U.S. patent application number 15/874521 was filed with the patent office on 2018-05-24 for corticosteriod containing foam compositions.
The applicant listed for this patent is Therapeutics Incorporated. Invention is credited to Robert T. Gauthier, James D. Hammer.
Application Number | 20180140614 15/874521 |
Document ID | / |
Family ID | 57681682 |
Filed Date | 2018-05-24 |
United States Patent
Application |
20180140614 |
Kind Code |
A1 |
Gauthier; Robert T. ; et
al. |
May 24, 2018 |
CORTICOSTERIOD CONTAINING FOAM COMPOSITIONS
Abstract
The present invention provides a method of manufacturing
foamable, corticosteroid containing compositions as well as methods
for treating various skin diseases.
Inventors: |
Gauthier; Robert T.; (San
Diego, CA) ; Hammer; James D.; (Uxbridge,
MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Therapeutics Incorporated |
San Diego |
CA |
US |
|
|
Family ID: |
57681682 |
Appl. No.: |
15/874521 |
Filed: |
January 18, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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15365152 |
Nov 30, 2016 |
|
|
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15874521 |
|
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|
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62267773 |
Dec 15, 2015 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 47/12 20130101;
A61K 31/573 20130101; B65B 31/003 20130101; A61K 9/0014 20130101;
B65B 63/08 20130101; A61P 29/00 20180101; A61P 17/00 20180101; A61K
31/58 20130101; A61K 47/10 20130101; B65D 83/752 20130101; A61K
47/44 20130101; A61K 9/122 20130101; A61P 37/08 20180101; A61P
17/04 20180101; A61K 47/06 20130101; A61P 17/06 20180101 |
International
Class: |
A61K 31/573 20060101
A61K031/573; A61K 47/10 20060101 A61K047/10; A61K 9/12 20060101
A61K009/12; A61K 31/58 20060101 A61K031/58; B65D 83/14 20060101
B65D083/14; A61K 47/44 20060101 A61K047/44; B65B 63/08 20060101
B65B063/08; A61K 9/00 20060101 A61K009/00; A61K 47/06 20060101
A61K047/06; A61K 47/12 20060101 A61K047/12; B65B 31/00 20060101
B65B031/00 |
Claims
1. A foamable pharmaceutical composition comprising: a) a
corticosteroid or a pharmaceutically acceptable salt, ester, or
solvate thereof; b) an aliphatic alcohol; c) at least one foam
structuring agent comprising one or more fatty alcohols, non-ionic
surfactants, or combinations thereof; d) a polyol; e) a can
corrosion inhibitor; and e) water; and f) a propellant, wherein the
composition is void of a buffer.
2. The composition of claim 1, wherein the corticosteroid is
selected from the group consisting of methylprednisolone,
hydrocortisone, prednisolone, clobetasone, hydrocortisone butyrate,
flumetasone, fluocortin, fluperolone, fluorometholone,
fluprednidene, desonide, triamcinolone, alclometasone,
hydrocortisone buteprate, dexamethasone, clocortolone,
betamethasone, fluclorolone, desoximetasone, fluocinolone
acetonide, fluocortolone, diflucortolone, fludroxycortide,
fluocinonide, budesonide, diflorasone, amcinonide, halometasone,
mometasone furoate, methylprednisolone aceponate, beclomethasone,
hydrocortisone aceponate, fluticasone, prednicarbate,
difluprednate, halobetasol, resocortol butyrate, clobetasol and
halcinonide.
3. The composition of claim 2, wherein the corticosteroid is
halobetasol.
4. The composition of claim 1, wherein the aliphatic alcohol is
methyl, ethyl, isopropyl or butyl alcohol, or a combination
thereof.
5. The composition of claim 1, wherein the aliphatic alcohol is
ethyl alcohol.
6. The composition of claim 1, wherein the fatty alcohol is
selected from the group consisting of lauryl alcohol, myristyl
alcohol, cetyl alcohol, lauryl alcohol, stearyl alcohol,
octyldodecanol, and combinations thereof.
7. The composition of claim 1, wherein the fatty alcohol is a
mixture of cetyl alcohol and stearyl alcohol.
8. The composition of claim 1, wherein the polyol is selected from
the group consisting of glycerin, propylene glycol, butylene
glycol, dipropylene glycol, pentylene glycol, hexylene glycol,
polyethylene glycol and combinations thereof.
9. The composition of claim 1, wherein the polyol is propylene
glycol.
10. The composition of claim 1, wherein the at least one foam
structuring agent comprises an ethoxylated alcohol.
11. The composition of claim 10, wherein the ethoxylated alcohol is
polyoxyl 20 cetostearyl ether.
12. The composition of claim 1, wherein the at least one foam
structuring agent is a combination of one or more of cetyl alcohol,
stearyl alcohol, and an ethoxylated alcohol.
13. The composition of claim 1, wherein the at least one foam
structuring agent is Emulsifying Wax, NF.
14. The composition of claim 1, wherein the can corrosion inhibitor
is less than approximately 0.005%, 0.001% or 0.0005% w/w of benzoic
acid.
15. The composition of claim 1, wherein the composition has a pH of
about 4.0 to 6.3.
16. The composition of claim 1, wherein the propellant is selected
from propane, n-butane, isobutane, n-pentane, isopentane, dichloro
difluoro methane, dichloro tetrafluoro ethane, octafluoro
cyclobutane, 1,1,1,2-tetrafluoroethane, 1,1-difluoroethane,
1,1,1,2,3,3,3-heptafluoropropane and mixtures of two or more
thereof.
17. The composition of claim 1, further comprising one or more
members selected from the group consisting of one or more
additional therapeutic agents, coloring agents, preservatives,
viscosity control agents, and fragrances.
18. The composition of claim 1 comprising, on a weight basis: a)
0.02 to 0.10% corticosteroid or its pharmaceutically acceptable
salts, esters, and solvates; b) 40 to 60% ethyl alcohol; c) 0.1 to
5.0% Emulsifying Wax, NF; d) 0.05 to 1.0% cetostearyl alcohol; e)
0.05 to 1.0% polyoxyl 20 cetostearyl ether; f) 1 to 10% propylene
glycol; g) 30 to 40% water; h) less than 0.001% benzoic acid as the
can corrosion inhibitor; and i) 3.25 to 5.75% propellant, wherein
the composition has a pH of between about 4.0 to 6.3.
19. The composition of claim 18, wherein the composition has an
acceptable shelf-life of greater than about 24, 27, 30, 33, 36, 39,
42, 45 or 48 months.
20. The composition of claim 19, wherein the composition has an
acceptable shelf-life of greater than about 36 months.
