U.S. patent application number 16/906618 was filed with the patent office on 2020-11-12 for topical foam composition.
The applicant listed for this patent is MAYNE PHARMA LLC. Invention is credited to Leo LOUPENOK.
Application Number | 20200352892 16/906618 |
Document ID | / |
Family ID | 1000004989410 |
Filed Date | 2020-11-12 |
United States Patent
Application |
20200352892 |
Kind Code |
A1 |
LOUPENOK; Leo |
November 12, 2020 |
TOPICAL FOAM COMPOSITION
Abstract
The present invention relates to a novel oil in water emulsion
aerosol foam composition containing an active agent for the
treatment of various chronic and acute skin conditions,
particularly acne and psoriasis; and processes for preparing the
emulsion aerosol foam compositions. In particular, the present
invention relates to oil in water emulsion aerosol foam
compositions containing a retinoid in the oil phase.
Inventors: |
LOUPENOK; Leo; (Rowville,
AU) |
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Applicant: |
Name |
City |
State |
Country |
Type |
MAYNE PHARMA LLC |
Greenville |
NC |
US |
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Family ID: |
1000004989410 |
Appl. No.: |
16/906618 |
Filed: |
June 19, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12711337 |
Feb 24, 2010 |
10568859 |
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16906618 |
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61202403 |
Feb 25, 2009 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/203 20130101;
A61K 31/00 20130101; A61K 9/0014 20130101; Y10S 514/945 20130101;
A61K 9/1075 20130101; Y10S 514/938 20130101; A61K 31/192 20130101;
A61K 9/122 20130101; Y10S 514/939 20130101; A61K 31/4436 20130101;
Y10S 514/941 20130101; A61K 45/06 20130101 |
International
Class: |
A61K 31/203 20060101
A61K031/203; A61K 9/00 20060101 A61K009/00; A61K 9/107 20060101
A61K009/107; A61K 9/12 20060101 A61K009/12; A61K 31/192 20060101
A61K031/192; A61K 31/4436 20060101 A61K031/4436; A61K 45/06
20060101 A61K045/06; A61K 31/00 20060101 A61K031/00 |
Claims
1. An oil in water emulsion aerosol foam composition comprising an
oil phase and a water phase, said composition comprising: (i) at
least one pharmaceutically active agent which is tazarotene, (ii)
water, (iii) an oil present in an amount of less than about 10% by
weight, (iv) an oil miscible organic solvent, (v) a surfactant
component comprising a hydrophilic surfactant, in an amount from
about 0.1% to about 10% by weight, and (vi) a propellant; and
wherein the pharmaceutically active agent is solubilized in the oil
phase of the composition, and wherein the particle size of the oil
phase is less than about 1000 nm.
2. The aerosol foam composition according to claim 1, wherein the
composition comprises a second pharmaceutically active agent.
3. The aerosol foam composition according to claim 1, wherein the
composition comprises water in an amount from about 65% to about
90% by weight.
4. The aerosol foam composition according to claim 3, wherein the
composition comprises water in an amount from about 70% to about
85% by weight.
5. The aerosol foam composition according to claim 1, wherein the
oil is selected from the group consisting of azulene, chamazulene,
isoparaffin, linear alpha olefins, cyclohexlidenediphenyl methane,
didecene, diethylhexylcyclohexane, eicosane, isododecane,
isoeicosane, isohexadecane, longifolene, mineral oil, paraffin,
pentahydrosqualene, petrolatum, squalane, squalene, tetradecene,
and mixtures thereof.
6. The aerosol foam composition according to claim 1, wherein the
oil is present in an amount from about 1% to about 9% by
weight.
7. The aerosol foam composition according to claim 6, wherein the
oil is present in an amount from about 3% to about 8% by
weight.
8. (canceled)
9. (canceled)
10. The aerosol foam composition according to claim 5, wherein the
oil miscible organic solvent is selected from the group consisting
of diisopropyl adipate, isopropyl myristate, octyl dodecanol and
caprylic/capric triglyceride, and mixtures thereof.
11. The aerosol foam composition according to claim 10, wherein the
oil is mineral oil.
12. The aerosol foam composition according to claim 1, wherein the
surfactant component is present in amount from about 1% to about 8%
by weight.
13. The aerosol foam composition according to claim 1, wherein the
surfactant component is present in amount from about 2% to about 6%
by weight.
14. The aerosol foam composition according to claim 1, wherein the
surfactant component comprises a non-ionic surfactant.
15. The aerosol foam composition according to claim 12 wherein the
non-ionic surfactant is a PEG derivative, a propylene glycol ester,
a fatty alcohol, a glycerol ester or derivative thereof, a
polymeric ether, a sorbitan ester or a mixture thereof.
16. The aerosol foam composition according to claim 1, wherein the
propellant comprises one or more hydrocarbon propellants.
17. A method of treating a skin disease, disorder or condition,
comprising administering to the skin of a patient requiring such
treatment an effective amount of a composition according to claim
1.
18. An oil in water emulsion aerosol foam composition comprising an
oil phase and a water phase, said composition comprising: i)
tazarotene; ii) water; iii) an oil selected from the group
consisting of azulene, chamazulene, isoparaffin, linear alpha
olefins, cyclohexlidenediphenyl methane, didecene,
ethylhexylcyclohexane, eicosane, isododecane, isoeicosane,
isohexadecane, longifolene, mineral oil, paraffin,
pentahydrosqualene, petrolatum, squalane, squalene, tetradecene,
and mixtures thereof; and wherein the oil is present in an amount
from about 3% to about 8% by weight; iv) an oil miscible organic
solvent selected from the group consisting of diisopropyl adipate,
isopropyl myristate, octyl dodecanol and caprylic I capric
triglyceride, and mixtures thereof v) a non-ionic surfactant
component comprising a hydrophilic surfactant, in an amount from
about 2% to about 6% by weight; and vi) a hydrocarbon propellant;
and wherein the tazarotene is solubilized in the oil phase of the
composition, and wherein the particle size of the oil phase is less
than about 1000 nm.
19. A method of treating a skin disease, disorder or condition,
comprising administering to the skin of a patient requiring such
treatment an effective amount of a composition according to claim
18.
20. A process for the preparation of an oil in water submicron or
micro emulsion aerosol foam composition, comprising tazarotene,
water, an oil present in an amount of less than about 10% by
weight, an oil miscible organic solvent, a surfactant component
comprising a hydrophilic surfactant in an amount from about 0.1% to
about 10% by weight, and a propellant, the process comprising: a.
admixing the pharmaceutically active agent, a first aliquot of
water, oil, oil miscible organic solvent and surfactant component
to form an oil in water emulsion, b. heating the oil in water
emulsion of step (a) to a phase inversion temperature wherein the
oil in water emulsion forms a water in oil emulsion, c. cooling the
water in oil emulsion to below the phase inversion temperature to
form a submicron or micro oil in water emulsion, d. adding a second
aliquot of water to cool the submicron or micro oil in water
emulsion, e. actuating a sample of the submicron or micro oil in
water emulsion with a propellant to form an oil in water submicron
or micro emulsion aerosol foam.
21. The process according to claim 20, wherein the first aliquot of
water comprises about 10% to about 40% by weight of the total water
content of the submicron or micro emulsion aerosol foam and the
second aliquot of water comprises about 90% to about 60% by weight
of the total water content of the submicron or micro emulsion
aerosol foam.
22. The product produced by the process according to claim 20.
Description
RELATED APPLICATIONS
[0001] This Application is a continuation of application Ser. No.
12/711,337, filed 24 Feb. 2010, which claims the benefit of U.S.
Provisional Application No. 61/202,403, filed 25 Feb. 2009, which
are incorporated by reference in their entireties.
FIELD OF THE INVENTION
[0002] The present invention relates to novel aerosol foam
compositions containing a pharmaceutically active agent for the
treatment of skin disease.
BACKGROUND OF THE INVENTION
[0003] There are many challenges in topical drug delivery. The
topical composition should deliver the active agent to the site of
treatment, have desirable sensory characteristics, not leave an
unpleasant residue on the surface of the skin, and not cause
irritation or discomfort. Aerosol foams are known to be suitable
for this purpose.
[0004] U.S. Pat. No. 7,387,807 to Callaghan et al. discloses a
topical composition comprising an extract of feverfew,
pharmaceutical excipients, cosmetic agents, and other biologically
active substances, such as retinoids. The composition may be in the
form of an emulsion such as a cream or lotion.
[0005] U.S. Pat. No. 7,326,408 to Angel et al. discloses a
composition for the topical treatment of acne comprising one or
more sunscreen agents and an antibacterial medication, where the
composition may be in the form of a gel, spray, foam, lotion or
other form suitable for application to the skin. The composition
may further comprise an additional anti-acne medication, such as a
retinoid (e.g. tretinoin, adapalene or tazarotene).
[0006] U.S. Pat. No. 6,730,288 to Abram describes an aerosol foam
composition including an effective amount of a pharmaceutically
active ingredient, an occlusive agent, an aqueous solvent, an
organic cosolvent, the pharmaceutically active ingredient being
insoluble in both water and the occlusive agent, and the occlusive
agent being present in an amount sufficient to form an occlusive
layer on the skin, in use,
[0007] US published application No. 2006/0292080 to Abram et al.
describes an oil in water emulsion foam comprising: a vitamin or
analogue thereof solubilized in the water phase and a stabilizer
solubilized in the oil phase, an emulsifier, an occlusive agent,
arid an organic co-solvent, and no description of the particle size
of the oil phase.
[0008] US published application No. 2006/0057168 to Larm et al.
describes a process for the preparation of an oil in water
microemulsion or sub-micron emulsion composition, in particular an
oil in water microemulsion or sub-micron emulsion foam composition.
These submicron or micro emulsion foams have a comparatively high
oil content and require both a hydrophilic and a hydrophobic
surfactant.
