U.S. patent application number 15/476241 was filed with the patent office on 2017-07-20 for combination/association of adapalene and benzoyl peroxide for treating acne.
The applicant listed for this patent is Galderma Research & Development. Invention is credited to Denis GROSS, Christian LOESCHE, Michel PONCET, Marie-Line Abou Chacra VERNET.
Application Number | 20170202803 15/476241 |
Document ID | / |
Family ID | 37763873 |
Filed Date | 2017-07-20 |
United States Patent
Application |
20170202803 |
Kind Code |
A1 |
VERNET; Marie-Line Abou Chacra ;
et al. |
July 20, 2017 |
COMBINATION/ASSOCIATION OF ADAPALENE AND BENZOYL PEROXIDE FOR
TREATING ACNE
Abstract
Acne lesions, whether of inflammatory and/or non-inflammatory
type, are simultaneously or sequentially treated and their number
reduced, via daily topical regimen, with the combination or
association of adapalene or pharmaceutically acceptable salt
thereof and benzoyl peroxide (BPO).
Inventors: |
VERNET; Marie-Line Abou Chacra;
(Nice, FR) ; GROSS; Denis; (Callian, FR) ;
LOESCHE; Christian; (Valbonne, FR) ; PONCET;
Michel; (Mougins, FR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Galderma Research & Development |
Biot |
|
FR |
|
|
Family ID: |
37763873 |
Appl. No.: |
15/476241 |
Filed: |
March 31, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14301816 |
Jun 11, 2014 |
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15476241 |
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13351986 |
Jan 17, 2012 |
8785420 |
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14301816 |
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11826364 |
Jul 13, 2007 |
8129362 |
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13351986 |
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60833491 |
Jul 27, 2006 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 29/00 20180101;
A61K 31/192 20130101; A61K 9/06 20130101; A61K 31/192 20130101;
A61K 47/10 20130101; A61P 17/10 20180101; A61K 47/26 20130101; Y10S
514/859 20130101; A61K 31/327 20130101; A61K 9/0014 20130101; A61K
31/327 20130101; A61K 47/20 20130101; A61K 2300/00 20130101; A61P
17/00 20180101; A61K 47/32 20130101; A61P 43/00 20180101; A61K
47/18 20130101; A61K 2300/00 20130101 |
International
Class: |
A61K 31/327 20060101
A61K031/327; A61K 9/06 20060101 A61K009/06; A61K 31/192 20060101
A61K031/192 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 13, 2006 |
FR |
06/52968 |
Claims
1. A method of treating acne of severe intensity, the method
comprising topically administering to a patient having acne of
severe intensity and in need of treatment thereof, a fixed-dose
combination of 0.1 wt % to 0.3 wt % adapalene and 2.5 wt % benzoyl
peroxide relative to the total weight of the fixed-dose
combination, wherein the adapalene and benzoyl peroxide are
combined in a single formula that delivers the adapalene and
benzoyl peroxide together synergistically to achieve, in a group of
subjects in need of treatment for acne of severe intensity, a
degree of success of at least about 20%, wherein the adapalene and
the benzoyl peroxide are the only active agents present in the
fixed-dose combination and in the method; and wherein the single
formula is applied once daily for a period of at least 12
weeks.
2. The method of claim 1, wherein the degree of success achieved is
at least about 30% within 12 weeks of treatment.
3. The method of claim 1, wherein the fixed-dose combination
comprises 0.3 wt % adapalene.
4. The method of claim 1, wherein the single formula is a gel.
5. A method of achieving success rates better than a vehicle in
patients having acne of severe intensity, the method comprising
topically administering to a patient having acne of severe
intensity and in need of treatment thereof, a fixed-dose
combination of 0.1 wt % to 0.3 wt % adapalene and 2.5 wt % benzoyl
peroxide relative to the total weight of the fixed-dose
combination, wherein the adapalene and benzoyl peroxide are
combined in a single formula that delivers the adapalene and
benzoyl peroxide together synergistically to achieve, in a group of
subjects in need of treatment for acne of severe intensity, a
degree of success of at least about 20%, wherein the degree of
success for a subject is a clear or almost clear rating; wherein
the adapalene and the benzoyl peroxide are the only active agents
present in the fixed-dose combination and in the method; and
wherein the single formula is applied once daily for a period of at
least 12 weeks.