21. The composition of claim 20, wherein the shelf-life is
determined at International Conference on Harmonisation (ICH)
long-term storage condition by: a) the 95% one-sided lower
confidence interval of the linear regression of the assay for
halobetasol or its pharmaceutically acceptable salts, esters, and
solvates; b) the 95% one-sided upper confidence interval of the
linear regression of the degradant products for halobetasol or its
pharmaceutically acceptable salts, esters, and solvates; or c) the
pH stability of the composition.
Description
RELATED APPLICATION DATA
[0001] This application is a divisional of U.S. patent application
Ser. No. 15/365,152, filed Nov. 30, 2016; which claims the benefit
of priority under 35 U.S.C. .sctn. 119(e) of U.S. Provisional
Patent Application Ser. No. 62/267,773, filed Dec. 15, 2015, the
entire contents of which is incorporated herein by reference in its
entirety.
BACKGROUND
Field of Invention
[0002] This invention relates to foamable compositions including a
corticosteroid, and more particularly to a method of manufacturing
stable foamable compositions.
Background Information
[0003] Corticosteroids are well known anti-inflammatory compounds,
which are recognizably utilized in the treatment of inflammatory
diseases such as allergic contact dermatitis, eczema, asteatotic
eczema, discoid eczema, infantile eczema and diaper dermatitis,
psoriasis; including plaque psoriasis, palmoplantar psoriasis,
etc., seborrheic dermatitis, atopic dermatitis, dermatitis
herpetiformis, neurodermatitis, lichen simplex chronicus, lichen
planus, subacute cutaneous lupus erythematosus, urticaria, discoid
lupus erythematosus, chronic hypertrophic lichen planus, granuloma
annulare, keloid scars, reactions to insect and spider bites,
pityriasis rosea, erythema, and pruritus. Formulations containing
such active substances have conventionally been applied to the skin
site in the form of foams, ointments, gels, creams, sprays and
lotions.
[0004] Foamable compositions are particularly desirable for topical
application of cortico steroids. However, a number of problems
exist in conventional methods of manufacturing cortico steroid
foams, such as degradation and inactivation of the corticosteroid
during manufacture and canning of the foam composition. Additional
problems include cortico steroid degradation over the shelf life of
the composition.
[0005] As such, there exists a need in the treatment of skin
disorders requiring treatment with cortico steroids for improved
formulations manufactured by methods which prevent degradation and
inactivation of the corticosteroid and which exhibit prolonged
stability of the cortico steroid thereby exhibiting extended shelf
life as compared to conventional foam compositions manufactured by
conventional means.
SUMMARY
[0006] The manufacturing method and foamable compositions produced
by such method as presented herein do not utilize a traditional
buffer system which adds manufacturing complexity. However,
compositions manufactured by the presently described method exhibit
a stable pH, enhanced stability of cortico steroids, and enhanced
efficacy in treatment as compared to other treatment options.
[0007] The compositions of the present invention demonstrate a
clinical efficacy which is superior to comparable corticosteroid
containing compositions. In addition, it has been found that the
compositions of the present invention are stable and demonstrate
very good long term storage stability.
[0008] As will be further explained herein below, compositions
manufactured by the presently described method achieve a high level
of clinical efficacy without appreciably reducing transepidermal
water loss (TEWL). Skin conductance studies have also demonstrated
that the compositions of the present invention do not appreciably
increase skin hydration. The compositions of the present invention
comprise particular combinations of ingredients which interact
synergistically to produce the enhanced results described herein
without increasing skin hydration or reducing transepidermal water
loss.
[0009] Accordingly, in one aspect, the present invention provides a
method for single-stream manufacture of a foamable composition
including a corticosteroid. The method includes forming a
homogenous solution which includes: i) an aliphatic alcohol; ii) a
can corrosion inhibitor; iii) a polyol; iv) at least one foam
structuring agent comprising one or more fatty alcohols, non-ionic
surfactants, or combinations thereof; and v) water. In embodiments,
the solution is formed in a single batch vessel at a constant
temperature of between about 55.degree.-75.degree. C. while
minimizing evaporative losses. Subsequently, the mixture is cooled
to a temperature of between about 40.degree.-55.degree. C. and a
corticosteroid is then added to the solution and mixed to
homogeneity while maintaining a temperature of between about
40.degree.-55.degree. C. The solution is then filled into
dispensing canisters while the solution is maintained at a
temperature of between about 40.degree.-50.degree. C. The filled
canisters are then charged with a propellant thereby forming a
single-phase foamable composition.
[0010] In another aspect, the present invention provides a greater
than 36-month storage stable, corticosteroid containing foamable
composition produced by the method of manufacture described herein.
The composition includes: a) a corticosteroid, or its
pharmaceutically acceptable salts, esters, and solvates; b) an
aliphatic alcohol; c) at least one foam structuring agent
(including one or more fatty alcohols, one or more non-ionic
surfactants, or combinations thereof); d) a polyol; e) water; f) a
can corrosion inhibitor; and g) a propellant. In embodiments, the
composition is void of a buffer.
[0011] In one embodiment, the present invention is a stable,
therapeutically effective composition consisting essentially of: a)
halobetasol or its pharmaceutically acceptable salts, esters, and
solvates; b) an aliphatic alcohol; c) at least one foam structuring
agent selected from one or more fatty alcohols, one or more
non-ionic surfactants, or combinations thereof; d) a polyol; f)
water; and g) optionally, if the composition is stored in a metal
container or can, benzoic acid as a can corrosion inhibitor. The
composition is devoid of a buffer. The composition may be devoid of
a second therapeutic agent in addition to halobetasol.
[0012] In another embodiment, the present invention is a stable
composition consisting of: a) halobetasol or its pharmaceutically
acceptable salts, esters, and solvates; b) an aliphatic alcohol; c)
at least one foam structuring agent selected from one or more fatty
alcohols, one or more non-ionic surfactants, or combinations
thereof; d) a polyol; f) water; and g) optionally, if the
composition is stored in a metal container or can, benzoic acid as
a can corrosion inhibitor. The composition is devoid of a buffer.
The composition may be devoid of a second therapeutic agent in
addition to halobetasol.
[0013] In another aspect, the present invention provides a method
for treating a subject having, or at risk of having, a
corticosteroid-responsive condition, such as a skin disease or
disorder. The method includes topically administering to the
subject in need thereof a foamable composition of the present
invention, thereby treating the corticosteroid-responsive
condition. In some embodiments, the condition is a skin disorder or
disease, such as a corticosteroid-responsive dermatosis, including
for example, atopic dermatitis, seborrheic dermatitis, contact
dermatitis, psoriasis, atopic eczema, infantile eczema, discoid
eczema, lichen simplex, lichen planus, skin inflammation, miliaria,
pityriasis rosea, erythema, and pruritus.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] FIG. 1 is a graphical representation presenting clinical
data relating to administration of compositions of the present
invention in one embodiment of the invention.
