U.S. patent application number 14/593272 was filed with the patent office on 2015-04-30 for topical steroid composition and method.
The applicant listed for this patent is MiCal Pharmaceuticals LLC - H Series, a Series of MiCal Pharmaceuticals LLC, a Multi-Div. Invention is credited to Keith A. Johnson, Karl F. Popp.
Application Number | 20150119827 14/593272 |
Document ID | / |
Family ID | 50485547 |
Filed Date | 2015-04-30 |
United States Patent
Application |
20150119827 |
Kind Code |
A1 |
Johnson; Keith A. ; et
al. |
April 30, 2015 |
TOPICAL STEROID COMPOSITION AND METHOD
Abstract
Storage stable, topical lotion compositions for treating
corticosteroid-responsive dermatoses are provided by the present
invention which include a halobetasol material comprising
halobetasol or its pharmaceutically acceptable salts, esters, and
solvates; and a pharmaceutically acceptable carrier which includes:
(a) one or more fatty alcohols and/or one or more alkoxylated fatty
alcohols, (b) one or more polyol humectants, and (c) diisopropyl
adipate. Storage stable, topical lotion compositions for treating
corticosteroid-responsive dermatoses are provided by the present
invention which include 0.05% halobetasol propionate; and a
pharmaceutically acceptable carrier which includes: (a) one or more
fatty alcohols and/or one or more alkoxylated fatty alcohols, (b)
one or more polyol humectants, and (c) diisopropyl adipate.
Inventors: |
Johnson; Keith A.; (Durham,
NC) ; Popp; Karl F.; (Schodack Landing, NY) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
MiCal Pharmaceuticals LLC - H Series, a Series of MiCal
Pharmaceuticals LLC, a Multi-Div |
San Diego |
CA |
US |
|
|
Family ID: |
50485547 |
Appl. No.: |
14/593272 |
Filed: |
January 9, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
13921833 |
Jun 19, 2013 |
8962028 |
|
|
14593272 |
|
|
|
|
61715467 |
Oct 18, 2012 |
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Current U.S.
Class: |
604/290 ;
424/400; 514/171; 514/180 |
Current CPC
Class: |
A61Q 19/00 20130101;
A61K 9/06 20130101; A61K 47/14 20130101; A61P 17/16 20180101; A61K
31/573 20130101; A61K 9/107 20130101; A61K 47/08 20130101; A61K
47/44 20130101; A61P 17/06 20180101; A61P 17/00 20180101; A61K
47/12 20130101; A61K 47/10 20130101; A61K 9/0014 20130101 |
Class at
Publication: |
604/290 ;
514/180; 424/400; 514/171 |
International
Class: |
A61K 47/14 20060101
A61K047/14; A61K 47/10 20060101 A61K047/10; A61K 9/00 20060101
A61K009/00; A61K 31/573 20060101 A61K031/573; A61K 9/107 20060101
A61K009/107 |
Claims
1. A storage stable, topical lotion composition for treating a skin
disorder or condition, said composition comprising: a halobetasol
material comprising halobetasol or its pharmaceutically acceptable
salts, esters, and solvates; and a pharmaceutically acceptable
carrier which includes: (a) one or more fatty alcohols and/or one
or more alkoxylated fatty alcohols, (b) one or more polyol
humectants, and (c) diisopropyl adipate.
2. The topical lotion of claim 1, wherein the fatty alcohol is
selected from the group consisting of lauryl alcohol, myristyl
alcohol, cetyl alcohol, stearyl alcohol, octyldodecanol, and
mixtures of any two or more thereof.
3. The topical lotion of claim 1, wherein the alkoxylated fatty
alcohol is an ethoxylated alcohol selected from the group
consisting of lauryl alcohol ethoxylate, myristyl alcohol
ethoxylate, cetyl alcohol ethoxylate, stearyl alcohol ethoxylate,
octyldodecanol ethoxylate, and mixtures of any two or more
thereof.
4. The topical lotion of claim 1, wherein the polyol humectant is
selected from the group consisting of glycerin, propylene glycol,
butylene glycol, dipropylene glycol, pentylene glycol, hexylene
glycol, polyethylene glycol and mixtures of any two or more
thereof.
5. The topical lotion of claim 1, wherein the amount of said
halobetasol material after storage for six months at 40.degree. C.
is >98.5% of the total amount of halobetasol material present at
the time of manufacture of the topical lotion, wherein the amount
of degradation of said halobetasol material after storage for 26
months at 30.degree. C. is <1% of the total amount of
halobetasol material present at the time of manufacture of the
topical lotion and wherein the amount of degradation of said
halobetasol material after storage at 25.degree. C. for 30 months
is <3% of the total amount of halobetasol material present at
the time of manufacture of the topical lotion.
6. The topical lotion of claim 1, wherein the amount of degradation
of said halobetasol material after storage for six months at
40.degree. C. is <1.5% of the total amount of said halobetasol
material, wherein the amount of degradation of said halobetasol
material after storage for 26 months at 30.degree. C. is <1% of
said halobetasol material and wherein the amount of degradation of
said halobetasol material after storage at 25.degree. C. for 30
months is <3% of said halobetasol material.
7. The topical lotion of claim 1 wherein said halobetasol material
is halobetasol propionate.
8. The topical lotion of claim 1, further including one or more
members selected from the group consisting of: one or more
additional therapeutic agents, coloring agents, preservatives, pH
control agents, viscosity control agents, and fragrances.
9. The topical lotion of claim 1, wherein the ratio of said fatty
alcohols and alkoxylated fatty alcohols to said humectants, to said
diisopropyl adipate is, on a weight basis, in the range of
30-60:30-60:5-15.
10. The topical lotion of claim 1, wherein the ratio of said fatty
alcohols and alkoxylated fatty alcohols to said humectants, to said
diisopropyl adipate is, on a weight basis, in the range of
39-48:39-50:10-15.
11. The topical lotion of claim 9, wherein the weight ratio of said
fatty alcohols and ethoxylated fatty alcohols to said polyol
humectants to said diisopropyl adipate is in the range of
44-46:40-43:11-13.
12. The topical lotion of claim 9, wherein the weight ratio of said
fatty alcohols and ethoxylated fatty alcohols to said polyol
humectants to said diisopropyl adipate is 46:42:12.
13. The topical lotion of claim 1, wherein said topical lotion
composition is an oil-in-water emulsion of droplets having a mean
particle size in the range of 0.1-50 microns and a distribution of
particle sizes in the range of 0.1-50 microns.
14. The topical lotion of claim 1, wherein said topical lotion
composition is an oil-in-water emulsion of droplets having a mean
particle size in the range of 1-10 microns and a distribution of
particle sizes in the range of 0.15-15 microns.
15. The topical lotion of claim 1, wherein said topical lotion
composition is an oil-in-water emulsion of droplets having a mean
particle size in the range of 1.5-7 microns and a distribution of
particle sizes in the range of 0.175-10 microns.
16. A storage stable, topical lotion composition comprising, on a
weight basis: 0.02-0.10% of a halobetasol material; 1-5% of
diisopropyl adipate; 5-15% octyl dodecanol; 0.50-2% of polyethylene
glycol 1000 cetyl ether; 0.50-2% of a surfactant; 1-3% cetyl
alcohol; 1-2% stearyl alcohol; 0.05-0.2% of a preservative; 5-15%
propylene glycol; 1-5% glycerin; a pH adjustment agent an amount
sufficient to adjust the pH of the composition to a range of
approximately 5-6.5; and water q.s.
17. The storage stable, topical lotion composition of claim 16,
further comprising a viscosity control agent in an amount of
0.1-0.5% w/w.
18. A storage stable, topical lotion composition comprising, on a
weight basis: 0.05% of a halobetasol material; 3.5% of diisopropyl
adipate; 10% octyl dodecanol; 1% of polyethylene glycol 1000 cetyl
ether; 1% of a surfactant; 2% cetyl alcohol; 0.66% stearyl alcohol;
0.15% of a preservative; 10% propylene glycol; 2.5% glycerin; a pH
adjustment agent in an amount sufficient to adjust the pH of the
composition to a range of approximately 5-6.5; and water q.s.
19. The storage stable, topical lotion composition of claim 18
wherein the preservative is propyl paraben, butyl paraben or a
combination of propyl paraben and butyl paraben.
20. The storage stable, topical lotion composition of claim 18,
further comprising a viscosity control agent in an amount of 0.25%
w/w.
21. A method for treating corticosteroid-responsive dermatoses
comprising: topically administering to a patient in need thereof,
the topical lotion composition of claim 1.
22. The method of claim 21, wherein said topical lotion composition
is packaged in a container suitable for storage and delivery of
said composition.
23. The method of claim 22, wherein said container is comprised of
a ferrous alloy, aluminum, glass, plastic, or combinations
thereof.
24. The method of claim 22, wherein said container further includes
one or more protective coatings.
25. The method of claim 22, wherein said container includes at
least two separate compartments wherein said topical lotion
composition of claim 1 is disposed in one of said compartments.
26. The method of claim 21, wherein the patient is further
instructed to prepare the area to be treated by cleansing with a
suitable surfactant-containing composition.
27. The method of claim 21, wherein said method is as effective to
reduce transepidermal water loss as a cream formulation, Ultravate
cream.RTM. compared to a shaved skin control.
28. The method of claim 21, wherein said method is effective to
produce an improvement in skin surface hydration levels as measured
with a skin conductance or capacitance measuring apparatus.
29. The method of claim 28, wherein said improvement is observed at
2 hours post treatment.
30. The method of claim 28, wherein said improvement is observed at
4 hours post treatment.
31. A method for the preparation of the topical lotion composition
of claim 1, said method comprising the steps of: preparing an
aqueous phase that includes a first portion of the components of
said topical lotion composition; maintaining said aqueous phase at
a temperature in the range of 45-70.degree. C.; preparing an oil
phase that includes a second portion of the components of said
topical lotion composition; adding said oil phase to said aqueous
phase while stirring at a temperature of about 45-70.degree. C. so
as to obtain an emulsion; cooling said emulsion to a temperature of
about 25-35.degree. C.; and adjusting the pH of said emulsion to a
pH in the range of 5.0-6.5.
