U.S. patent application number 14/038419 was filed with the patent office on 2014-01-30 for combinations of adapalene and benzoyl peroxide for treating acne lesions.
This patent application is currently assigned to GALDERMA RESEARCH & DEVELOPMENT. Invention is credited to Marie-Line ABOU-CHACRA VERNET, Denis GROSS, Christian LOESCHE, Michel PONCET.
Application Number | 20140031427 14/038419 |
Document ID | / |
Family ID | 41380579 |
Filed Date | 2014-01-30 |
United States Patent
Application |
20140031427 |
Kind Code |
A1 |
ABOU-CHACRA VERNET; Marie-Line ;
et al. |
January 30, 2014 |
COMBINATIONS OF ADAPALENE AND BENZOYL PEROXIDE FOR TREATING ACNE
LESIONS
Abstract
Adapalene or a pharmaceutically acceptable salt thereof
formulated into a pharmaceutical composition is useful for reducing
the number of acne lesions, via daily topical application, in
combination or in association with benzoyl peroxide (BPO); such
treatment may be via administration of a pharmaceutical composition
combining adapalene and BPO or by a concomitant application of two
pharmaceutical compositions, one containing adapalene and the other
containing BPO.
Inventors: |
ABOU-CHACRA VERNET; Marie-Line;
(Nice, FR) ; GROSS; Denis; (Callian, FR) ;
LOESCHE; Christian; (Valbonne, FR) ; PONCET;
Michel; (Mougins, FR) |
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Applicant: |
Name |
City |
State |
Country |
Type |
& |
Biot |
|
FR |
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Assignee: |
GALDERMA RESEARCH &
DEVELOPMENT
Biot
FR
|
Family ID: |
41380579 |
Appl. No.: |
14/038419 |
Filed: |
September 26, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13892392 |
May 13, 2013 |
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14038419 |
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13308413 |
Nov 30, 2011 |
8445543 |
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13892392 |
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12473981 |
May 28, 2009 |
8080537 |
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13308413 |
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12318937 |
Jan 13, 2009 |
8071644 |
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12473981 |
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PCT/EP2007/057207 |
Jul 12, 2007 |
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12318937 |
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60833491 |
Jul 27, 2006 |
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Current U.S.
Class: |
514/569 |
Current CPC
Class: |
A61K 9/0014 20130101;
Y10S 514/859 20130101; A61K 47/10 20130101; A61P 29/00 20180101;
A61K 31/327 20130101; A61K 47/18 20130101; A61K 31/192 20130101;
A61K 31/194 20130101; A61K 47/20 20130101; A61P 17/10 20180101;
A61K 47/26 20130101; A61K 47/32 20130101; A61K 31/192 20130101;
A61K 2300/00 20130101; A61K 31/327 20130101; A61K 2300/00
20130101 |
Class at
Publication: |
514/569 |
International
Class: |
A61K 31/194 20060101
A61K031/194 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 13, 2006 |
FR |
0652968 |
Claims
1.-10. (canceled)
11. A method for achieving early onset of action in treatment of
acne lesions, said method comprising topically applying to a
subject's skin, said subject being in need of said treatment, as
active ingredients, 0.1% to 0.3% adapalene or pharmaceutically
acceptable salt thereof and 2.5% benzoyl peroxide, combined at
fixed doses in a single formula that delivers said active
ingredients together, wherein the percentages of adapalene and
benzoyl peroxide are percentages by weight relative to the total
weight of said single formula, wherein said single formula is
applied daily for a period of 4 weeks or 1 month, and wherein the
reduction in total lesion counts in a group of such subjects
achieved at week 4 is synergistic and numerically superior to the
reduction in total lesion counts achieved by the same dose of
adapalene alone or of benzoyl peroxide alone at the same time
point.
12. The method according to claim 11, wherein the amount of
adapalene in the single formula is 0.1%.
13. The method according to claim 11, wherein the single formula is
a gel.
14. The method according to claim 12, wherein the single formula is
a gel.
15. A method for achieving early onset of action in treatment of
acne lesions, said method comprising topically applying to a
subject's skin, said subject being in need of said treatment, as
active ingredients, 0.1% to 0.3% adapalene or pharmaceutically
acceptable salt thereof and 2.5% benzoyl peroxide, combined at
fixed doses in a single formula that delivers said active
ingredients together, wherein the percentages of adapalene and
benzoyl peroxide are percentages by weight relative to the total
weight of said single formula, wherein said single formula is
applied daily for a period of 2 weeks to 4 weeks or 1 month, and
wherein the reduction in total lesion counts in a group of such
subjects achieved at week 2 is synergistic and numerically superior
to the reduction in total lesion counts achieved by the same dose
of adapalene alone or of benzoyl peroxide alone at the same time
point.
16. The method according to claim 15, wherein the amount of
adapalene in the single formula is 0.1%.
17. The method according to claim 15, wherein the single formula is
a gel.
18. The method according to claim 16, wherein the single formula is
a gel.
19. A method for achieving early onset of action in treatment of
acne lesions, said method comprising topically applying to a
subject's skin, said subject being in need of said treatment, as
active ingredients, 0.1% to 0.3% adapalene or pharmaceutically
acceptable salt thereof and 2.5% benzoyl peroxide, combined at
fixed doses in a single formula that delivers said active
ingredients together, wherein the percentages of adapalene and
benzoyl peroxide are percentages by weight relative to the total
weight of said single formula, wherein said single formula is
applied daily for a period of 2 weeks to 4 weeks or 1 month, and
wherein the reduction in total lesion counts in a group of such
subjects achieved at week 1 is synergistic and numerically superior
to the reduction in total lesion counts achieved by the same dose
of adapalene alone or of benzoyl peroxide alone at the same time
point.
20. The method according to claim 19, wherein the amount of
adapalene in the single formula is 0.1%.
21. The method according to claim 19, wherein the single formula is
a gel.
22. The method according to claim 20, wherein the single formula is
a gel.
23. A method for achieving early onset of action in treatment of
acne lesions, said method comprising topically applying to a
subject's skin, said subject being in need of said treatment, as
active ingredients, 0.1% to 0.3% adapalene or pharmaceutically
acceptable salt thereof and 2.5% benzoyl peroxide, combined at
fixed doses in a single formula that delivers said active
ingredients together, wherein the percentages of adapalene and
benzoyl peroxide are percentages by weight relative to the total
weight of said single formula, wherein said single formula is
applied daily for a period of 4 weeks or 1 month, and wherein the
reduction in inflammatory lesion counts in a group of such subjects
achieved at week 4 is synergistic and numerically superior to the
reduction in inflammatory lesion counts achieved by the same dose
of adapalene alone or of benzoyl peroxide alone at the same time
point.
24. The method according to claim 23, wherein the amount of
adapalene in the single formula is 0.1%.
25. The method according to claim 23, wherein the single formula is
a gel.
26. The method according to claim 24, wherein the single formula is
a gel.