[0015] FIG. 2 is a graphical representation presenting clinical
data relating to administration of compositions of the present
invention in one embodiment of the invention.
[0016] FIG. 3 is a graphical representation presenting stability
data relating to the projected shelf-life of the compositions of
the present invention in one embodiment of the invention, based on
assaying the active ingredient.
[0017] FIG. 4 is a graphical representation presenting stability
data relating to the projected shelf-life of the compositions of
the present invention in one embodiment of the invention, based on
assaying a degradation product of the active ingredient.
[0018] FIG. 5 is a graphical representation presenting stability
data relating to the pH of the compositions of the present
invention in one embodiment of the invention.
DETAILED DESCRIPTION
[0019] Before the present compositions and methods are further
described, it is to be understood that this invention is not
limited to particular compositions, methods, and experimental
conditions described, as such compositions, methods, and conditions
may vary. It is also to be understood that the terminology used
herein is for purposes of describing particular embodiments only,
and is not intended to be limiting, since the scope of the present
invention will be limited only in the appended claims.
[0020] As used in this specification and the appended claims, the
singular forms "a", "an", and "the" include plural references
unless the context clearly dictates otherwise. Thus, for example,
references to "the method" includes one or more methods, and/or
steps of the type described herein which will become apparent to
those persons skilled in the art upon reading this disclosure and
so forth.
[0021] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention belongs. Although
any methods and materials similar or equivalent to those described
herein can be used in the practice or testing of the invention, the
preferred methods and materials are now described.
[0022] Preparation and Canning
[0023] One aspect of the present invention is a process for
manufacturing a foamable corticosteroid containing composition as
described herein. Generally, the method includes forming a carrier
solution by admixing an aliphatic alcohol, a can corrosion
inhibitor, one or more foam structuring agents, such as a fatty
alcohol and a non-ionic surfactant, a polyol, and water and heating
to a temperature of at least 45.degree. C., more preferably at
least 65.degree. C., while minimizing evaporative losses.
[0024] According to a feature of the present invention, a
corticosteroid is added to the carrier at a temperature below
60.degree. C., more preferably below 50.degree. C. By adding
corticosteroid at a lower temperature in the manufacturing process
the rate of degradation of the corticosteroid is markedly reduced
and thus the amount of degradant products is reduced.
[0025] According to yet another feature of the present invention
the corticosteroid containing solution is filled into canisters at
a temperature above 35.degree. C., most preferably above 42.degree.
C. Filled canisters are then charged with a propellant to produce a
clear single-phase foamable composition.
[0026] In particular, the method of the invention includes first
forming a homogenous carrier solution which includes: i) an
aliphatic alcohol; ii) a can corrosion inhibitor; iii) a polyol;
iv) at least one foam structuring agent comprising one or more
fatty alcohols, non-ionic surfactants, or combinations thereof; and
v) water. In embodiments, the solution is formed in a single batch
vessel at a constant temperature of between about
55.degree.-75.degree. C., and more preferably between about
65.degree.-70.degree. C., while minimizing evaporative losses.
[0027] In one embodiment, an aliphatic alcohol, such as ethanol, is
first heated in a single batch vessel to between about
65.degree.-70.degree. C. and a can corrosion inhibitor, such as
benzoic acid, is then added. The solution is mixed to homogeneity
and subsequently the following components are admixed in series
while maintaining a temperature of between about
65.degree.-70.degree. C.: a polyol (e.g., propylene glycol); and
foam structuring agents (e.g., combinations of Emulsifying wax,
polyoxyl 20 cetostearyl ether, and cetostearyl alcohol). Water is
added in multiple aliquots to maintain a temperature greater than
55.degree. C. and the completed carrier solution is heated to
65.degree.-70.degree. C. and mixed to homogeneity.
[0028] Subsequently, the solution is cooled to a temperature of
between about 45.degree.-50.degree. C. and a corticosteroid is then
added to the solution and mixed to uniformity while maintaining a
temperature of between about 45.degree.-50.degree. C. Total
evaporative losses are kept below 1.0% w/w, and more preferably
below 0.25% w/w, during compounding through the use of a suitable
manufacturing vessel with a pressure and/or vacuum rated lid that
seals onto the vessel.
[0029] Throughout the admixing process, the bulk solution may be
analyzed to ensure proper mixing and temperature of the solution.
Once the corticosteroid is added, the solution is mixed to
uniformity. The solution is then filled into aerosol canisters
while the solution is maintained at a temperature of between about
42.degree.-48.degree. C. Preferably, the solution is mixed for at
least 30 minutes or more before being filled into the dispensing
canisters. The filled canisters are then charged with a propellant
thereby forming a single-phase foamable composition.
[0030] According to one embodiment of the present invention the
canisters are made of metal having an internal resistance burst
pressure of at least 270 PSIG, more preferably tin or aluminum, and
are lined to prevent degradation and corrosion. Another feature of
the present invention is an aerosol valve, more preferably an
inverted-dispensing valve. Yet another feature of the present
invention is an actuator and valve combination capable of
dispensing foam at a controlled rate with preferred cosmetic
characteristics.
[0031] Compositions
[0032] The present invention provides a greater than 36-month
storage stable, foamable composition produced by the method
described herein for treating a corticosteroid-responsive
condition, including skin diseases and disorders, such as
corticosteroid-responsive dermatoses. The composition includes: a)
a corticosteroid, or its pharmaceutically acceptable salts, esters,
and solvates; b) an aliphatic alcohol; c) one or more foam
structuring agents (including one or more fatty alcohols, one or
more non-ionic surfactants, or combinations thereof); d) a polyol;
e) water; f) a can corrosion inhibitor; and g) a propellant. The
composition is preferably void of a buffer. It should be understood
that the stable, therapeutic composition can consist essentially
of, or consist of, the above components.
[0033] The composition of the present invention is applied to the
treatment site (after foaming) or a secondary site, such as a hand
(after foaming), for application to the treatment site as a foam.
Upon application, the composition is initially in the form of a
mousse-like foam which is engineered to break down at skin
temperature under low application shear allowing the halobetasol or
other corticosteroid to saturate the treatment site. The presently
described system provides enhanced penetration of the halobetasol
or other corticosteroid through the epidermis. The composition
exhibits ideal characteristics between traditional rigid
(mousse-like) and thermolabile (quick-break) foams that is achieved
without buffering. It has been found that improved stabilization of
corticosteroid is achieved through addition of a small amount of
the can corrosion inhibitor benzoic acid. It should be understood
that reference to the "can" herein refers to the canister from
which the composition is delivered.
