U.S. patent application number 14/084172 was filed with the patent office on 2014-03-20 for methods and compositions for treating or preventing erythema.
This patent application is currently assigned to GALDERMA LABORATORIES INC.. The applicant listed for this patent is GALDERMA LABORATORIES INC.. Invention is credited to Isabelle Jean DEJOVIN, Jack A. DEJOVIN, Philip FREIDENREICH, Michael GRAEBER, Matthew James LEONI, Yin-sang LIU, Christian LOESCHE.
Application Number | 20140080836 14/084172 |
Document ID | / |
Family ID | 44972985 |
Filed Date | 2014-03-20 |
United States Patent
Application |
20140080836 |
Kind Code |
A1 |
GRAEBER; Michael ; et
al. |
March 20, 2014 |
METHODS AND COMPOSITIONS FOR TREATING OR PREVENTING ERYTHEMA
Abstract
Methods and products for treating or preventing erythema or a
symptom associated with erythema in a subject are described. The
methods involve topically applying to an affected skin area a
topical aqueous gel composition comprising about 0.01% to about 10%
by weight of at least one .alpha.-adrenergic receptor agonist and a
pharmaceutically acceptable carrier.
Inventors: |
GRAEBER; Michael;
(Lawrenceville, NJ) ; LOESCHE; Christian;
(Valbonne, FR) ; FREIDENREICH; Philip; (Yardley,
PA) ; DEJOVIN; Jack A.; (New Brunswick, NJ) ;
DEJOVIN; Isabelle Jean; (New Brunswick, NJ) ; LIU;
Yin-sang; (Princeton Junction, NJ) ; LEONI; Matthew
James; (Hampton, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
GALDERMA LABORATORIES INC. |
Fort Worth |
TX |
US |
|
|
Assignee: |
GALDERMA LABORATORIES INC.
Fort Worth
TX
|
Family ID: |
44972985 |
Appl. No.: |
14/084172 |
Filed: |
November 19, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13791059 |
Mar 8, 2013 |
8586586 |
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14084172 |
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13072104 |
Mar 25, 2011 |
8410102 |
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13791059 |
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12544663 |
Aug 20, 2009 |
8231885 |
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13072104 |
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11449079 |
Jun 8, 2006 |
7838563 |
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12544663 |
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10853585 |
May 25, 2004 |
7439241 |
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11449079 |
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60473611 |
May 27, 2003 |
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61282754 |
Mar 26, 2010 |
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Current U.S.
Class: |
514/249 ;
514/401; 514/626; 514/653; 514/654 |
Current CPC
Class: |
A61K 31/00 20130101;
A61K 31/165 20130101; A61K 31/498 20130101; A61K 9/06 20130101;
A61K 47/38 20130101; A61K 31/137 20130101; A61K 45/06 20130101;
A61K 31/498 20130101; A61K 47/32 20130101; A61K 31/4164 20130101;
A61K 31/137 20130101; A61K 31/4174 20130101; A61P 17/00 20180101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 9/0014 20130101;
A61K 31/4164 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/249 ;
514/401; 514/653; 514/654; 514/626 |
International
Class: |
A61K 9/06 20060101
A61K009/06; A61K 31/4174 20060101 A61K031/4174; A61K 45/06 20060101
A61K045/06; A61K 47/32 20060101 A61K047/32; A61K 31/165 20060101
A61K031/165; A61K 31/498 20060101 A61K031/498; A61K 31/137 20060101
A61K031/137 |
Claims
1. A method of treating erythema or a symptom associated therewith
in a subject, the method comprising topically administering to a
skin area of the subject a topical composition comprising about
0.01% to about 10% by weight of at least one alpha adrenergic
receptor agonist and a pharmaceutically acceptable carrier, wherein
the skin area is, or is prone to be, affected by the erythema or
the symptom associated therewith.
2. The method of claim 1, wherein the topical composition is
selected from the group consisting of an aqueous solution topical
formulation, cream topical formulation, and ointment
formulation.
3. The method of claim 1, wherein the erythema is erythema of
rosacea.
4. The method of claim 1, wherein the at least one alpha-adrenergic
receptor agonist is an agonist selective for an alpha 1-adrenergic
receptor.
5. The method of claim 1, wherein the at least one alpha-adrenergic
receptor agonist is an agonist selective for an alpha 2-adrenergic
receptor.
6. The method of claim 1, wherein the at least one alpha-adrenergic
receptor agonist is a non-selective alpha-adrenergic receptor
agonist.
7. The method of claim 1, wherein the at least one alpha-adrenergic
receptor agonist is brimonidine.
8. The method of claim 1, wherein the at least one alpha-adrenergic
receptor agonist is oxymetazoline.
9. The method of claim 1, wherein the at least one alpha-adrenergic
receptor agonist is naphazoline.
10. The method of claim 1, wherein the at least one
alpha-adrenergic receptor agonist is selected from the group
consisting of tetrahydrozoline, xylometazoline, phenylephrine,
methoxamine, mephentermine, metaraminol, midodrine, epinephrine and
norepinephrine.
11. The method of claim 1, further comprising administering to the
subject at least one additional treatment and medication for
erythema or the symptom associated therewith.
12. The method of claim 1, wherein the topical aqueous gel
composition is administered to the skin area once daily.
13. The method of claim 1, wherein the topical composition
comprises about 0.6%-3% by weight of the at least one alpha
adrenergic receptor agonist.
14. The method of claim 1, wherein the topical composition
comprises about 0.05%-1% by weight of the at least one alpha
adrenergic receptor agonist.
15. The method of claim 1, wherein the topical composition
comprises about 0.3%-0.6% by weight of the at least one alpha
adrenergic receptor agonist.
16. The method of claim 1, wherein the topical composition
comprises about 0.4%-0.6% by weight of the at least one alpha
adrenergic receptor agonist.
17. The method of claim 1, wherein the topical composition
comprises about 0.5% by weight of the at least one alpha adrenergic
receptor agonist.
18. The method of claim 1, wherein the topical administration of
the topical composition to the skin area results in significantly
more reduction of the erythema and the symptom compared to a
vehicle control as measured by a 12 hour success profile evaluated
on both CEA and PSA scales, without causing any unacceptable
adverse effect, wherein the 12 hour success profile comprises a
noticeable effect of 1-grade improvement of the erythema or the
symptom and about 1 hour to about 8 hours of 2-grade improvement of
the erythema or the symptom.
19. A method of treating erythema or a symptom associated therewith
in a subject, the method comprising topically administering to a
skin area of the subject a topical composition comprising about 0.4
(w/w) to about 0.6% (w/w) brimonidine tartrate and about 0.8% (w/w)
to about 1.5% (w/w) carbomer and a pharmaceutically acceptable
carrier, wherein the skin area is, or is prone to be, affected by
the erythema or the symptom associated therewith.
20. The method of claim 19, wherein the erythema is facial erythema
associated with rosacea, and the topical administration of the
topical aqueous gel composition to the skin area results in
significantly more reduction of the facial erythema compared to a
vehicle control as measured by a 12 hour success profile evaluated
on both CEA and PSA scales, without causing any unacceptable
adverse effect, wherein the 12 hour success profile comprises a
noticeable effect of 1-grade improvement of the facial erythema and
about 3 hours to about 6 hours of 2-grade improvement of the facial
erythema.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation of U.S. patent
application Ser. No. 13/791,059, filed Mar. 8, 2013, which is a
continuation of U.S. patent application Ser. No. 13/072,104, filed
Mar. 25, 2011, which is a continuation-in-part of U.S. patent
application Ser. No. 12/544,663, filed Aug. 20, 2009, issued as
U.S. Pat. No. 8,231,885 on Jul. 31, 2012, which is a
continuation-in-part of U.S. patent application Ser. No. 11/449,079
filed Jun. 8, 2006, issued as U.S. Pat. No. 7,838,563 on Nov. 23,
2010, which is a continuation-in-part of U.S. patent application
Ser. No. 10/853,585 filed May 25, 2004, issued as U.S. Pat. No.
7,439,241 on Oct. 21, 2008, which claims priority to U.S.
Provisional Patent Application No. 60/473,611, filed May 27, 2003.
U.S. patent application Ser. No. 13/072,104 is also entitled to
priority pursuant to 35 U.S.C. .sctn.119(e) to U.S. Provisional
Patent Application No. 61/282,754, filed Mar. 26, 2010. The
contents of all of these applications are hereby incorporated by
reference in their entireties.
BACKGROUND OF THE INVENTION
[0002] Erythema is a skin condition characterized by redness or
rash of the skin. It occurs with any skin injury, infection, or
inflammation. It can also occur as a reaction to medications,
illness or emotions. It can further occur for reasons currently
unknown. Erythema is difficult to treat. Currently available
treatments for erythema mainly treat the underlying diseases and
avoid known triggers. These treatments are of limited
effectiveness, particularly for erythema with unknown causes.