Description
REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 13/921,833, filed Jun. 19, 2013, which claims
priority to U.S. Provisional Patent Application Ser. No.
61/715,467, filed Oct. 18, 2012, the entire content of both of
which is incorporated herein by reference.
FIELD OF THE INVENTION
[0002] This invention relates to topical preparations for the
treatment of skin conditions. More particularly the invention
relates to a storage stable, lotion based composition of a
corticosteroid material such as halobetasol propionate and related
species, and to methods for the use of such compositions in the
treatment of dermatoses.
BACKGROUND OF THE INVENTION
[0003] Halobetasol propionate, is in widespread use for the
treatment of various dermatological conditions. Typically,
halobetasol materials are used in cream or ointment based
preparations, and one such product in wide commercial use is sold
under the trade name "Ultravate.RTM. Cream" (halobetasol propionate
0.05% cream). Ultravate.RTM. Cream is generally regarded as a
standard in the art. While, in many instances, physicians and/or
patients prefer lotion-based preparations, it is generally believed
that lotion-based preparations of corticosteroids are inferior in
their therapeutic performance as compared to corresponding
cream-based preparations.
[0004] As will be explained in detail hereinbelow, the present
invention is directed to lotion-based preparations of halobetasol
propionate and its salts, as well as other halobetasol esters and
their salts, solvates, and the like (collectively "halobetasol
materials"). Examples of halobetasol esters include, but are not
limited to, acetate and butyrate esters. Halobetasol propionate
0.05% lotion of the present invention has high patient
acceptability and demonstrates a clinical efficacy which is equal
to, and in many instances superior to, that of cream-based
halobetasol propionate 0.05% preparations. In addition, it has been
found that the compositions of the present invention are stable and
demonstrate very good long term storage stability. As will be
further explained herein below, experimental data demonstrates that
compositions of the present invention are very effective in
reducing transepidermal water loss (TEWL) which is a highly
desirable benefit in the management of dry and inflammatory skin
conditions. Skin conductance studies have also demonstrated that
the compositions of the present invention very rapidly penetrate
outer skin layers ensuring optimal hydration. The compositions of
the present invention comprise particular combinations of
ingredients which interact synergistically to produce the enhanced
results described above.
SUMMARY OF THE INVENTION
[0005] Storage stable, topical lotion compositions for treating
corticosteroid-responsive dermatoses are provided by the present
invention which include a halobetasol material comprising
halobetasol or its pharmaceutically acceptable salts, esters, and
solvates; and a pharmaceutically acceptable carrier which includes:
(a) one or more fatty alcohols and/or one or more alkoxylated fatty
alcohols, (b) one or more polyol humectants, and (c) diisopropyl
adipate.
[0006] Optionally, the fatty alcohol included in compositions of
the present invention is selected from the group consisting of
lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol,
octyldodecanol, and mixtures thereof.
[0007] Optionally, the alkoxylated fatty alcohol is an ethoxylated
alcohol selected from the group consisting of lauryl alcohol,
myristyl alcohol, cetyl alcohol, stearyl alcohol, octyldodecanol,
and mixtures thereof.
[0008] Optionally, the polyol humectant is selected from the group
consisting of glycerin, propylene glycol, butylene glycol,
dipropylene glycol, pentylene glycol, and mixtures thereof.
[0009] Storage stable, topical lotion compositions for treating
corticosteroid-responsive dermatoses are provided by the present
invention which include halobetasol propionate; and a
pharmaceutically acceptable carrier which includes: (a) one or more
fatty alcohols and/or one or more alkoxylated fatty alcohols, (b)
one or more polyol humectants, and (c) diisopropyl adipate.
[0010] Storage stable, topical lotion compositions for treating
corticosteroid-responsive dermatoses are provided by the present
invention which include halobetasol propionate; and a
pharmaceutically acceptable carrier which includes: (a) one or more
fatty alcohols and/or one or more alkoxylated fatty alcohols,
wherein the fatty alcohol is selected from the group consisting of
lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol,
octyldodecanol, and mixtures thereof, (b) one or more polyol
humectants, and (c) diisopropyl adipate.
[0011] Storage stable, topical lotion compositions for treating
corticosteroid-responsive dermatoses are provided by the present
invention which include halobetasol propionate; and a
pharmaceutically acceptable carrier which includes: (a) one or more
fatty alcohols and/or one or more alkoxylated fatty alcohols,
wherein the alkoxylated fatty alcohol is an ethoxylated alcohol
selected from the group consisting of lauryl alcohol, myristyl
alcohol, cetyl alcohol, stearyl alcohol, octyldodecanol, and
mixtures thereof, (b) one or more polyol humectants, and (c)
diisopropyl adipate.
[0012] Storage stable, topical lotion compositions for treating
corticosteroid-responsive dermatoses are provided by the present
invention which include halobetasol propionate; and a
pharmaceutically acceptable carrier which includes: (a) one or more
fatty alcohols, wherein the fatty alcohol is selected from the
group consisting of lauryl alcohol, myristyl alcohol, cetyl
alcohol, stearyl alcohol, octyldodecanol, and mixtures thereof,
and/or one or more alkoxylated fatty alcohols, wherein the
alkoxylated fatty alcohol is an ethoxylated alcohol selected from
the group consisting of lauryl alcohol, myristyl alcohol, cetyl
alcohol, stearyl alcohol, octyldodecanol, and mixtures thereof, (b)
one or more polyol humectants, and (c) diisopropyl adipate.
[0013] Storage stable, topical lotion compositions for treating
corticosteroid-responsive dermatoses are provided by the present
invention which include halobetasol propionate; and a
pharmaceutically acceptable carrier which includes: (a) one or more
fatty alcohols and/or one or more alkoxylated fatty alcohols, (b)
one or more polyol humectants, wherein the polyol humectant is
selected from the group consisting of glycerin, propylene glycol,
butylene glycol, dipropylene glycol, pentylene glycol, and mixtures
thereof, and (c) diisopropyl adipate.
[0014] Storage stable, topical lotion compositions for treating
corticosteroid-responsive dermatoses are provided by the present
invention which include halobetasol propionate; and a
pharmaceutically acceptable carrier which includes: (a) one or more
fatty alcohols and/or one or more alkoxylated fatty alcohols,
wherein the fatty alcohol is selected from the group consisting of
lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol,
octyldodecanol, and mixtures thereof, (b) one or more polyol
humectants, wherein the polyol humectant is selected from the group
consisting of glycerin, propylene glycol, butylene glycol,
dipropylene glycol, pentylene glycol, and mixtures thereof, and (c)
diisopropyl adipate.
[0015] Storage stable, topical lotion compositions for treating
corticosteroid-responsive dermatoses are provided by the present
invention which include halobetasol propionate; and a
pharmaceutically acceptable carrier which includes: (a) one or more
fatty alcohols and/or one or more alkoxylated fatty alcohols,
wherein the alkoxylated fatty alcohol is an ethoxylated alcohol
selected from the group consisting of lauryl alcohol, myristyl
alcohol, cetyl alcohol, stearyl alcohol, octyldodecanol, and
mixtures thereof, (b) one or more polyol humectants, wherein the
polyol humectant is selected from the group consisting of glycerin,
propylene glycol, butylene glycol, dipropylene glycol, pentylene
glycol, and mixtures thereof, and (c) diisopropyl adipate.
[0016] Storage stable, topical lotion compositions for treating
corticosteroid-responsive dermatoses are provided by the present
invention which include halobetasol propionate; and a
pharmaceutically acceptable carrier which includes: (a) one or more
fatty alcohols, wherein the fatty alcohol is selected from the
group consisting of lauryl alcohol, myristyl alcohol, cetyl
alcohol, stearyl alcohol, octyldodecanol, and mixtures thereof,
and/or one or more alkoxylated fatty alcohols, wherein the
alkoxylated fatty alcohol is an ethoxylated alcohol selected from
the group consisting of lauryl alcohol, myristyl alcohol, cetyl
alcohol, stearyl alcohol, octyldodecanol, and mixtures thereof, (b)
one or more polyol humectants, wherein the polyol humectant is
selected from the group consisting of glycerin, propylene glycol,
butylene glycol, dipropylene glycol, pentylene glycol, and mixtures
thereof, and (c) diisopropyl adipate.
[0017] Storage stable, topical lotion compositions for treating
corticosteroid-responsive dermatoses provided by the present
invention which include halobetasol propionate; and a
pharmaceutically acceptable carrier which includes: (a) one or more
fatty alcohols and/or one or more alkoxylated fatty alcohols, (b)
one or more polyol humectants, and (c) diisopropyl adipate, wherein
the amount of said halobetasol propionate after storage for six
months at 40.degree. C. is >98.5% of the total amount of
halobetasol propionate present at the time of manufacture of the
topical lotion, wherein the amount of degradation of said
halobetasol propionate after storage for 26 months at 30.degree. C.
is <1% of the total amount of halobetasol propionate present at
the time of manufacture of the topical lotion and wherein the
amount of degradation of said halobetasol propionate after storage
at 25.degree. C. for 30 months is <3% of the total amount of
halobetasol propionate present at the time of manufacture of the
topical lotion.
[0018] Storage stable, topical lotion compositions for treating
corticosteroid-responsive dermatoses provided by the present
invention which include halobetasol propionate; and a
pharmaceutically acceptable carrier which includes: (a) one or more
fatty alcohols and/or one or more alkoxylated fatty alcohols, (b)
one or more polyol humectants, and (c) diisopropyl adipate, wherein
the amount of degradation of said halobetasol propionate after
storage for six months at 40.degree. C. is <1.5% of the total
amount of said halobetasol propionate, wherein the amount of
degradation of said halobetasol propionate after storage for 26
months at 30.degree. C. is <1% of said halobetasol propionate
and wherein the amount of degradation of said halobetasol
propionate after storage at 25.degree. C. for 30 months is <3%
of said halobetasol propionate.