[0009] The present invention is directed to low oil and low
surfactant submicron emulsions or microemulsion aerosol foams
containing a pharmaceutically active agent, which are cosmetically
elegant, chemically and physically stable, well tolerated, easy to
formulate, and suitable for application to the face.
BRIEF SUMMARY OF THE INVENTION
[0010] The present invention is directed to an oil in water
emulsion aerosol foam composition having an oil phase and a water
phase, said composition comprising a pharmaceutically active agent,
water, oil, an oil miscible organic solvent, a surfactant, and a
propellant. The present invention provides for a low oil and a low
surfactant content in an oil in water emulsion aerosol foam
composition.
[0011] In one embodiment, the present invention provides an oil in
water emulsion aerosol foam composition comprising an oil phase and
a water phase, said composition comprising:
[0012] a pharmaceutically active agent,
[0013] water.
[0014] an oil present in an amount of less than about 10% by
weight,
[0015] an oil miscible organic solvent,
[0016] a surfactant component comprising a hydrophilic surfactant,
in an amount from about 0.1% to about 10% by weight, and
[0017] a propellant; and wherein the pharmaceutically active agent
is solubilized in the oil phase of the composition, and wherein the
particle size of the oil phase is less than about 1000 nm.
[0018] According to another embodiment, the present invention
provides a process for the preparation of an oil in water submicron
or micro emulsion aerosol foam composition, comprising a
pharmaceutically active agent, water, an oil present in an amount
of less than about 10% by weight, an oil miscible organic solvent,
a surfactant component comprising a hydrophilic surfactant in an
amount from about 0.1% to about 10% by weight, and a propellant,
the process comprising: [0019] a) admixing the pharmaceutically
active agent, a first aliquot of water, oil, oil miscible organic
solvent and surfactant component to form an oil in water emulsion,
[0020] b) heating the oil in water emulsion of step (a) to a phase
inversion temperature wherein the oil in water emulsion forms a
water in oil emulsion, [0021] c) cooling the water in oil emulsion
to below the phase inversion temperature to form a submicron or
micro oil in water emulsion, [0022] d) adding a second aliquot of
water to cool the submicron or micro oil in water emulsion, [0023]
e) actuating a sample of the submicron or micro oil in water
emulsion with a propellant to form an oil in water submicron or
micro emulsion aerosol foam.
[0024] According to an embodiment, the present invention provides a
product produced by this process.
[0025] According to a further embodiment, the present invention
provides a method of treating a skin disease, disorder or
condition, comprising administering to the skin of a patient
requiring such treatment an effective amount of a composition of
the present invention.
[0026] According to yet another embodiment, the present invention
relates to the use of the compositions described herein for the
preparation of a medicament for the treatment of a skin disease,
disorder or condition.
BRIEF DESCRIPTION OF THE DRAWINGS
[0027] FIG. 1 is a schematic flow diagram showing one preferred
embodiment of the present invention in which a low oil and low
surfactant content, oil in water submicron or micro emulsion
aerosol foam composition (730/2/1) is prepared. The method is
described in detail in Example 1.
[0028] FIG. 2 shows the distribution of tazarotene within the
epidermis after application of tazarotene formulations of the
present invention (706/8/2 and 706/8/3) compared to commercially
available tazarotene cream and gel formulations (i.e. TAZORAC.RTM.
cream and gel).
[0029] FIG. 3 shows the distribution of tazarotene within the
dermis after application of tazarotene formulations of the present
invention (706/8/2 and 706/8/3) compared to commercially available
tazarotene cream and gel formulations (i.e. TAZORAC.RTM. cream and
gel).
[0030] FIG. 4 shows the compatibility of high HLB ethoxylated fatty
alcohol ether surfactant with tazarotene (tazarotene stability). A
comparison is made against various low HLB surfactants.
[0031] FIG. 5 shows the compatibility of high HLB ethoxylated fatty
alcohol ether surfactant with tazarotene (tazarotene sulfoxide
formation). A comparison is made against various low HLB
surfactants.
[0032] FIG. 6 shows the particle size distribution of the oil phase
of the present submicron or micro emulsions (730/2/1).
DETAILED DESCRIPTION
[0033] The present invention is directed to an oil in water
emulsion aerosol foam composition having an oil phase and a water
phase, said composition comprising a pharmaceutically active agent,
water, oil, an oil miscible organic solvent, a surfactant, and a
propellant. In an embodiment, the present invention provides low
oil and low surfactant content, oil in water emulsion aerosol foam
compositions. According to a further embodiment, the compositions
are formulated as a submicron emulsion or microemulsion.
[0034] Thus, according to an embodiment, the present invention
provides an oil in water emulsion aerosol foam composition
comprising an oil phase and a water phase, said composition
comprising:
[0035] a pharmaceutically active agent,
[0036] water,
[0037] an oil present in an amount of less than about 10% by
weight,
[0038] an oil miscible organic solvent,
[0039] a surfactant component comprising a hydrophilic surfactant,
in an amount from about 0.1% to about 10% by weight, and
[0040] a propellant; and wherein the pharmaceutically active agent
is solubilized in the oil phase of the composition, and wherein the
particle size of the oil phase is less than about 1000 nm.
[0041] Together, the oil and oil miscible organic solvent comprise
the oil phase of the composition, along with any oil miscible
excipients.
[0042] According to an embodiment, the mean particle size of the
oil phase is about 100 nm.
[0043] In one embodiment, the present compositions are
substantially free or free from a water miscible organic solvent,
such as propylene glycol.
[0044] In one alternative embodiment, the pharmaceutically active
agent is solubilized in the water phase of the composition.
[0045] The characteristics of oil particles in their delivery of
pharmaceutically active agents across the skin barrier are
summarised in Table 1 below:
TABLE-US-00001 TABLE 1 Particle size Description Characteristics
<10,000 nm Emulsion Blue-white, milky liquid, reasonable
physical stability. Particles reside on skin surface .fwdarw.
percutaneous delivery. 100-1000 nm Submicron Bluish, translucent
liquid. Enhanced emulsion physical stability. Particles reside on
skin surface .fwdarw. enhanced percutaneous delivery. 10-100 nm
Microemulsion Translucent-transparent liquid. Excellent physical
stability. Particles reside on skin surface .fwdarw. enhanced
percutaneous delivery. 1-100 nm Nanoemulsion
Translucent-transparent liquid. Excellent physical stability.
Particles reside on skin surface, within stratum corneum and in
hair follicles .fwdarw. optimal percutaneous delivery.
Oil Component
[0046] Suitably, the oil is present in the composition in an amount
from about 1% to about 9% by weight. In another embodiment the oil
is present in an amount from about 3% to about 8% by weight, such
as about 3%, 4%, 5%, 6%, 7% or 8% by weight.
[0047] The oil is in the discontinuous phase of the oil in water
emulsion system. In an embodiment, the oil is a hydrocarbon.
Suitably, the hydrocarbon is selected from an aromatic compound, or
a linear, branched or cyclic alkane or alkene, or mixtures
thereof.
[0048] According to an embodiment, the aromatic compound is
selected from the group consisting of azulene, chamazulene and
cyclohexylidene-diphenylmethane, and mixtures thereof.
[0049] According to a further embodiment, the linear, branched or
cyclic alkane or alkene is selected from the group consisting of
isoparaffin, didecene, diethylhexylcyclohexane, eicosane,
isododecane, isoeicosane, isohexadecane, longifolene, mineral oil,
paraffin, pentahydrosqualene, petrolatum, squalane, squalene,
tetradecene, derivatives theoreof, and mixtures thereof.
[0050] According to an embodiment, the oil is mineral oil. In one
embodiment, the mineral oil is present in an amount from about 1%
to about 9% by weight. In another embodiment the mineral oil is
present in about 3% to about 8% by weight, such as about 3%, 4%,
5%, 6%, 7% or 8% by weight.
[0051] In another embodiment, the oil is a vegetable oil. Suitably,
the vegetable oil is selected from palm oil, soybean oil, rapeseed
oil, sunflower oil, peanut oil, corn oil, olive oil, coconut oil,
cottonseed oil, linseed oil, grapeseed oil, hazelnut oil or sesame
oil, and mixtures thereof.
Surfactant Component
[0052] The present topical foam compositions comprise a surfactant
component. Suitably, the surfactant is present in the composition
in an amount from about 1% to about 8% by weight. In another
embodiment the surfactant is present in an amount from about 2% to
about 6% by weight, such as about 2%, 3%, 4%, 5% or 6% by
weight.
[0053] A surfactant's hydrophilic/lipophilic balance (HLB)
describes the surfactant'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 surfactants tend to form water-in-oil
(w/o) emulsions, and hydrophilic surfactants tend to form
oil-in-water (o/w) emulsions. The HLB of a blend of two surfactants
equals the weight fraction of surfactant A times its HLB value plus
the weight fraction of surfactant B times its HLB value (weighted
average).
[0054] In one embodiment the surfactant component comprises a
hydrophilic surfactant. In an another embodiment, the surfactant
component consists of a single hydrophilic surfactant, and in
another embodiment, the surfactant component comprises more than
one surfactant and the weighted average of their HLB values is
between about 10 and about 20. In another embodiment, the
surfactant component consists of non-ionic surfactants.
[0055] Suitable non-ionic surfactants include but are not limited
to ethoxylated fatty alcohol ethers, PEG derivatives, ethoxylated
fatty acids, propylene glycol esters, fatty alcohols, glycerol
esters and derivatives, polymeric ethers and sorbitan esters, and
mixtures thereof.
[0056] Exemplary ethoxylated fatty alcohol ethers include
steareth-2, steareth-10, steareth-20, ceteareth-2, ceteareth-3,
ceteareth-5, ceteareth-6, ceteareth-10, ceteareth-12, ceteareth-15,
ceteareth-20, ceteareth-21, ceteareth-22, ceteareth-25,
ceteareth-30, ceteareth-31, ceteareth-32, ceteareth-33, laureth-3,
laureth-4, laureth-5, laureth-9, laureth-10, laureth-12,
laureth-15, laureth-20, laureth-21, laureth-22, laureth-23,
nonoxynol-9, oleth-2, oleth-5, oleth-10 and oleth-20.
