U.S. patent application number 11/394848 was filed with the patent office on 2006-08-03 for corticosteroid-containing pharmaceutical composition.
This patent application is currently assigned to Connetics Australia Pty Ltd. Invention is credited to Anthony Richard Baker, Neil Graham Halls, Julie Irene Jones, Peter Marriott, Peter Watmough.
Application Number | 20060171898 11/394848 |
Document ID | / |
Family ID | 10770568 |
Filed Date | 2006-08-03 |
United States Patent
Application |
20060171898 |
Kind Code |
A1 |
Jones; Julie Irene ; et
al. |
August 3, 2006 |
Corticosteroid-containing pharmaceutical composition
Abstract
The present invention provides a foamable pharmaceutical
composition comprising a corticosteroid active substance, a
quick-break foaming agent, a propellant and a buffering agent. The
quick-break foaming agent typically comprises an aliphatic alcohol,
water, a fatty alcohol and surface active agent. The compositions
of the invention can be used to treat various skin disease, and in
particular scalp psoriasis.
Inventors: |
Jones; Julie Irene;
(Harpenden, GB) ; Baker; Anthony Richard; (West
Horsley, GB) ; Halls; Neil Graham; (Glen Waverley,
AU) ; Watmough; Peter; (Grimsby, GB) ;
Marriott; Peter; (Grimsby, GB) |
Correspondence
Address: |
TOWNSEND AND TOWNSEND AND CREW, LLP
TWO EMBARCADERO CENTER
EIGHTH FLOOR
SAN FRANCISCO
CA
94111-3834
US
|
Assignee: |
Connetics Australia Pty Ltd
Rowville
AU
|
Family ID: |
10770568 |
Appl. No.: |
11/394848 |
Filed: |
March 30, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10256754 |
Sep 27, 2002 |
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11394848 |
Mar 30, 2006 |
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09624473 |
Jul 24, 2000 |
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10256754 |
Sep 27, 2002 |
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08913144 |
Jan 12, 1998 |
6126920 |
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PCT/GB96/00490 |
Mar 1, 1996 |
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09624473 |
Jul 24, 2000 |
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Current U.S.
Class: |
424/45 ; 514/179;
514/724 |
Current CPC
Class: |
A61K 9/0014 20130101;
A61P 17/00 20180101; Y10S 514/945 20130101; A61P 17/06 20180101;
A61K 31/573 20130101; A61K 9/122 20130101; A61P 17/02 20180101;
A61P 17/08 20180101 |
Class at
Publication: |
424/045 ;
514/179; 514/724 |
International
Class: |
A61K 31/573 20060101
A61K031/573; A61L 9/04 20060101 A61L009/04; A61K 31/045 20060101
A61K031/045 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 3, 1995 |
GB |
9504265.1 |
Claims
1. A foamable pharmaceutical composition adapted for topical
administration, the composition comprising a corticosteroid, a
quick-break foaming agent, a propellant and an amount of a
buffering agent, wherein the composition has a pH within the range
of 3.0 to 6.0.
2. The foamable pharmaceutical composition according to claim 1
having a pH within the range of 4.0 to 5.0.
3. The foamable pharmaceutical composition according to claim 1,
wherein the buffering agent is present in an amount from 0.01 to
1.0% w/w.
4. The foamable pharmaceutical composition according to claim 3,
wherein the buffering agent is present in an amount in the range of
0.05 to 0.2% w/w.
5. A foamable pharmaceutical composition adapted for topical
administration, the composition comprising a corticosteroid, a
quick-break foaming agent, a propellant and an amount of a
buffering agent, selected from the group consisting of a citrate
buffer, an acetic acid/sodium acetate buffer and a phosphoric
acid/sodium phosphate buffer, wherein the composition has a pH
within the range of 3.0 to 6.0.
6. The foamable pharmaceutical composition according to claim 5,
wherein said citrate buffering agent is a citric acid/sodium
citrate buffer.
7. The foamable pharmaceutical composition according to claim 5,
wherein said citrate buffering agent is an anhydrous citric
acid/potassium citrate buffer.