[0034] The aliphatic alcohol may preferably be chosen from methyl,
ethyl, isopropyl and butyl alcohols, and mixtures of two or more
thereof. In one embodiment, the aliphatic alcohol is ethyl alcohol.
In embodiments, the aliphatic alcohol, such as ethyl alcohol, is
included in the composition at between about 40-70%, 45-65%,
50-60%, or 55-60% w/w; or in an amount of about 45%, 46%, 47%, 48%,
49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%,
62%, 63%, 64% or 65% w/w.
[0035] The present composition further includes one or more foam
structuring agents, such as one or more fatty alcohols. The one or
more fatty alcohols included in the composition of the present
invention have a linear or branched carbon backbone that has 6-22
carbon atoms. In embodiments of the invention, the one or more
fatty alcohols have a linear or branched carbon backbone that has
10-18 carbon atoms. In various embodiments the fatty alcohol is
selected from the group consisting of lauryl alcohol, myristyl
alcohol, cetyl alcohol, lauryl alcohol, stearyl alcohol,
octyldodecanol, and combinations thereof. Yet other fatty alcohols
will be apparent to those of skill in the art. In an embodiment,
mixtures of cetyl alcohol and a stearyl alcohol are preferred, for
example cetostearyl alcohol.
[0036] In embodiments, the fatty alcohol, such as cetostearyl
alcohol, is included in the composition at between about 0.05-1.0%,
0.06-0.95%, 0.07-0.9%, 0.08-0.75%, 0.09-0.7%, 0.1-0.65%, 0.15-0.6%,
0.2-0.5%, 0.2-0.4% or 0.2-0.3% w/w; or in an amount of about 0.15%,
0.16%, 0.17%, 0.18%, 0.19%, 0.2%, 0.21%, 0.22%, 0.23%, 0.24%,
0.25%, 0.26%, 0.27%, 0.28%, 0.29%, 0.3%, 0.31%, 0.32%, 0.33%,
0.34%, 0.35% or 0.36% w/w.
[0037] The present composition further includes one or more foam
structuring agents, such as one or more non-ionic surfactants.
Non-ionic surfactants that may be used in the composition of the
present invention generally include ethoxylated alcohols. Non-ionic
surfactants that may be used in the composition of the present
invention include glyceryl stearate, PEG 100-stearate,
polyoxyl-20-cetostearyl ether, glyceryl monooleate, glyceryl
palmitostearate, polyoxyl-20-stearate, polyoxyl-40-stearate,
polyoxyl-60-stearate, polyoxyl-80-stearate, polyoxyl-20-oleate,
polyoxyl-40-oleate, polyoxyl-60-oleate, polyoxyl-80-oleate,
polyoxyl-20-palmitate, polyoxyl-40-palmitate,
polyoxyl-60-palmitate, polyoxyl-80-palmitate, polyoxyethylene (20)
sorbitan monolaurate, polyoxyethylene (20) sorbitan monopalmitate,
polyoxyethylene (20) sorbitan monostearate, polyoxyethylene (20)
sorbitan monooleate, laureth-2, laureth-4, laureth-6, and
laureth-8. Yet other non-ionic surfactants will be apparent to
those of skill in the art. In a preferred embodiment, the non-ionic
surfactant is polyoxyl-20-cetostearyl ether. In embodiments, the
non-ionic surfactant, such as polyoxyl-20-cetostearyl ether, is
included in the composition at between about 0.05-1.0%, 0.06-0.95%,
0.07-0.9%, 0.08-0.75%, 0.09-0.7%, 0.1-0.65%, 0.15-0.6%, 0.2-0.5%,
0.2-0.4% or 0.2-0.3% w/w; or in an amount of about 0.15%, 0.16%,
0.17%, 0.18%, 0.19%, 0.2%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25%,
0.26%, 0.27%, 0.28%, 0.29%, 0.3%, 0.31%, 0.32%, 0.33%, 0.34%, 0.35%
or 0.36% w/w.
[0038] The present composition further includes one or more foam
structuring agents including combinations of one or more fatty
alcohols and one or more non-ionic surfactants. The fatty alcohol
component is selected from the group consisting of lauryl alcohol,
myristyl alcohol, cetyl alcohol, lauryl alcohol, stearyl alcohol,
octyldodecanol, and combinations thereof. The non-ionic component
is selected from the group consisting of glyceryl stearate, PEG
100-stearate, polyoxyl-20-cetostearyl ether, glyceryl monooleate,
glyceryl palmitostearate, polyoxyl-20-stearate,
polyoxyl-40-stearate, polyoxyl-60-stearate, polyoxyl-80-stearate,
polyoxyl-20-oleate, polyoxyl-40-oleate, polyoxyl-60-oleate,
polyoxyl-80-oleate, polyoxyl-20-palmitate, polyoxyl-40-palmitate,
polyoxyl-60-palmitate, polyoxyl-80-palmitate, polyoxyethylene (20)
sorbitan monolaurate, polyoxyethylene (20) sorbitan monopalmitate,
polyoxyethylene (20) sorbitan monostearate, polyoxyethylene (20)
sorbitan monooleate, laureth-2, laureth-4, laureth-6, and
laureth-8. Yet other fatty alcohols and other non-ionic surfactants
will be apparent to those skilled in the art. In a preferred
embodiment, the fatty alcohol and non-ionic surfactant combination
includes cetyl alcohol, stearyl alcohol, and one or more of
polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20)
sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate,
polyoxyethylene (20) sorbitan monooleate, for example, Emulsifying
Wax, NF.
[0039] In embodiments, the foam structuring agent(s) is included in
the composition at between about 0.1-4.0%, 0.1-3.5%, 0.1-3.0%,
0.1-2.5%, 0.1-2.0%, 0.5-2.0%, 1.0-2.0%, 1.5-2.0% or 1.6-1.9% w/w;
or in an amount of about 1.05%, 1.1%, 1.15%, 1.2%, 1.25%, 1.3%,
1.35%, 1.4%, 1.45%, 1.5%, 1.55%, 1.6%, 1.65%, 1.7%, 1.75%, 1.8%,
1.85%, 1.9%, 1.95% or 2.0% w/w.
[0040] In embodiments, Emulsifying Wax, NF, is included in the
composition at between about 0.1-4.0%, 0.1-3.5%, 0.1-3.0%,
0.1-2.5%, 0.1-2.0%, 0.5-2.0%, 1.0-2.0%, 1.0-1.5% or 1.0-1.1% w/w;
or in an amount of about 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1.0%,
1.05%, 1.1%, 1.15%, 1.2%, 1.25%, 1.3%, 1.35%, 1.4%, 1.45%, 1.5%,
1.55%, 1.6%, 1.65% or 1.70%, 1.75%, 1.8%, 1.85%, 1.9%, 1.95% or
2.0% w/w.