[0057] In one embodiment the hydrophilic ethoxylated fatty alcohol
ether is selected from the group consisting of steareth-10,
steareth-20, ceteareth-10, ceteareth-12, ceteareth-15,
ceteareth-20, ceteareth-21, ceteareth-22, ceteareth-25,
ceteareth-30, ceteareth-31, ceteareth-32, ceteareth-33,
ceteareth-6, laureth-5, laureth-9, laureth-10, laureth-12,
laureth-15, laureth-20, laureth-21,1aureth-22, laureth-23,
nonoxynol-9, oleth-10 and oleth-20.
[0058] In another embodiment the wherein the hydrophilic
ethoxylated fatty alcohol ether is Macrogol Cetostearyl Ether 12
(ceteareth-12). In one embodiment the Macrogol Cetostearyl Ether 12
is present in the composition in an amount from about 1% to about
8% by weight. In another embodiment the Macrogol Cetostearyl Ether
12 is present in an amount from about 2% to about 6% by weight,
such as about 2%, 3%, 4%, 5% or 6% by weight.
[0059] Exemplary PEG derivatives include PEG-7 hydrogenated castor
oil, PEG-25 hydrogenated castor oil, PEG-30 castor oil, PEG-31
castor oil, PEG-32 castor oil, PEG-33 castor oil, PEG-34 castor
oil, PEG-35 castor oil, PEG-40 hydrogenated castor oil, PEG-50
castor oil and PEG-60 hydrogenated castor oil.
[0060] Exemplary ethoxylated fatty acids include PEG-5 oleate,
PEG-6 oleate, PEG-10 oleate, PEG-6 stearate, PEG-8 stearate and
PEG-9 stearate, PEG-20 stearate, PEG-40 stearate, PEG-41 stearate,
PEG-42 stearate, PEG-43 stearate, PEG-44 stearate, PEG-45 stearate,
PEG-46 stearate, PEG-47 stearate, PEG-48 stearate, PEG-49 stearate,
PEG-50 stearate and PEG-100 stearate.
[0061] Exemplary propylene glycol esters include propylene glycol
palmitate and propylene glycol stearate.
[0062] Exemplary fatty alcohols include cetyl alcohol and stearyl
alcohol.
[0063] Exemplary glyceryl esters and derivatives include glyceryl
behenate, glyceryl dibehenate, glyceryl dioleate, glyceryl
distearate, glyceryl linoleate, glyceryl oleate, glyceryl stearate,
PEG-23 glyceryl cocoate, PEG-6 caprylic/capric glycerides, PEG-7
glyceryl cocoate, polyglyceryl-10 diisostearate, polyglyceryl-2
diisostearate, polyglyceryl-3 diisostearate and polyglyceryl-6
diisostearate.
[0064] Exemplary polymeric ethers include poloxamer 124, poloxamer
182, poloxamer 184, poloxamer 188, poloxamer 237, poloxamer 331,
poloxamer 338 and poloxamer 407.
[0065] Exemplary sorbitan derivatives include polysorbate 20,
polysorbate 40, polysorbate 60, polysorbate 80, sorbitan laurate,
sorbitan oleate, sorbitan palmitate, sorbitan sesquioleate,
sorbitan stearate and sorbitan trioleate.
[0066] In one embodiment, the surfactant component comprises one or
more hydrophilic non-ionic surfactants and is substantially free,
or free of lipophilic surfactant. According to an embodiment, the
surfactant component is substantially free, or free of fatty
alcohol.
[0067] In one embodiment, the surfactant component comprises a
hydrophilic ethoxylated fatty alcohol ether. In another embodiment,
the surfactant component comprises a hydrophilic ethoxylated fatty
alcohol ether and is substantially free, or free of lipophilic
surfactant.
Pharmaceutical Active Agent
[0068] Suitably, the pharmaceutically acceptable active agent for
use in the compositions herein is selected from retinoids, retinoic
acid metabolic blocking agents (RAMBAs), immune response modifier
compounds, vitamin D analogues, corticosteroids, antihistamines,
antibacterial agents, antifungal agents, antiviral agents,
cytotoxic agents, psoralens, antialopecia agents, anti-androgens,
antipruritic agents, keratolytic agents, tars, dithranol,
antiseptics, sunscreens, anaesthetics, analgesics, skin
conditioning agents and nutritional agents, salts thereof,
derivatives thereof and mixtures thereof. In one embodiment, the
compositions may comprise more than one pharmaceutically active
agent, salt or derivative thereof. Suitable concentration ranges
for the pharmaceutically active agent range from about 0.001% to
about 30% by weight, depending on the nature of the active agent or
combination of active agents.
[0069] In one embodiment, the pharmaceutically active agent is a
retinoid. Examples of suitable retinoids include, but are not
limited to, tazarotene, tretinoin, isotretinoin, acitretin,
etretinate, adapalene, bexarotene, alitretinoin, retinol, retinal,
retinyl palmitate, retinyl acetate, retinyl propionate, retinyl
linoleate, ethyl
5-(2-(4,4-dimethylthiochroman-6-yl)ethynyl)thiophene-2-carboxylate,
6-(2-4,4-dimethylthiochroman-6-yl)-ethynyl)-3-pyridylmethanol and
6-(2-(4,4-dimethylthiochroman-6-yl)-ethynyl)
pyridine-3-carbaldehyde, salts thereof, derivatives thereof and
mixtures thereof. In one embodiment, the retinoid is tazarotene. In
an alternative embodiment, the retinoid is tretinoin. In another
embodiment, the composition comprises a retinoid in combination
with a second pharmaceutically active agent. In one embodiment the
combination is tazarotene and a second pharmaceutically active
agent. In another embodiment the combination is tretinoin and a
second pharmaceutically active agent.
[0070] Suitably, one combination of the retinoid is with a
corticosteroid, such as clobetasol propionate; or in combination
with a vitamin D analogue such as calcipotriene; or in combination
with an antibacterial such as clindamycin or a pharmaceutically
acceptable salt thereof (e.g. clindamycin phosphate).
Alternatively, in an embodiment, the present compositions comprise
tretinoin in combination with an antibacterial agent, such as
clindamycin or a pharmaceutically acceptable salt thereof (e.g.
clindamycin phosphate).
[0071] Suitable concentration ranges for the retinoid in the
composition include, for example, about 0.001% to about 5% by
weight. In one embodiment the retinoid is present in an amount from
about 0.01% to about 1%. In another embodiment the retinoid is
present in an amount from about 0.025% to about 0.5%. In one
embodiment when the retinoid is tazarotene, it is present in an
amount from about 0.05% or 0.1% by weight. In another embodiment
when the retinoid is tretinoin, it is present in an amount from
about 0.025%, 0.05% or 0.1%.
[0072] A suitable retinoic acid metabolic blocking agents (RAMBAs)
for use herein as a pharmaceutically acceptable active agent is
rambazole.
[0073] Suitable immune response modifier compounds,
immunosuppressant agents, immunoregulating agents and
immunomodulators for use herein include chemically or
biologically-derived agents that modify the immune response or the
functioning of the immune system (by the stimulation of antibody
formation or the inhibition of white blood cell activity).
Exemplary agents or compounds include, but are not limited to
cyclic peptides (such as cyclosporine), tacrolimus, tresperimus,
pimecrolimus, sirolimius (rapamycin), verolimus, laflunimus,
laquinimod, mycophenolic acid, and imidazoquinoline amines such as
imiquimod, salts thereof, derivatives thereof, and mixtures
thereof,
[0074] Suitable vitamin D analogues include, but are not limited
to, calcidiol, calcitriol, calcipotriene, paricalcitol,
22-oxacolcitriol, dihydrotachysterol, calciferol, salts thereof,
derivatives thereof, and mixtures thereof.
[0075] Suitable corticosteroids include, but are not limited to,
alclometasone dipropionate, amcinonide, beclomethasone
dipropionate, betamethasone benzoate, betamethasone dipropionate,
betamethasone valerate, budesonide, clobetasol propionate,
clobetasone butyrate, cortisone acetate, desonide, desoximetasone,
diflorasone diacetate, diflucortolone valerate, fluclorolone
acetonide, flumethasone pivalate, fluocinolone acetonide,
fluocinonide, fluocortin butyl, fluocortolone, fluprednidene
acetate, flurandrenolide, flurandrenolone, fluticasone propionate,
halcinonide, halobetasol propionate, hydrocortisone, hydrocortisone
acetate, hydrocortisone butyrate, hydrocortisone propionate,
hydrocortisone valerate, methylprednisolone acetate, mometasone
furoate, pramoxine hydrochloride, prednisone acetate, prednisone
valerate, triamcinolone acetonide, prednicarbate, salts thereof,
derivatives thereof, and mixtures thereof.
[0076] Suitable antihistamines include, but are not limited to,
cetirizine, vapitadine, diphenhydramine, triprolidine, pyrilamine,
chlorcyclizine, promethazine, carbinoxamine, tripelennamine,
brompheniramine, hydroxyzine, terfenadine, chlorpheniramine, salts
thereof, derivatives thereof, and mixtures thereof.
[0077] Suitable antibacterial agents include, but are not limited
to, gentamicin, neomycin, streptomycin, cefpodoxime proxetil,
clindamycin, lincomycin, erythromycin, bacitracin, gramicidin(s),
vancomycin, doxycycline, minocycline, oxytetracycline,
tetracycline, fosfomycin, fusidic acid, mupirocin, sulfacetamide,
metronidazole and dapsone, salts thereof, derivatives thereof, and
mixtures thereof.