8. The foamable pharmaceutical composition according to claim 1,
wherein the corticosteroid is a topically effective corticosteroid
selected from the group consisting of alclometasone dipropionate,
amcinonide, beclomethasone dipropionate, betamethasone benzoate,
betamethasone dipropionate, betamethasone valerate, budesonide,
clobetasol propionate, clobetasone butyrate, desonide,
desoxymethasone, diflorasone diacetate, diflucortolone valerate,
flumethasone pivalate, fluclorolone acetonide, fluocinolone
acetonide, fluocinonide, fluocortin butyl, fluocortolone,
fluprednidene acetate, flurandrenolone, halcinonide,
hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate,
methylprednisolone acetate, mometasone furoate, triamcinolone
acetonide, and pharmacologically effective mixtures thereof.
9. The foamable pharmaceutical composition according to claim 1,
wherein the corticosteroid is betamethasone or a pharmacologically
effective ester or salt thereof.
10. The foamable pharmaceutical composition according to claim 7,
wherein the corticosteroid is selected from betamethasone benzoate,
betamethasone dipropionate and betamethasone valerate.
11. The foamable pharmaceutical composition according to claim 8,
wherein the corticosteroid is betamethasone valerate.
12. The foamable pharmaceutical composition according to claim 1,
wherein the corticosteroid is present in an amount from 0.01 to
1.0% w/w.
13. The foamable pharmaceutical composition according to claim 12,
wherein the corticosteroid is present in an amount from 0.05 to
0.2% w/w.
14. The foamable pharmaceutical composition according to claim 1,
wherein the quick-break foaming agent comprises an aliphatic
alcohol, water, a fatty alcohol and a surface active agent.
15. The foamable pharmaceutical composition according to claim 14,
wherein the aliphatic alcohol is present in an amount corresponding
to 7 to 90% by weight of the total weight of the composition.
16. The foamable pharmaceutical composition according to claim 15,
wherein the aliphatic alcohol is present in an amount corresponding
to 55 to 70% by weight of the composition.
17. The foamable pharmaceutical composition according to claim 19,
wherein the aliphatic alcohol is present in an amount corresponding
to 57 to 59% by weight of the composition.
18. The foamable pharmaceutical composition according to claim 14,
wherein the aliphatic alcohol is selected from the group consisting
of methanol, ethanol, isopropyl alcohol, butyl alcohol, and
mixtures thereof.
19. The foamable pharmaceutical composition according to claim 18,
wherein the aliphatic alcohol is ethanol.
20. The foamable pharmaceutical composition according to claim 14,
wherein the water is present in an amount in the range of 10 to 40%
by weight of the composition.
21. The foamable pharmaceutical composition according to claim 14,
wherein the fatty alcohol is present in an amount corresponding to
0.5 to 10% by weight of the composition.
22. The foamable pharmaceutical composition according to claim 14,
wherein the fatty alcohol is selected from the group consisting of
cetyl, stearyl, lauryl, myristyl, and palmityl alcohols, and
mixtures thereof.
23. The foamable pharmaceutical composition according to claim 22,
wherein the fatty alcohol component is a mixture of cetyl alcohol
and a stearyl alcohol.
24. The foamable pharmaceutical composition according to claim 14,
wherein the surface active agent is present in an amount from 0.1
to 15% w/w of the composition.
25. The foamable pharmaceutical composition according to claim 14,
wherein the surface active agent is selected from the group
consisting of ethoxylated sorbitan stearate, ethoxylated sorbitan
palmitate, ethoxylated sorbitan oleate, nonyl phenol ethoxylates,
fatty alcohol ethoxylates, and mixtures thereof.
26. The foamable pharmaceutical composition according to claim 25,
wherein the surface active agent is a mixture of partial stearic
esters of sorbitol and its anhydrides, copolymerized with
approximately 20 moles of ethylene oxide for each mole of sorbitol
and its anhydrides.
27. A pharmaceutical product comprising the foamable pharmaceutical
composition of claim 1 contained within a container capable of
withstanding the pressure of the propellant and having a valve or
nozzle for dispensing the foamable composition as a foam under
pressure.
28. A foamable pharmaceutical composition adapted for topical
administration having the following composition: TABLE-US-00003 %
w/w Betamethasone Valerate 0.120 Cetyl Alcohol BP 1.100
Octadecan-1-ol BP 0.500 Polysorbate 60 BP 0.400 Ethanol 57.790
Purified Water 33.690 Propylene Glycol BP 2.000 Citric Acid
Anhydrous BP 0.073 Potassium Citrate 0.027 Butane/Propane 4.300
100.000.
Description
[0001] The present invention relates to an improved composition for
the topical application of corticosteroid active substances to the
skin of a subject.