[0003] It has been described that a adrenoceptor agonists, such as
brimonidine and oxymetazoline, can be used for topical treatment of
erythema. See U.S. Pat. No. 7,439,241 to DeJovin et al., the
priority of which is properly claimed by the present application
and the disclosure of which is hereby incorporated by reference in
its entirety; and U.S. Pat. No. 7,812,049 to Shanler et al.
[0004] Side effects following topical administration of an .alpha.
adrenoceptor agonist, particularly those resulting from systemic
exposure, may impose limitations on the chronic topical application
of a adrenoceptor agonists to the skin. For example, brimonidine,
available as either a monotherapy or an adjunctive therapy to lower
intraocular pressure (IOP) in the treatment of glaucoma and ocular
hypertension (OHT), can be absorbed systemically to a limited
extent following ophthalmic application as demonstrated by
reduction in blood pressure and decrease in heart rate. The most
common side effects associated with brimonidine therapy are dry
mouth, fatigue/drowsiness, headache, mild hyperemia, blurred vision
and foreign body sensation. Hypertension, palpitations and syncope
have been reported by less than 3% patients in clinical trials
involving brimonidine ophthalmic treatment. See McGhie, Journal of
the Pharmacy Society of Wisconsin, May/June 2001, at World Wide
Web: pswi.org/professional/pharmaco/brimonidine.pdf, and references
therein. Results from the dose-ranging study in patients with
glaucoma or ocular hypertension showed that although 0.5% (w/w) had
higher efficacy in the early phase of treatment, the 0.5% (w/w) and
0.2% (w/w) had similar efficacy after two weeks of treatment, and
that 0.5% (w/w) had more systemic and ocular side effects than 0.2%
(w/w). See, e.g., Walters, Survey of Ophthalmology, 1996, 41:
S19-S26). Ophthalmic formulations containing 0.2% (w/w) brimonidine
have been used for chronic applications to treat glaucoma and
ocular hypertension, while that containing 0.5% (w/w) brimonidine
has been only used for acute therapy for the prevention of
postoperative intraocular pressure spikes. In order to reduce a
variety of ocular and systemic side-effects associated with the
ophthalmic application of 0.2% (w/w) brimonidine, ophthalmic
formulations containing lower concentrations of brimonidine, e.g.,
0.15% (w/w) or 0.1% (w/w), have been subsequently developed and
used for chronic ophthalmic applications.
[0005] DeJovin et al. recognizes the need of a topical skin
composition that insures that the a adrenoceptor agonists are
effective in the skin of a patient but do not penetrate the skin in
sufficient amounts to induce serious systemic side effects. It
describes topical formulations containing an a adrenoceptor agonist
at about 0.01% (w/w) to about 5% (w/w), preferably about 0.05%
(w/w) to about 1% (w/w), more preferably about 0.1% (w/w) to about
0.2% (w/w), for treating erythema associated with rosacea. It
provides examples on various possible topical formulations that can
be used for topical administration of a adrenoceptor agonists,
e.g., aqueous solution topical formulation, cream topical
formulation, ointment formulation, and aqueous gel formulations.
DeJovin et al. also includes examples demonstrating the therapeutic
effectiveness of a adrenoceptor agonists, such as brimonidine,
oxymetazoline and naphazoline, in treating erythema. However, it
contains no example or illustration on the safety of the
treatment.
[0006] To ensure the safety and avoid unacceptable side effects, a
previous clinical study used 0.2% (w/w) brimonidine tartrate as the
"high" dosage for treating erythema. See US 2009/0061020 to
Theobald et al.
[0007] Oxymetazoline, available in 0.025% (w/w) or 0.05% (w/w)
solution as a topical decongestant, has been recommended not to be
used for more than three days, because rebound congestion, rhinitis
medicamentosa, and other side effects may occur, see Ramey et al.,
J Investig Allergol Clin Immunol 2006; Vol. 16(3): 148-155.
[0008] Shanler et al. describes the use of a composition comprising
about 0.05% (w/w) to about 30% (w/w), preferably about 0.001% (w/w)
up to about 3% (w/w), .alpha.1 adrenoceptor agonist, such as
oxymetazoline, for treating erythema resulting from rosacea. It
generally describes that the "compositions according to the
invention may comprise all pharmaceutical forms normally utilized
for the topical route of administration and known to practitioners
of this art including solutions, gels, lotions creams, ointments,
foams, mousses, emulsions, microemulsions, milks, serums, aerosols,
sprays, dispersions, microcapsules, vesicles and microparticles
thereof." Shanler et al. does not provide examples on possible
formulations that may be used, nor examples on the effectiveness or
safety of any treatment.
[0009] There remains the need of a safe and effective treatment of
erythema or a related symptom by using a topical skin composition
that delivers a therapeutically effective amount of a adrenoceptor
agonist to the affected skin area without causing unacceptable side
effects.
[0010] In the present invention, it has been discovered that
topical administration to an affected skin area an .alpha.
adrenoceptor agonist, such as brimonidine, in a topical aqueous gel
composition resulted in significantly less systemic exposure than
topical ophthalmic application. It has been found that although
systemic exposure increased with the applied dose of brimonidine,
statistical analysis showed that the increase in systemic exposure
(C.sub.max) was not dose proportional, i.e., the increase in the
mean C.sub.max was much less than the increase in the dose. It has
also been discovered that, unlike the topical ophthalmic
application, topical administration to an affected skin area a
higher concentration of an .alpha. adrenoceptor agonist, such as
0.5% (w/w) brimonidine, in a topical aqueous gel composition
resulted in increased efficacy without observable loss of
effectiveness over time. No unacceptable adverse event was observed
with the treatment of higher concentration of an .alpha.-adrenergic
receptor agonist tested.
[0011] Accordingly, it has unexpectedly been discovered that a
topical aqueous gel composition has achieved superior clinical
properties, e.g., allowing more effective treatment of erythema
without causing unacceptable side effect, even at higher
concentrations of the .alpha. adrenoceptor agonist.
BRIEF SUMMARY OF THE INVENTION
[0012] In one general aspect, embodiments of the present invention
relate to a method of treating or preventing erythema or a symptom
associated therewith in a subject, the method comprising topically
administering to a skin area of the subject a topical aqueous gel
composition comprising about 0.01% (w/w) to 10% (w/w) of at least
one a adrenergic receptor agonist and a pharmaceutically acceptable
carrier, wherein the skin area is, or is prone to be, affected by
the erythema or the symptom associated therewith.
[0013] In another general aspect, embodiments of the present
invention relate to a method of producing a packaged product for
providing a safe and effective treatment of erythema or a symptom
associated therewith in a subject. The method comprises:
[0014] (1) obtaining a topical aqueous gel composition comprising
about 0.01% (w/w) to about 10% (w/w) of at least one a adrenergic
receptor agonist and a pharmaceutically acceptable carrier;
[0015] (2) devising instructions for topically administering the
topical aqueous gel composition to a skin area that is, or is prone
to be, affected by the erythema or the symptom associated therewith
to obtain the safe and effective treatment, and
[0016] (3) providing the topical aqueous gel composition and the
instructions in a unified package.
[0017] In another general aspect, embodiments of the present
invention relate to a topical aqueous gel composition for providing
a safe and effective treatment of erythema or a symptom associated
therewith in a subject, comprising about 0.4 (w/w) to about 0.6%
(w/w) brimonidine tartrate and about 0.8% to 1.5% carbomer.
[0018] In a preferred embodiment, the .alpha. adrenergic receptor
agonist used in or encompassed by embodiments of the present
invention is selected from the group consisting of brimonidine,
oxymetazoline and naphazoline.
[0019] In another preferred embodiment, the topical aqueous gel
composition used in or encompassed by embodiments of the present
invention comprises about 0.4% (w/w) to about 0.6% (w/w)
brimonidine tartrate.
[0020] In yet another preferred embodiment, the erythema is
erythema of rosacea.
[0021] Other aspects, features and advantages of the invention will
be apparent from the following disclosure, including the detailed
description of the invention and its preferred embodiments and the
appended claims.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
[0022] The foregoing summary, as well as the following detailed
description of the invention, will be better understood when read
in conjunction with the appended drawings. For the purpose of
illustrating the invention, there are shown in the drawings
embodiments which are presently preferred. It should be understood,
however, that the invention is not limited by the drawings.