[0078] Suitable antifungal agents include, but are not limited to,
those selected from the group consisting of echinocandins such as
anidulafunin, caspofungin and micafungin; polyenes such as
amphotericin B, candicidin, filipin, fungichromin, hachimycin,
hamycin, lucensomycin, mepartricin, natamycin, nystatin, pecilocin,
perimycin; allylamines such as butenafine, naftifine and
terbinafine; imidazoles such as bifonazole, butoconazole,
chlormidazole, cloconazole, clotrimazole, econazole, enilconazole,
fenticonazole, flutrimazole, isoconazole, ketoconazole,
lanoconazole, miconazole, neticonazole, omoconazole, oxiconazole
nitrate, sertaconazole, sulconazole and tioconazole; thiocarbamates
such as liranaftate, tolciclate, tolindate and tolnafate; triazoles
such as albaconazole, fluconazole, itraconazole, posaconazole,
ravuconazole, saperconazole, terconazole and voriconazole; and
other antifungal agents such as acrisorcin, amorolfine,
biphenamine, bromosalicylchloranilide, buclosamide, calcium
propionate, chlorphenesin, ciclopirox, cloxyquin, coparaffinate,
exalamide, flucytosine, haloprogin, hexetidine, loflucarban,
nifuratel, potassium iodide, propionic acid, pyrithione,
salicylanilide, sodium propionate, sulbentine, tenonitrozole,
triacetin, undecylenic acid, zinc propionate, griseofulvin,
oligomycins, pyrrolnitrin, siccanin, viridian, salts thereof,
derivatives thereof, and mixtures thereof.
[0079] Suitable antivirals include, but are not limited to,
acyclovir, desciclovir, carbovir, famciclovir, foscarnet sodium,
ganciclovir, interferons, penciclovir, valaciclovir, salts thereof,
derivatives thereof, and mixtures thereof.
[0080] Suitable cytotoxic agents include, but are not limited to,
azathioprine, cyclophosphamide, cyclosporine, methotrexate,
hydroxyurea, thalidomide, bleomycin, fluorouracil, salts thereof,
derivatives thereof, and mixtures thereof.
[0081] An exemplary psoralen is methoxsalen.
[0082] Suitable anti-androgens include, but are not limited to,
spironolactone, cyproterone, flutamide, finasteride, salts thereof,
derivatives thereof, and mixtures thereof.
[0083] An exemplary antialopecia agent is minoxidil.
[0084] Suitable antipruritics include, but are not limited to,
calamine, camphor and menthol, salts thereof, derivatives thereof,
and mixtures thereof.
[0085] Suitable keratolytic agents include, but are not limited to,
benzoyl peroxide, salicylic acid, urea, resorcinol, sulphur, salts
thereof, derivatives thereof, and mixtures thereof.
[0086] Suitable tars include, but are not limited to, coal tar,
pine tar, wood tar, salts thereof, derivatives thereof, and
mixtures thereof.
[0087] Suitable antiseptics include, but are not limited to,
hydrogen peroxide, chlorhexidine, cetrimide, povidone iodine,
triclosan, salts thereof, derivatives thereof, and mixtures
thereof.
[0088] Suitable sunscreens include, but are not limited to,
aminobenzoic acid, avobenzone, bemotrizinol, bisoctrizole,
.beta.-carotene, cinoxate, 4-(dimethylamino)benzoic acid,
dioxybenzone, drometrizole, ecamsule, ensulizole, ethylhexyl
triazone, homosalate, lawsone, menthyl anthranilate,
4-methylbenzylidene camphor, mexenone, octabenzone, octocrylene,
octyl methoxycinnamate, octyl salicylate, oxybenzone,
sulisobenzone, zinc oxide, titanium dioxide, salts thereof,
derivatives thereof, and mixtures thereof.
[0089] Suitable anaesthetics and analgesics include, but are not
limited to, benzocaine, lidocaine, prilocaine and choline
salicylate, salts thereof, derivatives thereof, and mixtures
thereof.
[0090] Suitable skin-conditioning agents include, but are not
limited to, hydrocarbon oils and waxes, silicones, fatty acid
derivatives, cholesterol, di- and tri-glycerides, vegetable oils,
acetoglyceride esters, alkyl esters, alkenyl esters, lanolin, milk
tri-glycerides, wax esters, beeswax, sterols, phospholipids,
derivatives thereof, and mixtures thereof.
[0091] Exemplary nutritional agents include vitamins, essential
amino acids, essential fats, antioxidants, salts thereof,
derivatives thereof, and mixtures thereof.
Water Phase
[0092] The topical foam compositions of the present invention also
comprise water. Water forms the continuous phase of the emulsion
system. In an embodiment, the foam compositions comprise water in
an amount from about 65% to about 90% by weight. In another
embodiment the water is present in an amount from about 70% to
about 85% by weight. In another embodiment the water is present at
about 77% by weight.
Oil Miscible Organic Solvent
[0093] The present topical foam compositions comprise an oil
miscible organic solvent to facilitate solubilisation of the active
agent in the oil. Together, the oil miscible organic solvent and
oil comprise the oil phase of the composition.
[0094] The oil miscible organic solvent is present in the
composition in an amount from about 1% to about 20% by weight. In
one embodiment the oil miscible organic solvent is present in an
amount from about 3% to about 15% by weight. In another embodiment
the oil miscible organic solvent is present in an amount of about
5% by weight.
[0095] Suitable, non-limiting examples of oil miscible organic;
solvents include alcohols such as caprylic alcohol, decyl alcohol,
dodecylhexadecanol, dodecyltetradecanol, hexyl alcohol,
hexyldecanol, hexyldecyloctadecanol, isocetyl alcohol, isostearyl
alcohol, lauryl alcohol, myristyl alcohol, octyldecanol,
octyldodecanol, oleyl alcohol, tridecyl alcohol; esters such as
butyl stearate, C12-15 alkyl benzoate, C12-15 alkyl lactate,
caprylic/capric triglyceride, cetearyl ethylhexanoate, cetearyl
isononanoate, cetyl octanoate, cetyl palmitate, cocci-caprylate
caprate, cocoglycerides, decyl oleate, dibutyl adipate, dicaprylyl
carbonate, diethylhexyl adipate, di-ethylhexyl succinate,
diisopropyl adipate, dioctyl malate, di-PPG-2 myreth-10 adipate,
di-PPG-3 myristyl ether adipate, ethyl oleate, ethylhexyl cocoate,
ethylhexyl hydroxystearate, ethylhexyl palmitate, ethylhexyl
pelargonate, ethylhexyl stearate, hexyl laurate, hexyldecyl
laurate, hexyldecyl stearate, isocetyl stearate, isocetyl stearoyl
stearate, isodecyl oleate, isopropyl myristate, isopropyl
palmitate, isostearyl neopentanoate, isotridecyl isononanoate,
lauryl lactate, myristyl lactate, myristyl myristate, octyldodecyl
stearoyl stearate, oleyl erucate, oleyl oleate, pentaerythrityl
tetracaprylate/caprate, pentaerythrityl tetraisostearate, PPG-2
myristyl ether propionate, propylene glycol dicaprylate/dicaprate,
propylene glycol isostearate, propylheptyl caprylate, stearyl
octanoate; ethers such as dicaprylyl ether, PPG-10 cetyl ether,
PPG-11 stearyl ether, PPG-14 butyl ether, PPG-15 stearyl ether,
PPG-3 hydrogenated castor oil, PPG-3 myristyl ether; carboxylic
acids such as C10-40 hydroxyalkyl acid, C10-40 isoalkyl acid,
C32-36 isoalkyl acid, capric acid, caproic acid, caprylic acid,
coconut acid, lauric acid, linoleic acid, linolenic acid, linseed
acid, myristic acid, oleic acid, ricinoleic acid and lanolin.
[0096] According to an embodiment, the oil miscible organic solvent
is selected from the group consisting of diisopropyl adipate,
isopropyl myristate, dodecanol and caprylic/ capric
triglycerides.
[0097] In one embodiment, the oil miscible organic solvent is
diisopropyl adipate (also referred to herein as DIPA). In one
embodiment the DIPA is present in the composition in an amount from
about 1% to about 20% by weight. In another embodiment the DIPA is
present in an amount from about 3% to about 15% by weight. In
another embodiment the DIPA is present in an amount of about 5% by
weight.
[0098] According to a further embodiment, the present compositions
comprise a second pharmaceutically acceptable active agent. In one
embodiment, the second active agent is solubilized in the water
phase (Le. the continuous phase). This may be achieved by
dissolving the second active agent in an aliquot of water or an
aliquot of a water miscible organic solvent, and subsequently
solubilising the aliquot in the composition.
[0099] According to an embodiment, the water miscible organic
solvent is present in an amount from about 1% to about 20% by
weight. According to a further embodiment, the water miscible
organic solvent is present in an amount of about 10% by weight.
[0100] Suitably, water miscible organic solvents include, but are
not limited to, alcohols, including amyl alcohol, benzyl alcohol,
cyclohexanedimethanol, diacetone alcohol, ethyl alcohol, hexyl
alcohol, isobutyl alcohol, isopropyl alcohol, methyl alcohol,
n-butyl alcohol, propyl alcohol, t-butyl alcohol,
tetrahydrofurfuryl alcohol; carboxylic acids, including acetic
acid; diols, including 1,2-hexanediol, butylene glycol, diethylene
glycol, dipropylene glycol, ethyl hexanediol, ethylene glycol,
hexylene glycol, pentylene glycol, propylene glycol, tetraethylene
glycol, triethylene glycol, tripropylene glycol; and polyols
including polyethylene glycol, butanetriol, glycerol and
1,2,6-hexanetriol. [0101] In one embodiment, the water miscible
organic solvent is propylene glycol.