[0002] Corticosteroids, particularly in the form of the ester
compounds, are used, inter alia, in the treatment of skin diseases
in humans, such as eczema, infantile eczema, atopic dermatitis,
dermatitis herpetiformis, contact dermatitis, seborrhoeic
dermatitis, neurodermatitis, psoriasis and intertrigo. Formulations
containing such active substances have conventionally been applied
to the skin site in the form of alcoholic solutions, lotions or
creams. However, there is a high degree of ineffectiveness with
such formulations. Lotions and creams are generally too viscous to
allow efficient penetration of the active to the epidermis, and
solutions have a tendency to evaporate before penetrating the
epidermis. In addition, conventional cream bases are irritating to
the skin, particularly over the often long exposure that is
required, and the fluidity of lotions often makes the physical
application difficult to control. Moreover, it is necessary to rub
such formulations into the target site to improve the penetration
of the active substance into the epidermis, an action which itself
produces irritation.
[0003] There has therefore been a very real need in the treatment
of skin disorders requiring treatment with corticosteroids for
improved formulations which target the most effective
corticosteroid to the skin site with improved delivery of active,
with decreased inconvenience and irritation, and increased ease of
use for the patient.
[0004] The present invention provides an improved composition which
addresses this need.
[0005] In one aspect, the present invention provides a foamable
pharmaceutical composition comprising a corticosteroid active
substance, a quick-break foaming agent, a propellant and a
buffering agent.
[0006] Such a composition is applied to the skin site (after
foaming) as a foam which is a thermophobic (heat sensitive)
quick-break foam. On application to the skin, the composition is
initially in the form of a mousse-like foam. The quick-break foam
slowly breaks down at the skin temperature to a liquid to allow the
alcohol and active substance to saturate the treatment site. Such a
system provides enhanced penetration of the alcohol and active
substance through the epidermis. Because the composition is
supplied as a mousse, the semi-rigid behaviour of the composite
makes it easier to handle and physically control. The foamed
composition, when applied, provides a thick ball of foam which
disintegrates easily when spread, allowing proper coverage of the
skin site to be treated without premature evaporation of the
solvent. It has been found important to include a buffering agent
in the composition to stabilize the active isomer of the
corticosteroid active substance in the complex foamable
composition, otherwise the complex interactions within the foamable
composition may result in the instability of the more active
isomer.
[0007] Use of a quick-break foaming agent is required in the
present invention. Such agents are known. Suitable quick-break
foaming agents in the present invention are those described in
Australian Patent No. 463216 and International Patent Application
WO 85/01876. It is generally preferred that the quick-breaking
foaming agent comprises an aliphatic alcohol, water, a fatty
alcohol and a surface active agent. Particularly preferred is a
quick-break foaming agent having the following composition: [0008]
(a) an aliphatic alcohol, preferably in amounts of 40-90% w/w
composition, more preferably 55-70% w/w, especially 57-59% w/w;
[0009] (b) water, preferably in amounts of 10-40% w/w; [0010] (c)
at least one fatty alcohol, preferably in amounts of 0.5-10% w/w;
and [0011] (d) a surface active agent, preferably an ethoxylated
sorbitan ester (as emulsifier), typically in amounts of 0.1-15%
w/w.
[0012] In the quick-break foaming agent, the fatty alcohol may be
chosen from, for example, cetyl, stearyl, lauryl, myristyl and
palmityl alcohols and mixtures of two or more thereof. Mixtures of
cetyl alcohol and a stearyl alcohol such as octadecan-1-ol have
been found to be particularly preferred; the ratio between these
two components may be adjusted to maintain foam viscosity
throughout the broadest possible temperature range. In this
situation, the stearyl alcohol maintains the viscosity at
temperatures above 20.degree. C. whilst cetyl alcohol maintains the
viscosity below 20.degree. C.
[0013] The aliphatic alcohol may preferably be chosen from methyl,
ethyl, isopropyl and butyl alcohols, and mixtures of two or more
thereof. Ethanol has been found to be particularly preferred.
[0014] Surface active agents utilised in the quick-break foaming
agent may preferably be chosen from ethoxylated sorbitan stearate,
palmitate, oleate, nonyl phenol ethoxylates and fatty alcohol
ethoxylates, and mixtures of two or more thereof. Thus, for
example, Polysorbate 60 (a mixture of partial stearic esters of
sorbitol and its anhydrides copolymerised with approximately 20
moles of ethylene oxide for each mole of sorbitol and its
anhydrides) has been found to be particularly preferred. The
surface active agent enhances the fatty alcohol solubility in the
system and enhances foam formation.