27. A method for achieving early onset of action in treatment of
acne lesions, said method comprising topically applying to a
subject's skin, said subject being in need of said treatment, as
active ingredients, 0.1% to 0.3% adapalene or pharmaceutically
acceptable salt thereof and 2.5% benzoyl peroxide, combined at
fixed doses in a single formula that delivers said active
ingredients together, wherein the percentages of adapalene and
benzoyl peroxide are percentages by weight relative to the total
weight of said single formula, wherein said single formula is
applied daily for a period of 2 weeks to 4 weeks or 1 month, and
wherein the reduction in inflammatory lesion counts in a group of
such subjects achieved at week 1 is synergistic and numerically
superior to the reduction in inflammatory lesion counts achieved by
the same dose of adapalene alone or of benzoyl peroxide alone at
the same time point.
28. The method according to claim 27, wherein the amount of
adapalene in the single formula is 0.1%.
29. The method according to claim 27, wherein the single formula is
a gel.
30. The method according to claim 28, wherein the single formula is
a gel.
31. A method for achieving early onset of action in treatment of
acne lesions, said method comprising topically applying to a
subject's skin, said subject being in need of said treatment, as
active ingredients, 0.1% to 0.3% adapalene or pharmaceutically
acceptable salt thereof and 2.5% benzoyl peroxide, combined at
fixed doses in a single formula that delivers said active
ingredients together, wherein the percentages of adapalene and
benzoyl peroxide are percentages by weight relative to the total
weight of said single formula, wherein said single formula is
applied daily for a period of 4 weeks or 1 month, and wherein the
reduction in non-inflammatory lesion counts in a group of such
subjects achieved at week 4 is synergistic and numerically superior
to the reduction in non-inflammatory lesion counts achieved by the
same dose of adapalene alone or of benzoyl peroxide alone at the
same time point.
32. The method according to claim 31, wherein the amount of
adapalene in the single formula is 0.1%.
33. The method according to claim 31, wherein the single formula is
a gel.
34. The method according to claim 32, wherein the single formula is
a gel.
35. A method for treatment of acne lesions, said method comprising
topically applying to a subject's skin, said subject being in need
of said treatment, as active ingredients, 0.2% to 0.3% adapalene or
pharmaceutically acceptable salt thereof and 2.5% benzoyl peroxide,
combined at fixed doses in a sing formula that delivers said active
ingredients together, wherein the percentages of adapalene and
benzoyl peroxide are percentages by weight relative to the total
weight of said single formula, wherein said single formula is
applied daily for a period of 4 weeks or 1 month, and wherein the
reduction in total lesion counts, in inflammatory lesion counts or
in non-inflammatory lesion counts in a group of such subjects
achieved at week 4 is synergistic and numerically superior to the
reduction in total lesion counts, in inflammatory lesion counts or
in non-inflammatory lesion counts, respectively, achieved by the
same dose of adapalene alone or of benzoyl peroxide alone at the
same time point.
Description
CROSS-REFERENCE TO EARLIER APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 13/892,392, filed May 13, 2013, which is a
continuation of U.S. patent application Ser. No. 13/308,413, filed
Nov. 30, 2011, now U.S. Pat. No. 8,445,543, which is a continuation
of U.S. patent application Ser. No. 12/473,981, filed May 28, 2009,
now U.S. Pat. No. 8,080,537, which is a continuation-in-part of
U.S. patent application Ser. No. 12/318,937, filed Jan. 13, 2009,
now U.S. Pat. No. 8,071,644, which is a continuation of
PCT/EP2007/057207, filed Jul. 12, 2007 and designating the United
States (published in the English language on Jan. 17, 2008 as WO
2008/006888 A1), which claims benefit of U.S. Provisional
Application No. 60/833,491, filed Jul. 27, 2006, and also claims
priority of Application No. 06/52968, filed in France on Jul. 13,
2006, each earlier application hereby expressly incorporated by
reference in its entirety and each assigned to the assignee
hereof.
CROSS-REFERENCE TO RELATED APPLICATIONS
[0002] This application is also related to copending U.S.
application Ser. No. 13/296,186, filed Nov. 14, 2011, which is a
continuation of the aforementioned U.S. application Ser. No.
12/318,937, filed Jan. 13, 2009, now U.S. Pat. No. 8,071,644; and
is also related to U.S. application Ser. No. 11/826,364, filed Jul.
13, 2007, now U.S. Pat. No. 8,129,362.
BACKGROUND OF THE INVENTION
[0003] 1. Technical Field of the Invention
[0004] The present invention relates to the combined or associated
administration of adapalene and of benzoyl peroxide for reducing
the number of acne lesions.
6-[3-(1-Adamantyl)-4-methoxyphenyl]-2-naphthoic acid (referred to
herein below as adapalene) is a naphthoic acid derivative with
retinoid and anti-inflammatory properties. This molecule was
developed for the topical treatment of common acne and of
dermatoses sensitive to retinoids.
[0005] 2. Description of Background and/or Related and/or Prior
Art
[0006] Adapalene is marketed under the trademark Differin.RTM. at a
weight concentration of 0.1%, in the form of an "alcoholic lotion"
solution, an aqueous gel and a cream. These compositions are useful
for treating acne. FR 2,837,101 describes adapalene compositions at
a weight concentration of 0.3%, for treating acne.
[0007] WO 03/0555 472 and corresponding US 2003/0170196 moreover
describe stable pharmaceutical compositions comprising adapalene
and benzoyl peroxide (BPO).
[0008] An article by Korkut and Piskin, J. Dermatology, 2005, 32:
169-173, reports the results of a study comparing a treatment
combining application of adapalene in the evening and application
of BPO in the morning, relative to an application of each of the
active principles alone. The authors do not observe any superiority
of the combined treatment over a period of 11 weeks of
treatment.
SUMMARY OF THE INVENTION
[0009] It has now been demonstrated, surprisingly, that a
therapeutic association or combination of adapalene and BPO can
provide a degree of success in reducing the number of acne lesions
and an improvement in the clinical condition of patients that are
markedly superior to those of a treatment based on adapalene alone
or on BPO alone, while at the same time maintaining the same skin
tolerance.
[0010] The recommended treatment may take the form of a
pharmaceutical composition combining adapalene and BPO, or a
concomitant application of two pharmaceutical compositions, one
comprising adapalene and the other comprising BPO.
[0011] The present invention thus features formulation of adapalene
or a pharmaceutically acceptable salt thereof into a pharmaceutical
composition, especially at set doses, intended to be administered
in combination or in association with benzoyl peroxide (BPO), for
the treatment of acne lesions, especially to reduce the number of
acne lesions and to improve the clinical condition of patients.
[0012] Preferably, the acne lesions are of inflammatory and/or
non-inflammatory type.
[0013] Acne is initially characterized by keratinization disorders,
which are sometimes invisible to the naked eye. Visible acne
lesions then develop, while the size of the sebaceous glands and
the production of sebum increase.
[0014] The present invention specifically concerns acne lesions.
