline and within treatments) during
the study.
[0184] As shown in the table, non-treated areas maintained
practically constant hydration values throughout the study. The
composition of Example 3 afforded elevated skin hydration of about
20-45% during the 6-hours follow up, while Atopiclair was effective
for one hour only. Notable, the change from baseline was
statistically significant for both the composition of Example 3
throughout the 6-hours assessment (T-Test). Moreover, the
superiority of the composition of Example 3 to Atopiclair was
statistically evident at the 3 hours and 6 hours measurements.
TABLE-US-00004 TABLE Skin hydration values for the composition of
Example 3, Atopiclair and no-treatment, at Baseline and 1, 3 and 6
hours after treatment, the percent change of skin hydration from
Baseline and p Values (vs. Baseline and within treatments) No Exam-
Treatment ple 3 Atopiclair Base- Skin hydration value 43.75 45.16
46.50 line STD 4.19 4.48 4.36 1 Hour Skin hydration value 45.50
55.62 52.04 STD 4.25 8.77 6.05 % Change from baseline 3% 23% 12% p
Value (vs. Baseline) NA 0.0311 0.3092 P Value (vs. Atopiclair)
0.5213 3 Hour Skin hydration value 45.62 62.50 47.75 STD 5.32 7.47
5.11 % Change from baseline 4% 38% 3% p Value (vs. Baseline) NA
0.0046 0.3945 P Value (vs. Atopiclair) 0.0033 6 Hour Skin hydration
value 48.58 65.04 49.50 STD 4.41 8.99 5.12 % Change from baseline
11% 44% 6% p Value (vs. Baseline) NA 0.001 0.700 P Value (vs.
Atopiclair) 0.001
EXAMPLE 5
Foamable Composition Containing Aculyn and Pemulen as Film Forming
Agents
TABLE-US-00005 [0185] Ingredient % w/w Mineral Oil 1.50 Dow Corning
245 (film forming agent) 0.70 Dow Corning 2502 (film forming agent)
1.00 Alkyl Benzoate 8.00 Stearic Acid 1.00 Brij 72 1.00 Brij 721
2.00 Propylen glycol 5.00 Stearyl Alcohol 1.00 Pemulen TR2 (film
forming agent) 0.05 Glycerin 3.00 Dow 2501 1.50 Aculyn 46 (film
forming agent) 1.80 TEA 0.10 Water 63.90 Phenonip 0.25 Fragance
0.20 Propellant 8.00 Total 100.00
EXAMPLE 6
Foamable Composition Containing Chitosan as Film Forming Agent
TABLE-US-00006 [0186] Ingredient % w/w % w/w % w/w Zinc oxide 10.00
10.00 10.00 Mineral oil 20.00 20.00 20.00 IPP 10.00 10.00 10.00
Beeswax 2.00 2.00 2.00 Glyceryl oleate 1.00 1.00 1.00 Lanolin 5.00
5.00 5.00 Lipocol C 2 3.00 3.00 3.00 Sucrose ester SP10 1.00 1.00
1.00 Aloe vera extract 0.10 0.10 0.10 Alpha Bisabolol 0.20 0.20
0.20 Xanthan gum -- 0.40 0.40 Chitosan (film 0.18 0.18 0.18 forming
agent)* Lactic acid 0.35 0.35 0.35 D-Panthenol 4.00 4.00 4.00
Benzalkonium chlorid 0.20 0.20 0.20 Propellant 8.00 8.00 8.00 Water
To 100.00 To 100.00 To 100.00 Foam Quality G G E Density 0.1141
0.0897 0.1058 *CAS-no.: 9012-76-4; Formula: (C6H11O4N).sub.n; Mol.
weight: 30.000-1.000.000 Dalton I
[0187] Example 6 provides a foam based on chitosan as a film
forming agent. The composition contains zinc oxide, lactic acid,
aloe vera extract, alpha bisabolol and panthenol as active
agents.
EXAMPLE 7
Foamable Composition Containing Natrosol as Film Forming Agent
TABLE-US-00007 [0188] Ingredient % w/w IPM/MCT 6.00 Glyceryl
monooleate 2.00 Glyceryl monostearate 1.00 Span 60 1.00 Arlamol E
0.50 Xanthan Gum 0.30 Hydroxyethylcellulose (Natrasol 0.60 250 HF;
film forming agent) Glycerin 5.00 Phenonip 0.60 Lactic acid or
Sodium hydroxide To pH = 5 Propellant 6.00 Water To 100
Centrifugation 10000/3 min stable 10000/10 min stable Foam Quality
E
* * * * *