[0023] In the drawings:
[0024] FIG. 1 illustrates composite success on Day 1, Day 15 and
Day 29 after the initial treatment, using last observation carried
forward (LOCF) approach in the intent to treat (ITT)
population;
[0025] FIG. 2 illustrates CEA success on Day 1, Day 15 and Day 29
after the initial treatment, using LOCF approach in the ITT
population; and
[0026] FIG. 3 illustrates PSA-5 success on Day 1, Day 15 and Day 29
after the initial treatment using LOCF approach in the ITT
population.
DETAILED DESCRIPTION OF THE INVENTION
[0027] Various publications, articles and patents are cited or
described in the background and throughout the specification, each
of these references is herein incorporated by reference in its
entirety. Discussion of documents, acts, materials, devices,
articles or the like which have been included in the present
specification is for the purpose of providing context for the
present invention. Such discussion is not an admission that any or
all of these matters form part of the prior art with respect to any
inventions disclosed or claimed.
[0028] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood to one of
ordinary skill in the art to which this invention pertains.
Otherwise, certain terms used herein have the meanings as set in
the specification. All patents, published patent applications and
publications cited herein are incorporated by reference as if set
forth fully herein. It must be noted that as used herein and in the
appended claims, the singular forms "a," "an," and "the" include
plural reference unless the context clearly dictates otherwise.
[0029] As used herein, "erythema or a symptom associated therewith"
is intended to encompass any type or classification of abnormal
skin redness associated with or resulting from rosacea, e.g.,
erythema or a symptom associated therewith in a patient with
rosacea. A major symptom of rosacea is erythema, which is a skin
disorder that generally affects the cheeks, nose, chin, and
forehead of a patient.
[0030] The term "erythema or a symptom associated therewith"
encompasses different degrees or grades of erythema or a symptom
associated therewith, from mild to severe.
[0031] For example, erythema or a symptom associated therewith can
be rated by a clinician based on Clinician's Erythema Assessment
Score (CEA) on a scale from 0 to 4, with 0 being clear skin with no
signs of erythema; 1 being almost clear, slight redness; 2 being
mild erythema, definite redness; 3 being moderate redness; and 4
being severe redness.
[0032] Erythema or a symptom associated therewith can also be rated
by a patient based on Patient's Self Assessment (PSA, also called
PSA-5 herein) on a scale from 0 to 4, with 0 being no redness; 1
being very mild redness; 2 being mild redness; 3 being moderate
redness and 4 being severe redness.
[0033] In view of the present disclosure, a skin area that is
affected by erythema or that is prone to be affected by erythema
can be identified using any diagnostic signs or means known in the
art, and can be treated by methods according to embodiments of the
present invention.
[0034] The efficacy of the treatment can be measured using method
known in the art. For example, the efficacy can be measured by the
grades of improvement as evaluated by CEA, PSA or the combination
of CEA and PSA, and the duration of the improvement.
[0035] .alpha.-adrenergic receptor agonists of the present
teachings include any .alpha.-adrenergic receptor agonist known to
skilled artisans. In some aspects, an .alpha.-adrenergic receptor
agonist can be an .alpha.-adrenergic receptor agonist selective for
.alpha.1-adrenergic receptors, an .alpha.-adrenergic receptor
agonist selective for .alpha.2-adrenergic receptors, or an
.alpha.-adrenergic receptor agonist non-selective for either
.alpha.1 or .alpha.2-adrenergic receptors.
[0036] As used herein, a selective .alpha.1-adrenergic receptor
agonist is an agonist for which the EC.sub.50 with respect to an
.alpha.1-adrenergic receptor is less than the EC.sub.50 with
respect to an .alpha.2-adrenergic receptor, while a selective
.alpha.2-adrenergic receptor agonist is an agonist for which the
EC.sub.50 with respect to an .alpha.2-adrenergic receptor is less
than the EC.sub.50 with respect to an .alpha.1-adrenergic receptor,
wherein the EC.sub.50 for an agonist is defined as the molar
concentration of the agonist which produces 50% of the maximum
possible response of a receptor to that agonist.
[0037] Some non-limiting examples of .alpha.-adrenergic receptor
agonists which can be used in the present compositions and methods
include: amphetamine, apraclonidine, brimonidine, clonidine,
clonidine, dexmedetomidine, dextroamphetamine, dopamine,
I-dobutamine, ephedrine, epinephrine, epinine (N-methyl-dopamine),
ethylnorepinephrine, guanabenz, guanfacine, levarterenol,
lofexidine, mephentermine, metaraminol, methamphetamine,
methoxamine, .alpha.-methyldopa, .alpha.-methylnorepinephrine,
methylphenidate, mivazerol, mitodrine, moxonidine, naphazoline,
norepinephrine, norphenylephrine, oxymetazoline,
pemolinepropylhexedrine, phenylephrine, phenylpropanolamine,
propylhexedrine, tetrahydrozoline, tizanidine, xylometazoline,
(8-bromo-quinoxalin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine,
(8-bromo-quinoxalin-5-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine,
(5-bromo-3-methyl-quinoxalin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine,
(5-bromo-2-methoxy-quinoxalin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine,
(4,5-dihydro-1H-imidazol-2-yl)-(8-methyl-quinoxalin-6-yl)-amine,
and (4,5-dihydro-1H-imidazol-2-yl)-quinoxalin-5-yl-amine.
[0038] Compositions of the present teachings include one or more
.alpha.-adrenergic receptor agonists, prodrugs thereof,
pharmaceutically acceptable salts thereof, hydrates thereof,
solvates thereof and combinations thereof, such as those described
in U.S. Pat. No. 7,439,241, which are incorporated herein by
reference.
[0039] As used herein, the term "brimonidine" refers to the
compound
(5-bromo-quinoxalin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine
having the structure of formula (I):
##STR00001##
and any pharmaceutically acceptable salt of the compound,
including, but not limited to, brimonidine tartrate.
[0040] The phrase "pharmaceutically acceptable salt(s)", as used
herein, means those salts of a compound of interest that are safe
and effective for topical use in mammals and that possess the
desired biological activity. Pharmaceutically acceptable salts
include salts of acidic or basic groups present in the specified
compounds. Pharmaceutically acceptable acid addition salts include,
but are not limited to, hydrochloride, hydrobromide, hydroiodide,
nitrate, sulfate, bisulfate, phosphate, acid phosphate,
isonicotinate, acetate, lactate, salicylate, citrate, tartrate,
pantothenate, bitartrate, ascorbate, succinate, maleate,
gentisinate, fumarate, gluconate, glucaronate, saccharate, formate,
benzoate, glutamate, methanesulfonate, ethanesulfonate,
benzensulfonate, p-toluenesulfonate and pamoate (i.e.,
1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Certain
compounds used in the present invention can form pharmaceutically
acceptable salts with various amino acids. Suitable base salts
include, but are not limited to, aluminum, calcium, lithium,
magnesium, potassium, sodium, zinc, and diethanolamine salts. For a
review on pharmaceutically acceptable salts see BERGE ET AL., 66 J.
PHARM. SCI. 1-19 (1977), incorporated herein by reference.
[0041] The term "topical aqueous gel composition," as used herein,
means any aqueous gel formulation or composition which is
pharmaceutically and/or cosmetically acceptable for topical
delivery of the specified compounds according to embodiments of the
invention.
[0042] As used herein, the term "composition" is intended to
encompass a product comprising the specified ingredient in the
specified amount, as well as any product which results, directly or
indirectly, from combinations of the specified ingredient in the
specified amount.
[0043] As used herein, the term "subject" means any animal,
preferably a mammal, most preferably a human, to whom will be or
has been administered compounds or topical formulations according
to embodiments of the invention. Preferably, a subject is in need
of, or has been the object of observation or experiment of,
treatment or prevention of erythema or a symptom associated
therewith.
[0044] As used herein, the term "instructions" when used in the
context of a packaged product includes a publication, a recording,
a diagram or any other medium of expression which can be used to
communicate the usefulness of the packaged product for its
designated use. The instructions can, for example, be affixed to or
included within a container for the packaged product.
[0045] As used herein, the term "treatment" or "treating" refers to
an amelioration, prophylaxis, or reversal of erythema or a symptom
associated therewith, for example, by lessening or delaying the
onset of the redness of the skin affected by the erythema or the
symptom.
[0046] As used herein, a "safe and effective amount" means the
amount of an .alpha.-adrenergic receptor agonist that is effective
to treat erythema or a symptom associated therewith, without
causing unacceptable drug related adverse events, when administered
to a subject.
[0047] As used herein, the phrase "unacceptable drug related
adverse events," "unacceptable adverse drug events," and
"unacceptable adverse drug reaction," shall all mean harm or
undesired outcome associated with or caused by a proposed use of a
drug, and the harm or undesired outcome reaches such a severity
that a regulatory agency deems the drug unacceptable for the
proposed use.