The term "acne lesions" means non-inflammatory lesions (open and
closed comedones) and inflammatory lesions (papules, pustules,
nodules and cysts) caused by acne. Preferably, the inflammatory
lesions are treated with the association or the combination
according to the invention.
[0015] More preferably, the pharmaceutical composition is
administered by daily cutaneous topical application. In other
words, the invention relates to the administration of adapalene as
an agent for potentiating the action of BPO. Reciprocally, BPO
potentiates the action of adapalene.
[0016] The term "adapalene salts" means the salts formed with a
pharmaceutically acceptable base, especially mineral bases such as
sodium hydroxide, potassium hydroxide and ammonia or organic bases
such as lysine, arginine or N-methylglucamine. The term "adapalene
salts" also means the salts formed with fatty amines such as
dioctylamine and stearylamine.
[0017] The expression "combination of adapalene or salts thereof
with benzoyl peroxide" means a single composition comprising both
adapalene or salts thereof and benzoyl peroxide.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] FIGS. 1-3 are graphs showing the change in the number of
lesions over time, upon treatment either according to the invention
or not;
[0019] FIG. 4 is a graph showing the degree of success over time of
treatment according to the invention or not;
[0020] FIG. 5 is a bar graph evaluating the anti-inflammatory
effect on ear edema of treatment according to the invention or
not;
[0021] FIG. 6 is a chart showing the patient disposition and
baseline disease characteristics for clinical trials of 3855 acne
vulgaris patients;
[0022] FIG. 7A is a graph of the median percentage change from
baseline in total lesion counts for the effect of treatments,
.sup..dagger.P<0.05 vs. adapalene, BPO and vehicle for the 3855
patient clinical trials;
[0023] FIG. 7B is a graph of the median percentage change from
baseline in total lesion counts for the net effect of treatment
(active minus vehicle), *adapalene and BPO acted synergistically,
i.e., net effect of adapalene-BPO greater than the sum of net
effects of adapalene alone and BPO alone, for the 3855 patient
clinical trials;
[0024] FIG. 7C is a chart showing the contribution of synergy to
efficacy of adapalene-BPO in the total lesion counts (synergy
divided by net effect of adapalene-BPO) at selected time points
over the course of the 3855 patient clinical trials;
[0025] FIG. 8A is a graph of the median percentage change from
baseline in inflammatory lesion counts for the effect of
treatments, .sup..dagger.P<0.05 vs. adapalene, BPO and vehicle
for the 3855 patient clinical trials;
[0026] FIG. 8B is a graph of the median percentage change from
baseline in inflammatory lesion counts for the net effect of
treatment (active minus vehicle), *adapalene and BPO acted
synergistically, i.e., net effect of adapalene-BPO greater than the
sum of net effects of adapalene alone and BPO alone, for the 3855
patient clinical trials;
[0027] FIG. 8C is a chart showing the contribution of synergy to
the net effect of adapalene-BPO in inflammatory lesion counts
(synergy divided by net effect of adapalene-BPO) at selected time
points over the course of the 3855 patient clinical trials;
[0028] FIG. 9A is a graph of the median percentage change from
baseline in non-inflammatory lesion counts for the effect of
treatments, P<0.05 vs. adapalene, BPO and vehicle for the 3855
patient clinical trials;
[0029] FIG. 9B is a graph of the median percentage change from
baseline in non-inflammatory lesion counts for the net effect of
treatment (active minus vehicle), *adapalene and BPO acted
synergistically, i.e. net effect of adapalene-BPO greater than the
sum of net effects of adapalene alone and BPO alone, for the 3855
patient clinical trials;
[0030] FIG. 9C is a chart showing the contribution of synergy to
the efficacy of adapalene-BPO in non-inflammatory lesion counts
(synergy divided by net effect of adapalene-BPO) at selected time
points over the course of the 3855 patient clinical trials;
[0031] FIG. 10A is a graph of the success rate for the effect of
treatments in the 3855 patient clinical trials,
.sup..dagger.P<0.05 vs. adapalene, .sup..sctn. P<0.05 vs.
BPO; .sup.#P<0.05 vs. vehicle;
[0032] FIG. 10B is a graph of the net effect of treatments (active
minus vehicle) for the 3855 patient clinical trials, *adapalene and
BPO acted synergistically, i.e., net effect of adapalene-BPO
greater than the sum of net effects of adapalene alone and BPO
alone;
[0033] FIG. 10C is a chart showing the contribution of synergy to
efficacy of adapalene-BPO (synergy divided by net effect of
adapalene-BPO) at selected time points over the course of the 3855
patient clinical trials;
[0034] FIG. 11A is a graph of local tolerability signs showing mean
scores for the severity of dryness over the course of the 3855
patient clinical trials;
[0035] FIG. 11B is a graph of local tolerability signs showing mean
scores for the severity of erythema over the course of the 3855
patient clinical trials;
[0036] FIG. 11C is a graph of local tolerability signs showing mean
scores for the severity of scaling over the course of the 3855
patient clinical trials;
[0037] FIG. 11D is a graph of local tolerability signs showing mean
scores for the severity of stinging/burning over the course of the
3855 patient clinical trials.
DETAILED DESCRIPTION OF BEST MODE AND SPECIFIC/PREFERRED
EMBODIMENTS OF THE INVENTION
[0038] According to one preferred embodiment, the pharmaceutical
composition is a fixed combination and comprises, in a
pharmaceutically acceptable medium, (i) at least one compound
selected from among adapalene and pharmaceutically acceptable salts
thereof, and (ii) benzoyl peroxide (BPO). Preferably, the
pharmaceutical composition is intended for a single topical
application per day.
[0039] The term "pharmaceutically acceptable medium" means a medium
that is compatible with the skin, mucous membranes and the
integuments.
[0040] The term "fixed combination" should be understood as meaning
a combination whose active principles are combined at fixed doses
in the same vehicle (single formula) that delivers them together to
the point of application. Preferably, the pharmaceutical
composition in the form of a fixed combination is a gel; in this
case, the two active principles are dispersed and intimately mixed,
during production, in the same vehicle, which delivers them
together during the application of the gel.
[0041] In another embodiment of the invention, the pharmaceutical
composition is in the form of a composition A comprising adapalene,
suited to be applied concomitantly with a composition B comprising
BPO. Preferably, composition A and composition B are presented in
the form of a kit, preferably comprising two isolated compartments
each containing one of the two pharmaceutical compositions A or B
(dual pack) and allowing simultaneous administration of the two
compositions, or alternatively in the form of a kit combining in
the same presentation at least the two products (compositions A and
B) in two separate packages, preferably in the form of tubes
(co-packaging).
[0042] In this case, one skilled in this art will adapt the formula
that is the most appropriate in terms of viscosity, additives, etc.
to the selected kit.