[0041] The polyol component of the composition may function as a
solubility enhancer for the corticosteroid and may have traditional
humectant properties. Such polyols may include 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. In a
preferred embodiment, the polyol is propylene glycol. In
embodiments, the polyol solubility enhancer is included in the
composition at between about 1-10%, 2-8%, 3-7%, or 4-6% w/w; or in
an amount of about 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%,
5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5% or 10.0%
w/w; or in an amount of about 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%,
4.6%, 4.7%, 4.8%, 4.9%, 5.0%, 5.1%, 5.2%, 5.25%, 5.3%, 5.4%, 5.5%,
5.6%, 5.7%, 5.9%, 6.0%, 6.1%, 6.2%, 6.3%, 6.4%, 6.5%, 6.6%, 6.7%,
6.8%, 6.9% or 7.0% w/w.
[0042] The composition of the present invention may be contained in
and dispensed from a container capable of withstanding the pressure
of the propellant gas and having an appropriate valve and actuator
for dispensing the composition as a foam under pressure. If the
container is made of a material such as aluminum or tin that is
likely to suffer corrosion under the action of the composition, in
the event the internal lining suffers a breach, the composition may
include a single corrosion inhibitor as an additive. Suitable
corrosion inhibitors include organic acids, such as but not limited
to sorbic acid, benzoic acid, formic acid, acetic acid, propionic
acid, butyric acid, valeric acid, caproic acid, oxalic acid, lactic
acid, malic acid, citric acid and carbonic acid. In embodiments,
the can corrosion inhibitor is included in the composition at less
than about 0.0015%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%,
0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001%, w/w.
[0043] The propellant used may be chosen from conventional aerosol
propellants. Thus, one may select the propellant from propane,
n-butane, isobutane, n-pentane, isopentane, dichloro difluoro
methane, dichloro tetrafluoro ethane, octafluoro cyclobutane,
1,1,1,2-tetrafluoroethane, 1,1-difluoroethane,
1,1,1,2,3,3,3-heptafluoropropane and mixtures of two or more
thereof. The propellant level should be adjusted to optimize the
quality of the foam and to produce traditional rigid (mousse-like)
and thermolabile (quick-break) characteristics. In embodiments, the
propellant is included in the composition at between about
2.75-6.25%, 3-6%, or 3.25-5.75% w/w; or in an amount of about
2.75%, 3%, 3.25%, 3.5%, 3.75%, 4%, 4.25%, 4.5%, 4.75%, 5%, 5.25%,
5.5%, 5.75%, 6%, or 6.25% w/w.
[0044] The present composition further includes an aqueous
component, such as water. In embodiments, water is included in the
composition at between about 25-45%, 30-40% or 35-40% w/w; or in an
amount of about 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%,
35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44% or 45% w/w.
[0045] In specific embodiments of the present invention, the
foregoing ingredients are present in particular ratios. A number of
formulations may be prepared in accord with the present invention
shown in Tables I-VI below, which list compositional ranges for
such formulations.
TABLE-US-00001 TABLE I Formulation Component Ranges Component % w/w
Aliphatic alcohol 40-60 Foam structuring agents (fatty 0.1-4.0
alcohols, non-ionic surfactants, and combinations thereof) Polyol
solubility enhancer 1-10 Water 30-40 Corrosion inhibitor less than
0.001
TABLE-US-00002 TABLE II Formulation Component Ranges Component %
w/w Aliphatic alcohol 50-60 Fatty alcohol and/or non-ionic 0.1-1.0
surfactant Emulsifying Wax, NF 0.5-2.0 Polyol solubility enhancer
2-8 Water 35-40 Corrosion inhibitor less than 0.001
TABLE-US-00003 TABLE III Formulation Component Ranges Component %
w/w Aliphatic alcohol 50-60 Emulsifying Wax, NF 0.5-2.0 Fatty
alcohol 0.1-0.4 Non-ionic surfactant 0.1-0.4 Polyol solubility
enhancer 2-8 Water 35-40 Corrosion inhibitor less than 0.001
TABLE-US-00004 TABLE IV Formulation Component Ranges Component %
w/w Aliphatic alcohol 50-60 Emulsifying Wax, NF 1.0-1.1 Fatty
alcohol 0.2-0.3 Non-ionic surfactant 0.2-0.3 Polyol solubility
enhancer 2-8 Water 35-40 Corrosion inhibitor less than 0.001
TABLE-US-00005 TABLE V Formulation Component Ranges Component % w/w
Ethyl alcohol 40-60 Emulsifying Wax, NF 0.1-5.0 Cetostearyl alcohol
0.05-1.0 Polyoxyl 20 cetostearyl ether 0.05-1.0 Propylene glycol
1-10 Water 30-40 Benzoic acid less than 0.001
TABLE-US-00006 TABLE VI Corticosteroid Formulations Component % w/w
Corticosteroid 0.05 Ethyl alcohol 50-60 Emulsifying Wax, NF 1.0-1.1
Cetostearyl alcohol 0.2-0.3 Polyoxyl 20 cetostearyl ether 0.2-0.3
Propylene glycol 2-8 Water 35-40 Benzoic acid less than 0.001
[0046] Preparations based upon the ratios set forth in Tables I-VI,
include, or will further include the corticosteroid material and a
propellant, and may also include ancillary ingredients such as
preservatives, fragrances, coloring agents, viscosity control
agents and the like. The corticosteroid is preferably present in an
amount of about 0.01-1.0% w/w more preferably about 0.05-0.2% w/w.
In embodiments, corticosteroids for use in the present invention
include, by way of illustration and in no way limiting, the
following: methylprednisolone, hydrocortisone, prednisolone,
clobetasone, hydrocortisone butyrate, flumetasone, fluocortin,
fluperolone, fluorometholone, fluprednidene, desonide,
triamcinolone, alclometasone, hydrocortisone buteprate,
dexamethasone, clocortolone, betamethasone, fluclorolone,
desoximetasone, fluocinolone acetonide, fluocortolone,
diflucortolone, fludroxycortide, fluocinonide, budesonide,
diflorasone, amcinonide, halometasone, mometasone furoate,
methylprednisolone aceponate, beclometasone, hydrocortisone
aceponate, fluticasone, prednicarbate, difluprednate, halobetasol,
resocortol butyrate, clobetasol and halcinonide. In a preferred
embodiment, the corticosteroid is halobetasol, such as halobetasol
propionate.