6. The method of claim 5, wherein the degree of success achieved is
at least about 30% within 12 weeks of treatment.
7. The method of claim 5, wherein the fixed-dose combination
comprises 0.3 wt % adapalene.
8. The method of claim 5, wherein the single formula is a gel.
Description
CROSS-REFERENCE TO EARLIER APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 14/301,816, filed Jun. 11, 2014, now allowed,
which is a continuation of earlier copending U.S. patent
application Ser. No. 13/351,986, filed Jan. 17, 2012, now U.S. Pat.
No. 8,785,420, which is a continuation of earlier copending U.S.
patent application Ser. No. 11/826,364, filed Jul. 13, 2007, now
U.S. Pat. No. 8,129,362, which claims benefit of U.S. Provisional
Application No. 60/833,491, filed Jul. 27, 2006, and claims
priority of FR 06/52968, filed Jul. 13, 2006, each hereby expressly
incorporated by reference and each assigned to the assignee
hereof.
BACKGROUND OF THE INVENTION
[0002] 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] Description of Background and/or Related and/or Prior
Art
[0005] 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 the subject of development for the topical treatment
of common acne and of dermatoses sensitive to retinoids.
[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 surprisingly been demonstrated that a therapeutic
association or combination of adapalene and BPO can produce a
degree of success in reducing the number of acne lesions and an
improvement in the clinical condition of patients that is markedly
superior to 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 for the preparation
of a pharmaceutical composition, especially at set doses, suited 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. Stated
differently, the invention relates to the use 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.
[0018] 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 adapalene and pharmaceutically acceptable salts
thereof, and (ii) benzoyl peroxide (BPO). Preferably, the
pharmaceutical composition is intended for a single topical
application per day.
[0019] The term "pharmaceutically acceptable medium" means a medium
that is compatible with the skin, mucous membranes and the
integuments.
[0020] 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 the manufacture, in the same vehicle, which delivers them
together during the application of the gel.
[0021] In another embodiment of the invention, the pharmaceutical
composition is in the form of a composition A comprising adapalene,
intended 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).
[0022] In this case, one skilled in the art will adapt the formula
that is the most appropriate in terms of viscosity, additives, etc.
to the selected kit.
[0023] The expression "concomitant" application means that the
compositions are 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.
[0024] The invention thus also features a composition in kit form
comprising at least two components:
a first component comprising at least adapalene or a
pharmaceutically acceptable salt thereof, a second component
comprising benzoyl peroxide, these two components to be applied
concomitantly to the skin, mucous membranes and/or the
integuments.
[0025] Compositions A and B are preferably suited for a single
cutaneous topical application per day.
[0026] 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 or regimen 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.
BRIEF DESCRIPTION OF THE DRAWINGS
[0027] FIGS. 1-4 are graphs showing the efficacy of adapalene+BPO
according to the invention versus adapalene alone, BPO alone and
vehicle alone; and
[0028] FIG. 5 is a bar graph showing the effects on ear edema of a
variety of test compounds.
DETAILED DESCRIPTION OF BEST MODE AND SPECIFIC/PREFERRED
EMBODIMENTS OF THE INVENTION
[0029] All the pharmaceutical compositions according to 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.
[0030] All the percentages are indicated by weight relative to the
total weight of the composition.
[0031] The adapalene:BPO ratio is from 1:1 and 1:200 and,
conversely, the BPO:adapalene ratio is from 1:1 and 1:200.
Preferably, the adapalene:BPO ratio is from 1:1 and 1:200 and the
adapalene:BPO ratio is preferably 1:25.
[0032] 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.
[0033] 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.
[0034] When compositions A and B are used 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.
[0035] In this regard, the examples to follow demonstrate that due
to 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.
[0036] 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.
[0037] 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.
[0038] Preferably, the pharmaceutical compositions combining
adapalene and BPO, or the pharmaceutical compositions A and/or B,
are gels.
[0039] The pharmaceutical compositions according to the invention
may contain inert additives or combinations of these additives,
such as:
wetting agents; texture enhancers; preservatives such as
para-hydroxybenzoic acid esters; stabilizers; humidity regulators;
pH regulators; osmotic pressure modifiers; emulsifiers; UV-A and
UV-B screening agents; and antioxidants, such as a-tocopherol,
butylhydroxyanisole or butylhydroxytoluene, superoxide dismutase,
ubiquinol, or certain metal-chelating agents.