[0043] The expression "concomitant" application means that the
compositions are suited to be applied to the skin simultaneously or
one after the other, in any order, or in a sequential order (for
example, in which the application of a pharmaceutical composition B
comprising BPO precedes the application of the pharmaceutical
composition A comprising adapalene), but within a time interval of
less than 1 hour, preferably less than 30 minutes, preferably less
than 15 minutes, more preferably less than 5 minutes or even less
than 1 minute.
[0044] The present invention thus also features compositions in kit
form comprising at least two components:
[0045] a first component comprising at least adapalene or a
pharmaceutically acceptable salt thereof,
[0046] a second component comprising benzoyl peroxide,
these two components being suited to be applied concomitantly to
the skin, mucous membranes and/or the integuments.
[0047] Compositions A and B are preferably useful for a single
cutaneous topical application per day.
[0048] The treatments have a variable duration, depending on the
patient and the severity of his acne. The treatment period may thus
run from several weeks to several months. A suitable treatment
period is at least two weeks, preferably from 1 to 6 months and
more preferably a duration of about 3 months is preferable, the
duration of the treatment possibly being prolonged, if
necessary.
[0049] All the pharmaceutical compositions of the invention may
comprise from 0.01% to 2%, preferably from 0.05% to 0.5% and
preferentially from 0.1% to 0.3% of adapalene, and from 0.1% to 20%
and preferably from 0.5% to 10% of BPO, more preferably from 2% to
5% of BPO and preferentially 2.5% of BPO.
[0050] All the percentages are indicated by weight relative to the
total weight of the composition.
[0051] The adapalene:BPO ratio ranges from 1:1 to 1:200 and,
conversely, the BPO:adapalene ratio ranges from 1:1 to 1:200.
Preferably, the adapalene:BPO ratio ranges from 1:1 to 1:200 and
the adapalene:BPO ratio is preferably 1:25.
[0052] Preferably, the effect of the combination of the two active
principles is at least an additive effect and preferentially a
potentiation or synergistic effect. The terms "potentiation effect"
and "synergistic effect" mean a therapeutic effect (degree of
success) greater than the effect resulting from the addition of the
effects obtained by each of the two active principles taken
separately.
[0053] When they are combined in the same pharmaceutical
composition, the adapalene and the BPO are present in the
pharmaceutical composition in synergistic amounts, i.e., such that
a synergistic or potentiation effect on the acne lesions and on the
clinical condition of the patient is observed. Preferably, the
pharmaceutical composition comprises 0.1% of adapalene and 2.5% of
BPO.
[0054] When compositions A and B are administered separately, the
adapalene and the BPO are, respectively, present in composition A
and composition B in synergistic amounts, i.e., such that a
synergistic or potentiation effect on the acne lesions and on the
clinical condition of the patient is observed, especially when the
compositions are applied in association in equal amounts.
Preferably, composition A comprises 0.1% of adapalene and
composition B comprises 2.5% of BPO.
[0055] In this regard, the examples to follow demonstrate that
because of the synergistic effect of adapalene and BPO, the
invention provides greater efficacy for the treatment of acne in
general and of acne lesions in particular and a quicker onset of
action relative to monotherapies.
[0056] The pharmaceutical compositions according to the invention
may be in the form of ointments, emulsions preferably in the form
of creams, milks or pomades; powders, impregnated pads, solutions,
gels, sprays, lotions or suspensions. They may also be in the form
of suspensions of microspheres or nanospheres or of lipid or
polymer vesicles or of polymer patches and/or of hydrogels allowing
controlled release. These compositions may be in anhydrous form, in
aqueous form or in the form of an emulsion.
[0057] In one preferred embodiment of the invention, the
pharmaceutical compositions are in the form of a gel, a cream or a
solution referred to as a lotion.
[0058] Preferably, the pharmaceutical compositions combining
adapalene and BPO, or the pharmaceutical compositions A and/or B,
are gels.
[0059] The pharmaceutical compositions of the invention may contain
inert additives or combinations of these additives, such as:
[0060] wetting agents;
[0061] texture enhancers;
[0062] preservatives such as para-hydroxybenzoic acid esters;
[0063] stabilizers;
[0064] humidity regulators;
[0065] pH regulators;
[0066] osmotic pressure modifiers;
[0067] emulsifiers;
[0068] UV-A and UV-B screening agents; and
[0069] antioxidants, such as .alpha.-tocopherol,
butylhydroxyanisole or butylhydroxytoluene, superoxide dismutase,
ubiquinol, or certain metal-chelating agents.
[0070] Needless to say, one skilled in this art will take care to
select the optional compound(s) to be added to these compositions
such that the advantageous properties intrinsically associated with
the present invention are not, or are not substantially, adversely
affected by the envisaged addition.
[0071] According to one particular embodiment, the pharmaceutical
composition A comprising adapalene may be an aqueous gel especially
containing one or more ingredients selected from among the carbomer
940 (BF Goodrich Carbopol 980) and propylene glycol, or a cream
especially containing one or more ingredients selected from among
perhydrosqualene, cyclomethicone, PEG-20 methylglucose
sesquistearate and methylglucose sesquistearate or an "alcoholic
lotion" solution based on polyethylene glycol.
[0072] Useful pharmaceutical compositions, comprising adapalene and
BPO, are moreover described in WO 03/055 472. Examples of such
compositions comprise, besides the active principles adapalene and
BPO:
[0073] from 5% to 25% of water;
[0074] from 0 to 10%, preferably from 0 to 2% and preferably less
than 0.5% of liquid wetting surfactant;
[0075] from 0 to 10% of pro-penetrating agent; and
[0076] an aqueous phase comprising a pH-independent gelling
agent.
[0077] According to one preferred embodiment, the preferred
pharmaceutical composition, comprising adapalene and BPO, is an
aqueous gel having the following formulation:
[0078] 2.5% of BPO;
[0079] 0.1% of adapalene;
[0080] 0.10% of disodium EDTA;
[0081] 4.00% of glycerol;
[0082] 4.00% of propylene glycol;
and also, preferably:
[0083] 0.05% of sodium docusate;
[0084] 0.20% of poloxamer 124;
[0085] 4.00% of sodium acryloyldimethyltaurate copolymer and
isohexadecane and polysorbate 80;
[0086] NaOH, in an amount sufficient to obtain a pH of 5.
[0087] The acne targeted comprises all forms of acne, including
common acne, comedones, polymorphs, nodulocystic acne, acne
conglobata, and secondary acne such as solar, medicational or
occupational acne. The acne may in particular be of mild to severe
intensity and preferably of mild to moderate intensity. The
compositions according to the invention may be administered as a
firstline treatment, and also after failure of other specific
treatments including the administration of adapalene and/or of BPO
according to the conditions described by Korkut et al.
[0088] The association or combination of adapalene and of BPO makes
it possible to reduce not only the number of inflammatory acne
lesions but also the non-inflammatory acne lesions and to observe
an improvement in the patient's clinical condition. A potentiation
or synergistic effect is observed. This potentiation effect
described in the example to follow is shown in the reduced number
of lesions and in the percentage of cured patients (clear) and
almost cured patients (almost clear) by the size of the superiority
of the combination at fixed doses of adapalene and of BPO, relative
to the active substances taken individually at the same doses as
the combination.