[0015] The propellant used may be chosen from conventional aerosol
propellants. Thus, one may select the propellant from propane,
butane, dichloro difluoro methane, dichloro tetrafluoro ethane,
octafluoro cyclobutane, and mixtures of two or more thereof. It is
necessary to select a propellant most compatible with the entire
system. It is particularly preferred that the propellant be present
in amounts preferably of 3-30% w/w, more preferably 3-10% w/w,
especially 3-5% w/w. The maximum level of propellant will be
determined as the amount miscible with the utilized water/aliphatic
alcohol ratio. In addition to acting as a propellant, the
propellant will also act as a solvent for the fatty acids and
active substances in the aqueous/alcoholic system.
[0016] It is possible that other additives may be used. Thus, it is
preferred to add a humectant to reduce the drying effects of the
aqueous aliphatic alcohol. Such a humectant may preferably be
present in an amount of 0.1-10.0% w/w, more preferably 0.5-3.0%
w/w. It is particularly preferred that the humectant be propylene
glycol, but other humectants such as glycerine, panthenol and
sorbitol may be used.
[0017] The composition of the present invention may be used to
deliver corticosteroid compounds which have utility in the topical
treatment of skin disorders. Thus, for example, the composition of
the present invention may be used to deliver the following
topically-effective corticosteroids: TABLE-US-00001 alclometasone
dipropionate fluclorolone acetonide amcinonide fluocinolone
acetonide beclamethasone dipropionate fluocinonide betamethasone
benzoate fluocortin butyl betamethasone dipropionate fluocortolone
preparations betamethasone valerate fluprednidene acetate
budesonide flurandrenolone clobetasol propionate halcinonide
clobetasone butyrate hydrocortisone desonide hydrocortisone acetate
desoxymethasone hydrocortisone butyrate diflorasone diacetate
mothylprednisolone acetate diflucortolone valerate mometasone
furoate flumethasone pivalate triamcinolone acetonide
and pharmacologically effective mixtures thereof.
[0018] Compositions according to the invention are especially
advantageous for the topical administration to the skin of human
subjects of betamethasone and its derivatives such as betamethasone
benzoate, betamethasone dipropionate, and betamethasone valerate.
It is particularly preferred to use the valerate ester, especially
in the treatment of psoriasis.
[0019] The corticosteroid active substance is preferably present in
an amount of 0.01-1.0% w/w more preferably 0.05-0.2% w/w.
[0020] In view of the complexity of the composition, it has been
found that unexpectedly in order to ensure stability of the active
isomer of the corticosteroid in the composition and thus to ensure
delivery of the most active isomer to the epidermis, it is
necessary to buffer the composition by including a suitable
buffering agent. Suitable buffering agents are acetic acid/sodium
acetate, citric acid/sodium citrate and phosphoric acid/sodium
phosphate, and it is desirable generally to buffer the composition
to pH 3.0-6.0, preferably 4.0-5.0 and to this end the buffering
agent may preferably be present in an amount of 0.01-1.0% w/w, more
preferably 0.05-0.2% w/w. It is particularly preferred to use a
citrate buffer system, more preferably anhydrous citric
acid/potassium citrate, to buffer the composition to pH 4.5, when
betamethasone valerate is used as the active substance; in this
case citrate buffering stabilises the more active 17-valerate ester
over the less active 21-valerate ester in the complex composition
and ensures that the most effective form of the active substance is
efficiently delivered to the epidermis.
[0021] Preparation of the composition may be effected by
conventional means so as to produce a homogeneous solution of fatty
alcohol(s) (wax[es]) in an alcohol/water base. The relative
proportions of the fatty alcohol(s), water/aliphatic alcohol and
propellant are conveniently controlled according to conventional
means so as to provide a homogeneous clear solution and so as to
provide a homogeneous clear solution and so as to allow the
formation of a suitable quick-break foam. Generally speaking the
fatty alcohol(s), surface active agent, aliphatic alcohol and
humectant (if present) are preferably mixed together with the
corticosteroid active substance to produce an "Alcohol Phase". An
"Aqueous Phase" is preferably produced by mixing the buffering
agent and water. These phases are then mixed, preferably in the
final container, in the required amounts. The propellant is then
added under pressure to produce the composition according to the
invention.