Propellant
[0102] It is recognized that the present topical foam compositions
must utilize a propellant in order to produce the foam upon
application. The propellant may be any suitable liquefied gas or
mixture thereof, such as a hydrocarbon, a chlorofluorocarbon,
dimethyl ether, hydrofluorocarbons and a mixture thereof.
[0103] Other suitable propellants include compressed gases such as
nitrogen, carbon dioxide, nitrous oxide and air. In a preferred
embodiment, the propellant is a mixture of hydrocarbons. In a
further preferred embodiment, the mixture of hydrocarbons is a
mixture of propane, n-butane and isobutane.
[0104] The propellant is present in an amount from about 1% to
about 20% by weight, or about 3% to about 15% by weight. In one
embodiment, the propellant is present in an amount from about 5% to
about 10% by weight, such as about 5%, 6%, 7%, 8%, 9% or 10% by
weight. The propellant may be introduced into the composition at
the time of filling, utilizing a pressurized container such as a
standard aerosol dispenser.
[0105] When the composition is released from the pressurized
container, the composition is an aerosol foam (also known as a
mousse). According to one embodiment, the aerosol foam is
homogeneous. In another embodiment, the aerosol foam breaks easily
with shear, such as gentle mechanical action e.g. rubbing or
spreading.
[0106] In another embodiment the propellant is absent from the
composition. According to such an embodiment, the composition may
be expelled from its container by mechanical means, such as by a
pump action or a squeezing action on the container.
[0107] Suitable pressurized containers for use herein include
aluminium, tin-plate and glass containers.
[0108] In one embodiment, the pressurized container is a one-piece
aluminium container in which the inner surface is lined with a
chemically inert lining. One suitable inner surface lining for use
herein is polyimide-imide (PAM), such as that supplied by Exal
Corporation, of Youngstown, Ohio. The container may be fitted with
an upright-use or inverted-use valve and a conventional foam spout
actuator. Alternatively, the container may be fitted with a
metered-dose valve.
Dermatologically Acceptable Excipients
[0109] According to an embodiment, the compositions may further
comprise one or more dermatologically acceptable excipients.
Non-limiting examples of such dermatologically acceptable
excipients include diluents, suspending agents, adjuvants,
preservatives, colorants, emollients, pH adjusting agents
(including buffers), thickeners, humectants, fragrances,
stabilizers, chelating agents, anticaking agents, viscosity
increasing agents, solubilizers, plasticizers, penetration
enhancing agents, film forming agents, antioxidants, wetting
agents, foam boosters or any mixture of these components.
[0110] In one embodiment, the one or more dermatologically
acceptable excipients comprise a preservative, an antioxidant and a
pH adjusting agent.
Preservative
[0111] The present topical aerosol foam compositions may
additionally comprise a preservative. The preservative is present
in the composition in an amount from about 0.01% to about 2% by
weight. In one embodiment the preservative is present in an amount
from about 0.1% to about 1% by weight. In another embodiment the
preservative is present in an amount of about 0.3% by weight.
[0112] Suitable preservatives include, but are not limited to
benzyl alcohol, diazolidinyl urea, methyl paraben, ethyl paraben,
propyl paraben, butyl paraben, phenoxyethanol, sorbic acid and
salts thereof such as potassium sorbate, benzoic acid and salts
thereof such as sodium benzoate, and mixtures thereof.
[0113] According to an embodiment, the preservative is a
combination of sorbic acid and potassium sorbate.
Antioxidant
[0114] The present topical aerosol foam compositions may further
comprise an antioxidant. The antioxidant is present in the
composition in an amount from about 0.001% to about 1% by weight.
In one embodiment the antioxidant is present from about 0.05% to
about 0.5% by weight. In another embodiment the antioxidant is
present in an amount of about 0.1% by weight.
[0115] Suitable antioxidants include, but are not limited to,
butylated hydroxytoluene (BHT), butylated hydroxyanisole,
tocopherol, propyl gallate, vitamin E TPGS, derivatives thereof,
and mixtures thereof. In one embodiment, the antioxidant is
BHT.
pH Adjusting Agent
[0116] The present topical aerosol foam compositions may further
comprise a pH adjusting agent to aid in stabilizing the active
agent. According to an embodiment, the pH adjusting agent is
present in an amount from about 0.01% to about 10% by weight. In
one embodiment, the pH adjusting agent is a base. Suitable pH
adjusting bases include but are not limited to bicarbonates,
carbonates and hydroxides (such as alkali or alkaline earth metal
hydroxides, as well as transition metal hydroxides). The pH
adjusting agent may also be an acid, an acid salt, or mixtures
thereof. The pH adjusting agent may also be a buffer. Suitable
buffers include, but are not limited to citrate/citric acid,
acetate/acetic acid, phosphate/phosphoric acid, formate/formic
acid, propionate/propionic acid, lactate/lactic acid,
carbonate/carbonic acid, ammonium/ammonia, edentate/edetic acid,
derivatives thereof, and combinations thereof. According to an
embodiment, the pH adjusting agent is a citrate/citric acid buffer.
According to an embodiment, the citrate/citric acid buffer is
present in an amount from about 0.02% to about 2% by weight.
[0117] In another embodiment, the present invention relates to an
oil in water emulsion aerosol foam composition comprising:
tazarotene, water, an oil in an amount from about 3% to about 8% by
weight, an oil miscible organic solvent, a surfactant component
comprising a non-ionic hydrophilic surfactant in an amount from
about 2% to about 6% by weight, and a hydrocarbon propellant,
wherein the tazarotene is solubilized in the oil phase of the
composition and wherein the particle size of the oil phase is less
than about 1000 nm.
[0118] According to an embodiment, the mean particle size of the
oil phase of the tazarotene aerosol foam is about 100 nm.
[0119] The tazarotene foam formulation exemplified by these
embodiments is particularly suited for application to small regions
of the face for the treatment of acne. In one embodiment, the
tazarotene aerosol foam formulation is dispensed from a metered
dose actuator. In another alternative embodiment, the tazarotene
aerosol foam composition is formulated as a macro emulsion (i.e.
the particle size of the oil phase is greater than 1000 nm).
[0120] In another embodiment, a second pharmaceutically active
agent is solubilized in the composition. In another embodiment the
second pharmaceutically active agent is solubilized in the water
phase of the composition. This may be achieved by dissolving the
further pharmaceutically active agent in an aliquot of water which
is subsequently solubilized in the composition. Alternatively, the
second pharmaceutically active agent is dissolved in an aliquot of
water miscible organic solvent which is subsequently solubilized in
the composition. In another embodiment the second pharmaceutically
active agent is in a composition comprising the retinoid
tazarotene.
Definitions
[0121] As used herein, the terms "administering" and
"administered," refer to any method which delivers the composition
to a subject in such a manner as to provide a therapeutic
effect.
[0122] As used herein, the term "derivative(s) thereof" refers to
prodrugs, solvates, hydrates, esters and acids of the
pharmaceutically active agent.
[0123] As used herein, the phrase an "effective amount" of an
active agent or ingredient, or pharmaceutically active agent or
ingredient, which are synonymous herein, refers to an amount of the
pharmaceutically active agent sufficient to have a therapeutic
effect upon administration. An effective amount of the active agent
may, will, or is expected to cause relief of symptoms. Effective
amounts of the active agent will vary with the particular disease
or diseases being treated, the severity of the disease, the
duration of the treatment, and the specific components of the
composition being used.
[0124] As used herein, the term "fatty alcohol" refers to an
alcohol having an aliphatic chain from about 9 to about 22 carbon
atoms long.
[0125] As used herein, an "emulsion" refers to a mixture of two or
more immiscible (unblendable) liquids wherein the particle size of
the dispersed phase (i.e. oil in the case of an oil in water
emulsion) is less than about 10,000 nm.
[0126] As used herein, a "submicron emulsion" refers to a mixture
of two or more immiscible (unblendable) liquids wherein the
particle size of the dispersed phase (i.e. oil in the case of an
oil in water emulsion) is in the range from about 100 nm to about
1000 nm.
[0127] As used herein, a "rnicroemulsion" refers to a mixture of
two or more immiscible (unblendable) liquids wherein the particle
size of the dispersed phase (i.e. oil in the case of an oil in
water emulsion) is in the range from about 10 nm to about 100
nm.
[0128] As used herein, "nanoemulsion" refers to a mixture of two or
more immiscible (unblendable) liquids wherein the particle size of
the dispersed phase (i.e. oil in the case of an oil in water
emulsion) is in the range from about 1 nm to 100 nm.
[0129] As used herein, the term "phase inversion temperature"
refers to a temperature where an oil in water emulsion inverts to a
water in oil emulsion (or vice versa).
[0130] As used herein, a "pH adjusting agent" refers to a specific
pH adjusting agent or agents, including but not limited to, a
buffer, a base or an acid, salts thereof and mixtures thereof,
added to a composition.
[0131] The phrase "dermatologically acceptable excipient" as used
herein refers to any inactive ingredient present in the herein
described compositions.
[0132] As used herein, the phrase "pharmaceutically acceptable
salts" refers to salts that are pharmaceutically acceptable and
that possess the desired pharmacological activity of the parent
compound. Such salts include: (1) acid addition salts, formed with
acids such as, for example, acetic acid, benzoic acid, citric acid,
gluconic acid, glutamic acid, glutaric acid, glycolic acid,
hydrochloric acid, lactic acid, maleic acid, malic acid, malonic
acid, mandelic acid, phosphoric acid, propionic acid, sorbic acid,
succinic acid, sulfuric acid, tartaric acid, naturally and
synthetically derived amino acids, and mixtures thereof; or (2)
salts formed when an acidic proton present in the parent compound
is either (i) replaced by a metal ion e.g. an alkali metal ion, an
alkaline earth metal ion, or an aluminium ion; or (ii) protonates
an organic base such as, for example, ethanolamine, diethanolamine,
triethanolamine, tromethamine and N-methylglucamine.