[0089] Moreover, the results of the potentiation effect of the
combination of adapalene and BPO presented in the example are
statistically different from the results obtained for the active
substances taken individually.
[0090] The combination or association of adapalene and of BPO is
thus particularly useful for reducing the number of inflammatory
and/or non-inflammatory acne lesions. Preferably, the reduction is
at least about 40%, preferably at least about 50% and more
preferably the reduction is at least about 60%. Similarly, it is
demonstrated in the example that the reduction of the total lesions
is from about 35% to 80% and preferably from about 50% to 70%.
[0091] According to another embodiment, this invention also
features a pharmaceutical assembly (product) comprising:
[0092] i) a container delimiting at least one compartment, the said
container being closed by means of a closing member; and
[0093] ii) a pharmaceutical composition comprising adapalene or a
pharmaceutically acceptable salt thereof and benzoyl peroxide as
described above, and placed inside the said compartment.
[0094] The container may be in any suitable form. It may especially
be in the form of a bottle, a tube, a jar, a case, a can, a sachet
or a box.
[0095] Preferably, the container comprises two compartments, and
each of these compartments comprises either composition A or
composition B.
[0096] The closing member may be in the form of a removable
stopper, a lid, a cover, a tear-off strip or a cap, especially of
the type comprising a body fixed to the container and a cap
articulated on the body. It may also be in the form of a member
ensuring the selective closure of the container, especially a pump,
a valve or a clapper.
[0097] The closing member may be coupled to the container by
screwing. Alternatively, the coupling from the closing member and
the container may take place other than by screwing, especially via
a bayonet mechanism, by click-fastening, gripping, welding, bonding
or magnetic attraction. The term "click-fastening" in particular
means any system involving the passing of a rim or bead of material
by elastic deformation of a portion, especially of the closing
member, followed by return to the elastically unstressed position
of the said portion after the rim or bead has been passed.
[0098] The container may be at least partly made of thermoplastic
material. Examples of thermoplastic materials include polypropylene
and polyethylene.
[0099] Alternatively, the container is made of a non-thermoplastic
material, especially of glass or metal (or alloy).
[0100] The container may have rigid walls or deformable walls,
especially in the form of a tube or a tube bottle.
[0101] The container may comprise means for causing or facilitating
the distribution of the composition. By way of example, the
container may have deformable walls so as to make the composition
come out in response to a positive pressure inside the container,
this positive pressure being caused by elastic (or non-elastic)
squeezing of the walls of the container. Alternatively, especially
when the product is in the form of a stick, this stick may be
driven by a piston mechanism. Still in the case of a stick,
especially of makeup product, the container may comprise a
mechanism, especially a wishbone mechanism, or a mechanism with a
threaded stem, or with a helical ramp, which is capable of moving a
stick in the direction of the said opening. Such a mechanism is
described, for example, in FR 2,806,273 or in FR 2,775,566. Such a
mechanism for a liquid product is described in FR 2,727,609.
[0102] In order to further illustrate the present invention and the
advantages thereof, the following specific examples are given, it
being understood that same are intended only as illustrative and in
nowise limitative. In said examples to follow, all parts and
percentages are given by weight, unless otherwise indicated.
EXAMPLES
Example 1
Clinical Study Results
[0103] A clinical study for confirmation of efficacy was performed
for a topical gel combining adapalene+benzoyl peroxide (BPO).
[0104] This gel has the following formulation (expressed as %
weight/total weight):
TABLE-US-00001 Adapalene 0.10% Benzoyl peroxide 2.50% Copolymer of
acrylamide & sodium 4.00% acryloyldimethyltaurate Sodium
docusate 0.05% Disodium EDTA 0.10% Glycerol 4.00% Poloxamer 124
0.20% Propylene glycol 4.00% Purified water qs 100%
[0105] Protocol:
[0106] The clinical study was a multi-center, randomized,
double-blind study in parallel groups, to evaluate the tolerance
and the efficacy of the above formulation, in comparison with its
own individual active substances placed at the same doses in gels
of the same formula as that of the fixed combination (individual
formulae referred to as "monads") and in comparison with the gel
vehicle (placebo formula): adapalene gel (0.1%), BPO gel (2.5%) and
vehicle gel.
[0107] All the treatments were applied once a day for 12 weeks, to
517 patients suffering from acne.
[0108] The main efficacy criteria were:
[0109] the degree of success, defined as the percentage of patients
considered as being "clear", i.e., the patient has no more acne
lesions (neither comedones nor inflammatory lesions), reflecting an
improvement in the patient's clinical condition, or "almost clear"
on the evaluation scale;
[0110] the reduction of the percentage of inflammatory and
non-inflammatory lesions after 12 weeks of treatment.
[0111] Results:
[0112] The results are presented in the Table that follows.
TABLE-US-00002 Efficacy in week 12 ITT* Adapalene BPO 0.1% +
Adapalene 2.5% Vehicle BPO 2.5% 0.1% alone alone (gel) N = 149 N =
148 N = 149 N = 71 Degree of success (see 27.5% 15.5% 15.4% 9.9%
FIG. 4) Progress of the lesions (median percentages) Number of
inflammatory -62.8% -45.7% -43.6% -37.8% lesions (see FIG. 2)
Number of non- -51.2% -33.3% -36.4% -37.5% inflammatory lesions
(see FIG. 3) Total number of lesions -51.0% -35.4% -35.6% -31.0%
(see FIG. 1) Progress of the lesions (as median absolute numbers)
Number of inflammatory -17 -13.0 -13.0 -11.0 lesions Number of non-
-22.0 -17.0 -16.0 -14.0 inflammatory lesions Total number of
lesions -40.0 -29.0 -27 -26.0 ITT* (analysis of intention to
treat): all the patients randomized in a clinical test because they
come under the indication selected for the treatment to be
prescribed. The missing data are imputed by the last observation
(LOCF method ** (Last Observation Carried Forward).
[0113] 1) For the 4 main criteria of the study: degree of success
and progress as a percentage of the three types of lesion, the
fixed combination was found to be statistically superior to the two
monads and to the vehicle.
[0114] 2) When the effect of the gel used as vehicle (V) is
subtracted from the effect of the fixed combination (C), the net
clinical benefit of the fixed combination (C-V) is numerically
superior to the sum of the net clinical benefits of each of the
individual substances after subtraction of the vehicle effect from
the adapalene (A) and BPO (B) branches, respectively, according to
the equation:
(C-V)>(A-V)+(B-V).
[0115] These results systematically show a potentiation effect
since the net benefit is in favor of the gel combining
adapalene+BPO, with results, in terms of degree of success, that
are superior to the addition of adapalene and BPO (28% for the
combination, as opposed to 16%, 15% to 10% for adapalene, BPO and
vehicle, respectively). In this case, the above equation shows
(28-10)>(16-10)+(15-10), i.e., 18>11, which is true.