[0048] It has been discovered in the present invention that topical
administration of a topical aqueous gel composition comprising
about 0.01% to about 10% by weight of an .alpha.-adrenergic
receptor agonist, such as brimonidine, to a skin area affected by
erythema or a symptom associated therewith, provides effective
treatment of erythema or a symptom associated therewith, without
causing unacceptable drug related adverse events. For example, it
has been discovered that topical administration to a skin area
affected by erythema or a symptom associated therewith with a
topical aqueous gel composition comprising increasing concentration
of an .alpha.-adrenergic receptor agonist, such as brimonidine,
resulted in a clear dosage responsive increase in the efficacy and
an increase in the systemic exposure. However, statistical analysis
showed that the increase in systemic exposure (C.sub.max) was not
dose proportional, e.g., the increase in mean C.sub.max was much
less than the increase in dose. It has also been discovered that,
unlike the topical ophthalmic application, topical administration
to an affected skin area a higher concentration of an .alpha.
adrenoceptor agonist, such as 0.5% (w/w) brimonidine, in a topical
aqueous gel composition resulted in increased efficacy without
observable loss of efficacy over time. No unacceptable adverse
event was observed with the treatment of higher concentrations of
an .alpha.-adrenergic receptor agonist tested. Topical skin
treatments of erythema or a symptom associated therewith with all
concentrations and regimens tested resulted in significantly lower
systemic exposure to brimonidine than the treatment with eye drops
applied as recommended in the label of the ophthalmic products.
[0049] Such superior clinical activities of the topical aqueous gel
composition comprising about 0.01% to about 10% by weight of an
.alpha.-adrenergic receptor agonist have not been previously
reported. The present discovery is surprising and unexpected,
particularly in view of the previously reported efficacy and safety
profiles of .alpha.-adrenergic receptor agonists in other
applications, such as brimonidine in ophthalmic applications, where
a significant loss of effectiveness over time was seen with the
brimonidine 0.5% (w/w) formulation and the chronic use of much
lower concentrations of brimonidine, e.g., 0.1% or 0.15% by weight,
is preferred, because the lower concentrations provide improved
tolerability while maintaining IOP-lowering efficacy.
[0050] Accordingly, in one general aspect, embodiments of the
present invention relate to a method of treating or preventing
erythema or a symptom associated therewith in a subject. The method
comprising topically administering to a skin area of the subject a
topical aqueous gel composition comprising about 0.01% (w/w) to
about 10% (w/w) of at least one cc adrenergic receptor agonist and
a pharmaceutically acceptable carrier, wherein the skin area is, or
is prone to be, affected by the erythema or the symptom associated
therewith.
[0051] According to an embodiment of the present invention, the
topical administration of the topical aqueous gel composition
comprising a safe and effective amount of brimonidine, such as
about 0.01% (w/w) to about 10% (w/w) brimonidine, to an affected
skin area effects a serum or plasma profile of brimonidine having a
mean C.sub.max of about 54.+-.28 pg/mL or less and a mean
AUC.sub.0-24hr of about 568.+-.277 pghr/mL or less. The mean
C.sub.max and the mean AUC.sub.0-24hr correspond to the serum or
plasma profile of brimonidine after ophthalmic treatment with 0.2%
(w/w) brimonidine tartrate eye drops as recommended in the label of
the ophthalmic product.
[0052] According to an embodiment of the present invention, upon
topically administering the topical aqueous gel formulation to the
affected skin area, the onset of noticeable effect, i.e., at least
1-grade improvement of the erythema or the symptom, is observed.
When sufficiently high concentration of an .alpha. adrenergic
receptor agonist is included in the topical aqueous gel
formulation, the noticeable effect is then progressed to maximum
improvement, which includes 2-grade improvement of the erythema or
the symptom that lasts for a sustained period of time. The maximum
improvement then declines to noticeable effect, which then
disappears. The grades of improvement of the erythema or the
symptom can be evaluated by Clinician's Erythema Assessment Score
(CEA), a Patient's Self Assessment (PSA), or a combination of CEA
and PSA.
[0053] According to an embodiment of the present invention, the
topical administration of a topical aqueous gel composition
comprising about 0.01% (w/w) to about 10% (w/w) .alpha. adrenergic
receptor agonist, such as brimonidine, to a skin area affected by
erythema or a symptom associated therewith results in significantly
more effective treatment of the erythema and the symptom than a
vehicle control for reduction of the erythema and the symptom as
measured by a 12 hour success profile evaluated on both CEA and PSA
scales, without causing any unacceptable adverse effect.
[0054] In one embodiment, the 12 hour success profile comprises at
least 1-grade improvement of the erythema or the symptom.
[0055] According to another embodiment of the present invention,
the topical administration of a topical aqueous gel composition
comprising about 0.3% (w/w) to about 10% (w/w) a adrenergic
receptor agonist, such as brimonidine, to a skin area affected by
erythema or a symptom associated therewith resulted in
significantly more reduction of the erythema and the symptom
compared to a vehicle control as measured by a 12 hour success
profile evaluated on both CEA and PSA scales, without causing any
unacceptable adverse effect. In a particular embodiment, the
erythema and the symptom is facial erythema associated with
rosacea.
[0056] In an embodiment of the present invention, the 12 hour
success profile comprises a noticeable effect of 1-grade
improvement of the erythema or the symptom and about 1 hour to
about 8 hours of a 2-grade improvement of the erythema or the
symptom. According to embodiments of the present invention, the
2-grade improvement lasts, for example, at least about 6 hours, at
least about 5 hours, at least about 4 hours, at least about 3
hours, at least about 2 hours or at least about 1 hour, depending
on the .alpha. adrenergic receptor agonist used, the applied dose,
the particular subject, the severity and complications of erythema
being treated, etc.
[0057] In a preferred embodiment, the 12 hour success profile
comprises a noticeable effect of 1-grade improvement of the
erythema or the symptom and about 2 hours to about 7 hours of a
2-grade improvement of the erythema or the symptom.
[0058] In another preferred embodiment, the 12 hour success profile
comprises a noticeable effect of 1-grade improvement of the
erythema or the symptom and about 3 hours to about 6 hours of a
2-grade improvement of the erythema or the symptom.
[0059] In yet another preferred embodiment, the 12 hour success
profile comprises a noticeable effect of 1-grade improvement of the
erythema or the symptom and about 2 hours to about 5 hours of a
2-grade improvement of the erythema or the symptom.
[0060] In a preferred embodiment, the erythema is erythema of
rosacea.
[0061] In an embodiment of the present invention, the topical
aqueous gel composition comprises about 0.01%, 0.05%, 0.1%, 0.2%,
0.3%, 0.5%, 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%, by
weight of an .alpha. adrenergic receptor agonist selected from the
group consisting of brimonidine, oxymetazoline, naphazoline,
tetrahydrozoline, xylometazoline, phenylephrine, methoxamine,
mephentermine, metaraminol, midodrine, epinephrine and
norepinephrine.
[0062] In another embodiment of the present invention, the topical
aqueous gel composition comprises about 0.4%, about 0.45%, about
0.5%, about 0.55% or about 0.6%, by weight of an .alpha. adrenergic
receptor agonist selected from the group consisting of brimonidine,
oxymetazoline, naphazoline, tetrahydrozoline, xylometazoline,
phenylephrine, methoxamine, mephentermine, metaraminol, midodrine,
epinephrine and norepinephrine.
[0063] In a preferred embodiment, the topical aqueous gel
composition comprises about 0.5% by weight of an .alpha. adrenergic
receptor agonist, such as about 0.5% by weight of brimonidine
tartrate, or 0.5% by weight of an .alpha. adrenergic receptor
agonist selected from the group consisting of oxymetazoline,
naphazoline, tetrahydrozoline, xylometazoline, phenylephrine,
methoxamine, mephentermine, metaraminol, midodrine, epinephrine and
norepinephrine.
[0064] To treat or prevent erythema or a symptom associated
therewith, in view of the present disclosure, the topical aqueous
gel composition of the invention can be topically applied directly
to the affected area in any conventional manner known in the art,
e.g., by dropper, applicator stick, or cotton swab, as a mist via
an aerosol applicator, via an intradermal or transdermal patch, or
by simply spreading a formulation of the invention onto the
affected area with fingers, a sponge, a pad, or wipes. Generally,
the amount of a topical formulation of the invention applied to the
affected skin area ranges from about 0.0001 g/cm.sup.2 of skin
surface area to about 0.05 g/cm.sup.2, preferably, 0.002 g/cm.sup.2
to about 0.005 g/cm.sup.2 of skin surface area. Typically, one to
four applications per day are recommended during the term of
treatment.