[0133] As used herein, a "subject". "individual" or "patient"
refers to any subject, particularly a human, for whom therapy is
desired.
[0134] As used herein, a "treatment" or "treating" of a disease,
disorder or condition encompasses alleviation of at least one
symptom thereof, a reduction in the severity thereof, or the delay,
prevention or inhibition of the progression thereof. Treatment need
not mean that the disease, disorder or condition is totally cured.
A useful composition herein need only to reduce the severity of a
disease, disorder or condition, reduce the severity of symptoms
associated therewith, provide improvement to a patient's quality of
life, or delay, prevent or inhibit the onset of a disease, disorder
or condition.
[0135] Any concentration range, percentage range or ratio range
recited herein is to be understood to include concentrations,
percentages or ratios of any integer within that range and
fractions thereof, such as one tenth and one hundredth of an
integer, unless otherwise indicated.
[0136] It should be understood that the terms "a" and "an" as used
above and elsewhere herein refer to "one or more" of the enumerated
components. It will be clear to one of ordinary skill in the art
that the use of the singular includes the plural unless
specifically stated otherwise. Therefore, the terms "a," "an" and
"at least one" are used interchangeably in this application.
[0137] Throughout the application, descriptions of various
embodiments use "comprising" language, however in some specific
instances, an embodiment can alternatively be described using the
language "consisting essentially of" or "consisting of".
[0138] For the purposes of better understanding the present
teachings and in no way limiting their scope, unless otherwise
indicated, all numbers expressing quantities, percentages or
proportions, and other numerical values used in the specification
and claims, are to be understood as being modified in all instances
by the term "about."
[0139] As used herein, the term "substantially free" of a specified
component refers to a composition with less than about 1% of the
specified component.
[0140] Other terms used herein are intended to be defined by their
well-known meanings in the art.
Process of Preparation
[0141] In one embodiment, the present invention provides a process
for the preparation of an oil in water submicron or micro emulsion
aerosol foam composition, comprising a pharmaceutically active
agent, water, an oil present in an amount of less than about 10% by
weight, an oil miscible organic solvent, a surfactant component
comprising a hydrophilic surfactant in an amount from about 0.1% to
about 10% by weight, and a propellant, the process comprising:
[0142] a) admixing the pharmaceutically active agent, a first
aliquot of water, oil, oil miscible organic solvent and surfactant
component to form an oil in water emulsion, [0143] b) heating the
oil in water emulsion of step (a) to a phase inversion temperature
wherein the oil in water emulsion forms a water in oil emulsion,
[0144] c) cooling the water in oil emulsion to below the phase
inversion temperature to form a submicron or micro oil in water
emulsion, [0145] d) adding a second aliquot of water to cool the
submicron or micro oil in water emulsion, [0146] e) actuating a
sample of the submicron or micro oil in water emulsion with a
propellant to form an oil in water submicron or micro emulsion
aerosol foam.
[0147] According to an embodiment, the first aliquot of water
comprises about 10% to about 40% by weight of the total water
content of the submicron or micro oil in water emulsion aerosol
foam and the second aliquot of water comprises about 90% to about
60% by weight of the total water content of the submicron or micro
oil in water emulsion aerosol foam.
[0148] According to an embodiment, the first aliquot of water
comprises about 10% to about 40% by weight of the total water
content of the submicron or micro oil in water emulsion aerosol
foam and the second aliquot of water comprises about 90% to about
60% by weight of the total water content of the submicron or micro
oil in water emulsion aerosol foam.
[0149] According to another embodiment, the first aliquot of water
comprises about 15% to about 35% of the total water content of the
submicron or micro oil in water emulsion aerosol foam and the
second aliquot of water comprises about 85% to about 65% of the
total water content of the submicron or micro oil in water emulsion
aerosol foam.
[0150] According to a further embodiment, the first aliquot of
water comprises about 20% to about 30% of the total water content
of the submicron or micro oil in water emulsion aerosol foam and
the second aliquot of water comprises about 80% to about 70% of the
total water content of the submicron or micro oil in water emulsion
aerosol foam.
[0151] According to yet a further embodiment, the first aliquot of
water comprises about 25% of the total water content of the
submicron or micro oil in water emulsion aerosol foam and the
second aliquot of water comprises about 75% of the total water
content of the submicron or micro oil in water emulsion aerosol
foam.
[0152] The presently described process provides for the preparation
of a low oil and low surfactant submicron or micro emulsion aerosol
foam, where a concentrated submicron or micro emulsion is prepared
(comprising the first aliquot of water) and is subsequently diluted
(with the second aliquot of water) to ultimately afford the desired
low oil and low surfactant submicron or micro emulsion. By
initially preparing a concentrated submicron or micro emulsion, a
sufficient concentration of surfactant is present in the
composition to stabilize the submicron or micro sized oil phase.
The dilution step then provides the desired low oil and low
surfactant submicron or micro emulsion. It is thought that the
addition of the second aliquot of water (which is at a temperature
substantially below the phase inversion temperature) serves to fix
the submicron or micro emulsion structure of the composition and,
of course, dilutes the composition to provide the low oil and low
surfactant composition.
[0153] According to an embodiment, a second pharmaceutically active
agent is solubilized in the water phase of the composition. This
may be achieved by dissolving the second pharmaceutically active
agent in an aliquot of water or water miscible organic solvent,
which is subsequently solubilized in the composition.
[0154] In one embodiment, the second pharmaceutically active agent
dissolved in an aliquot of water or water miscible organic solvent
is added to the submicron or micro oil in water emulsion following
step (d)). That is, the second pharmaceutically active agent is
solubilized in the water phase of the composition after formation
of the submicron or micro emulsion. [0155] Another aspect of the
invention is the product produced by this process.
Methods of Treatment
[0156] The emulsion aerosol foam compositions of the present
invention are cosmetically elegant and suitable for application to
the face for treating a skin disorder or condition. The
compositions are easily spread, non-greasy, non-drying and leave
minimal residue on the skin.
[0157] The present invention provides for a method of treating a
skin disease, disorder or condition, comprising administering to
the skin of a patient requiring such treatment an effective amount
of a composition of the present invention. In one embodiment, the
skin disease, disorder or condition is acne. In another embodiment,
the skin disease, disorder or condition is psoriasis.
[0158] The present invention also relates to the use of the
compositions as described herein for the preparation of a
medicament for the treatment of a skin disease, disorder or
condition.
[0159] The present invention also relates to a method of treating a
skin disease, disorder or condition by administering to the skin of
a patient requiring such treatment an effective amount of a
composition of the present invention.
[0160] Exemplary, non-limiting, skin diseases, disorders or
conditions treatable by the present compositions include acne,
rosacea, dermatitis, psoriasis and fungal disorders. According to
an embodiment, the skin disease, disorder or condition is acne.
According to another embodiment, the skin disease, disorder or
condition is psoriasis.
[0161] In an embodiment, the present compositions are used in
combination with a suitable additional pharmaceutical dosage form.
The additional pharmaceutical dosage form is administered to a
patient either prior to, concomitantly with, or after the
compositions described herein.
[0162] In one embodiment in this regard, the present composition
and the additional pharmaceutical dosage form are administered to a
patient at the same time. In an alternative embodiment, one of the
present compositions and the additional pharmaceutical dosage form
is administered in the morning and the other is administered in the
evening.
[0163] In another embodiment, the additional pharmaceutical dosage
form can be a suitable oral pharmaceutical. In this regard, the
present composition can be applied to the target area of the
patient, prior to, concomitantly with, or after ingestion of the
oral medication.
[0164] According to an embodiment, the present composition
comprises a retinoid and the oral pharmaceutical dosage form
comprises a pharmaceutically active agent selected from the group
consisting of an antibiotic, a contraceptive, a retinoid such as
isotretioin, and a nutritional agent.
[0165] Furthermore, the foam compositions of the present invention
may be used with other adjunct therapies and treatments, such as
pre-washing with soaps or cleansers. However, care is needed in
this regard, since antibacterial soaps arid abrasive soaps may
increase irritation.
EXAMPLES
[0166] The following examples are illustrative or preferred
embodiments herein and are not to be construed as limiting the
present invention thereto. All percentages are based on the percent
by weight of the final delivery system or formulation prepared,
unless otherwise indicated and all totals equal 100% by weight.
Tables 2a, 2b, 2c and 2d
Oil in Water Submicron/Micro Emulsion Foam Formulations--Tazarotene
(0.1%)
TABLE-US-00002 [0167] TABLE 2a 706/8/2 - absent propellant*
Component % w/w BHT 0.10 Macrogol Cetostearyl Ether 12 5.00
(Ceteareth 12) Light Mineral Oil 6.00 Sorbic Acid 0.40 DIPA 5.00
Tazarotene 0.10 Citric Acid Anhydrous 0.03 Potassium Citrate
Monohydrate 0.57 Deionized Water 82.80 Total 100.000
TABLE-US-00003 TABLE 2b 706/8/3 - absent propellant* Component %
w/w BHT 0.10 Macrogol Cetostearyl Ether 12 5.00 (Ceteareth 12)
Light Mineral Oil 8.00 Sorbic Acid 0.40 DIPA 7.00 Tazarotene 0.10
Citric Acid Anhydrous 0.03 Potassium Citrate Monohydrate 0.54
Deionized Water 78.83 Total 100.000
*The formulations described in Tables 2a & 2b were dispensed as
a foam following the addition of approximately 7 to 8 grams of AP70
propellant per 100 grams of aerosol base.