[0019] Optionally, a topical composition of the present invention
further includes a coloring agent, a preservative, a pH control
agent, a viscosity control agent, a fragrance; or a combination of
any two or more thereof.
[0020] Storage stable, topical lotion compositions for treating
corticosteroid-responsive dermatoses are provided by the present
invention which include halobetasol propionate; and a
pharmaceutically acceptable carrier which includes: (a) one or more
fatty alcohols and/or one or more alkoxylated fatty alcohols, (b)
one or more polyol humectants, and (c) diisopropyl adipate, wherein
the ratio of said fatty alcohols and alkoxylated fatty alcohols to
said humectants, to said diisopropyl adipate is, on a weight basis,
in the range of 30-60:30-60:5-15.
[0021] Storage stable, topical lotion compositions for treating
corticosteroid-responsive dermatoses are provided by the present
invention which include halobetasol propionate; and a
pharmaceutically acceptable carrier which includes: (a) one or more
fatty alcohols and/or one or more alkoxylated fatty alcohols, (b)
one or more polyol humectants, and (c) diisopropyl adipate, wherein
the ratio of said fatty alcohols and alkoxylated fatty alcohols to
said humectants, to said diisopropyl adipate is, on a weight basis,
in the range of 39-48:39-50:10-15.
[0022] Storage stable, topical lotion compositions for treating
corticosteroid-responsive dermatoses are provided by the present
invention which include halobetasol propionate; and a
pharmaceutically acceptable carrier which includes: (a) one or more
fatty alcohols and/or one or more alkoxylated fatty alcohols, (b)
one or more polyol humectants, and (c) diisopropyl adipate, wherein
the weight ratio of said fatty alcohols and ethoxylated fatty
alcohols to said polyol humectants to said diisopropyl adipate is
in the range of 44-46:40-43:11-13.
[0023] Storage stable, topical lotion compositions for treating
corticosteroid-responsive dermatoses are provided by the present
invention which include halobetasol propionate; and a
pharmaceutically acceptable carrier which includes: (a) one or more
fatty alcohols and/or one or more alkoxylated fatty alcohols, (b)
one or more polyol humectants, and (c) diisopropyl adipate, wherein
the weight ratio of said fatty alcohols and ethoxylated fatty
alcohols to said polyol humectants to said diisopropyl adipate is
46:42:12.
[0024] Storage stable, topical lotion compositions for treating
corticosteroid-responsive dermatoses are provided by the present
invention which include on a weight basis: 0.02-0.10% of a
halobetasol material; 1-5% of diisopropyl adipate; 5-15% octyl
dodecanol; 0.50-2% of polyethylene glycol 1000 cetyl ether; 0.50-2%
of a surfactant such as poloxamer 407; 1-3% cetyl alcohol; 1-2%
stearyl alcohol; 0.05-2% of a preservative such as a paraben
preservative, for example propyl paraben and/or butyl paraben;
5-15% propylene glycol; 1-5% glycerin; an alkali such as sodium
hydroxide, potassium hydroxide, or the like in an amount sufficient
to adjust the pH of the composition to a range of approximately
5-6.5, and in particular 5.2-6.2; optionally a viscosity control
agent which may be a cross-linked polyacrylate such as a carbomer
in an amount of 0.1-0.2%; and water q.s.
[0025] Storage stable, topical lotion compositions for treating
corticosteroid-responsive dermatoses are provided by the present
invention which include on a weight basis: 0.05% of a halobetasol
material; 3.5% of diisopropyl adipate; 10% octyl dodecanol; 1% of
polyethylene glycol 1000 cetyl ether; 1% of a surfactant such as
poloxamer 407; 2% cetyl alcohol; 0.66% stearyl alcohol; 0.15% of a
preservative such as a paraben preservative, for example propyl
paraben and/or butyl paraben; 10% propylene glycol; 2.5% glycerin;
an alkali such as sodium hydroxide, potassium hydroxide, or the
like in an amount sufficient to adjust the pH of the composition to
a range of approximately 5-6.5; optionally a viscosity control
agent which may be a cross-linked polyacrylate such as a carbomer
in an amount of 0.15%; and water q.s.
[0026] Storage stable, topical lotion compositions for treating
corticosteroid-responsive dermatoses provided by the present
invention which include halobetasol propionate; and a
pharmaceutically acceptable carrier which includes: (a) one or more
fatty alcohols and/or one or more alkoxylated fatty alcohols, (b)
one or more polyol humectants, and (c) diisopropyl adipate, wherein
said topical lotion composition is an oil-in-water emulsion of
droplets having a mean particle size in the range of 0.1-50 microns
and a distribution of particle sizes in the range of 0.1-50
microns.
[0027] Storage stable, topical lotion compositions for treating
corticosteroid-responsive dermatoses provided by the present
invention which include halobetasol propionate; and a
pharmaceutically acceptable carrier which includes: (a) one or more
fatty alcohols and/or one or more alkoxylated fatty alcohols, (b)
one or more polyol humectants, and (c) diisopropyl adipate, wherein
said topical lotion composition is an oil-in-water emulsion of
droplets having a mean particle size in the range of 1-10 microns
and a distribution of particle sizes in the range of 0.15-15
microns.
[0028] Storage stable, topical lotion compositions for treating
corticosteroid-responsive dermatoses provided by the present
invention which include halobetasol propionate; and a
pharmaceutically acceptable carrier which includes: (a) one or more
fatty alcohols and/or one or more alkoxylated fatty alcohols, (b)
one or more polyol humectants, and (c) diisopropyl adipate, wherein
said topical lotion composition is an oil-in-water emulsion of
droplets having a mean particle size in the range of 1.5-7 microns
and a distribution of particle sizes in the range of 0.175-10
microns.
[0029] Methods for treating steroid responsive dermatoses are
provided by the present invention that include topically
administering to a patient in need thereof, a storage stable,
topical lotion composition of the present invention. According to
aspects of the present invention, said topical lotion composition
is packaged in a container suitable for storage and delivery of
said composition.
[0030] A container suitable for storage and delivery of a storage
stable, topical lotion composition of the present invention is
optionally comprised of a ferrous alloy, aluminum, glass, plastic,
or combinations thereof and further optionally includes one or more
protective coatings.
[0031] A container suitable for storage and delivery of a storage
stable, topical lotion composition of the present invention is
optionally includes at least two separate compartments wherein said
storage stable, topical lotion composition of the present invention
is disposed in one of said compartments.
[0032] Methods for treating steroid responsive dermatoses are
provided by the present invention that include topically
administering to a patient in need thereof, a storage stable,
topical lotion composition of the present invention and wherein the
patient is further instructed to prepare the area to be treated by
cleansing with a suitable surfactant-containing composition.
[0033] Methods for treating steroid responsive dermatoses are
provided by the present invention that include topically
administering to a patient in need thereof, a storage stable,
topical lotion composition of the present invention wherein said
treatment is as effective to reduce transepidermal water loss as a
cream formulation, Ultravate.RTM. cream, compared to a shaved skin
control.
[0034] Methods for treating steroid responsive dermatoses are
provided by the present invention that include topically
administering to a patient in need thereof, a storage stable,
topical lotion composition of the present invention wherein said
treatment is effective to produce an improvement in skin surface
hydration levels as measured with a Skicon-200 conductance
apparatus and wherein said improvement is observed at 2 hours post
treatment and/or at 4 hours post treatment.
[0035] Methods for the preparation of a storage stable, topical
lotion composition are provided according to the present invention
including the steps of: preparing an aqueous phase that includes a
first portion of the components of said topical lotion composition;
maintaining said aqueous phase at a temperature in the range of
40-50.degree. C.; preparing an oil phase that includes a second
portion of the components of said topical lotion composition;
adding said oil phase to said aqueous phase while stirring at a
temperature of about 40-50.degree. C. so as to obtain an emulsion;
cooling said emulsion to a temperature of about 25-35.degree. C.;
and adjusting the pH of said emulsion to a pH in the range of
5.0-6.5, preferably 5.2-6.2.
BRIEF DESCRIPTION OF THE DRAWINGS
[0036] FIG. 1 is a graph showing results of Skicon-200 skin
conductance analysis comparing a topical lotion composition of the
present invention halobetasol propionate lotion (HBP Lotion) with
Ultravate.RTM. cream; and
[0037] FIG. 2 is a graph showing results of skin water loss
analysis comparing a topical lotion composition of the present
invention (HBP Lotion) with Ultravate.RTM. cream.
DETAILED DESCRIPTION OF THE INVENTION
[0038] The singular terms "a," "an," and "the" as used herein are
not intended to be limiting and include plural referents unless
explicitly stated otherwise or the context clearly indicates
otherwise.
[0039] Compositions
[0040] Storage stable, topical lotion compositions for treating a
steroid-responsive skin disorder or condition are provided by the
present invention which include a halobetasol material comprising
halobetasol and/or a pharmaceutically acceptable salt, ester, or
solvate thereof; and a pharmaceutically acceptable carrier which
includes: (a) one or more fatty alcohols and/or one or more
alkoxylated fatty alcohols, (b) one or more polyol humectants, and
(c) diisopropyl adipate.
[0041] Storage stable, topical lotion compositions for treating a
steroid-responsive skin disorder or condition are provided by the
present invention which include a halobetasol material comprising
halobetasol propionate; and a pharmaceutically acceptable carrier
which includes: (a) one or more fatty alcohols and/or one or more
alkoxylated fatty alcohols, (b) one or more polyol humectants, and
(c) diisopropyl adipate.
[0042] The one or more fatty alcohols and/or one or more
alkoxylated fatty alcohols included in compositions of the present
invention have a linear or branched carbon backbone that has 6-22
carbon atoms. According to certain aspects of the invention, the
one or more fatty alcohols and/or one or more alkoxylated fatty
alcohols included in compositions of the present invention have a
linear or branched carbon backbone that has 10-18 carbon atoms.