[0047] Unlike typical foam formulations, the composition of the
present invention does not include a buffer system. As such, the
composition is void of a traditional buffer. During preparation the
minute amount of the can corrosion inhibitor added serves to
maintain the product at a pH in the general range of about 4.0-6.3
and preferably about 5.0-5.5 at the time of manufacture. In
embodiments, the preferred can corrosion inhibitor is benzoic acid
at less than about 0.0015%, 0.001% or 0.0005% w/w.
[0048] Upon dispensing from the can the composition of the present
invention is found to produce a rigid, mousse-like foam that
remains thermally stable on the surface of the skin until applied
with light shear to the application site. The thermal stability of
the foam at about 32-37.degree. C. has been demonstrated for up to
at least 600 seconds. The thermal stability of the foam at about
20-25.degree. C. has been demonstrated for up to at least 1200
seconds. Unexpectedly, it remains rigid and mousse-like at skin
temperature but the foam behaves like a traditional thermolabile
(quick-break) foam during application of shear forces, allowing for
ease of use and application at the treatment site.
[0049] The composition of the present invention is found to exhibit
very good stability under storage conditions. As is known in the
art, corticosteroids may degrade under storage conditions. For
example, halobetasol propionate can degrade under storage
conditions with some of the degradation products or impurities
produced including: halobetasol .DELTA..sub.16 analog; and
halobetasol spiro analog.
[0050] 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.
[0051] Compositions 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
less than 5% and at storage for 24 months at 25.degree. C. is less
than 2% of the total amount of the halobetasol material contained
therein at the time of manufacture.
[0052] The storage stability of compositions of the present
invention can be demonstrated by the pH stability of the
formulation, 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.
[0053] In one embodiment, the composition of the present invention
exhibits an acceptable shelf-life of greater than about 36, 39, 42,
45, 48 or more months. For example, in embodiments, the shelf-life
of the present invention can be projected at greater than 36 months
using standard analysis techniques, such as those described in the
International Conference on Harmonisation of Technical Requirements
for Registration of Pharmaceuticals for Human Use (ICH) Q1A (R2)
guidance for industry, Stability Testing of New Drug Substances and
Products (available on the World Wide Web at
fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances-
/ucm073369.p df; and incorporated by reference herein in its
entirety in particular for its teaching of analysis techniques that
should be used). According to the guidance it is normally
unnecessary to perform a formal statistical analysis on data that
show little degradation and little variability. The recommended
approach for analyzing data expected to change with time is to
apply the 95 percent, one-sided confidence limit to the mean and to
determine the time at which the confidence interval intersects the
acceptance criterion.
[0054] In various embodiments, the composition of the present
invention is stable, having an acceptable shelf-life of at least
six months. In some embodiments the composition has an acceptable
shelf-life of at least one year. In some embodiments the
composition has an acceptable shelf-life of at least 15, 18, 21,
24, 27, 30, 33, 36, 39, 42, 45, 48 or more months at ambient
temperature as determined by the analysis method described above
(and used in Example 4 herein) in the International Conference on
Harmonisation of Technical Requirements for Registration of
Pharmaceuticals for Human Use (ICH) Q1A (R2) guidance for industry,
Stability Testing of New Drug Substances and Products.
[0055] In some embodiments, compositions of the present invention
are storage stable such that the amount of degradation products of
a halobetasol material therein after storage for at least 15, 18,
21, 24, 27, 30, 33, 36, 39, 42, 45 or 48 months at 40.degree. C. is
less than about 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1% of the
total amount of the halobetasol material contained therein at the
time of manufacture.
[0056] Methods of Treatment
[0057] In another aspect, the present invention provides a method
for treating a subject having, or at risk of having, a
corticosteroid-responsive condition, such as a skin disease or
disorder. The method includes topically administering to the
subject in need thereof a foamable composition manufactured as
described herein, thereby treating the skin disorder or
disease.
[0058] Particular corticosteroid-responsive conditions, such as
corticosteroid-responsive dermatoses, that are treated using
methods and topical foamable compositions of the present invention
include but are not limited to inflammatory diseases such as
allergic contact dermatitis, eczema, asteatotic eczema, discoid
eczema, infantile eczema and diaper dermatitis, psoriasis;
including plaque psoriasis, palmoplantar psoriasis, etc.,
seborrheic dermatitis, atopic dermatitis, dermatitis herpetiformis,
neurodermatitis, lichen simplex chronicus, lichen planus, subacute
cutaneous lupus erythematosus, urticaria, discoid lupus
erythematosus, chronic hypertrophic lichen planus, granuloma
annulare, keloid scars, reactions to insect and spider bites,
pityriasis rosea, erythema, and pruritus.
[0059] Methods and 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.
[0060] A therapeutically effective amount of a topical foam
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 composition of the present invention is effective to
detectably decrease inflammation, crusting, scaling, erythema,
induration, skin thickening and/or itching in a patient being
treated for corticosteroid-responsive dermatosis.
[0061] Patients are identified as having, or at risk of having, a
corticosteroid-responsive dermatosis using well-known medical
diagnostic techniques.
[0062] The term "patient" or "subject" refers to an individual in
need of treatment for a corticosteroid-responsive dermatosis. Human
patients are particularly referred to herein although the terms are
not limited to humans and encompass mammals as well as other
animals, 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.
[0063] The composition of the present invention may be administered
acutely or over a period of weeks. For example, a composition as
described herein may be topically administered at least once or
twice, a day. Administration may include multiple doses
administered topically over a period of days or weeks, such as for
treatment of corticosteroid-responsive dermatosis or as multiple
short courses of therapy over a period of months or years to
prevent recurrence or flares of the inflammatory disease.
[0064] A therapeutically effective amount of a composition
according to the present invention will vary depending on the
particular formulation 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 determined by the area of body
surface involved in the disease or condition and would likely be in
the range of 0.5 gm-3.5 gm per application if administered twice a
day. Further, dosage may be adjusted depending on whether treatment
is to be acute or continuing.
[0065] 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. The
product can also be used in conjunction with a skin
moisturizer.
[0066] The following examples are provided to further illustrate
the embodiments of the present invention, but are not intended to
limit the scope of the invention. While they are typical of those
that might be used, other procedures, methodologies, or techniques
known to those skilled in the art may alternatively be used.
Example 1
Foamable Halobetasol Propionate Composition
[0067] A composition was prepared in accord with the present
invention utilizing the formulation of Table VI above. Listed in
Table VI is a specific composition based upon the ranges set forth
hereinabove in Table I.