[0116] Similarly, the gel combining adapalene+BPO was numerically
superior in terms of efficacy in comparison with the individual
active substances and with the vehicle as regards the reduction in
the number of all the lesions (reduction in the percentage of
inflammatory and non-inflammatory lesions).
[0117] A potentiation effect of adapalene and BPO together is thus
noted, since a 51% reduction in lesions is observed for the
combination, as opposed to 35% for adapalene alone, 36% for BPO
alone and 31% for the vehicle, which is expressed as a net benefit
of efficacy with the above equation by (51-31)>(35-31)+(36-31),
i.e., 20>9, which is true.
Example 2
Evaluation of the Anti-Inflammatory in Ear Oedema Model on Balb/c
Mice
[0118] The study was carried out with 45 (5 par groups) female 9
weeks aged Balb/c ByJIc mice.
[0119] The Edema was induced by a single application of 20 .mu.l of
TPA dissolved in acetone at 0.01%.
[0120] The treatment was administrated by single topical
application of tested compounds dissolved in TPA at 0.01% (groups
3, 4, 5, 6 and 7) and dissolved in TPA 0.01%+BPO (groups 8, 9 and
10).
[0121] The treatments activity was measured by inflammation
evaluation with ear thickness at T+6 hours.
[0122] The results are presented in the following table and in FIG.
5.
TABLE-US-00003 Repeated Repeated Annova Testing Annova Testing Ear
edema Inhibition vs TPA alone vs TPA + BPO Mean sem vs TPA (%)
(Dose balanced) (Dose balanced) Acetone TPA 0.01% 26.80 3.35 TPA
0.01 + CD153 0.01% (controle) 2.20 0.37 91.8 0.042 TPA 0.01% + BPO
at 2.5% 22.40 2.23 16.4 TPA 0.01% + BPO at 5% 20.40 2.62 23.9 TPA
0.01% + BPO at 10% 16.20 4.03 39.6 TPA 0.01% + Adapalene at 0.1%
23.40 2.01 12.7 0.0015 TPA 0.01% + Adapalene at 0.1% + BPO at 2.5%
14.00 2.51 47.8 TPA 0.01% + Adapalene at 0.1% + BPO at 5% 10.00
2.26 62.7 TPA 0.01% + Adapalene at 0.1% + BPO at 10% 11.00 3.03
59.0
[0123] Conclusion:
[0124] After a single topical application of the positive control
CD0153 (0.01%) diluted in TPA solution, we observed a decrease of
92% of the ear thickness.
[0125] BPO at 2.5%, 5% and 10% has a slight anti-inflammatory
effect, reducing the TPA-induced ear edema respectively by 16%, 24%
and 40%, with a statistically significant dose balanced effect
(0.042).
[0126] Adapalene alone has a low anti-inflammatory effect, reducing
the TPA-induced ear edema by 13%.
[0127] Variation of concentration of BPO was measured in
combination with adapalene. Therefore, combinations of BPO at 2.5%,
5% and 10% with Adapalene at 0.1% reduce the TPA-induced ear edema
respectively by 48%, 63% and 59%. Combination treatment is
statistically more efficient than BPO alone (0.0015) even though
the dose effect of the latest group is non-significant regarding
the TPA alone group (0.1089).
[0128] Adapalene at 0.1% increases the anti-inflammatory effect
obtained with BPO whatever the tested doses.
[0129] Lower doses of BPO will be used to attempt to show a dose
related effect for the association.
[0130] These results show a potential synergistic anti-inflammatory
effect of the combination compared to the compounds singly
applied.
[0131] Further Clinical Testing
[0132] The results of several clinical trials (total of 3855 acne
vulgaris patients) were analyzed to determine whether adapalene and
benzoyl peroxide (BPO) demonstrate a synergistic efficacy in the
fixed dose combination of 0.1% adapalene and 2.5% benzoyl
peroxide.
Introduction
[0133] Combination therapy is frequently employed for management of
acne vulgaris due to the multi-factorial pathogenesis of the
disease..sup.1-4 Acne development involves multiple
pathophysiologic factors, including increase of sebum production,
ductal hypercornification, P. acnes proliferation and
inflammation/immunological response..sup.5 Topical monotherapies
such as retinoids, antibiotics and benzoyl peroxide (BPO) target
one or two of those factors; whereas combination therapy utilizing
agents with complementary mode of action provides possibility of
targeting multiple factors simultaneously. Combination therapy with
topical retinoids and antimicrobial agents is faster and more
efficacious than antimicrobial therapy alone in reducing both
inflammatory and non-inflammatory lesions,.sup.6-9 and is therefore
recommended in an international consensus guideline..sup.5
[0134] A fixed-dose topical combination gel containing adapalene
0.1% and BPO 2.5% has recently been developed for once-daily
treatment of acne. The distinct mechanisms of action and good
efficacy/safety profiles of adapalene and BPO make them a logical
choice for combination agents. Adapalene is as efficacious as other
retinoids but has a much lower irritation potential..sup.10 It
possesses anticomedogenic, comedolytic and anti-inflammatory
properties, and can be also used for long-term maintenance..sup.10
BPO is the most potent bactericidal agent among all topical
antibiotics,.sup.11 and has the additional advantage of not being
associated with selective pressure of bacterial resistance..sup.12
In addition, adapalene remains stable when combined with BPO even
in the presence of light..sup.13 Furthermore, it has been
demonstrated that adapalene can be used in conjunction with other
therapies without notably increasing the incidence of skin
irritation..sup.14-18 Three multicenter, double-blind, randomized
and controlled studies on adapalene-BPO were conducted, and the
results demonstrated a favorable efficacy/safety profile of the
combination gel..sup.19-21 Patients also reported to be more
satisfied with the effectiveness and the overall treatment of
adapalene-BPO than with the respective monotherapies and the gel
vehicle..sup.20,21
[0135] Several combination treatments of acne utilizing antibiotics
and BPO or tretinoin are currently available..sup.22-24 The
synergistic efficacy of individual components in those combinations
had never been reported, although the combinations were
demonstrated to be more efficacious than the corresponding
monotherapies. In the present report, we perform a pooled analysis
on the data of three adapalene-BPO studies involving a total of
3855 patients, and demonstrate a unique synergistic therapeutic
activity of adapalene and BPO when used in the fixed-dose
combination gel for treatment of acne vulgaris.
Methods and Material
Study Design
[0136] Three multicenter, double-blind, randomized and controlled
studies on the efficacy and safety of adapalene-BPO were conducted
in 157 centers in the U.S, Puerto Rico, Canada, Germany, Poland and
Hungary..sup.19-21 Patients were randomized to receive adapalene
0.1%-BPO 2.5% (Epiduo.RTM., Galderma Laboratories), adapalene 0.1%,
BPO 2.5% or vehicle once daily in the evening for 12 weeks.