[0043] The fatty alcohol may, in some instances, comprise a long
chain alcohol such as lauryl alcohol, myristyl alcohol, cetyl
alcohol, stearyl alcohol, and octyldodecanol, used either singly or
in combination. Yet other fatty alcohols will be apparent to those
of skill in the art.
[0044] In the preparations of the present invention, the
compositions may further include alkoxylated forms of the fatty
alcohols; and in specific instances, these will comprise
ethoxylated fatty alcohols and/or propoxylated fatty alcohols.
[0045] Included ethoxylated fatty alcohols have a linear or
branched carbon backbone that has 6-22 carbon atoms and an average
of 1-40 ethylene oxide groups. Non-limiting examples of ethoxylated
alcohols included in compositions of the present invention are
lauryl alcohol ethoxylate, myristyl alcohol ethoxylate, cetyl
alcohol ethoxylate, stearyl alcohol ethoxylate, octyldodecanol
ethoxylate, and mixtures thereof
[0046] The polyol humectant component of the composition functions
as a humectant for the skin and may comprise materials such as
glycerin, propylene glycol, butylene glycol, dipropylene glycol,
pentylene glycol, hexylene glycol, polyethylene glycol, and the
like; and these polyol materials may be used either singly or in
combination in the preparations of the present invention.
[0047] In specific embodiments of the present invention, the
foregoing ingredients are present in particular ratios. In this
regard, the fatty alcohols and alkoxylated fatty alcohols are
collectively considered to be fatty alcohol excipients, and the
polyols are collectively referred to as humectants. In specific
compositions of the present invention the ratio of fatty alcohol
excipients to humectants to the diisopropyl adipate (DIA) generally
comprises, on a weight basis, 30-60 fatty alcohol excipients:30-60
humectants:5-15 DIA. According to aspects of inventive topical
lotions, the ratio of fatty alcohols and alkoxylated fatty
alcohols:humectants:diisopropyl adipate is, on a weight basis,
39-48:39-50:10-15. In some specific instances, the ratios are 44-46
fatty alcohol excipients:40-43 humectants:11-13 DIA, on a weight
basis. An exemplary composition of the present invention comprises
a ratio of fatty alcohol excipients 46:humectants 42:DIA 12, on a
weight basis. Preparations based upon these ratios will further
include the halobetasol material and may also include ancillary
ingredients such as preservatives, fragrances, coloring agents,
viscosity control agents and the like.
[0048] Nonionic surfactants included in topical lotion compositions
of the present invention are exemplified by, but not limited to,
fatty acid esters and alkoxylated fatty alcohols. One or more
additional surfactants is optionally included in topical lotion
compositions of the present invention. An included surfactant may
be an anionic, cationic or nonionic surfactant. Propoxylated
polyoxyethylene ethers, such as poloxamer 407, are non-limiting
examples of additional nonionic surfactants included in topical
lotion compositions of the present invention.
[0049] One or more preservatives is optionally included in topical
lotion compositions of the present invention. Included
preservatives are exemplified by, but not limited to parabens, such
as methylparaban, ethylparaben, propylparaben, butylparaben and
heptylparaben.
[0050] Other excipients commonly known as useful in the preparation
of topical compositions are further contemplated as within the
scope of the present invention. These other materials include, for
example, those listed in the current edition of the Ingredients
Buyers Guide published by the Personal Care Products Council, 1101
17th Street, NW, Suite 300, Washington D.C. 20036-4702 the entire
contents of which are hereby incorporated by reference.
[0051] Typically, preparations of the present invention will
include a pH adjustment agent as necessary to maintain the product
at a pH in the general range of 4.0-6.5 at the time of manufacture,
and in particular at a pH of about 5.2-6.2. Such pH adjustment is
accomplished by the use of basic materials such as ammonium salts;
alkali metal salts, including sodium and potassium salts; alkaline
earth metal salts such as calcium and magnesium salts; salts with
organic bases such as dicyclohexylamine salts; methyl-D-glucamine;
amines, amino acids such as arginine, lysine, and the like, and
salts of amino acids. pH adjustment may also be accomplished by the
use of nitrogen-containing materials such as quaternized compounds
as well as inorganic materials such as sodium, potassium, and
ammonium hydroxides.
[0052] Viscosity of compositions of the present invention is in the
range of 10-70,000 cps. As is well-known in the art, a lotion
formulation is an emulsion, pourable at room temperature. A lotion
flows at room temperature and conforms to a container when the
lotion is inserted into the container at room temperature. A lotion
displays Newtonian or pseudoplastic flow behavior, and is generally
for external application to the skin. In contrast, creams and
ointments are not pourable and do not flow at room temperature and
will not conform to a container when placed into the container at
room temperature. A cream is an emulsion, semisolid dosage form,
usually containing >20% water and volatiles and/or <50%
hydrocarbons, waxes, or polyols as the vehicle. A cream dosage form
is generally for external application to the skin or mucous
membranes. A cream does not flow at low shear stress and generally
exhibits plastic flow behavior. Percent water and volatiles in such
preparations are measured by a loss on drying test in which the
sample is heated at 105.degree. C. until constant weight is
achieved. Room temperature is defined as a temperature in the range
of 20-25.degree. C.
[0053] As indicated in Wound Care, Lippincott Williams and Wilkins;
Ed. Patricia Nale; 2007, page 190, creams are considered more
occlusive than lotions. Creams do not have to be applied as often
as lotions and are generally considered better for preventing
moisture loss due to evaporation. It is surprising and unexpected
that lotion compositions of the present invention are statistically
indistinguishable from a cream formulation, Ultravate cream, in
tests of transepidermal water loss compared to a control, see FIG.
2. The formulation of Ultravate.RTM. cream is known in the art to
be composed of 0.05% w/w halobetasol propionate, 3% w/w isopropyl
isostearate, 2% w/w isopropyl palmitate, 3% w/w steareth-213, 6%
w/w cetyl alcohol, 2% w/w glycerin, 0.05% w/w Kathon. CG and 0.2%
w/w Germall II, see U.S. Pat. No. 5,326,566.
[0054] One or more viscosity control agents may be included in
order to adjust to the desired viscosity. Viscosity control agents
that may be included are exemplified by, but not limited to, one or
more cross-linked polyacrylates, such as carbomers. Carbomers also
function as emulsion stabilizers.
[0055] The compositions of the present invention are found to
exhibit very good stability under storage conditions. As is known
in the art, halobetasol propionate can degrade under storage
conditions, and some of the degradation products or impurities
produced thereby include: diflorasone 17-propionate; diflorasone
21-propionate; diflorasone 17-propionate, 21-mesylate; diflorasone
17-propionate, 21-acetate; halobetasol .DELTA..sub.16 analog;
halobetasol spiro analog; and B16AN.
[0056] Topical lotions of the present invention are storage stable
such that the amount of degradation of a halobetasol material
therein after storage for six months at 40.degree. C. is <1.5%
of the total amount of the halobetasol material contained therein
at the time of manufacture, the amount of degradation of the
halobetasol material after storage for 26 months at 30.degree. C.
is <1% of the total amount of the halobetasol material contained
therein at the time of manufacture, and the amount of degradation
of the halobetasol material after storage at 25.degree. C. for 30
months is <3% of the halobetasol material contained therein at
the time of manufacture.
[0057] The amount of degradation products of halobetasol material,
such as degradation products of halobetasol propionate, is directly
related to the amount of degradation of the halobetasol material.
Thus, topical lotions of the present invention are storage stable
such that the amount of degradation products of a halobetasol
material therein after storage for six months at 40.degree. C. is
<1.5% of the total amount of the halobetasol material contained
therein at the time of manufacture, the amount of degradation
products of the halobetasol material after storage for 26 months at
30.degree. C. is <1% of the total amount of the halobetasol
material contained therein at the time of manufacture, and the
amount of degradation products of the halobetasol material after
storage at 25.degree. C. for 30 months is <3% of the halobetasol
material contained therein at the time of manufacture.
[0058] The storage stability of topical lotions of the present
invention can be demonstrated by assay of the amount of halobetasol
material, such as halobetasol propionate, and/or by assay of the
amount of one or more degradation products of the halobetasol
material, such as the amount of degradation products of halobetasol
propionate.
[0059] In some specific instances, the lotion of the present
invention is an emulsified preparation comprising droplets of an
oil phase dispersed in an aqueous phase, and the droplets have a
mean particle size in the range of 0.1-50 microns, and in more
particular instances a mean particle size in the range of about 1
to 10 microns. In some particular instances, the mean particle size
of the droplets ranges from about 1.5 to 7 microns.
[0060] Topical lotion compositions of the present invention
typically contain droplets having a variety of particle sizes in
the range of 0.1-50 microns, such as in the range of 0.15-15
microns and in particular aspects, in the range of 0.175-10
microns.
[0061] According to aspects of topical lotions of the present
invention, the droplets have a mean particle size in the range of
0.1-50 microns and a distribution of particle sizes ranging from
0.1-50 microns, and in more particular instances a mean particle
size in the range of about 1 to 10 microns and a distribution of
particle sizes ranging from 0.15-15 microns. In some particular
instances, the mean particle size of the droplets ranges from about
1.5 to 7 microns and distribution of particle sizes ranges from
0.175-10 microns.
[0062] There are a number of formulations which may be prepared in
accord with the present invention. Table 1 hereinbelow lists
compositional ranges for one such formulation.
TABLE-US-00001 TABLE 1 Component % W/W Diisopropyl Adipate 1-5%
Octyldodecanol, NF 5-15% Ceteth-20 0.5-2.0% Poloxamer 407, NF
0.5-2.0% Cetyl Alcohol, NF 1-3% Stearyl Alcohol, NF 0.3-2.0%
Propylparaben, NF 0.05-0.2% Butylparaben, NF 0.02-0.1% Glycerin,
USP 1-5% Propylene Glycol, USP 5-15% Carbomer Homopolymer, NF
0.1-0.2% Sodium Hydroxide, NF As necessary to adjust pH Halobetasol
Propionate, USP 0.02-0.1% Purified Water, USP To make 100%
[0063] In this composition, ceteth-20 is a polyethylene glycol-1000
cetyl alcohol ether, and other similar materials may be substituted
therefor.