[0065] According to a preferred embodiment of the present
invention, the topical aqueous gel composition is topically applied
to the affected skin area once daily.
[0066] Methods of the present invention can be used in conjunction
with one or more other treatments and medications for erythema or a
symptom associated therewith, such as the medications used to treat
the underlying disease that causes erythema, antihistamines to
control itching, antibiotics, corticosteroids, intravenous
immunoglobulins, acetaminophen, etc.
[0067] The other medicament or treatment can be administered to the
subject simultaneously with, or in a sequence and within a time
interval of, the administration of brimonidine, such that the
active ingredients or agents can act together to treat or prevent
erythema and symptoms associated therewith. For example, the other
medicament or treatment and brimonidine can be administered in the
same or separate formulations at the same or different times, i.e.,
before or after. Any suitable route of administration can be
employed to deliver the additional treatment or medication.
[0068] Another aspect of the invention relates to a packaged
product for providing a safe and effective treatment of erythema or
a symptom associated therewith in a subject. The method
comprises:
[0069] (1) obtaining a topical aqueous gel composition comprising
about 0.01% (w/w) to about 10% (w/w) of an .alpha. adrenergic
receptor agonist and a pharmaceutically acceptable carrier;
[0070] (2) devising instructions for topically administering the
topical composition to a skin area affected by the erythema or the
symptom to obtain the safe and effective treatment; and
[0071] (3) providing the topical aqueous gel composition and the
instructions in a unified package.
[0072] In one embodiment of the invention, the topical aqueous gel
composition is contained within one suitable container, such as a
dropper, a jar, or a tube with a suitable small orifice size, such
as an extended tip tube, made of any pharmaceutically suitable
material. The topical formulations according to embodiments of the
invention can be filled and packaged into a plastic squeeze bottle
or tube. Suitable container-closure systems for packaging a topical
formulations of the invention are commercially available for
example, from Wheaton Plastic Products, 1101 Wheaton Avenue,
Millville, N.J. 08332. Optionally, an applicator can be provided in
or attached to the container, or separately from the container.
[0073] In one embodiment of the invention, the instructions are,
for example, a pamphlet or package label. The instructions explain
how to administer topical aqueous gel formulations of the
invention, in an amount and for a period of time sufficient to
provide a safe and effective treatment of erythema or a symptom
associated therewith. Preferably, the instructions include, for
example, the dosage and administration instructions, the topical
aqueous gel formulation's composition, the clinical pharmacology,
drug resistance, pharmacokinetics, absorption, bioavailability, and
contraindications.
[0074] Another aspect of the present invention relates to a topical
aqueous gel composition for providing a safe and effective
treatment of erythema or a symptom associated therewith in a
subject. The topical gel composition comprises:
[0075] about 0.01% (w/w) to about 10% (w/w) an .alpha. adrenergic
receptor agonist; and
[0076] about 0.20% (w/w) to about 4.0% (w/w) gelling agent.
[0077] The topically administrable composition are prepared by
mixing a pharmaceutically acceptable carrier with the safe and
effective amount of the .alpha. adrenergic receptor agonist, such
as brimonidine, according to known methods in the art, for example,
methods provided by standard reference texts such as, REMINGTON:
THE SCIENCE AND PRACTICE OF PHARMACY 1577-1591, 1672-1673, 866-885
(Alfonso R. Gennaro ed. 19th ed. 1995); Ghosh, T. K.; et al.
TRANSDERMAL AND TOPICAL DRUG DELIVERY SYSTEMS (1997), both of which
are hereby incorporated herein by reference.
[0078] In a preferred embodiment, the topical aqueous gel
composition comprises about 0.4% to about 0.6% by weight of an
.alpha. adrenergic receptor agonist selected from the group
consisting of brimonidine, oxymetazoline, naphazoline,
tetrahydrozoline, xylometazoline, phenylephrine, methoxamine,
mephentermine, metaraminol, midodrine, epinephrine and
norepinephrine.
[0079] More preferably, the topical aqueous gel composition
comprises about 0.5% by weight of brimonidine tartrate.
[0080] Suitable gelling agents known in the art, including those
used in the two-phase or single-phase gel systems, can be used in
the present invention. Some examples of suitable gelling agents are
disclosed in REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY
1517-1518 (Alfonso R. Gennaro ed. 19th ed. 1995), which is hereby
incorporated herein by reference. The gelling agents used in
embodiments of the present invention, include, but are not limited
to, one or more hydrophilic and hydroalcoholic gelling agents used
in the cosmetic and pharmaceutical industries. Preferably, the
hydrophilic or hydroalcoholic gelling agent comprises
"CARBOPOL.RTM." (B.F. Goodrich, Cleveland, Ohio), "HYPAN.RTM."
(Kingston Technologies, Dayton, N.J.), "NATROSOL.RTM." (Aqualon,
Wilmington, Del.), "KLUCEL.RTM." (Aqualon, Wilmington, Del.), or
"STABILEZE.RTM." (ISP Technologies, Wayne, N.J.). The preferred
compositional weight percent range for "CARBOPOL.RTM." is between
about 0.5% to about 2%, while the preferred weight percent range
for "NATROLSOL.RTM." and "KLUCEL.RTM." is between about 0.5% to
about 4%. The preferred compositional weight percent range for both
"HYPAN.RTM." and "STABILEZE.RTM." is between 0.5% to about 4%.
Other preferred gelling agents include hydroxyethylcellulose,
cellulose gum, MVE/MA decadiene crosspolymer, PVM/MA copolymer,
glycerine polyacrylate, or a combination thereof.
[0081] Examples of carbomers that can be used in the present
invention include, but are not limited to, Carbomer 910, 934P, 940,
941, 980 and 1342, and Carbopol.RTM. 974P and Carbopol.RTM. 980.
Preferably, the carbomer is Carbomer 934P or Carbopol.RTM. 974P,
and Carbopol.RTM. 980.
[0082] According to embodiments of the present invention, the
amount of the carbomer in the composition is about 0.5%, 0.6%,
0.7%, 0.8%, 0.85%, 0.95%, 1.05%, 1.15%, 1.25%, 1.35%, 1.45%, 1.5%,
1.6%, 1.7%, 1.8%, 1.9% or 2.0% (w/w).
[0083] In a preferred embodiment, the topical aqueous gel
composition comprises about 0.4 (w/w) to about 0.6% (w/w)
brimonidine tartrate and about 0.8% to 1.5% carbomer.
[0084] Polyol gel formulations with various ingredients solubilized
therein have been used to minimize irritation when applied to the
skin of a subject, while ensuring bioavailability of the active
agent in the formulation. See Ofher III et al. "Gels and Jellies,"
pp. 1327-1344 of Encyclopedia of Pharmaceutical Technology, vol. 3
(ed. by Swarbrick, et al, pub. by Marcel Dekker, 2002); or Pena,
"Gel Dosage Forms: Theory, Formulation, and Processing," pp.
381-388 of Topical Drug Delivery Formulations, (ed. by Osborne et
al., pub. by Marcel Dekker, Inc., 1990). Polyols in gel
formulations can serve one or more functions such as solubilizing
agents, moisturizers, emollients, skin humectant, skin-penetration
agents, etc. Suitable polyols that can be used in embodiments of
the present invention include, but are not limited to, glycerine,
propylene glycol, dipropylene glycol, hexylene glycol, butylene
glycol, and liquid polyethylene glycols, such as polyethylene
glycol 200 to 600.
[0085] According to embodiments of the present invention, the
amount of the total polyols in the composition is about 5.0% to
30.0% (w/w), for example, about 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%,
8.0%, 8.5%, 9.0%, 9.5%, 10.0%, 10.5%, 11.0%, 11.5%, 12.0%, 12.5%,
13.0%, 13.5%, 14.0%, 14.5%, 15.0%, 17%, 20%, 25% or 30% (w/w).
[0086] Preferably, the topical gel composition comprises a first
polyol and a second polyol, such as propylene glycol and glycerine,
respectively.
[0087] According to embodiments of the present invention, the
amount of each of the first and second polyols in the composition
is independently about 4 to 15%, such as 4.5% to 6.5% (w/w), for
example, 4.5%, 5.0%, 5.5%, 6.0% or 6.5% (w/w).
[0088] The pH of the topical formulations of the invention are
preferably within a physiologically acceptable pH, e.g., within the
range of about 4 to about 8, preferably, of about 6 to about 7.5,
and more preferably about 4.5 to 6.5. To stabilize the pH,
preferably, an effective amount of a buffer is included. In one
embodiment, the buffering agent is present in the aqueous topical
formulation in an amount of from about 0.05 to about 1 weight
percent of the formulation.
