U.S. patent application number 13/296186 was filed with the patent office on 2012-03-08 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 | 20120059063 13/296186 |
Document ID | / |
Family ID | 37763873 |
Filed Date | 2012-03-08 |
United States Patent
Application |
20120059063 |
Kind Code |
A1 |
ABOU-CHACRA VERNET; Marie-line ;
et al. |
March 8, 2012 |
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) |
Assignee: |
Galderma Research &
Development
Biot
FR
|
Family ID: |
37763873 |
Appl. No.: |
13/296186 |
Filed: |
November 14, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12318937 |
Jan 13, 2009 |
8071644 |
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13296186 |
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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 ;
206/438 |
Current CPC
Class: |
A61K 47/26 20130101;
A61K 47/32 20130101; A61K 47/20 20130101; A61K 47/18 20130101; A61K
9/0014 20130101; A61K 31/327 20130101; A61P 17/10 20180101; A61K
2300/00 20130101; A61K 2300/00 20130101; A61K 47/10 20130101; A61K
9/06 20130101; A61P 43/00 20180101; A61K 31/192 20130101; A61K
31/327 20130101; A61P 29/00 20180101; A61P 17/00 20180101; A61K
31/192 20130101; Y10S 514/859 20130101 |
Class at
Publication: |
514/569 ;
206/438 |
International
Class: |
A61K 31/327 20060101
A61K031/327; B65D 85/00 20060101 B65D085/00; A61P 17/10 20060101
A61P017/10 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 13, 2006 |
FR |
0652968 |
Claims
1. A method for reducing the number of acne lesions, comprising
administering to an individual afflicted therewith, a thus
effective amount of a pharmaceutical composition which comprises
adapalene or a pharmaceutically acceptable salt thereof,
administered in combination or in a concomitant application with
benzoyl peroxide.
2. The method as defined by claim 1, comprising administering a
pharmaceutical composition which comprises fixed combination which
comprises (i) at least one compound selected from among adapalene
and pharmaceutically acceptable salts thereof, and (ii) benzoyl
peroxide, formulated into a pharmaceutically acceptable medium
therefor.
3. The method as defined by claim 1, said acne lesions being of
inflammatory and/or non-inflammatory type.
4. The method as defined by claim 3, in which the reduction of the
number of inflammatory and/or non-inflammatory acne lesions is at
least about 40%.
5. The method as defined by claim 2, comprising administering a
pharmaceutical composition in which the adapalene and the benzoyl
peroxide are present in synergistic amounts. 25
6. The method as defined by claim 2, wherein the pharmaceutical
composition comprises 0.1% of adapalene and 2.5% of benzoyl
peroxide.
7. The method as defined by claim 2, wherein the pharmaceutical
composition is a gel.
8. The method as defined by claim 1, wherein the pharmaceutical
composition is adapted for topical application.
9. The method as defined by claim 1, wherein the pharmaceutical
composition is in the form of a composition A comprising adapalene,
to be applied concomitantly with a composition B comprising benzoyl
peroxide.
10. The method as defined by claim 9, wherein the adapalene and the
benzoyl peroxide are present, respectively, in compositions A and B
in synergistic amounts.
11. The method as defined by claim 9, wherein composition A
comprises 0.1% of adapalene and composition B comprises 2.5% of
benzoyl peroxide.
12. The method as defined by claim 9, wherein the compositions A
and B are gels.
13. The method as defined by claim 9, wherein the composition A and
composition B are presented in the form of a kit.
14. The method as defined by claim 13, wherein the kit comprises
two isolated compartments each containing one of the two
pharmaceutical compositions A or B.
15. The method as defined by claim 13, wherein the kit comprises at
least one association of the two compositions A and B, in two
separate packages in the same presentation.
16. The method as defined by claim 9, wherein the said
pharmaceutical composition is composition A, to be applied in any
order or sequentially, within a time interval of less than 1 hour,
with composition B.
17. The method as defined by claim 9, wherein the compositions A
and B are adapted for topical application.
18. The method as defined by claim 3, wherein the pharmaceutical
composition is useful for reducing the number of inflammatory acne
lesions.
19. The method as defined by claim 3, wherein the pharmaceutical
composition is useful for reducing the number of non-inflammatory
acne lesions.