[0064] Poloxamer 407 is a particular hydrophilic nonionic
surfactant comprising a triblock copolymer consisting of a central
hydrophobic block of polypropylene glycol flanked by two
hydrophilic blocks of polyethylene glycol. Other such surfactants
may be substituted therefor.
[0065] The present preparation further includes parabens,
specifically propylparaben and butylparaben; and as is known in the
art, these materials are antimicrobial agents which function as
preservatives.
[0066] The composition further includes carbomer 980 which is a
cross-linked polyacrylate gelling agent, and other such viscosity
control agents may be substituted therefor.
[0067] The composition is preferably adjusted to a pH in the range
of 5-6.5, and in particular instances 5.2-6.2 and this may be
accomplished by the use of an alkali such as sodium hydroxide,
potassium hydroxide, or the like.
[0068] As discussed above, the topical lotion compositions of the
present invention may be fabricated as emulsified materials; and in
a general procedure for doing so, one portion of the components is
dissolved in water to prepare an aqueous phase. This phase is
typically maintained at an elevated temperature in the range of
50-70.degree. C. A second portion of the components is used to
prepare a nonaqueous oil phase, and this oil phase is then mixed
into the aqueous phase under conditions which will favor formation
of an emulsion structure. This mixing is carried out at an elevated
temperature, again typically in the range of 50-70.degree. C.
Following mixing, the composition is cooled to form a thickened
emulsified lotion.
[0069] Methods of Treatment
[0070] Methods and topical lotion compositions of the present
invention are useful for use in the treatment of
corticosteroid-responsive dermatoses.
[0071] Methods for treating corticosteroid-responsive dermatoses
provided herein includes topical administration of a dermal topical
lotion composition of the present invention to a patient in need
thereof.
[0072] Particular corticosteroid-responsive dermatoses treated
using methods and topical lotion compositions of the present
invention include but are not limited to: dermatitis, including but
not limited to atopic dermatitis, seborrhoeic dermatitis, and
contact dermatitis; psoriasis; eczemas, including but not limited
to atopic, infantile, and discoid eczemas; lichen simplex; lichen
planus; reactions to insect and spider bites; miliaria, pityriasis
rosea, erythema, and pruritus. Methods and topical lotion
compositions of the present invention can be used for prophylaxis
as well as amelioration of signs and/or symptoms of
corticosteroid-responsive dermatoses. The terms "treating" and
"treatment" used to refer to treatment of a
corticosteroid-responsive dermatosis in a patient include:
preventing, inhibiting or ameliorating the
corticosteroid-responsive dermatosis in the patient, such as
slowing progression of the corticosteroid-responsive dermatosis
and/or reducing or ameliorating a sign or symptom of the
corticosteroid-responsive dermatosis.
[0073] A therapeutically effective amount of a topical lotion
composition of the present invention is an amount which has a
beneficial effect on a corticosteroid-responsive dermatosis in a
patient being treated. For example, a therapeutically effective
amount of a topical lotion composition of the present invention is
effective to detectably decrease itching and/or inflammation in a
patient being treated for corticosteroid-responsive dermatosis.
[0074] Patients are identified as having, or at risk of having, a
corticosteroid-responsive dermatosis using well-known medical and
diagnostic techniques.
[0075] The term "patient" refers to an individual in need of
treatment for a corticosteroid-responsive dermatosis. Human
patients are particularly referred to herein although the term
"patient" is not limited to humans and encompasses mammals and
birds, such as, but not limited to, non-human primates, cats, dogs,
cows, horses, rodents, pigs, sheep, goats and poultry, and other
animals in need of treatment for a corticosteroid-responsive
dermatosis seen in veterinary practice.
[0076] An inventive composition may be administered acutely or
chronically. For example, a topical lotion composition as described
herein may be administered topically as a unitary dose or in
multiple doses over a relatively limited period of time, such as
hours. Administration may include multiple doses administered
topically over a period of days-years, such as for chronic
treatment of corticosteroid-responsive dermatosis or as multiple
short courses of therapy over a period of months or years.
[0077] A therapeutically effective amount of a topical lotion
composition according to the present invention will vary depending
on the particular topical lotion composition used, the severity of
the corticosteroid-responsive dermatosis to be treated, the species
of the patient, the age and sex of the subject and the general
physical characteristics of the patient to be treated. One of skill
in the art could determine a therapeutically effective amount in
view of these and other considerations typical in medical practice.
In general it is contemplated that a therapeutically effective
amount, applied topically, would be in the range of about 0.001
mg/kg-150 mg/kg body weight, optionally in the range of about
0.01-10 mg/kg, and further optionally in the range of about 0.1-5
mg/kg. Further, dosage may be adjusted depending on whether
treatment is to be acute or continuing.
[0078] Treatment of a patient having a corticosteroid-responsive
dermatosis by topical administration of a topical lotion
composition of the present invention to the affected area is
effective to reduce transepidermal water loss in the affected area
over a range of greater than 0 and up to about 100%.
[0079] Treatment of a patient having a corticosteroid-responsive
dermatosis by topical administration of a topical lotion
composition of the present invention to the affected area is
effective to reduce transepidermal water loss in the affected area
by at least 10%, in the range of at least 10% to about 40% and/or
by at least 12% to 25%.
[0080] Treatment of a patient having a corticosteroid-responsive
dermatosis by topical administration of a topical lotion
composition of the present invention to the affected area is
effective to produce an improvement in skin surface hydration
levels of the affected area, as measured by determining skin
conductance and/or capacitance. Methods and devices for determining
skin conductance and/or capacitance are well-known in the art, for
example as described in Clarys P et al., Skin Res Technol. 2012,
18(3):316-23. A commercially available device for measuring skin
conductance is the Skicon-200 skin surface hygrometer.
[0081] Improvement in skin surface hydration levels of the affected
area is observed at 2 hours post treatment and/or at 4 hours post
treatment.
[0082] Methods of treatment according to the present invention
optionally include preparation of the area to be treated by
cleansing with a suitable surfactant containing composition.
[0083] Combination Treatments
[0084] Combinations of therapeutic agents are administered
according to aspects of the present invention. According to aspects
of methods of the present invention, a topical lotion composition
of the present invention is administered topically to a patient
having a corticosteroid-responsive dermatosis and at least one
additional therapeutic agent is administered to the patient to
treat the corticosteroid-responsive dermatosis. In still further
aspects, a topical lotion composition of the present invention is
administered topically to a patient having a
corticosteroid-responsive dermatosis and at least two additional
therapeutic agents are administered to the patient to treat the
corticosteroid-responsive dermatosis.
[0085] The term "additional therapeutic agent" is used herein to
denote a chemical compound, a mixture of chemical compounds, a
biological macromolecule, such as a lipid, carbohydrate, nucleic
acid, a protein or portion thereof, e.g., a peptide, an antibody, a
cytokine, or an extract made from biological materials such as
bacteria, plants, fungi, or animal, particularly mammalian, cells
or tissues which is a biologically, physiologically, or
pharmacologically active substance, or substances, that acts
locally or systemically in a patient to provide a beneficial effect
in treatment of a corticosteroid-responsive dermatosis.
[0086] Additional therapeutic agents included in aspects of methods
and compositions of the present invention include, but are not
limited to, antibiotics, antivirals, antifungals, analgesics,
antipyretics, antihistamines, antiinflammatory agents, anxiolytics,
cytokines, non-steroidal anti-inflammatory agents, steroids and
vasoactive agents.
[0087] Combination therapies utilizing a topical lotion composition
of the present invention and one or more additional therapeutic
agents may show synergistic effects, e.g., a greater therapeutic
effect than would be observed using either the topical lotion
composition of the present invention or one or more additional
therapeutic agents alone as a monotherapy.
[0088] According to aspects, combination therapies include: (1)
pharmaceutical compositions that include a topical lotion
composition of the present invention in combination with one or
more additional therapeutic agents; and (2) co-administration of a
topical lotion composition of the present invention with one or
more additional therapeutic agents wherein the topical lotion
composition of the present invention and the one or more additional
therapeutic agents have not been formulated in the same
composition. When using separate formulations, the topical lotion
composition of the present invention may be administered at the
same time, intermittent times, staggered times, prior to,
subsequent to, or combinations thereof, with reference to the
administration of the one or more additional therapeutic
agents.
[0089] Combination treatments can allow for reduced effective
dosage and increased therapeutic index of the topical lotion
composition of the present invention and the one or more additional
therapeutic agents used in methods of the present invention.
[0090] Additional therapeutic agents included in methods and/or
compositions of the present invention are described, for example,
in Goodman et al., Goodman and Gilman's The Pharmacological Basis
of Therapeutics, 12th Ed., McGraw-Hill Professional, 2010.
[0091] Commercial Packages
[0092] Commercial packages provided herein include a topical lotion
composition of the present invention in a container suitable for
storage and delivery of the topical lotion composition.
[0093] A container suitable for storage and delivery of the topical
lotion composition can be any of various sizes or shapes useful for
containing and/or delivering the topical lotion composition
exemplified by, but not limited to, a pump, canister, jar, bottle,
tube, sachet, or vial.
[0094] Optionally, the container is comprised of a ferrous alloy,
aluminum, glass, plastic, polymer, or combinations thereof. The
container further optionally includes one or more protective
coatings.
[0095] A container for a topical lotion composition of the present
invention optionally includes at least two separate compartments
wherein the topical lotion composition is disposed in one of the
compartments. A second therapeutic agent may be contained in a
second compartment, separate from the topical lotion composition of
the present invention, and may be dispensed therefrom for direct
use, or may be mixed with the topical lotion composition of the
present invention prior to use. For example, a barrier between
separate compartments may be pierced or removed to allow for mixing
of the topical lotion composition and the material in a second
compartment. In another application, the topical lotion may be
dispensed in combination with a second active pharmaceutical
ingredient for a number of dispensations after which only the
topical lotion or the second active pharmaceutical ingredient is
dispensed.