TABLE-US-00004 TABLE 2c 730/2/1 Component Function % w/w % w/w BHT
Antioxidant 0.100 0.093 Macrogol Cetostearyl Ether 12 Surfactant
5.000 4.635 (Ceteareth 12) Light Mineral Oil Oil 6.000 5.562 Sorbic
Acid Preservative 0.150 0.139 Potassium Sorbate Preservative 0.200
0.185 Diisopropyl adipate Organic Solvent 5.000 4.635 Tazarotene
Active ingredient 0.100 0.093 Citric Acid Anhydrous Buffer 0.037
0.034 Potassium Citrate Monohydrate Buffer 0.103 0.096 Deionized
Water Water 83.310 77.228 Propellant AP70 (propane, Propellant --
7.300 butane & isobutane) Total 100.000 100.000
TABLE-US-00005 TABLE 2d SFW0260-02 Component Function % w/w % w/w
BHT Antioxidant 0.100 0.093 Macrogol Cetostearyl Ether 12
Surfactant 5.000 4.648 (Ceteareth 12) Light Mineral Oil Oil 6.000
5.578 Sorbic Acid Preservative 0.150 0.139 Potassium Sorbate
Preservative 0.200 0.186 Diisopropyl adipate Organic Solvent 5.000
4.648 Tazarotene Active ingredient 0.100 0.093 Citric Acid
Anhydrous Buffer 0.037 0.034 Potassium Citrate Monohydrate Buffer
0.103 0.096 Deionized Water Water 83.310 77.445 Propellant AP70
(propane, Propellant -- 7.040 butane & isobutane) Total 100.000
100.000
Example 1
Method of Preparing Submicron/Micro Emulsion Foam
Formulation--Tazarotone
[0168] Procedure: aerosol base production (730/2/1): [0169] Phase 1
(Oil phase): BHT, ceteareth-12, mineral oil and sorbic acid [0170]
Phase 2 (Active phase): tazarotene dissolved in diisopropyl adipate
(DPA) [0171] Phase 3 (Buffer phase): deionized water (about 22.8%
of the total water content of aerosol base), citric acid, potassium
citrate and potassium sorbate [0172] Phase 4 (Water phase):
deionized water (about 77.2% of the total water content of aerosol
base) [0173] 1. Dissolve tazarotene in diisopropyl adipate in a
suitable stainless steel container at ambient temperature (Phase
2). [0174] 2. Prepare buffer solution at ambient temperature in a
stainless steel container (Phase 3). [0175] 3. Add oil phase
ingredients to the main batch vessel (Phase 1). [0176] 4. Combine
Phase 1, Phase 2 and Phase 3 in the main batch vessel. Commence low
heating with stirring. Continue heating to the phase inversion
temperature range of 70.degree. C. to 80.degree. C. until a water
in oil emulsion occurs. [0177] 5. Commence cooling to below the
phase inversion temperature. When the emulsion becomes an oil in
water submicron/micro emulsion, add ambient temperature Phase 4
deionized water at a moderate rate. Stir until uniform. Maintain
batch at 25.degree. C.-30.degree. C. [0178] 6. Test pH of the
aerosol base. [0179] 7. Adjust pH to a range of 4.70 to 5.50 with
1N potassium hydroxide solution or with 10% citric acid solution.
[0180] 8. Adjust to 100% with deionized water (to account for
evaporation water loss). The abovementioned procedure is
represented in schematic form in FIG. 1.
Alternative Procedure--Aerosol Base Production (SFW0260-02):
[0181] At ambient temperature, dissolve tazarotene in diisopropyl
adipate in a side vessel, while stirring.
[0182] Add mineral oil and BHT to the side vessel, while stirring
until the solution is homogenous.
[0183] At ambient temperature, add deionized water (about 28.8% of
total water content of aerosol base), citric acid and potassium
citrate to a main batch vessel, while stirring until all components
are fully dissolved.
[0184] Add potassium sorbate to the main batch vessel, while
stirring until the potassium sorbate is fully dissolved.
[0185] Continue to stir the contents of the main batch vessel and
add the contents of the side vessel (tazarotene, DIPA, mineral oil
and BHT) to the main batch vessel, followed by addition of sorbic
acid and ceteareth-12.
[0186] Commence heating and continue heating until the phase
inversion temperature is reached i.e. where the oil in water
emulsion inverts to a water in oil emulsion (as measured by
conductivity or visual observation). The phase inversion
temperature is in the range of about 70.degree. C. to about
80.degree. C.
[0187] Cool the main batch vessel to below the phase inversion
temperature (approximately 69.degree. C.) to facilitate the
formation of an oil in water submicron/micro emulsion.
[0188] Add ambient temperature deionized water (about 71.2% of
total water content of aerosol base). Continue stirring and
maintain main batch vessel at around 25.degree. C.-30.degree.
C.
[0189] Test the pH and adjust as necessary to a range of 4.70 to
5.50. Adjust with deionized water to account for evaporative water
loss.
Aerosol Filling and Crimping
[0190] The aerosol base is filled into suitable aluminium aerosol
containers, suitable valves are inserted, vacuum crimped and gassed
with a suitable propellant.
TABLE-US-00006 TABLE 3 Submicron/micro emulsion foam - tazarotene
(0.1%) plus calcipotriene (0.005%) Item Ingredient Function % w/w
First active phase 1 Diisopropyl adipate Organic solvent 5.000 2
Tazarotene Active ingredient 0.100 Hydrocarbon oil phase 3 BHT
Antioxidant 0.100 4 Macrogol Cetostearyl Ether 12 Surfactant 5.000
(Ceteareth 12) 5 Mineral oil (light) Hydrocarbon 6.000 6 Tocopherol
Antioxidant 0.002 First water phase 7 Water (deionized) Aqueous
solvent 19.000 8 EDTA, Na.sub.2 Buffer 0.060 9 Disodium phosphate
Buffer 0.080 Second water phase 10 Water (deionized) Aqueous
solvent 54.653 Second active phase 11 Propylene glycol Organic
solvent 10.000 12 Calcipotriene Active ingredient 0.005 Total
100.000 Finished product Items Ingredient Function % w/w 1 to 12
Aerosol base Concentrate 92.7 13 Hydrocarbon propellant AP70
Propellant 7.3 Total 100.0
Example 2
[0191] Method of Preparing Submicron/micro emulsion
foam--Tazarotene (0.1%) Plus Calcipotriene (0.005%)
Aerosol Base:
[0192] 1. Add BHT (Item 3), ceteareth-12 (Item 4), mineral oil
(Item 5) and tocopherol (Item 6) to the main mixing vessel. [0193]
2. Prepare the First active phase by adding diisopropyl adipate
(Item 1) and tazarotene (Item 2) to a small mixing vessel and mix
until tazarotene has dissolved. [0194] 3. Add the First active
phase solution (Items 1 and 2) to the main mixing vessel. [0195] 4.
Into a separate mixing vessel prepare First water phase by adding
water (Item 7). [0196] 5. Start stirring First water phase and add
EDTA, Na.sub.2 (Item 8) and disodium phosphate (Item 9) to water
and mix until dissolved. [0197] 6. Add First water phase (Items 7
to 9) to the main mixing vessel. [0198] 7. While monitoring the
conductivity of the contents of the main mixing vessel (Items 1 to
9) commence heating, to approximately 80.degree. C., and start
stirring. [0199] 8. As the temperature increases the mixture
inverts from an oil in water emulsion to a water in oil emulsion
and a corresponding decrease in the conductivity is observed.
[0200] 9. When the temperature reaches approximately 80.degree. C.
stop heating and commence slow cooling of the contents of the main
mixing vessel while maintaining stirring. [0201] 10. At
approximately 70.degree. C. the mixture inverts from a water in oil
emulsion to an oil in water emulsion and a corresponding increase
in the conductivity is observed. The appearance of the mixture also
changes from opaque to translucent.
[0202] 111. At this temperature, when the mixture is translucent,
add the Second water phase (Item 10), at ambient temperature, to
the main mixing vessel and continue stirring. The temperature of
the mixture will decrease to approximately 40.degree. C. following
the addition of the Second water phase. [0203] 12. While stirring
the mixture, continue cooling until the temperature range decreases
to approximately 25.degree. C. to 30.degree. C. [0204] 13. Prepare
the Second active phase by adding propylene glycol (Item 11) and
calcipotriene (Item 12) to a small mixing vessel and mix until
calcipotriene has dissolved. [0205] 14. Transfer the Second active
phase (Items 11 and 12) to the main mixing vessel and stir until
the mixture is uniform. [0206] Finished product: [0207] 1. Add
Aerosol base (Items 1 to 12) to an empty aerosol container. [0208]
2. Secure an aerosol valve onto the aerosol container. [0209] 3.
Add Propellant (Item 13) to the aerosol container. [0210] 4. Test
the aerosol container to confirm that there is no leakage. [0211]
5. Place an actuator onto the aerosol valve. [0212] 6. Shake the
aerosol container prior to dispensing at room temperature.
TABLE-US-00007 [0212] TABLE 4 Submicron/micro emulsion foam -
clindamycin phosphate (1%) plus tretinoin (0.05%) Item Ingredient
Function % w/w First active phase 1 Diisopropyl adipate Organic
solvent 10.000 2 Tretinoin Active ingredient 0.050 Hydrocarbon oil
phase 3 BHT Antioxidant 0.100 4 Macrogol Cetostearyl Ether 12
Surfactant 5.000 (Ceteareth 12) 5 Mineral oil (light) Hydrocarbon
6.000 First water phase 6 Water (deionized) Aqueous solvent 22.000
7 Anhydrous citric acid Buffer 0.037 8 Potassium citrate
monohydrate Buffer 0.103 Second water phase 9 Water (deionized)
Aqueous solvent 32.960 Second active phase 10 Water (deionized)
Aqueous solvent 20.000 11 Clindamycin phosphate Active ingredient
1.250 (80% active) Preservative phase 12 Propylene glycol 2.000 13
Benzyl alcohol 0.500 Total 100.000 Finished product Items
Ingredient Function % w/w 1 to 13 Aerosol base Concentrate 91.1 14
Hydrocarbon propellant AP70 Propellant 8.9 Total 100.0
Example 3
[0213] Method of preparing Submicron/Micro Emulsion Foam
Formulation--Clindamycin Phosphate (1%) Plus Tretinoin (0.05%)
[0214] Aerosol base: [0215] 1. Add BHT (Item 3), ceteareth-12 (Item
4) and mineral oil (Item 5) to the main mixing vessel. [0216] 2.