[0089] The topical gel composition of the present invention can
include one or more other ingredients, such as a protective agent,
a cosmetic agent, an adsorbent, a preservative, an antioxidant, a
surfactant, a skin-penetration agent, local anesthetics, analgesics
etc.
[0090] In a preferred embodiment, a topical gel composition
according to embodiments of the invention further comprises water
dispersible form of titanium dioxide (TiO2), preferably at an
amount that is sufficient to mask the color of brimonidine or
another colored ingredient in the formulation, but would not cause
irritation to the skin. TiO2 may cause mild irritation and
reddening to the eyes, thus eye contact with the TiO2-containing
topically administrable composition should be avoided. Titanium
dioxide imparts a whiteness to the topically administrable
composition and helps to increase the opacity and reduce the
transparency of the composition. Titanium dioxide absorbs,
reflects, or scatters light (including ultraviolet radiation in
light), which can help protect products from deterioration.
Titanium dioxide can also be used as a sunscreen to protect the
user from the harmful effects of ultraviolet radiation that is part
of sunlight.
[0091] According to embodiments of the present invention, the
amount of water dispersible form of titanium dioxide in the
composition is about 0.04 to 0.2%, such as 0.04%, 0.0425%, 0.0525%,
0.0625%, 0.0725%, 0.0825%, 0.09%, 0.10%, 0.15%, or 0.20% (w/w).
[0092] Suitable preservatives include, but are not limited to,
quaternary ammonium compounds, such as benzalkonium chloride,
benzethonium chloride, cetrimide, dequalinium chloride, and
cetylpyridinium chloride; alcoholic agents, for example,
chlorobutanol, phenylethyl alcohol, and benzyl alcohol; parabens
such as methylparaben, ethylparaben, propylparaben, and
butylparaben; antibacterial esters, for example, esters of
parahydroxybenzoic acid; and other anti-microbial agents such as
chlorhexidine, chlorocresol, benzoic acid, polymyxin, and
phenoxyethanol. Preferably, the preservative is selected from the
group consisting of sodium benzoate, phenoxyethanol, benzyl
alcohol, methylparaben, imidazolidinyl urea and diazolidinyl
urea.
[0093] In addition to the .alpha. adrenergic receptor agonist, such
as brimonidine, the topically administrable composition according
to embodiments of the invention can optionally include one or more
other pharmaceutically active ingredients, including, but not
limited to, one or more other .alpha. adrenergic receptor agonist,
medications used to treat the underlying disease that causes
erythema, antihistamines to control itching, antibiotics,
corticosteroids, intravenous immunoglobulins, acetaminophen,
etc.
[0094] This invention will be better understood by reference to the
non-limiting examples that follow, but those skilled in the art
will readily appreciate that the examples are only illustrative of
the invention as described more fully in the claims which follow
thereafter.
Example 1
Treatment of Erythema by .alpha.-Adrenergic Agonists
[0095] This example illustrates the therapeutic effectiveness of
various .alpha.-adrenergic agonists in treating erythema.
[0096] A number of .alpha.-adrenergic agonists were evaluated for
their ability to topically suppress erythema in human skin induced
by methyl nicotinate. The erythema produced in the skin results
from the vasodilatory effect on the dermal vasculature by methyl
nicotinate. In this model, the minimum erythemal dose (MED)
produced on the forearm by methyl nicotinate is determined for each
test subject. The MED is defined as the minimal dose that results
in a defined circle of erythema. The MED was determined by
saturating five 19 mm Hill Top Chambers with 220 .mu.l of 1, 2, 3,
4, and 5 mm methyl nicotinate. The Hill Top Chambers were applied
to the volar forearm of each test subject, removed after 30 seconds
and excess liquid lightly blotted from the skin. The MED of methyl
nicotinate was selected 10 minutes after application, by
determining the minimal dose that resulted in a defined circle of
erythema. The .alpha.-adrenergic agonists were dissolved in alcohol
and topically applied (2 .mu.l/cm2) to selected sites on the
contralateral volar forearm for 30 minutes prior to challenge with
methyl nicotinate. Hill Top Chambers (19 mm) were saturated with
220 .mu.l of the dose of methyl nicotinate determined to produce a
MED for each test subject. The chambers were applied to the volar
forearm treated with vehicle or test compounds, removed after 30
seconds and excess liquid was lightly blotted from the skin. Ten
minutes after application of methyl nicotinate the test sites were
evaluated for erythema. A numerical grading scale of 0 to 3 was
used: 0=none, 0.5=barely perceptible, 1.0=mild, 1.5=mild+(mild to
moderate), 2.0=moderate, 2.5=moderate+(moderate to severe),
3.0=severe.
[0097] The test results are shown in the table below and indicate
that each of the tested compounds reduced the formation of the
Methyl Nicotinate induced redness (erythema) in the test subjects.
With both Oxymetazoline HCl and Naphazoline HCl the redness was
fully blocked for two of the three subjects pursuant to the test
conditions as described above.
TABLE-US-00001 TABLE 1 The Effect of .alpha.-Adrenergic Agonists on
Methyl Nicotinate-Induced Erythema Pre-Treatment + Methyl
Nicotinate N Mean Erythema Grade Alcohol Vehicle Control 3 3.0 0.2%
Naphazoline HCl 3 0.33 0.2% Oxymetazoline HCl 3 1.0 0.2%
Brimonidine 3 0.83
Example 2
[0098] A possible gel formulation of the invention is described in
the Table 2 below.
TABLE-US-00002 TABLE 2 Possible Gel Formulation of the Invention
Ingredients Weight % Brimonidine tartrate 1.0% Methylparaben NF
0.15% Propylparaben NF 0.03% Hydroxyethylcellulose 1.25% NF
Disodium Edetate 0.05% USP Purified Water, USP QS 100%
Example 3
[0099] A possible gel formulation of the invention is described in
the Table 3 below.
TABLE-US-00003 TABLE 3 Possible Gel Formulation of the Invention
Ingredients Weight % Brimonidine tartrate 1.0% Methylparaben 0.20%
Propylparaben 0.05% Carbomer 934P NF 1.0% Sodium Hydroxide QS pH 7
Purified Water USP QS 100%
[0100] The ingredients are mixed together and aqueous sodium
hydroxide is slowly added to the mixture until a pH of about 7 is
reached and the gel is formed.
Example 4
[0101] A possible gel formulation of the invention is described in
the Table 4 below.
TABLE-US-00004 TABLE 4 Possible Gel Formulation of the invention
Ingredients Weight % Brimonidine tartrate 1.0% Methylparaben 0.2%
Propylparaben 0.05% "CARBOPOL .RTM." 1.0% Triethanolamine QS pH 7
Water QS 100%
[0102] The ingredients are mixed together and stirred.
Triethanolamine is added until a pH of about 7 is attained.
Example 5
[0103] This example illustrates additional topical aqueous gel
formulations that can be used in the present invention.
[0104] A first group of additional gel formulations is described in
Table 5 below.
TABLE-US-00005 TABLE 5 Ingredients % (w/w) % (w/w) % (w/w)
.alpha.-adrenergic agonist 0.3-0.6% 0.6-3% 3-10% Methylparaben NF
0.15% 0.20% 0.10% Propylparaben NF 0.03% 0.02% 0.04%
Hydroxyethylcellulose NF 1.0% 1.25% 1.5% Butylene glycol 1,3 3.0%
6.0% 18.0% Glycerine 2.0% 4.0% 12.0% Disodium Edetate USP 0.05%
0.05% 0.05% Purified Water, USP QS QS QS TOTAL 100% 100% 100%
[0105] The pH of the formulation is adjusted to about 4.5 to
7.0.
[0106] A second group of additional gel formulations is described
in Table 6 below.
TABLE-US-00006 TABLE 6 Ingredients % (w/w) % (w/w) % (w/w)
.alpha.-adrenergic agonist 0.3-0.6% 0.6-3.0% 3.0-10% Methylparaben
0.20% 0.20% 0.20% Propylparaben 0.05% 0.05% 0.05% KLUCEL .RTM. 2.0%
2.5% 1.0% Propylene glycol 3% 6% 15% Glycerine, USP 3% 6% 15% 10%
Titanium dioxide 0.5% 0.6% 0.7% Purified Water, USP QS QS QS TOTAL
100% 100% 100%
[0107] The ingredients are mixed together and aqueous sodium
hydroxide is slowly added to the mixture until a pH of about 4.5 to
6.5 is reached and the gel is formed.
[0108] A third group of additional gel formulations is described in
Table 7 below.