[0096] A topical lotion composition of the present invention may be
deposited on a bandage or dressing for application to a region
affected by a corticosteroid-responsive dermatosis.
[0097] Instructions for use of a topical lotion composition of the
present invention are optionally included in a commercial package,
wherein the instructions are directed to a physician and/or to the
patient. Included instructions to the patient optionally include
instructions to prepare the area to be treated by cleansing with a
suitable surfactant containing composition.
[0098] Embodiments of inventive compositions and methods are
illustrated in the following examples. These examples are provided
for illustrative purposes and are not considered limitations on the
scope of inventive compositions and methods.
EXAMPLES
Example 1
[0099] In one specific procedure, a lotion is prepared in accord
with the present invention utilizing the formulation of Table 2.
Listed in Table 2 is a specific composition based upon the ranges
set forth hereinabove.
TABLE-US-00002 TABLE 2 Component % W/W Quantity Diisopropyl Adipate
3.50% 105.0 g Octyldodecanol, NF 10.00% 300.0 g Ceteth-20 1.00%
30.0 g Poloxamer 407, NF 1.00% 30.0 g Cetyl Alcohol, NF 2.00% 60.0
g Stearyl Alcohol, NF 0.66% 19.8 g Propylparaben, NF 0.10% 3.0 g
Butylparaben, NF 0.05% 1.5 g Glycerin, USP 2.50% 75.0 g Propylene
Glycol, USP 10.00% 300.0 g Carbomer Homopolymer, NF 0.15% 4.5 g
Sodium Hydroxide, NF 0.012% 0.36 g Halobetasol Propionate, USP
0.05% 1.5 g Purified Water, USP 68.978% 2069.34 g Total % 100%
Theoretical Total Weight 3000.0 g
[0100] In this procedure, an aqueous phase is prepared by mixing
water with the glycerin, and propylene glycol. These materials are
then mixed at a temperature of approximately 65.degree. C. A second
mixture comprising a DIA, octyldodecanol, ceteth-20, poloxamer 407,
cetyl alcohol, stearyl alcohol, parabens, and halobetasol. This
mixture is stirred at approximately 65.degree. C. for a period of
time sufficient to dissolve the halobetasol material. The resulting
aqueous and oil phases are disposed in a high shear emulsifier and
mixed at a speed of approximately 6000 rpm to produce a homogenized
mixture. Carbomer is added, followed by another high shear mixing
and then neutralization with base. The resultant mixture is cooled
with mixing to a temperature of approximately 30.degree. C. under
vacuum, after which the preparation is complete. Clearly,
modifications and variations of this procedure will be readily
apparent to those of skill in the art.
Example 2
[0101] A series of studies was carried out to evaluate the
properties and advantages of the compositions of the present
invention. These studies were carried out utilizing an emulsified
lotion preparation having a formulation in accord with Table 2 as
prepared by the procedure set forth above. In a first study, the
efficacy of the composition with regard to skin hydration was
determined utilizing a Skicon-200 apparatus which determined the
net change in skin conductance as a function of time, following
application of a material. Compositions of the present invention
were compared with the industry standard. Ultravate.RTM. Cream and
with a shaved skin control sample. The resultant data are
summarized in FIG. 1. As will be seen from FIG. 1, skin conduction
increased very rapidly at the 2 hour point for the composition of
the present invention as compared to the Ultravate.RTM. Cream and
the control. At the 4 hour point, it will be seen that skin
conductance of the Ultravate.RTM. Cream has risen while that of the
composition of the present invention has fallen, although it is
still higher than that of the Ultravate.RTM. Cream. At the 6 hour
point, the composition of the present invention and the
Ultravate.RTM. Cream both have similar skin conductance
measurements. The data of experiment and FIG. 1 make clear that the
composition of the present invention very rapidly promotes skin
hydration whereas the action of the Ultravate.RTM. Cream is both
slower and of less magnitude in this regard. The data confirm that
the composition of the present invention produced a rapid onset and
sustained action of the therapeutic effect. This unexpected finding
was validated at both the 2 and 4-hour time points where the
conductance of the halobetasol lotion was statistically
significantly (p<0.001) greater than that of the Ultravate.RTM.
Cream.
[0102] Statistical Summary for Net Change in Skicon Conductance at
2, 4 and 6 Hrs Post Treatment is shown in Table 3.
TABLE-US-00003 TABLE 3 Net Change in Skicon Conductance (N = 15)
Statistical Differences Multiple Comparisons Comparison 2
Hours.sup.a 4 Hours.sup.a 6 Hours.sup.b HBP Lotion > Ultravate
Cream p < 0.001 p < 0.001 p > 0.05 HBP Lotion > NoRx
shaved p < 0.001 p < 0.001 p < 0.001 Ultravate Cream >
NoRx shaved p > 0.05 p > 0.05 p < 0.05 .sup.aTukey-Kramer
Multiple Comparisons Test .sup.bDunn's Multiple Comparisons
Test
Example 3
[0103] A study was carried out measuring transepidermal water loss
(TEWL) of skin treated with the lotion of the present invention and
skin treated with Ultravate.RTM. Cream, as compared to a dry shaved
control. Computerized evaporimetry was carried out utilizing a
state of the art Derm RG-1 Evaporometer; a research grade and
open-chamber device based on the time proven vapor pressure
gradient estimation method pioneered by Gert Nilsson. Data from
this evaluation are summarized in FIG. 2 and it will be seen that
over the 6 hour course of the study, the lotion of the present
invention was at least as effective as the Ultravate.RTM. Cream of
the prior art in preventing water loss. This finding is unexpected
in view of conventional wisdom in the prior art which holds that
with regard to minimizing TEWL the efficacy of ointments is greater
than that of creams/gels, which is greater than that of lotions,
which is greater than that of simple solutions. Therefore, the
study further evidences the unexpected and beneficial results
attendant upon the present invention.
[0104] Neither test product seems to be acting as an occlusive
since TEWL remains the same as the non-treated shaved control.
There were no statistically significant treatment differences at
any time point.
Example 4
[0105] A further experimental study evaluated the clinical efficacy
of the lotion of the present invention having the formulation
described above, in the treatment of subjects with plaque
psoriasis. The study involved a double-blind, randomized,
multicenter, vehicle-controlled parallel group study involving a 2
week course of treatment. The efficacy and safety of a topical
lotion composition composition of the present invention including
halobetasol propionate (HBP) 0.05%, applied twice daily for 14
consecutive days in subjects with moderate to severe plaque
psoriasis was determined and compared with Vehicle Lotion applied
twice daily for 14 consecutive days in subjects with moderate to
severe plaque psoriasis. The study involved 72 subjects, with
approximately 36 per treatment group, and was carried out at three
separate sites with approximately 24 subjects at each site.
Subjects were selected so that their plaque psoriasis involved a
minimum of 2% and no more than approximately 10% of their BSA
(excluding the face, scalp, groin, axillae, and other
intertriginous areas).
[0106] Definitions: In this study "treatment success" is indicated
by a score of 0 or 1 for overall disease severity (ODS) and the
clinical signs and symptoms of psoriasis. Further, the term
"improved" refers to at least a two (2) grade decrease in severity
score relative to Baseline for overall disease severity (ODS) and
the clinical signs and symptoms of psoriasis. Note: Dichotomization
of scores for clinical signs and symptoms of psoriasis will exclude
subjects with Baseline scores of 0 or 1 unless the corresponding
sign score at Day 8 or Day 15 is >1.
[0107] Efficacy Endpoints included a primary efficacy endpoint and
secondary efficacy endpoints. The primary efficacy endpoint is the
proportion of subjects with Overall Disease Severity (ODS)
"treatment success" at End of Treatment (EOT) where EOT is the last
visit (Day 8 if early termination or Day 15) with Last Observation
Carried Forward (LOCF) imputation for early terminations. Secondary
efficacy endpoints are: 1) the proportion of subjects with ODS
"treatment success" at Day 8 and Day 15 (no LOCF imputation); and
2) the proportion of subjects rated "improved" with respect to ODS
at Days 8 and 15, respectively.
[0108] Additional details of the study design and results of this
study are shown in Tables 4-8.