Prepare the First active phase by adding (item 1) and tretinoin
(item 2) to a small mixing vessel and mix until dissolved. [0217]
3. Add the First active phase solution (Items 1 and 2) to the main
mixing vessel. [0218] 4. Into a separate mixing vessel prepare
First water phase by adding water (Item 6). [0219] 5. Start
stirring First water phase and add anhydrous citric acid (Item 7)
and potassium citrate monohydrate (Item 8) to water and mix until
dissolved. [0220] 6. Add First water phase (Items 6 to 8) to the
main mixing vessel. [0221] 7. While monitoring the conductivity of
the contents of the main mixing vessel (items 1 to 8) commence
heating, to approximately 80.degree. C., and start stirring. [0222]
8. As the temperature increases the mixture inverts from an oil in
water emulsion to a water in oil emulsion and a corresponding
decrease in the conductivity is observed. [0223] 9. After the
mixture inverts from an oil in water emulsion to a water in oil
emulsion stop heating and commence slow cooling of the contents of
the main mixing vessel while maintaining stirring. [0224] 10. With
cooling, the mixture inverts from a water in oil emulsion back to
an oil in water emulsion and a corresponding increase in the
conductivity is observed. The appearance of the mixture also
changes from opaque to translucent. [0225] 11. At this temperature,
when the mixture is translucent, add the Second water phase (Item
9), at ambient temperature, to the main mixing vessel and continue
stirring. The temperature of the mixture will decrease following
the addition of the Second water phase. [0226] 12. While stirring
the mixture, continue cooling until the temperature range decreases
to approximately 25.degree. C. to 30.degree. C. [0227] 13. Prepare
the Second active phase by adding water (Item 10) and clindamycin
phosphate (Item 11) to a small mixing vessel and mix until
clindamycin phosphate has dissolved. [0228] 14. Transfer the Second
active phase (Items 10 and 11) to the main mixing vessel and stir
until the mixture is uniform. [0229] 15. Prepare the Preservative
phase by adding propylene glycol (Item 12) and benzyl alcohol (Item
13) to a small mixing vessel and mix until uniform. [0230] 16.
Transfer the Preservative phase (Items 12 and 13) to the main
mixing vessel and stir until the mixture is uniform. [0231]
Finished product: [0232] 1. Add Aerosol base (Items 1 to 13) to an
empty aerosol container. [0233] 2. Secure an aerosol valve onto the
aerosol container. [0234] 3. Add Propellant (Item 14) to the
aerosol container. [0235] 4. Test the aerosol container to confirm
that there is no leakage. [0236] 5. Place an actuator onto the
aerosol valve. 1
[0237] 6. Shake the aerosol container prior to dispensing at room
temperature. [0238] The formulations described in tables 5 to 9 are
further illustrative of the present invention.
TABLE-US-00008 [0238] TABLE 5 Submicron/micro emulsion foam -
tazarotene (0.1%) plus clobetasol propionate (0.05%) Item
Ingredient Function % w/w First active phase 1 Diisopropyl adipate
Organic solvent 5.000 2 Tazarotene Active ingredient 0.100
Hydrocarbon oil phase 3 BHT Antioxidant 0.100 4 Macrogol
Cetostearyl Ether 12 Surfactant 5.000 (Ceteareth 12) 5 Mineral oil
(light) Hydrocarbon 2.000 6 Sorbic acid Preservative 0.200 7
Petrolatum Hydrocarbon 2.000 First water phase 8 Water (deionized)
Aqueous solvent 22.030 9 Anhydrous citric acid Buffer 0.040 10
Potassium citrate monohydrate Buffer 0.100 11 Potassium sorbate
Preservative 0.270 Second water phase 12 Water (deionized) Aqueous
solvent 53.110 Second active phase 13 Propylene glycol Organic
solvent 10.000 14 Clobetasol propionate Active ingredient 0.050
Total 100.000 Finished product Items Ingredient Function % w/w 1 to
14 Aerosol base Concentrate 92.7 15 Hydrocarbon propellant AP70
Propellant 7.3 Total 100.0
TABLE-US-00009 TABLE 6 Submicron/micro emulsion foam - Vitamin D3
(0.02%) Item Ingredient Function % w/w Active phase 1 Diisopropyl
adipate Organic solvent 2.000 2 Vitamin D3 Active ingredient 0.020
Hydrocarbon oil phase 3 Macrogol Cetostearyl Ether 12 Surfactant
3.000 (Ceteareth 12) 4 Mineral oil (light) Oil 3.000 5 Tocopherol
Antioxidant 0.002 First water phase 6 Water (deionized) Aqueous
solvent 10.000 7 Citric acid Buffer q.s. 8 Potassium citrate Buffer
q.s. Second water phase 9 Water (deionized) Aqueous solvent to
100.000 10 Methyl paraben Preservative q.s. Total 100.000 Finished
product Items Ingredient Function % w/w 1 to 10 Aerosol base
Concentrate 92.7 11 Hydrocarbon propellant AP70 Propellant 7.3
Total 100.0
TABLE-US-00010 TABLE 7 Submicron/micro emulsion foam - Salicylic
acid (2%) Item Ingredient Function % w/w Active phase 1 Diisopropyl
adipate Organic solvent 9.000 2 Salicylic acid Active ingredient
2.000 Hydrocarbon oil phase 3 Macrogol Cetostearyl Ether 12
Surfactant 6.000 (Ceteareth 12) 4 Mineral oil (light) Oil 8.000
First water phase 5 Water (deionized) Aqueous solvent 26.000 6
Citric acid Buffer q.s. 7 Potassium citrate Buffer q.s. Second
water phase 8 Water (deionized) Aqueous solvent to 100.000 9 Benzyl
alcohol Preservative q.s. Total 100.000 Finished product Items
Ingredient Function % w/w 1 to 9 Aerosol base Concentrate 92.7 10
Hydrocarbon propellant AP70 Propellant 7.3 Total 100.0
TABLE-US-00011 TABLE 8 Submicron/micro emulsion foam - Adapalene
0.1% Item Ingredient Function % w/w Active phase 1 Diisopropyl
adipate Organic solvent 3.000 2 Adapalene Active ingredient 0.100
Hydrocarbon oil phase 3 BHT Antioxidant 0.100 4 Macrogol
Cetostearyl Ether 20 Surfactant 3.000 (Ceteareth 20) 5 Mineral oil
(light) Oil 4.000 First water phase 6 Water (deionized) Aqueous
solvent 15.000 7 Citric acid Buffer q.s. 8 Potassium citrate Buffer
q.s. Second water phase 9 Water (deionized) Aqueous solvent to
100.000 10 Benzyl alcohol Preservative q.s. Total 100.000 Finished
product Items Ingredient Function % w/w 1 to 9 Aerosol base
Concentrate 92.7 10 Hydrocarbon propellant AP70 Propellant 7.3
Total 100.0
TABLE-US-00012 TABLE 9 Submicron/micro emulsion foam - clobetasol
propionate (0.05%) Item Ingredient Function % w/w Active phase 1
Diisopropyl adipate Organic solvent 5.00 2 Clobetasol propionate
Active ingredient 0.05 Hydrocarbon oil phase 3 Macrogol Cetostearyl
Ether 20 Surfactant 5.00 (Ceteareth 20) 4 Mineral oil (light) Oil
5.00 5 BHT Antioxidant 0.10 First water phase 6 Water (deionized)
Water 20.00 7 Citric acid Buffer q.s. 8 Potassium citrate Buffer
q.s. Second water phase 9 Water (deionized) Water to 100% 10 Methyl
paraben Preservative q.s. Total 100.00 Finished product Items
Ingredient Function % w/w 1 to 10 Aerosol base Concentrate 92.7 11
Hydrocarbon propellant AP70 Propellant 7.3 Total 100.0
Example 4
Skin Penetration Study
[0239] A skin penetration study was performed, comparing the
topical delivery of the tazarotene submicron/micro emulsion foam
(base) formulations of Examples 2a and 2b to TAZORAC.TM. cream and
gel formulations using in-vitro skin distribution assays.
Split-thickness skin (-0.50 mm) sections were mounted in
flow-through diffusion cells and test agents were applied at a
finite dose of 15.63 mg/cm.sup.2 on 3 skin donors with 5 replicates
each.
[0240] The tissues were collected at various time points (t=0, 2, 6
hrs), washed, tape stripped, and split into epidermis and dermis.
The distribution of tazarotene within the epidermis, dermis, and
wash were quantified by LC/MS/MS with a 50 pg/mL LOQ.
[0241] As shown in FIGS. 2 and 3, the skin penetration of the
tazarotene foam (base) formulations in the epidermis and dermis was
similar to the commercial comparators (i.e. TAZORAC.RTM. cream and
gel).
Example 5
[0242] Compatibility of Surfactants with Tazarotene
[0243] An accelerated stability study (using HPLC) was conducted at
50.degree. C. to measure the compatibility of tazarotene with
various surfactants. FIGS. 4 and 5 show that tazarotene was most
stable in a hydrophilic ethoxylated fatty alcohol ether surfactant,
such as Ceteareth -12, in contrast to various lipophilic
surfactants.
Example 6
Measurement of Particle Size Distribution
[0244] The particle size distribution of the oil phase of the
submicron/micro emulsions (aerosol foam base) of the present
invention was measured using a Malvern Mastersizer 2000 instrument.
FIG. 6 illustrates the particle size distribution of the oil phase
of a preferred formulation (730/2/1). The mean particle size was
0.097 .mu.m, that is, about 0.1 .mu.m (i.e. about 100 nm).
* * * * *