Adapalene and BPO used in the studies were formulated in the same
gel vehicle as adapalene-BPO, instead of as the respective
commercial products (Differin.RTM. and Benzac.RTM., Galderma
Laboratories). Efficacy and safety assessments were performed at
each study visit, occurred at baseline, weeks 1, 2, 4, 8 and
12.
[0137] These three studies were conducted in accordance with the
Declaration of Helsinki, Good Clinical Practices (GCPs) and local
regulatory requirements. Studies were approved by institutional
review boards and ethics committees. All patients provided written
informed consent prior to entering the studies.
Patient Selection
[0138] Eligible patients were 12 years or older with 20 to 50
inflammatory lesions (IL), 30 to 100 non-inflammatory lesions
(NIL), no cysts and no more than 1 nodule on the face. Patients
enrolled in two of the three studies (a total of 3338) had an
investigator's global assessment (IGA) of 3, corresponding to
"moderate" acne. Lesion counts were performed on the face only
excluding the nose. Specified washout periods were required for
patients taking certain topical and systemic treatments. Patients
were excluded if they received systemic acne treatment or had
dermatological conditions requiring interfering treatments. Women
were excluded if they were pregnant, nursing, or planning a
pregnancy. Men were excluded if they had facial hair that would
interfere with assessments.
Efficacy and Safety Assessments
[0139] Efficacy assessments at each study visit included percentage
change from baseline in lesion counts (IL, NIL and total lesion)
and success rate, defined as the percentage of patients who had an
IGA of "clear" or "almost clear". IGA was evaluated on a scale from
0 (clear: residual hyperpigmentation and erythema may be present)
to 4 (severe: entire face is involved, covered with comedones,
numerous papules and pustules, and few nodules and cysts).
[0140] Safety of the treatments was evaluated through reporting of
adverse events (AE) and assessments of local facial tolerability.
At each study visit, the investigators rated signs of erythema,
scaling, dryness and stinging/burning on a scale from 0 (none) to 3
(severe).
Statistical Analyses
[0141] Data from the three studies were pooled and analyzed.
Efficacy was evaluated in the intent-to-treat (ITT) population,
which included all patients who were randomized and dispensed study
medicine. Safety was assessed in the safety population, which
included all patients who were randomized and treated at least
once.
[0142] Efficacy was evaluated by the Cochran-Mantel-Haenzsel (CMH)
test, using general association for success rate and row mean
differences by relative to identified distribution (RIDIT)
transformed scores for percent lesion change. All tests were
2-sided.
DEFINITION AND CALCULATION OF SYNERGY
[0143] Synergy was defined as the efficacy of combination
(adapalene-BPO) greater than the sum of efficacy of individual
components (adapalene alone and BPO alone). We took into account
the vehicle effect by deducting it from the effect of
treatments:.sup.25
Net effect of active agent=effect of active agent-effect of vehicle
Synergy=Net effect of adapalene-BPO-(Net effect of adapalene+Net
effect of BPO)>0
[0144] The degree of synergy was evaluated based on the
contribution of synergy to efficacy (net effect) of
adapalene-BPO:
Degree of synergy(%)=(synergy/Net effect of
adapalene-BPO).times.100
Results
Patient Disposition and Baseline Disease Characteristics
[0145] The ITT population included a total of 3855 patients:
adapalene-BPO (n=983), adapalene (n=986), BPO (n=979) and gel
vehicle (n=907) (FIG. 6). Patient disposition was similar among
treatment groups. On average, 87.2% of patients completed the
studies and only 1.2% discontinued due to "adverse event (AE)".
[0146] Table 1 summarizes the demographic and baseline disease
characteristics, which were comparable among treatment groups. Mean
age of enrolled patients was 18.3 years and the majority of
patients were Caucasians (72.0%).
TABLE-US-00004 TABLE 1 Demography and baseline disease
characteristics. Adapalene BPO Adapalene-BPO Vehicle Total (N =
986) (N = 979) (N = 983) (N = 907) (N = 3855) Age, year Mean 18.0
18.3 18.7 18.4 18.3 Min, max 12, 50 12, 56 12, 58 12, 51 12, 58
Gender, N (%) Male 478 (48.5) 489 (49.9) 475 (48.3) 410 (45.2) 1852
(48.0) Female 508 (51.5) 490 (50.1) 508 (51.7) 497 (54.8) 2003
(52.0) Race, N (%) Caucasian 712 (72.2) 701 (71.6) 709 (72.1) 653
(72.0) 2775 (72.0) Black 121 (12.3) 130 (13.3) 121 (12.3) 117
(12.9) 489 (12.7) Asian 19 (1.9) 22 (2.2) 20 (2.0) 24 (2.6) 85
(2.2) Hispanic 115 (11.7) 105 (10.7) 112 (11.4) 103 (11.4) 435
(11.3) Other 19 (1.9) 21 (2.1) 21 (2.1) 10 (1.1) 71 (1.8) Median
lesion counts total 77 75 76 76 76 inflammatory 27 27 27 27 27
Non-inflammatory 46 45 44 46 45 Global Severity, N (%) 2: Mild 28
(2.8) 15 (1.5) 25 (2.5) 13 (1.4) 81 (2.1) 3: Moderate 949 (96.2)
956 (97.7) 953 (97.0) 889 (98.3) 3747 (97.2) 4: Severe 9 (1.0) 8
(0.8) 5 (0.5) 3 (0.3) 25 (0.6)
Synergistic Efficacy of Adapalene and BPO in the Combination
Gel
[0147] Adapalene-BPO was significantly more efficacious than
monotherapies and vehicle in decreasing all types of lesion counts
at all time points (P<0.05; FIGS. 7A, 8A and 9A). Significant
difference in total, inflammatory and non-inflammatory lesion
counts reduction for adapalene-BPO was observed as early as week 1
(P<0.001). After week 4, the effect of vehicle stagnated;
whereas the lesion counts in adapalene-BPO group continued to
decrease throughout the study period without reaching a plateau. At
week 12, the median percentage reduction from baseline in the
adapalene-BPO group was 66%, 58% and 59% for IL, NIL and total
lesion, respectively.
[0148] The vehicle effect was subsequently deducted and the net
effect of combination and monotherapies were compared (FIGS. 7B, 8B
and 9B). Adapalene-BPO treatment led to a faster decrease in all
lesion counts compared to monotherapies during the entire study
period. For total lesions, the net effect of adapalene-BPO at week
1 (7.4%) was greater than the sum of net effects of adapalene alone
and BPO alone (1.4% plus 2.4%), indicating that the two components
acted synergistically in the combination (FIG. 7B). Synergistic
effect in total lesion reduction was observed at weeks 1, 2, 4 and
8. Similarly, it was observed from week 1 until week 4 for IL
reduction (FIG. 8B), and until week 8 for NIL reduction (FIG.
9B).
[0149] To quantify the synergy effect, the contribution of synergy
to the efficacy of adapalene-BPO was calculated. At week 1, synergy
contributed to 48.7%, 62.5% and 40.9% of the efficacy of
adapalene-BPO in decreasing total, IL and NIL counts, respectively
(FIGS. 7C, 8C and 9C). The degree of synergy was the highest at
week 1 and decreased at subsequent visits.