TABLE-US-00004 TABLE 4 Screening/Enrollment -Study Summary
Enrollment information Subject's Final Disposition Total Total
Screen Total Total Investigator Screened Enrolled Failures
Completed Early Terms Site 01 24 24 0 23 1 Site 02 24 24 0 24 0
Site 03 25 24 1 24 0 Totals 73 72 1 71 1
TABLE-US-00005 TABLE 5 Overall Disease Severity (ITT Population)
Observed HBP VEH ALL N (%) N (%) N (%) BASELINE Clear 0 (0.0%) 0
(0.0%) 0 (0.0%) Almost Clear 0 (0.0%) 0 (0.0%) 0 (0.0%) Mild 0
(0.0%) 0 (0.0%) 0 (0.0%) Moderate 30 (83.3%) 30 (85.7%) 60 (84.5%)
Severe/Very Severe 6 (16.7%) 5 (14.3%) 11 (15.5%) All 36 (100.0%)
35 (100.0%) 71 (100.0%) DAY 8 Clear 0 (0.0%) 0 (0.0%) 0 (0.0%)
Almost Clear 2 (5.6%) 0 (0.0%) 2 (2.8%) Mild 16 (44.4%) 6 (17.1%)
22 (31.0%) Moderate 18 (50.0%) 26 (74.3%) 44 (62.0%) Severe/Very
Severe 0 (0.0%) 3 (8.6%) 3 (4.2%) All 36 (100.0%) 35 (100.0%) 71
(100.0%) DAY 15 Clear 2 (5.6%) 0 (0.0%) 2 (2.8%) Almost Clear 9
(25.0%) 0 (0.0%) 9 (12.7%) Mild 16 (44.4%) 6 (17.1%) 22 (31.0%)
Moderate 9 (25.0%) 25 (71.4%) 34 (47.9%) Severe/Very Severe 0
(0.0%) 4 (11.4%) 4 (5.6%) All 36 (100.0%) 35 (100.0%) 71 (100.0%)
ITT = intent-to-treat; HBP = halobetasol propionate; VEH =
vehicle
TABLE-US-00006 TABLE 6 Overall Disease Severity (ITT Population)
Change From Baseline HBP VEH ALL N (%) N (%) N (%) DAY 8 -2 5
(13.9%) 0 (0.0%) 5 (7.0%) -1 16 (44.4%) 8 (22.9%) 24 (33.8%) 0 15
(41.7%) 27 (77.1%) 42 (59.2%) ALL 36 (100.0%) 35 (100.0%) 71
(100.0%) DAY 15 -3 3 (8.3%) 0 (0.0%) 3 (4.2%) -2 13 (36.1%) 0
(0.0%) 13 (18.3%) -1 11 (30.6%) 8 (22.9%) 19 (26.8%) 0 9 (25.0%) 26
(74.3%) 35 (49.3%) 1 0 (0.0%) 1 (2.9%) 1 (1.4%) ALL 36 (100.0%) 35
(100.0%) 71 (100.0%) ITT = intent-to-treat; HBP = halobetasol
propionate; VEH = vehicle
TABLE-US-00007 TABLE 7 Overall Disease Severity (ITT Population)
Success HBP VEH ALL N (%) N (%) N (%) DAY 8 YES 2 (5.6%) 0 (0.0%) 2
(2.8%) NO 34 (94.4%) 35 (100.0%) 69 (97.2%) ALL 36 (100.0%) 35
(100.0%) 71 (100.0%) DAY 15 YES 11 (30.6%) 0 (0.0%) 11 (15.5%) NO
25 (69.4%) 35 (100.0%) 60 (84.5%) ALL 36 (100.0%) 35 (100.0%) 71
(100.0%) ITT = intent-to-treat; HBP = halobetasol propionate; VEH =
vehicle Day 15: Fisher's Exact test p < 0.001
TABLE-US-00008 TABLE 8 Overall Disease Severity (ITT Population)
Improved HBP VEH ALL N (%) N (%) N (%) DAY 8 YES 5 (13.9%) 0 (0.0%)
5 (7.0%) NO 31 (86.1%) 35 (100.0%) 66 (93.0%) ALL 36 (100.0%) 35
(100.0%) 71 (100.0%) DAY 15 YES 16 (44.4%) 0 (0.0%) 16 (22.5%) NO
20 (55.6%) 35 (100.0%) 55 (77.5%) ALL 36 (100.0%) 35 (100.0%) 71
(100.0%) ITT = intent-to-treat; HBP = halobetasol propionate; VEH =
vehicle
[0109] The topical lotion composition of the present invention
exhibited very good results in the treatment of plaque psoriasis,
showing treatment being a complete success with regard to 30.6% of
the patients studied, and producing significant improvement with
regard to 44.4% of the patients in the study. These results are
very strong and significant particularly as compared to those
achieved through the use of Ultravate.RTM. Cream and other
comparable prior art compositions.
Example 5
[0110] Table 9 compares the results for the halobetasol propionate
lotion as achieved in the present study, to those previously
obtained utilizing FDA approved compositions of the prior art.
TABLE-US-00009 TABLE 9 FDA Approved Class 1 Topical Corticosteroid
Products (1-9) and Halobetasol Propionate Lotion, the present
invention (10 and 11) "Treatment Success" at 2 Weeks Year Study
Drug Results Control Drug Results Approved 1 Ultravate Cream 3/38
Vehicle 0/39 1991 (Study 1) (7.9%) (0.0%) 2 Ultravate Cream 7/40
Vehicle 0/40 1991 (Study 2) (17.5%) (0.0%) 3 Temovate E ITT 12/51
Vehicle 1/46 1994 (22%) (2%) Note: includes Cleared and Excellent 4
Clobetasol Lotion ITT 30/82 Temovate E 33/81 2003 4 wk. study
(36.6%) (40.7%) 5 Clobetasol Lotion PP 27/76 Temovate E PP 32/75
2003 4 wk. study (35.5%) (42.7%) 6 Vanos QD ITT 19/107 Vanos BID
ITT 33/107 2005 (18%) (31%) 7 Vanos QD PP 18/90 Vanos BID PP 31/97
2005 (20%) (32%) 8 Olux E ITT 41/253 Temovate Ointment 38/121 2007
(16%) (31%) 9 Olux E PP 39/234 Temovate Ointment 34/111 2007 (17%)
(31%) 10 Halobetasol Lotion 11/36 Vehicle 0/35 (Success) (P2) ITT
(30.6%) (0.0%) 2012 11 Halobetasol Lotion 16/36 Vehicle 0/35
(Improved) (P2) ITT (44.4%) (0.0%) 2012
[0111] In the current Halobetasol Lotion study "Treatment Success"
is defined at the End of Treatment as a score of 0 or 1 for overall
disease severity (ODS) and clinical signs and symptoms of
psoriasis. "Improved" means subjects had at least a two (2) grade
decrease in severity score relative to Baseline for overall disease
severity (ODS) and the clinical signs and symptoms of
psoriasis.
[0112] It should be noted that over the years the FDA has changed
the parameters defining clinical "success" and has each time raised
the bar. The results obtained with the present halobetasol
propionate lotion were unexpectedly strong. The Ultravate.RTM.
Cream results as shown in the first two rows of the TABLE 9 were
filed with the FDA as a basis of an NDA approval, and it will be
seen that the results achieved with the halobetasol propionate
lotion of the present invention are superior to those achieved
through the use of the Ultravate.RTM. Cream and are as good or
better than any of the other Class 1 topical corticosteroids. It
will be noted that the clobetasol propionate lotion results are
similar to those achieved utilizing the present halobetasol
propionate lotion; however, clobetasol propionate is generally
believed to be a more potent steroid molecule than halobetasol
propionate, and furthermore the clobetasol propionate studies ran
for 4 weeks as compared to 2 weeks for the study involving the
halobetasol propionate composition of the present invention. These
results are unexpected given the relative potencies of halobetasol
propionate and clobetasol propionate, and given the longer duration
of the clobetasol propionate treatment. These results show
unexpected therapeutic effects achieved through the composition of
the present invention.
Example 6
[0113] Six formulations were prepared including various amounts and
ratios of components. Three lotions, designated 30124-1, 30125-1
and 30125-2, had compositions with ratios of 30-60:30-60:5-15 for
fatty alcohol excipients (fatty alcohols and alkoxylated fatty
alcohols):humectants:DIA; and three formulations, designated
30128-1, 30129-1 and 30130-1, had compositions outside of these
ratio ranges. The formulations are summarized in TABLE 10 below
where the composition changes from the clinical formulation of
Example 1 are underlined.
TABLE-US-00010 TABLE 10 Formula name 30124-1 30125-1 30125-2
30128-1 30129-1 30130-1 Component Component Amount % w/w
Halobetasol 0.05 0.05 0.05 0.05 0.05 0.05 propionate DIA 4.5 3.5
3.5 3.5 0.75 3.5 Octyldodecanol 10 10 10 10 10 10 Ceteth-20 1 1 1 3
1 1 Poloxamer 407 1 1 1 1 1 1 Cetyl alcohol 2 2 2.5 5 2 2 Stearyl
alcohol 0.66 0.66 1 3 0.66 0.66 Propylparaben 0.1 0.1 0.1 0.1 0.1
0.1 Butylparaben 0.05 0.05 0.05 0.05 0.05 0.05 Glycerin 2.5 5 2.5 1
2.5 2.5 Propylene 9 12.5 10 7.5 10 0 glycol Carbomer 980 0.15 0.15
0.15 0.15 0.15 0.15 1.0N NaOH q.s. pH q.s. pH q.s. pH q.s. pH q.s.
pH q.s. pH 5.5 5.5 5.5 5.5 5.5 5.5 Water q.s. 100% q.s. 100% q.s.
100% q.s. 100% q.s. 100% q.s. 100% Ratio Ratio Ratio Ratio Ratio
Ratio fatty alcohols 46 39 48 64 51 69 and ethoxylated fatty
alcohols Humectants 39 50 41 26 46 13 DIA 15 10 11 11 3 18
Appearance Pass Pass Pass Fail.sup.1 Fail.sup.2 Pass Stability @
Stable for Stable for Stable for N/A N/A Fail.sup.3 40.degree. C.
at least 3 at least 3 at least 3 months months months .sup.1Thick
non-pourable cream; .sup.2Drug crystals precipitated; .sup.3Long
term stability failure.
[0114] All three formulations 30124-1, 30125-1 and 30125-2, which
had compositions with ratios of 30-60:30-60:5-15 for fatty alcohol
excipients:humectants:D1A; had acceptable appearance, i.e. a
homogeneous pourable lotion. Two of the formulations, 30128-1 and
30129-1, which had compositions outside of the ratios of
30-60:30-60:5-15 for fatty alcohol excipients:humectants:DIA had
unacceptable appearance, and the third, 30130-1, had acceptable
appearance but failed on stability.
[0115] Diisopropyl adipate (DIA) is a solvent for halobetasol
propionate (HP). Higher and lower levels of this ingredient were
evaluated in this series of experiments. The formulation with
higher DIA, 4.5% w/w, (30124-1) produced an acceptable composition.
The formulation with a low DIA level 0.75% w/w (30129-1) was
successfully prepared in that all of the HP was solubilized.
However, surprisingly, this formulation showed drug crystals within
12 hours of preparation, producing unacceptable appearance. This
was surprising since there was a significant amount of surfactant
and octyldodecanol in the formulation 30129-1 which can also
solubilize HP.
[0116] The fatty alcohols and alkoxylated fatty alcohols,
particularly ethoxylated fatty alcohols, have significant effects
on stabilization of the emulsion included in compositions of the
present invention. Formulation 30128-1 was prepared with higher
levels of these excipients and would be expected to be stable.