20. A method for potentiating the action of benzoyl peroxide,
comprising administering therewith adapalene or a pharmaceutically
acceptable salt thereof.
21. A kit comprising at least two components: a first component
which comprises at least adapalene or a pharmaceutically acceptable
salt thereof, and a second component which comprises benzoyl
peroxide.
22. A product comprising: (i) a container delimiting at least one
compartment, the said container being sealed by means of a closing
member; and (ii) a pharmaceutical composition which comprises
adapalene or a pharmaceutically acceptable salt thereof and benzoyl
peroxide, confined inside the said compartment.
Description
CROSS-REFERENCE TO EARLIER APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 12/318,937, filed Jan. 13, 2009, now allowed, which is a
continuation of PCT/EP 2007/057207, filed Jul. 12, 2007 and
designating the United States (published in the English language on
January 17, 2008 as WO 2008/006888 A1); which claims priority under
35 U.S.C. .sctn.119 of FR 0652968, filed Jul. 13, 2006 and claims
benefit of U.S. Provisional Application No. 60/833,491, filed Jul.
27, 2006; each earlier application hereby expressly incorporated by
reference in its entirety and each assigned to the assignee
hereof.
BACKGROUND OF THE INVENTION
[0002] 1. Technical Field of the Invention
[0003] The present invention relates to the combined or associated
administration of adapalene and of benzoyl peroxide for reducing
the number of acne lesions.
[0004] 6-[3-(1-Adamantyl)-4-methoxyphenyl]-2-naphthoic acid
(referred to hereinbelow 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 03/055 472 moreover describes 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; and
[0020] FIG. 5 is a bar graph evaluating the anti-inflammatory
effect on ear edema of treatment according to the invention or
not.
DETAILED DESCRIPTION OF BEST MODE AND SPECIFIC/PREFERRED
EMBODIMENTS OF THE INVENTION
[0021] 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.
[0022] The term "pharmaceutically acceptable medium" means a medium
that is compatible with the skin, mucous membranes and the
integuments.
[0023] 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.
[0024] 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).
[0025] 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.
[0026] 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.
[0027] The present invention thus also features compositions in kit
form comprising at least two components:
[0028] a first component comprising at least adapalene or a
pharmaceutically acceptable salt thereof,
[0029] a second component comprising benzoyl peroxide, these two
components being suited to be applied concomitantly to the skin,
mucous membranes and/or the integuments.
[0030] Compositions A and B are preferably useful for a single
cutaneous topical application per day.
[0031] 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.
[0032] 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.
[0033] All the percentages are indicated by weight relative to the
total weight of the composition.
[0034] 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.
[0035] 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.
[0036] 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.
[0037] 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.
[0038] 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.
[0039] 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.
[0040] 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.
[0041] Preferably, the pharmaceutical compositions combining
adapalene and BPO, or the pharmaceutical compositions A and/or B,
are gels.
[0042] The pharmaceutical compositions of the invention may contain
inert additives or combinations of these additives, such as:
[0043] wetting agents;
[0044] texture enhancers;
[0045] preservatives such as para-hydroxybenzoic acid esters;
[0046] stabilizers;
[0047] humidity regulators;
[0048] pH regulators;
[0049] osmotic pressure modifiers;
[0050] emulsifiers;
[0051] UV-A and UV-B screening agents; and
[0052] antioxidants, such as a-tocopherol, butylhydroxyanisole or
butylhydroxytoluene, superoxide dismutase, ubiquinol, or certain
metal-chelating agents.
[0053] 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.
[0054] 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.
[0055] 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:
[0056] from 5% to 25% of water;
[0057] from 0 to 10%, preferably from 0 to 2% and preferably less
than 0.5% of liquid wetting surfactant;
[0058] from 0 to 10% of pro-penetrating agent; and
[0059] an aqueous phase comprising a pH-independent gelling
agent.
[0060] According to one preferred embodiment, the preferred
pharmaceutical composition, comprising adapalene and BPO, is an
aqueous gel having the following formulation:
[0061] 2.5% of BPO;
[0062] 0.1% of adapalene;
[0063] 0.10% of disodium EDTA;
[0064] 4.00% of glycerol;
[0065] 4.00% of propylene glycol; and also, preferably:
[0066] 0.05% of sodium docusate;
[0067] 0.20% of poloxamer 124;
[0068] 4.00% of sodium acryloyldimethyltaurate copolymer and
isohexadecane and polysorbate 80;
[0069] NaOH, in an amount sufficient to obtain a pH of 5.