[0022] In the case of betamethasone valerate, for example, it is
particularly preferred to use a composition comprising cetyl
alcohol and octadecan-1-ol as fatty alcohols, together with
Polysorbate 60 surface active agent, with purified water and
ethanol as the aliphatic alcohol. The system is preferably buffered
with anhydrous citric acid/potassium citrate and the propellant is
preferably butane/propane. It is generally preferred to choose the
proportion of the components to achieve a fixed pressure in the
container of around 50-70 psi.
[0023] 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/nozzle for
dispensing the composition as a foam under pressure. If the
container is made of a metal material likely to suffer corrosion
under the action of the composition, the composition may include a
corrosion inhibitor as an additive. Thus, the presence of a
corrosion inhibitor may be necessary if the container is made of
tin plate. Suitable corrosion inhibitors include organic acid
salts, preferably chosen from sorbic acid, benzoic acid, sodium
benzoate and potassium sorbate. If used, the corrosion inhibitor
may be present in amounts of 0.1-15% w/w, more preferably 0.1-3%
w/w. In the present invention, aluminium cans are preferred as
containers, particularly when utilising the above-mentioned
composition for betamethasone valerate as the corticosteroid active
substance; in this case there is no corrosion problem and there is
no need for the inclusion of a corrosion inhibiting agent.
[0024] In use, the composition is sprayed, producing a semi-solid
form (a foam or mousse) which is suitable for the topical
application to the site of interest, eg the scalp when treating
dermatological conditions of the scalp. On application, heat from
the skin causes the mousse to break down into liquid form, thus
releasing the aliphatic alcohol and corticosteroid active substance
which penetrate the skin site, leaving a low amount of residue,
many times lower than those obtained when delivering active from a
cream base. This route of administration facilitates the ease of
specific local application, and the composition according to the
invention provides a convenient, controllable and efficient vehicle
for delivering topically active corticosteroids to the skin. This
gives greater physical control compared to conventional topical
corticosteroid formulations, minimises rubbing of the target site
and allows the alcoholic vehicle to penetrate the skin to deliver
the active to where it will have the greatest effect.
[0025] The composition of the present invention may be used in
treating skin diseases which are conventionally treated with
corticosteroid active substances. Thus, the composition may be used
in the treatment of, inter alia, eczema, infantile eczema, atopic
dermatitis, dermatitis herpetiformis, contact dermatitis,
seborrhoeic dermatitis, neurodermatitis, psoriasis and intertrigo.
The composition is especially useful in the treatment of scalp
psoriasis in human subjects.
[0026] The present invention will now be illustrated by means of
the following non-limiting Example:
EXAMPLE
Betamethasone Valerate Composition
[0027] A betamethasone valerate formulation having the following
composition was prepared: TABLE-US-00002 % w/w Betamethasone
Valerate 0.12 Cetyl Alcohol BP 1.10 Octadecan-1-ol BP 0.50
Polysorbate 60 BP 0.40 Ethanol 57.79 Purified Water 33.69 Propylene
Glycol BP 2.00 Citric Acid Anhydrous B.P 0.073 Potassium Citrate
0.027 Butane/Propane 4.30 100.00
[0028] Cetyl alcohol (HYFATOL 1698, Efkay Chemicals Limited,
London), octadecan-1-ol (HYFATOL 1898, Efkay Chemicals Limited,
London), Polysorbate 60 (CRILLET 3, Croda Chemicals, North
Humberside) and ethanol in the correct proportions were mixed and
heated to about 45.degree. C., with continuous stirring until the
mix became clear. Betamethasone valerate BP (Roussel Uclaf,
Virtolaye, France) was slowly transferred into the mix, again with
continuous stirring until the mix became clear. (Alcoholic
Phase)
[0029] Purified water was separately heated to 45.degree. C. and
anhydrous citric acid BP and potassium citrate BP transferred to
the water, with continuous stirring until dissolved. (Aqueous
Phase)
[0030] The Alcoholic and Aqueous phases were each filtered through
75 micron screens and the required weights filled into a can
(aluminium, epoxy lined) at room temperature. After attaching a
valve, the butane/propane propellant (Propellant P70) was added to
the mix in the can to the required weight, and an actuator added to
the valve.
[0031] The composition, on being sprayed from the can onto the
skin, produces a thermophobic foam which breaks down under heating
from the skin to release the active to the epidermis. The presence
of the citrate buffer stabilizes the 17-valerate configuration of
the betamethasone valerate over the less active 21-valerate
configuration, thus producing a composition which efficaciously
delivers active to the epidermis and which is particularly suitable
for the treatment of psoriasis, especially scalp psoriasis.
* * * * *