[0068] In this procedure as described in detail herein, a carrier
solution is prepared by mixing and heating ethyl alcohol to between
about 65.degree.-70.degree. C., adding benzoic acid, propylene
glycol, Polyoxyl 20 cetostearyl ether, cetostearyl alcohol, and
emulsifying wax and mixing to uniformity while maintaining a
temperature of between about 65.degree.-70.degree. C. Water is
added in multiple aliquots to maintain a temperature greater than
55.degree. C. and the completed carrier solution is heated to
65.degree.-70.degree. C. The carrier solution is prepared in a
vessel with a pressure and/or vacuum rated lid that seals onto the
vessel in order to minimize evaporative losses during compounding.
Then the carrier is cooled to about 45.degree.-50.degree. C. and
the halobetasol propionate is added and mixed to uniformity. The
solution is then filled into canisters while maintaining a
temperature of between about 42.degree.-48.degree. C. and
subsequently charged with propellant.
Example 2
Skin Hydration and Transepidermal Water Loss (TEWL)
[0069] A series of studies was carried out to evaluate the
properties and advantages of the composition of the present
invention. These studies were carried out utilizing a preparation
having a formulation in accord with Table VI as prepared by the
procedure set forth above. In a first study, skin hydration was
determined by use of an IBS Skicon-200 Conductance Meter equipped
with a Measurement Technologies probe [unit 2283, probe A] to
further enhance its ability to measure changes in skin surface
hydration.
[0070] The data confirm that the composition of the present
invention did not increase skin hydration when applied to shaved
skin and was not considered to be occlusive. In fact, the
composition decreased skin hydration (i.e., dehydrated) when
applied to shaved skin.
[0071] A further study was carried out measuring transepidermal
water loss (TEWL) of skin treated with the composition of the
present invention. Computerized evaporimetry was measured with a
recently calibrated cyberDERM RG1 Evaporimeter System (Broomall,
Pa.) with TEWL Probes [unit RG1-09-048, probes 715 & 716] that
were manufactured by Cortex Technology (Hadsund, Denmark).
[0072] The data confirm that the composition of the present
invention when applied to shaved skin did not decrease TEWL.
[0073] Increased hydration of the skin is typically associated with
an increased penetration of the active pharmaceutical ingredient
(i.e., halobetasol) and consequently and increased efficacy.
Similarly, a decrease in TEWL is associated with increased
hydration, an increased penetration of the active pharmaceutical
ingredient (i.e., halobetasol) and consequently an increased
efficacy.
[0074] Unexpectedly, the composition tested does not appear to be
acting as an occlusive since TEWL was not decreased and there was
no increase in skin hydration.
Example 3
Clinical Efficacy
[0075] A further experimental study evaluated the clinical efficacy
of the composition of the present invention having the formulation
of Table VI, described above, in the treatment of subjects with
plaque psoriasis.
[0076] Results
[0077] 52% of psoriasis subjects treated with the composition of
the present invention having the formulation described above, and
0.0% of subjects treated with an identical composition void of
halobetasol (Control Vehicle), achieved "treatment success".
Definitions
[0078] Overall Disease Severity (ODS): At every visit, the overall
severity of a subject's psoriasis in the Treatment Area, taking
into consideration the three individual clinical signs of psoriasis
(scaling, erythema, and plaque elevation) was assessed using a
five-point scale ranging from 0=clear to 4=severe/very severe. To
be enrolled in the study the subjects had to have at least a
moderate ODS score (.gtoreq.3).
TABLE-US-00007 Clear (0) Scaling No evidence of scaling. Erythema
No erythema (hyperpigmentation may be present). Plaque elevation No
evidence of plaque elevation above normal skin level.
TABLE-US-00008 Almost Clear (1) Scaling Limited amount of very fine
scales partially covers some of the plaques. Erythema Faint red
coloration. Plaque elevation Very slight elevation above normal
skin level, easier felt than seen.
TABLE-US-00009 Mild (2) Scaling Mainly fine scales; some plaques
are partially covered. Erythema Light red coloration. Plaque
elevation Slight but definite elevation above normal skin level,
typically with edges that are indistinct or sloped, on some of the
plaques.
TABLE-US-00010 Moderate (3) Scaling Somewhat coarser scales
predominate; most plaques are partially covered. Erythema Moderate
red coloration. Plaque elevation Moderate elevation with rounded or
sloped edges on most of the plaques.
TABLE-US-00011 Severe/Very Severe (4) Scaling Coarse, thick
tenacious scales predominate; virtually all or all plaques are
covered; rough surface. Erythema Dusky to deep red coloration.
Plaque elevation Marked to very marked elevation, with hard to very
hard sharp edges on virtually all or all of the plaques.
[0079] Clinical Signs of Plaque Psoriasis: At every visit, the
average severity of each of the three key characteristics of plaque
psoriasis (scaling, erythema and plaque elevation) in the Treatment
Area was assessed using a five-point scale ranging from 0=clear to
4=severe/very severe.
TABLE-US-00012 Scaling: 0 Clear No evidence of scaling. 1 Almost
clear Limited amount of very fine scales partially covers some of
the plaques. 2 Mild Mainly fine scales predominate; some plaques
are partially covered. 3 Moderate Somewhat coarser scales
predominate; most plaques are partially covered. 4 Severe/Very
Coarse, thick tenacious scales predominate; severe virtually all or
all plaques are covered; rough surface.
TABLE-US-00013 Erythema: 0 Clear No erythema (hyperpigmentation may
be present). 1 Almost clear Faint red coloration. 2 Mild Light red
coloration. 3 Moderate Moderate red coloration. 4 Severe/Very Dusky
to deep red coloration. severe
TABLE-US-00014 Plaque Elevation: 0 Clear No evidence of plaque
elevation above normal skin level. 1 Almost clear Very slight
elevation above normal skin level, easier felt than seen. 2 Mild
Slight but definite elevation above normal skin level, typically
with edges that are indistinct or sloped, on some of the plaques. 3
Moderate Moderate elevation with rounded or sloped edges on most of
the plaques. 4 Severe/Very Marked to very marked elevation, with
hard to severe very hard sharp edges on virtually all or all of the
plaques.
[0080] Pruritus: At every visit, the severity of pruritus was
scored on a six-point scale from 0=none to 5=severe according to
the following scale.
TABLE-US-00015 Pruritus 0 None No evidence of itching. 1 Mild Only
aware of itching at times, only present when relaxing, not present
when focused on other activities. 2 Mild to Moderate Intermediate
between 1 and 3. 3 Moderate Often aware of itching, annoying,
sometimes disturbs sleep and daytime activities. 4 Moderate to
Severe Intermediate between 3 and 5. 5 Severe Constant itching,
distressing; frequent sleep disturbance, interferes with
activities.
[0081] To be enrolled into the study, subjects had to have at least
moderate ODS score (at least 3). All ITT subjects satisfied that
requirement with at least 85% of each treatment group (HBP: 87% or
20/23; VEH: 85% or 17/20) having moderate ODS, with the remainder
of subjects having severe/very severe ODS
[0082] 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.