[0150] The significant and synergistic efficacy of adapalene-BPO
was also demonstrated in the global assessment of success rate.
Results of success rate began to diverge early in favor of
adapalene-BPO and continued throughout the study period. At week
12, adapalene-BPO (33.1%) was superior to adapalene alone (20.0%),
BPO alone (23.1%) and vehicle (14.2%) (P<0.001; FIG. 10A). In
addition, the combination was significantly better than
monotherapies and vehicle at week 8 (P<0.001), and better than
adapalene at all time points (P<0.05).
[0151] A synergistic efficacy of adapalene and BPO in success rate
was observed at weeks 1, 4, 8 and 12 (FIG. 10B). At week 1, the net
effect of adapalene-BPO was entirely due to the synergy. At weeks 8
and 12, when the efficacy of adapalene-BPO was significantly
superior to that of monotherapies, the contribution of synergy was
41.7% and 22.2%, respectively (FIG. 10C).
Safety Evaluation
[0152] The mean scores for dryness, erythema, scaling and
stinging/burning in all treatment groups were lower than 1 (mild)
at all study visits (FIGS. 11A, 11B, 11C, 11D). The scores of
adapalene-BPO at week 1 were the highest among treatment groups;
however, they decreased rapidly and became similar to the scores of
adapalene at subsequent visits. A majority of patients in all
treatment groups experienced no or only mild irritation.
[0153] The percentage of patients who experienced treatment-related
AEs was higher for adapalene-BPO (21.6%) than for other groups
(15.3%, 8.5% and 6.0% for adapalene, BPO and vehicle,
respectively). The majority of related AEs were of dermatological
nature, mild to moderate in severity, occurred early in the studies
and resolved without residual effects. In adapalene-BPO group, "dry
skin" occurred in 13.0% of patients and accounted for the vast
majority of related AEs.
Discussion
[0154] Although several acne combination therapies are currently
available, cooperative action among the individual components of
those combinations have never been reported..sup.22-24 Therefore,
the synergistic efficacy of adapalene and BPO observed in this
analysis is a unique feature of the fixed-dose combination therapy.
Synergy is defined as combination's effect greater than the sum of
components' effect. Since the vehicle in topical acne therapies is
known to be non-negligible, the vehicle effect was taken into
account and the net effect of each treatment was compared.
[0155] Lesion counts change from baseline provides precise
information about efficacy of the treatment. The combination
therapy is superior to monotherapies and vehicle, leading to
significantly greater reduction in all lesion counts at all time
points (P<0.05). Adapalene-BPO demonstrated an onset of action
as early as week 1, possibly explained by the highest degree of
synergy observed at this time point. Such an improvement at the
beginning stage of therapy may help to augment patient's confidence
on the treatment and encourage adherence, which was reported to be
poor in general in acne treatments..sup.26 Although synergy was not
observed after week 8, lesion counts continued to decrease in the
group of adapalene-BPO throughout the 12-week study period without
stagnating, confirming the previous results of a long-term efficacy
study..sup.16 The anti-comedogenic activity of adapalene might
contribute to the observed long-lasting efficacy of the
combination, since adapalene not only reduces the number of
existing comedones, but also controls the development of
microcomedoes and prevents the formation of new acne
lesions..sup.5
[0156] Compared to the change of lesion counts, the global
assessment of IGA is perhaps clinically more relevant. The rapid
reduction of lesion counts early during the study translated into
an obvious global improvement at a later stage: The success rate of
adapalene-BPO was the best numerically from week 1, increased
substantially after week 4 and became significantly greater than
the success rate of monotherapies and vehicle at weeks 8 and 12
(P<0.001). The synergy effect in success rate also had a longer
duration than in lesion counts: At weeks 8 and 12, synergy
contributed to 41.7% and 22.2% of the efficacy of adapalene-BPO
respectively, explaining the striking increase of success rate in
the third month of the study. Since lesion counts continued to
decrease after week 12,.sup.16 it is likely that the success rate
also continues to increase after the end of the study, leading to a
greater global improvement of acne. This long-lasting efficacy of
the combination gel is crucial for treatment success of acne, due
to the chronic nature of the disease.
[0157] Several unique features of adapalene and BPO provide
potential explanations for the synergistic efficacy observed in the
combination. First, both topical retinoids and BPO are keratolytic
agents and may affect skin permeability by reducing the number of
corneocytes layer..sup.27-29 Thus, the simultaneous application of
adapalene and BPO may facilitate absorption and penetration of each
other, leading to higher efficacy of both agents when used in
combination.
[0158] Furthermore, adapalene has a unique anti-inflammatory
activity..sup.30 The results of an in vitro study demonstrated that
adapalene antagonizes the effect of P. acnes on inducing the
expression of toll-like receptor 2,.sup.31 which is required by the
bacteria to induce the release of pro-inflammatory
cytokine..sup.32,33 In addition, adapalene can modulate immune
response by altering the expression of CD1d and IL-10,.sup.31 thus
further strengthens the antimicrobial activity of the innate immune
system.
[0159] Finally, BPO possesses weak comedolytic property, in
addition to its antimicrobial activity..sup.5 P. acnes induces the
release of IL-1 from follicular keratinocytes,.sup.34,35 which
leads to proliferation of keratinocytes and contributes to the
formation of comedones. Therefore, the activity of BPO against
non-inflammatory lesions is most likely to be indirect, through its
bactericidal action.
[0160] Adapalene-BPO provides synergistic efficacy without causing
notable increase of irritation. The good safety profile of the
combination gel demonstrated in this report is consistent with
findings of previous studies..sup.14-21 Although the peak scores at
week 1 were higher with adapalene-BPO, the overall tolerability
profile of the combination was comparable to that of adapalene
monotherapy at subsequent visits. The temporary increase of
tolerability scores can be explained by the enhanced absorption of
adapalene and BPO when applied simultaneously. However, irritation
was observed mostly during the first two weeks of treatment, while
the beneficial effect of synergy lasted much longer (up to 12
weeks). Furthermore, the irritation signs and dry skin condition
can be easily managed by the concomitant usage of non-comedogenic
moisturizers, which should be recommended when physicians
prescribing acne medications.
[0161] In conclusion, the fixed-dose once-daily adapalene-BPO
combination gel not only is significantly more efficacious than the
corresponding monotherapies, but also provides a unique synergistic
efficacy in the treatment of acne vulgaris.
[0162] Each patent, patent application, publication, text and
literature article/report cited or indicated herein is hereby
expressly incorporated by reference in its entirety.
[0163] While the invention has been described in terms of various
specific and preferred embodiments, the skilled artisan will
appreciate that various modifications, substitutions, omissions,
and changes may be made without departing from the spirit thereof.
Accordingly, it is intended that the scope of the present invention
be limited solely by the scope of the following claims, including
equivalents thereof.
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