However, the initial appearance of this formulation was a thick and
nonpourable emulsion. A key attribute of a topical lotion
composition of the present invention is that it is pourable and
easy to spread. Therefore, even though 30128-1 was expected to be
more stable than formulations that had ratios of 30-60:30-60:5-15
for fatty alcohol excipients:humectants:DIA components, 30128-1 had
unacceptable physical properties.
[0117] Formulation 30130-1 did not include propylene glycol and had
a composition outside of the ratio of 30-60:30-60:5-15 for fatty
acid excipients:humectants:DIA. Propylene glycol is not known as an
emulsion stabilizer. Surprisingly, this composition was found to be
unstable on long term storage. The emulsion of formulation 30130-1
showed a phase separation or syneresis.
[0118] Thus, compositions of the present invention having ratios of
30-60:30-60:5-15 for fatty alcohol excipients:humectants:DIA
components produce topical lotion compositions which are effective
in treatment of corticosteroid-responsive dermatoses, have
acceptable appearance, are homogeneous pourable lotions and are
stable on storage.
[0119] Items
[0120] 1. A storage stable, topical lotion composition for treating
a skin disorder or condition, said composition comprising:
[0121] a halobetasol material comprising halobetasol or its
pharmaceutically acceptable salts, esters, and solvates; and
[0122] a pharmaceutically acceptable carrier which includes: (a)
one or more fatty alcohols and/or one or more alkoxylated fatty
alcohols, (b) one or more polyol humectants, and (c) diisopropyl
adipate.
[0123] 2. The topical lotion of item 1, wherein the fatty alcohol
is selected from the group consisting of lauryl alcohol, myristyl
alcohol, cetyl alcohol, stearyl alcohol, octyldodecanol, and
mixtures of any two or more thereof.
[0124] 3. The topical lotion of item 1 or item 2, wherein the
alkoxylated fatty alcohol is an ethoxylated alcohol selected from
the group consisting of lauryl alcohol ethoxylate, myristyl alcohol
ethoxylate, cetyl alcohol ethoxylate, stearyl alcohol ethoxylate,
octyldodecanol ethoxylate, and mixtures of any two or more
thereof.
[0125] 4. The topical lotion of any of items 1-3, wherein the
polyol humectant is selected from the group consisting of glycerin,
propylene glycol, butylene glycol, dipropylene glycol, pentylene
glycol, hexylene glycol, polyethylene glycol and mixtures of any
two or more thereof.
[0126] 5. The topical lotion of any of items 1-4, wherein the
amount of said halobetasol material after storage for six months at
40.degree. C. is >98.5% of the total amount of halobetasol
material present at the time of manufacture of the topical lotion,
wherein the amount of degradation of said halobetasol material
after storage for 26 months at 30.degree. C. is <1% of the total
amount of halobetasol material present at the time of manufacture
of the topical lotion and wherein the amount of degradation of said
halobetasol material after storage at 25.degree. C. for 30 months
is <3% of the total amount of halobetasol material present at
the time of manufacture of the topical lotion.
[0127] 6. The topical lotion of any of items 1-5, wherein the
amount of degradation of said halobetasol material after storage
for six months at 40.degree. C. is <1.5% of the total amount of
said halobetasol material, wherein the amount of degradation of
said halobetasol material after storage for 26 months at 30.degree.
C. is <1% of said halobetasol material and wherein the amount of
degradation of said halobetasol material after storage at
25.degree. C. for 30 months is <3% of said halobetasol
material.
[0128] 7. The topical lotion of any of items 1-6, wherein said
halobetasol material is halobetasol propionate.
[0129] 8. The topical lotion of any of items 1-7, further including
one or more members selected from the group consisting of: one or
more additional therapeutic agents, coloring agents, preservatives,
pH control agents, viscosity control agents, and fragrances.
[0130] 9. The topical lotion of any of items 1-8, wherein the ratio
of said fatty alcohols and alkoxylated fatty alcohols to said
humectants, to said diisopropyl adipate is, on a weight basis, in
the range of 30-60:30-60:5-15.
[0131] 10. The topical lotion of any of items 1-9, wherein the
ratio of said fatty alcohols and alkoxylated fatty alcohols to said
humectants, to said diisopropyl adipate is, on a weight basis, in
the range of 39-48:39-50:10-15.
[0132] 11. The topical lotion of any of items 1-10, wherein the
weight ratio of said fatty alcohols and ethoxylated fatty alcohols
to said polyol humectants to said diisopropyl adipate is in the
range of 44-46:40-43:11-13.
[0133] 12. The topical lotion of any of items 1-11, wherein the
weight ratio of said fatty alcohols and ethoxylated fatty alcohols
to said polyol humectants to said diisopropyl adipate is
46:42:12.
[0134] 13. The topical lotion of any of items 1-12, wherein said
topical lotion composition is an oil-in-water emulsion of droplets
having a mean particle size in the range of 0.1-50 microns and a
distribution of particle sizes in the range of 0.1-50 microns.
[0135] 14. The topical lotion of any of items 1-13, wherein said
topical lotion composition is an oil-in-water emulsion of droplets
having a mean particle size in the range of 1-10 microns and a
distribution of particle sizes in the range of 0.15-15 microns.
[0136] 15. The topical lotion of any of items 1-14, wherein said
topical lotion composition is an oil-in-water emulsion of droplets
having a mean particle size in the range of 1.5-7 microns and a
distribution of particle sizes in the range of 0.175-10
microns.
[0137] 16. A storage stable, topical lotion composition comprising,
on a weight basis: 0.02-0.10% of a halobetasol material; 1-5% of
diisopropyl adipate; 5-15% octyl dodecanol; 0.50-2% of polyethylene
glycol 1000 cetyl ether; 0.50-2% of a surfactant; 1-3% cetyl
alcohol; 1-2% stearyl alcohol; 0.05-0.2% of a preservative; 5-15%
propylene glycol; 1-5% glycerin; a pH adjustment agent an amount
sufficient to adjust the pH of the composition to a range of
approximately 5-6.5; and water q.s.
[0138] 17. The storage stable, topical lotion composition of item
16, further comprising a viscosity control agent in an amount of
0.1-0.5% w/w.
[0139] 18. A storage stable, topical lotion composition comprising,
on a weight basis: 0.05% of a halobetasol material; 3.5% of
diisopropyl adipate; 10% octyl dodecanol; 1% of polyethylene glycol
1000 cetyl ether; 1% of a surfactant; 2% cetyl alcohol; 0.66%
stearyl alcohol; 0.15% of a preservative such as a paraben
preservative, for example propyl paraben and/or butyl paraben; 10%
propylene glycol; 2.5% glycerin; a pH adjustment agent in an amount
sufficient to adjust the pH of the composition to a range of
approximately 5-6.5; and water q.s.
[0140] 19. The storage stable, topical lotion composition of item
18, further comprising a viscosity control agent in an amount of
0.25% w/w.
[0141] 20. The topical lotion of any of items 1-19, wherein said
halobetasol material is halobetasol propionate.
[0142] 21. A method for treating corticosteroid-responsive
dermatoses comprising: topically administering to a patient in need
thereof, the topical lotion composition of any of items 1-20.
[0143] 22. The method of item 21, wherein said topical lotion
composition is packaged in a container suitable for storage and
delivery of said composition.
[0144] 23. The method of item 22, wherein said container is
comprised of a ferrous alloy, aluminum, glass, plastic, or
combinations thereof.
[0145] 24. The method of any of items 22-23, wherein said container
further includes one or more protective coatings.
[0146] 25. The method of any of items 22-24, wherein said container
includes at least two separate compartments wherein said topical
lotion composition of claim 1 is disposed in one of said
compartments.
[0147] 26. The method of any of items 21-25, wherein the patient is
further instructed to prepare the area to be treated by cleansing
with a suitable surfactant-containing composition.
[0148] 27. The method of any of items 21-26, wherein said method is
as effective to reduce transepidermal water loss as a cream
formulation compared to a shaved skin control.
[0149] 28. The method of any of items 21-27, wherein said method is
as effective to reduce transepidermal water loss as Ultravate.RTM.
cream compared to a shaved skin control.
[0150] 29. The method of any of items 21-28, wherein said method is
effective to produce an improvement in skin surface hydration
levels as measured with a skin conductance or capacitance measuring
apparatus.
[0151] 30. The method of any of items 21-29, wherein said method is
effective to produce an improvement in skin surface hydration
levels as measured with a skin conductance or capacitance measuring
apparatus, wherein said improvement is observed at 2 hours post
treatment.
[0152] 31. The method of any of items 21-30, wherein said method is
effective to produce an improvement in skin surface hydration
levels as measured with a skin conductance or capacitance measuring
apparatus, wherein said improvement is observed at 4 hours post
treatment.
[0153] 32. A method for the preparation of the topical lotion
composition of any of items 1-19, said method comprising the steps
of: preparing an aqueous phase that includes a first portion of the
components of said topical lotion composition; maintaining said
aqueous phase at a temperature in the range of 45-70.degree. C.;
preparing an oil phase that includes a second portion of the
components of said topical lotion composition; adding said oil
phase to said aqueous phase while stirring at a temperature of
about 45-70.degree. C. so as to obtain an emulsion; cooling said
emulsion to a temperature of about 25-35.degree. C.; and adjusting
the pH of said emulsion to a pH in the range of 5.0-6.5.
[0154] The present invention provides therapeutic compositions
which have unexpected therapeutic efficacy in the treatment of
dermatoses. The lotion compositions of the present invention
readily penetrate the skin to provide a rapid therapeutic effect
and operate to promote hydration and limit water loss of the skin.
While the foregoing describes some particular compositions based on
therapeutically active halobetasol materials, it will be readily
apparent to those of skill in the art that the principles of the
present invention may be readily extended to other corticosteroids
as well as other therapeutically active ingredients. All of such
modifications and variations thereof may be implemented by those of
skill in the art, without undue experimentation. The foregoing
drawings, discussion, and description are illustrative of specific
embodiments of the invention but are not meant to be limitations
upon the practice thereof. It is the following claims, including
all equivalents, which define the scope of the invention.
* * * * *