TABLE-US-00007 TABLE 7 Ingredient % (w/w) % (w/w) % (w/w)
.alpha.-adrenergic agonist 0.3-0.6% 0.6-3.0% 3.0-10% Carbomer 934P
1.25% 1.0% 1.5% Methylparaben 0.2% 0.15% 0.20% Phenoxyethanol 0.4%
0.35% 0.4% Glycerol 5.5% 10% 15% Kowet titanium dioxide 0.0625%
0.0725% 0.0825% Propylene glycol 5.5% 10% 15% DI Water QS QS QS
TOTAL 100% 100% 100%
[0109] The ingredients are mixed together and aqueous sodium
hydroxide is slowly added to the mixture until a pH of about 4.5 to
6.5 is reached and the gel is formed.
[0110] A fourth group of additional gel formulations is described
in Table 8 below.
TABLE-US-00008 TABLE 8 Ingredients % (w/w) % (w/w) % (w/w)
.alpha.-adrenergic agonist 0.3-0.6% 0.6-3.0% 3.0-10% Methylparaben
0.15% 0.125% 0.1% Propylparaben 0.05% 0.05% 0.06% Carbopol .RTM.
980 1.0% 0.8% 1.5% Glycerin 5.5% 10% 15% 10% Titanium dioxide
0.575% 0.675% 0.775% Polyethylene glycol 4.5% 8% 12% Water QS QS QS
TOTAL 100% 100% 100%
[0111] The ingredients are mixed together and stirred.
Triethanolamine is added until a pH of about 5.5 to 7.0 is
attained.
Example 6
Comparative Bioavailability and Pharmacokinetics Study of
Brimonidine Compositions
[0112] This study was a randomized, evaluator-blinded,
intra-individual comparative pharmacokinetic study of brimonidine
tartrate, ophthalmic solution (0.2%) and topical gel (0.07%, 0.18%
and 0.50%) applied under maximal use conditions for 29 days in
subjects with moderate to severe erythema associated with rosacea.
Major entrance criteria included clinical diagnosis of moderate to
severe facial erythema associated with rosacea, CEA score.gtoreq.3,
and IOP level 11-21 mmHg. Intra-subject comparison of topical to
ophthalmic exposure following one day treatment with brimonidine
tartrate ophthalmic solution 0.2% was performed.
[0113] A total of 102 subjects were randomized: 24, 26, 25, and 27
subjects in 0.5% Gel QD, 0.18% Gel BID, 0.18% Gel QD, and 0.07% Gel
BID, respectively. On the Day 1 visit, one drop of brimonidine
tartrate ophthalmic solution 0.2% was administered to each eye
every 8 hours over a 24 hour period. After a 2-day wash-out period,
one gram of topical gel (0.07%, 0.18%, or 0.50% of brimonidine
tartrate) was applied once (QD) or twice daily (BID) to the face of
subjects for 4 weeks.
[0114] Blood samples for complete PK profiling were taken during
the 24-hour ocular treatment (study Day 1) and during the first day
of topical application (study Day 4), fifteen days of topical
application (study Day 18) and after the last topical application
up to 72 hours post-dose (study Day 32). Additional blood samples
were collected before application (Day 10, Day 24). Brimonidine
plasma concentrations were determined by using a validated LC-MS/MS
method with a lower limit of quantification (LOQ) of 10 pg/mL.
[0115] The PK parameters for brimonidine were calculated using
standard non-compartmental method and C.sub.max, AUC.sub.0-24hr
were analyzed statistically using log-transformed data. For both
the differences between times administration routes and between
treatment groups, the limits of the intervals were back-transformed
into exponential to obtain 90% confidence intervals (90% CI) of the
ratios of geometric means on the original scale. The statistical
analysis was performed using all C.sub.max (BLQ values being
replaced by the LOQ) and using only quantifiable
AUC.sub.0-24hr.
[0116] PK results demonstrated that:
[0117] (1) Ocular treatment: Administration of brimonidine tartrate
0.2% by ophthalmic route resulted in quantifiable exposure (>10
pg/mL) in all patients receiving TID treatment. The pharmacokinetic
(PK) parameters of the ophthalmic solution have a mean C.sub.max of
54.+-.28 pg/mL (range: 16-134 pg/mL) and a mean AUC.sub.0-24hr of
568.+-.277 pghr/mL (range: 124-1490 pghr/mL) These were consistent
with the known data of brimonidine tartrate 0.2% (w/w) ophthalmic
solution, e.g., NDA:21-262, 0.2% Brimonidine Purite Multiple dose
TID, C.sub.max 65.+-.38 pg/mL.
[0118] (2) Topical treatments: Daily topical application of
brimonidine Gel for 29 days resulted in quantifiable (>10 pg/mL)
systemic exposure in 24%, 48%, 68% and 75% of subjects receiving
brimonidine Gel 0.07% BID, 0.18% QD, 0.18% BID or 0.5% QD,
respectively. At the end of the treatment period, the mean (.+-.SD)
C.sub.max were 13.+-.9 pg/mL 17.+-.20 pg/mL, 17.+-.10 pg/mL,
25.+-.24 pg/mL for brimonidine Gel 0.07% BID, 0.18% QD, 0.18% BID
or 0.5% QD, respectively. Quantifiable AUC.sub.0-24hr were
172.+-.87 pghr/mL, 183.+-.113 pghr/mL, 267.+-.119 pghr/mL,
364.+-.216 pghr/mL for brimonidine Gel 0.07% BID, 0.18% QD, 0.18%
BID or 0.5% QD, respectively.
[0119] The effect of multiple dose of brimonidine gel on PK profile
(Time effect: Day 4/Day 18/Day 32) was assessed for each topical
treatment groups. Systemic exposures of the first day of topical
application were comparable to those observed after 29 days topical
applications in all treatment groups, thus suggesting that there is
no drug accumulation throughout the treatment duration (i.e. 4
weeks) whatever the dose and the dose regimen. Whatever the dose
and dose regimen tested, the Ocular/Topical ratios calculated over
the entire topical treatment period (Day 4, Day 18 and Day 32) was
significantly lower than 1.
[0120] After topical application of brimonidine gel, systemic
exposure increases with applied dose. However, statistical analysis
showed that systemic exposure (C.sub.max) is not dose proportional.
The mean C.sub.max increased lower than dose proportionality.
[0121] The topical systemic exposure (expressed as C.sub.max or
AUC.sub.0-24hr) from the skin treatment was compared to the one
obtained after ocular treatment. See Table 9.
TABLE-US-00009 TABLE 9 statistical comparison of the ocular and
topical treatments CD07805/47 Gel CD07805/47 Gel CD07805/47 Gel
CD07805/47 Gel 0.5% QD 0.18% BID 0.18% QD 0.07% BID Parameter
Estimate (90% CI) Estimate (90% CI) Estimate (90% CI) Estimate (90%
CI) Cmax Ratio between Topical Administration Visit and Day 1
(Ophthalmic administration) Day 4/Day 1 0.3 (0.3, 0.3) 0.3 (0.2,
0.3) 0.2 (0.2, 0.3) 0.2 (0.2, 0.2) Day 18/Day 1 0.6 (0.5, 0.7) 0.3
(0.3, 0.4) 0.2 (0.2, 0.3) 0.2 (0.2, 0.2) Day 32/Day 1 0.4 (0.3,
0.4) 0.3 (0.3, 0.4) 0.3 (0.2, 0.3) 0.2 (0.2, 0.3) Quantifiable
AUC.sub.0-24 hr Ratio between Topical Administration Visit and Day
1 (Ophthalmic administration) Day 4/Day 1 0.6 (0.4, 0.7) 0.4 (0.3,
0.5) 0.3 (0.2, 0.4) 0.1 (0.1, 0.3).sup.a Day 18/Day 1 0.7 (0.6,
0.9) 0.5 (0.4, 0.6) 0.3 (0.2, 0.4) 0.5 (0.2, 0.8).sup.a Day 32/Day
1 0.5 (0.4, 0.7) 0.5 (0.4, 0.6) 0.3 (0.2, 0.4) 0.4 (0.3, 0.7).sup.a
.sup.ashould be taken with care due to the limited number of
quantifiable AUC.sub.0-24 hr (2 to 6) N.B.: Day 4 .fwdarw. first
topical administration; Day 18 .fwdarw. 15th topical
administration; Day 32 .fwdarw. 29th and last topical
administration
[0122] In all the dosages and dose regimens tested the
Ocular/Topical ratios calculated over the entire duration of the
topical treatment period (Day 4, Day 18 and Day 32) were
significantly lower than 1. The C.sub.max mean ratio was 0.2 for
0.07% BID group, ranged from 0.2 to 0.3 for 0.18% QD and BID groups
and ranged from 0.3 to 0.6 for 0.5% QD group. For C.sub.max, the
upper limit of the 90% confidence interval did not include 0.8
whatever the dose and dose regimen tested. The highest ratio was
observed in the 0.5% QD group (mean ratio 0.6, 90% CI [0.5-0.7])
after 15 days of application, but not confirmed at the end of the
29-day of topical treatment (mean ratio 0.4, 90% CI [0.3-0.4]). The
same tendency was observed with the quantifiable AUC.sub.0-24hr.