[0083] As illustrated in FIG. 1, the ODS score remained unchanged
(change=0) at Day 15 for the majority of vehicle group subjects
(18/20; 90%) with the remaining subjects experiencing, at most, a
one grade improvement. Only 21.7% (5/23) of the HBP subjects had no
change in ODS score at Day 15 with the remaining subjects having a
one to three grade decrease in score.
[0084] It was anticipated that a halobetasol cream would be more
efficacious than halobetasol foam because creams are determined to
be more occlusive. However, efficacy results for the composition
set forth in Table VI were materially better than those obtained in
the studies that supported Ultravate.RTM. Cream (halobetasol
propionate) approval by the FDA.
[0085] In fact, "treatment success" results for the composition set
forth in Table VI, were determined to be equal to or better than
those published for all other forms of Class 1 topical steroid
products containing halobetasol, fluocinonide and even what is
believed to be the most potent steroid: clobetasol propionate. (See
Table VII).
TABLE-US-00016 TABLE VII Treatment Success FDA Approved Class 1
Topical Corticosteroid Products (Study Drugs1-9) and the
Composition set forth in Table II herein (Study Drugs 10 and 11)
Treatment Success (or Improved) at 2 Weeks** Year Study Drug
Results Control Drug Results Approved 1 Ultravate .RTM. Cream 3/38
(7.9%) Vehicle 0/39 (0.0%) 1991 (halobetasol propionate) (Study 1)
2 Ultravate .RTM. Cream 7/40 (17.5%) Vehicle 0/40 (0.0%) 1991
(halobetasol propionate) (Study 2) 3 Temovate .RTM. E 12/51 (22%)
Vehicle 1/46 (2%) 1994 (clobetasol propionate) (Includes ITT
Cleared and Excellent) 4 Clobetasol propionate 30/82 (36.6%)
Temovate E 33/81 (40.7%) 2003 Lotion ITT (clobetasol propionate) 4
week study 5 Clobetasol propionate 27/76 (35.5%) Temovate E 32/75
(42.7%) 2003 Lotion PP (clobetasol propionate) 4 week study 6 Vanos
.RTM. (fluocinonide) 19/107 (18%) Vanos (fluocinonide) 33/107 (31%)
2005 QD ITT BID 7 Vanos .RTM. (fluocinonide) 18/90 (20%) Vanos
(fluocinonide) 31/97 (32%) 2005 QD PP BID 8 Olux .RTM. E Foam
41/253 (16%) Temovate Ointment 38/121 (31%) 2007 (clobetasol
propionate) (clobetasol propionate) ITT 9 Olux .RTM. E (clobetasol
39/234 (17%) Temovate Ointment 34/111 (31%) 2007 propionate) PP
(clobetasol propionate) 10 Present Invention 12/23 (52.2%) Vehicle
0/20 (0.0%) Currently In (halobetasol propionate) Development ITT
11 Present Invention 12/22 (54.5%) Vehicle 0/20 (0.0%) Currently In
(halobetasol propionate) Development PP **Note: Studies 4 and 5
show results collected after 4 weeks of treatment. All the rest
show results after only 2 weeks of treatment. BID = Twice per day;
ITT = Intent to Treat Population; PP = Per Protocol Population; QD
= Once per day
[0086] It should be noted that over the years the FDA has changed
the parameters defining clinical "success" and has progressively
elevated the efficacy standard for "treatment success". The results
obtained with the present halobetasol propionate foam composition
were unexpectedly strong. The Ultravate.RTM. Cream results as shown
in the first two rows of the Treatment Success Table VII were filed
with the FDA as a basis of the NDA approval. It should also be
noted that the results achieved with the halobetasol propionate
foam composition of the present invention are superior to those
achieved through the use of the Ultravate.RTM. Cream and are as
good as or better than any of the other Class 1 topical
corticosteroids.
[0087] Clobetasol propionate is generally believed to be a more
potent steroid molecule than halobetasol propionate. As shown in
Table VII, the results of a clinical trial that served as the basis
of the FDA approval of Olux.RTM. E Foam reported 16% of the
Olux.RTM. E Foam treated subjects and 31% of the Control subjects
receiving Temovate.RTM. Ointment (0.05% clobetasol propionate)
achieved "treatment success". Unexpectedly, inclusion of
halobetasol propionate (as opposed to clobetasol propionate) in a
foam formulation comparable to Olux.RTM. E Foam (which is not
produced as described herein) produced a "treatment success" in
52.2% of those patients treated as compared to 16% of those who had
been treated with Olux.RTM. E Foam.
[0088] The "treatment success" rate of 52% for the composition set
forth in Table VI is unexpected because the similar Olux.RTM. E
Foam formulation containing the more potent molecule (i.e.,
clobetasol propionate) only achieved a 16% rate. These results are
indeed unexpected given the relative potencies of halobetasol
propionate and clobetasol propionate. One would expect a comparable
composition including halobetasol (i.e., the formulation of Table
VI), which is considered less potent than clobetasol, to be less
efficacious than Olux.RTM. E Foam. These results show unexpected
beneficial therapeutic effects were achieved through use of the
composition of the present invention.
Example 4
Formulation Stability
[0089] A composition was prepared in accord with the present
invention utilizing the formulation of Table VI above. The
composition was filled into canisters that were charged with
propellant. The contents of the canister were analyzed by
high-performance liquid chromatography (HPLC) for halobetasol
propionate content and associated degradation products. The pH of
the canister contents was also measured. Additional canisters were
placed on stability at 25.degree..+-.2.degree. C. and 60%.+-.5%
relative humidity, the ICH long-term storage condition. Fresh
samples were analyzed after 1-, 3-, 6-, 9-, 12-, and 18-months of
storage.
[0090] The assay results were plotted against the storage duration
in months. The linear regression was determined for the assay data.
The 95% one-side lower confidence interval was determined for the
linear regression. The resulting predicted shelf-life was
unexpectedly greater than 36 months as shown in FIG. 3.
[0091] The degradant results were plotted against the storage
duration in months. The linear regression was determined for the
degradant data. The 95% one-side upper confidence interval was
determined for the linear regression. The resulting predicted
shelf-life was unexpectedly greater than 36 months as shown in FIG.
4.
[0092] Unexpectedly, no significant change and no trending were
observed with the pH data for the unbuffered formulation.
Therefore, no formal statistical analysis was performed on the pH
data in order to project the shelf-life. The pH data are shown in
FIG. 5.
[0093] Although the invention has been described with reference to
the above example, it will be understood that modifications and
variations are encompassed within the spirit and scope of the
invention. Accordingly, the invention is limited only by the
following claims.
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