[0070] 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.
[0071] 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.
[0072] 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.
[0073] 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%.
[0074] According to another embodiment, this invention also
features a pharmaceutical assembly (product) comprising:
[0075] i) a container delimiting at least one compartment, the said
container being closed by means of a closing member; and
[0076] ii) a pharmaceutical composition comprising adapalene or a
pharmaceutically acceptable salt thereof and benzoyl peroxide as
described above, and placed inside the said compartment.
[0077] 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.
[0078] Preferably, the container comprises two compartments, and
each of these compartments comprises either composition A or
composition B.
[0079] 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.
[0080] 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.
[0081] The container may be at least partly made of thermoplastic
material. Examples of thermoplastic materials include polypropylene
and polyethylene.
[0082] Alternatively, the container is made of a non-thermoplastic
material, especially of glass or metal (or alloy).
[0083] The container may have rigid walls or deformable walls,
especially in the form of a tube or a tube bottle.
[0084] 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.
[0085] 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
[0086] A clinical study for confirmation of efficacy was performed
for a topical gel combining adapalene+benzoyl peroxide (BPO).
[0087] 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% .sup.
Protocol
[0088] 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.
[0089] All the treatments were applied once a day for 12 weeks, to
517 patients suffering from acne.
[0090] The main efficacy criteria were:
[0091] 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;
[0092] the reduction of the percentage of inflammatory and
non-inflammatory lesions after 12 weeks of treatment.
Results
[0093] The results are presented in the Table that follows.
TABLE-US-00002 Efficacy in week 12 ITT* Adapalene Adapalene BPO
0.1% + 0.1% 2.5% Vehicle BPO 2.5% alone alone (gel) N = 149 N = 148
N = 149 N = 71 Degree of success 27.5% 15.5% 15.4% 9.9% (see FIG.
4) Progress of the lesions (median percentages) Number of -62.8%
-45.7% -43.6% -37.8% inflammatory lesions (see FIG. 2) Number of
non- -51.2% -33.3% -36.4% -37.5% inflammatory lesions (see FIG. 3)
Total number of -51.0% -35.4% -35.6% -31.0% lesions (see FIG. 1)
Progress of the lesions (as median absolute numbers) Number of -17
-13.0 -13.0 -11.0 inflammatory lesions Number of non- -22.0 -17.0
-16.0 -14.0 inflammatory lesions Total number of -40.0 -29.0 -27
-26.0 lesions
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).
[0094] 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.
[0095] 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).
[0096] 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.
[0097] 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).
[0098] 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
[0099] The study was carried out with 45 (5 par groups) female 9
weeks aged Balb/c ByJlc mice.
[0100] The Edema was induced by a single application of 20 .mu.l of
TPA dissolved in acetone at 0.01%.
[0101] 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).
[0102] The treatments activity was measured by inflammation
evaluation with ear thickness at T+6hours.
[0103] 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 Acetone Mean sem vs TPA
(%) (Dose balanced) (Dose balanced) TPA 0.01% 26.80 3.35 TPA 0.01 +
CD153 0.01% 2.20 0.37 91.8 0.042 (controle) 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% + 14.00 2.51 47.8 BPO at
2.5% TPA 0.01% + Adapalene at 0.1% + 10.00 2.26 62.7 BPO at 5% TPA
0.01% + Adapalene at 0.1% + 11.00 3.03 59.0 BPO at 10%
Conclusion
[0104] 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.
[0105] 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).
[0106] Adapalene alone has a low anti-inflammatory effect, reducing
the TPA-induced ear edema by 13%.
[0107] 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).
[0108] Adapalene at 0.1% increases the anti-inflammatory effect
obtained with BPO whatever the tested doses.
[0109] Lower doses of BPO will be used to attempt to show a dose
related effect for the association.
[0110] These results show a potential synergistic anti-inflammatory
effect of the combination compared to the compounds singly
applied.
[0111] Each patent, patent application, publication, text and
literature article/report cited or indicated herein is hereby
expressly incorporated by reference in its entirety.
[0112] 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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