The clinical results demonstrated that the systemic exposure
obtained after topical treatment with all concentrations and
regimens tested in the study is significantly lower compared to the
systemic exposure obtained with the eye drops applied as
recommended in the label of the ophthalmic products.
[0123] In conclusion, quantifiable PK profiles (at least C.sub.max)
were observed in all treatment groups. It has been found that
although systemic exposure increased with the applied dose of
brimonidine, statistical analysis showed that the increase in
systemic exposure (C.sub.max) was not dose proportional, i.e., the
increase in the mean C.sub.max was much less than the increase in
the dose. No evidence for systemic accumulation was observed.
[0124] All evaluated concentrations and regimens were well tolerate
and safe. No clinically meaningful reductions in mean IOP, vital
signs or routine laboratory parameters were observed with any of
the topical gel treatment groups. Increasing drug concentration or
regimen had no effect on the incidence of related cardiac/vascular
AEs. There is no identifiable relationship between any PK parameter
and the incidence or severity of any AEs related to the topical
gel. There were no SAEs reported during the treatment period with
the topical gel for skin application (DAY 4 through study
completion). Two SAEs were reported during the ophthalmic solution
treatment period (DAYS 1-3) in two subjects, with one SAE (Acute
Hypotensive Event) considered related to the ophthalmic solution.
Both subjects with SAEs were discontinued from the study prior to
any exposure to the topical gel.
[0125] The study results demonstrated that the systemic exposure
obtained after topical treatment of the affected skin areas with
all concentrations of brimonidine and regimens tested is
significantly lower compared to the systemic exposure obtained with
the eye drops (0.2% by weight brimonidine tartrate) applied as
recommended in the label of the ophthalmic products.
[0126] Based on results from this comparative bioavailability and
pharmacokinetics study, concentrations of brimonidine higher than
0.2% (w/w) can be used for topical administration to an affected
skin area for safe and effective treatment of a skin disorder.
Example 7
Clinical Study on the Effectiveness and Safety of Brimonidine
Tartrate Gel Compositions
[0127] This was a 4-week treatment with 4-week follow-up,
randomized, double-blind, parallel-group, vehicle-controlled,
multicenter study investigating the efficacy and safety of a
topical gel composition containing 0.5% brimonidine tartrate (Gel
0.5%) applied topically once daily (QD) and a topical gel
composition containing 0.18% brimonidine tartrate (Gel 0.18%)
applied topically once daily (QD) or twice daily (BID) compared to
Vehicle Gel applied topically once daily (QD) or twice daily (BID),
to affected skin areas of subjects with moderate to severe facial
erythema associated with rosacea.
[0128] Major entrance criteria included clinical diagnosis of
moderate to severe facial erythema associated with Rosacea, CEA
score and PSA-5 score presence of no more than 2 facial lesions,
and IOP level at least 10 mmHg.
[0129] Qualified subjects were randomized in a 1:1:1:1:1 ratio
(block size of 5) to one of the five treatment arms (0.5% QD, 0.18%
BID, 0.18% QD, Vehicle BID, Vehicle QD).
[0130] A total of 269 subjects from 17 clinical sites were
randomized to Topical Gel or Vehicle Gel: 53, 54, 54, 53, and 55
subjects in the 0.5% QD, 0.18% BID, 0.18% QD, Vehicle BID, and
Vehicle QD arms, respectively. All 269 subjects were included in
the ITT and Safety population, and 237 subjects were included in
the PP population.
[0131] CEA and PSA evaluation data were collected at each clinic
visit at Hours 3, 6, 9, and 12 after study drug application. Data
collected at 30 minutes after study drug application comprised the
secondary endpoints of CEA Initial Effect and PSA Initial Effect.
Subject-reported efficacy data were collected at clinic visits and
on non-clinic days during the treatment period. Safety were
assessed throughout the study.
[0132] The primary endpoint, Composite Success, is defined as a
2-grade improvement on both CEA and PSA-5 measured at Hours 3, 6, 9
and 12 on Day 29 after the treatment. Statistical analysis was
performed to compare each active treatment (0.5% QD, 0.18% BID and
QD) vs. the corresponding Vehicle QD or Vehicle BID, respectively.
Additional analyses for Composite Success on early treatment visits
Day 15 and Day 1 were performed to further investigate the early
treatment effect.
[0133] Maximal drug effect peaked between approximately 3 to 6
hours after dosing. On Day 29, statistically significant difference
between 0.5% QD vs. Vehicle QD was observed (p<0.001).
Consistently, the same superiority of 0.5% QD vs. Vehicle QD was
observed on Day 15 (p<0.001) and Day 1 (p<0.001). The
statistical results based on the ITT population (LOCF approach)
were confirmed in the population point (PP) population and three
sensitivity analyses (i.e. imputing missing data by assigning
failure, success, and average data, respectively).
[0134] As shown in FIG. 1, superior treatment effect was clearly
demonstrated in 0.5% QD, followed by 0.18% BID and QD.
Consistently, 0.5% QD showed strong and robust effect as measured
by Composite Success throughout the 12 hour duration, starting on
Day 1 and continued till Day 29. Therefore, no evidence of
tachyphylaxis was observed. The magnitude of the treatment effects
were general similar between 0.18% BID and 0.18% QD. The lower
vehicle effect in the Vehicle QD regimen resulted in better
statistical outcome for 0.18% QD vs. Vehicle QD comparison.
[0135] In addition to the analysis on Composite Success, which is
defined jointly by two independent static assessments, CEA-Success
and PSA-5 Success were also analyzed individually. The magnitudes
of the CEA-Success (FIG. 2) and PSA-5 (FIG. 3) Success were greater
in all treatment groups compared to Composite Success but the
pattern of the relative effects was same as observed in Composite
Success. Consistently, 0.5% QD showed the greatest effect for CEA
Success and PSA-5 Success; 0.18% QD and BID showed numerically
better effect compared to Vehicle QD and BID, respectively.
[0136] The conclusion based on Composite Success, CEA-Success and
PSA-5 Success was supported by PSA-5 Diary data (i.e. the subjects'
daily recording of their facial redness) during the study.
[0137] The overall incidence of related adverse events (AEs) for
the study was low. The number of related AEs was comparable between
the treatment groups, and there was no significant difference in
incidence of related adverse events between active and vehicle
treatment arms. There was no significant increase in the number or
severity of systemic or topical related AEs with increase in gel
concentration or application frequency. No severe related AEs were
reported during the study. There were no reported systemic cardiac
AEs considered related to the study medication. No case of related
facial flushing led to study discontinuation or interruption of
daily treatment.
[0138] No clinically meaningful abnormal trends or shifts were
observed in mean blood pressure (systolic and diastolic) or heart
rate for any of the treatment groups during the treatment phase
(Days 1, 15, and 29) or at the end of the follow-up period, and
there was no observable difference in mean blood pressure or heart
rate changes between active and vehicle arms. Increasing drug
concentration or application frequency had no effect on the
incidence of isolated vital sign abnormalities. There were no
reported adverse events of acute hypotension, bradycardia, or
syncope during the study.
[0139] This clinical study demonstrated that Gel 0.5% QD possessed
superior efficacy compared to the corresponding vehicle and Gel
0.18% QD and BID treatments evaluated in the study (primary
endpoint: Composite Success defined as a 2-grade improvement on
both CEA and PSA-5 at Hours 3, 6, 9, and 12 on Day 29). The primary
outcome was supported by the secondary endpoints. No unacceptable
drug related adverse event was observed. Safety and tolerability of
Gel 0.5% QD is favorable. No evidence of tachyphylaxis or rebound
was found in the study.
[0140] Unlike ophthalmic applications of brimonidine, where the
chronic use of lower concentration of brimonidine, e.g., 0.1%
(w/w), provides improved tolerability while maintaining
IOP-lowering efficacy, the present clinical studies unexpectedly
discovered that higher concentrations of brimonidine provide
significantly improved clinical efficacy in treating erythema or
related symptoms, while not causing any observable change in
patient safety and tolerability as compared to lower concentrations
of brimonidine.
[0141] It will be appreciated by those skilled in the art that
changes could be made to the embodiments described above without
departing from the broad inventive concept thereof. It is
understood, therefore, that this invention is not limited to the
particular embodiments disclosed, but it is intended to cover
modifications within the spirit and scope of the present invention
as defined by the appended claims.
* * * * *