[0040] 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.
[0041] According to one particular embodiment, the pharmaceutical
composition A comprising adapalene may be an aqueous gel especially
containing one or more ingredients selected from the carbomer 940
(BF Goodrich Carbopol 980) and propylene glycol, or a cream
especially containing one or more ingredients selected from
perhydrosqualene, cyclomethicone, PEG-20 methylglucose
sesquistearate and methylglucose sesquistearate or an "alcoholic
lotion" solution based on polyethylene glycol.
[0042] 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:
from 5% to 25% of water; from 0 to 10%, preferably from 0 to 2% and
preferably less than 0.5% of liquid wetting surfactant; from 0 to
10% of pro-penetrating agent; and an aqueous phase comprising a
pH-independent gelling agent.
[0043] According to one preferred embodiment, the preferred
pharmaceutical composition, comprising adapalene and BPO, is an
aqueous gel having the following formulation:
2.5% of BPO;
[0044] 0.1% of adapalene; 0.10% of disodium EDTA; 4.00% of
glycerol; 4.00% of propylene glycol; and also, preferably: 0.05% of
sodium docusate; 0.20% of poloxamer 124; 4.00% of sodium
acryloyldimethyltaurate copolymer and isohexadecane and polysorbate
80; NaOH, in an amount sufficient to obtain a pH of 5.
[0045] 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.
[0046] 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 below 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.
[0047] 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.
[0048] 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%.
[0049] According to another aspect, the invention also features a
pharmaceutical assembly (product) comprising:
i) a container delimiting at least one compartment, the said
container being closed by means of a closing member; and ii) a
pharmaceutical composition comprising adapalene or a
pharmaceutically acceptable salt thereof and benzoyl peroxide as
described above, and placed inside the said compartment.
[0050] 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.
[0051] Preferably, the container comprises two compartments, and
each of these compartments comprises either composition A or
composition B.
[0052] 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.
[0053] 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.
[0054] The container may be at least partly made of thermoplastic
material. Examples of thermoplastic materials that are
representative include polypropylene and polyethylene.
[0055] Alternatively, the container is made of a non-thermoplastic
material, especially of glass or metal (or alloy).
[0056] The container may have rigid walls or deformable walls,
especially in the form of a tube or a tube bottle.
[0057] 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.
[0058] 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 Result:
[0059] A clinical study for confirmation of efficacy was performed
for a topical gel combining adapalene+benzoyl peroxide (BPO).
[0060] 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%
[0061] Protocol:
[0062] The clinical study was a multi-centre, 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.
[0063] All the treatments were applied once a day for 12 weeks, to
517 patients suffering from acne.
[0064] The main efficacy criteria were:
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; the reduction of the percentage of
inflammatory and non-inflammatory lesions after 12 weeks of
treatment.
[0065] Results:
[0066] The results are presented in the table that follows and in
FIGS. 1-4.
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).
[0067] 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.
[0068] 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).
[0069] 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% and 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.
[0070] 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).
[0071] 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 accurate.
Example 2
Evaluation of the Anti-Inflammatory in Ear Edema Model on Balb/c
Mice:
[0072] The study was carried out with 45 (5 par groups) female 9
weeks aged Balb/c ByJIc mice.
[0073] The Edema was induced by a single application of 20 .mu.l of
TPA dissolved in acetone at 0.01%.
[0074] 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).
[0075] The treatments activity was measured by inflammation
evaluation with ear thickness at T+6hours.
[0076] The results are presented in the following table and in FIG.
5.
TABLE-US-00003 Repeated Repeated Annova Annova Testing Testing Ear
Edema vs TPA vs TPA + Inhibition alone BPO sem vs (Dose (Dose Mean
TPA (%) Balanced) Balanced) Acetone TPA 0.01% 26.80 3.35 TPA 0.01%
+ CD153 0.01 2.20 0.37 91.8 -- (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 0.042 -- TPA 0.01% + Adapalene at
23.40 2.01 12.7 -- -- 0.1% TPA 0.01% + Adapalene at 14.00 2.51 47.8
-- 0.0015 0.1% + BPO at 2.5% TPA 0.01% + Adapalene at 10.00 2.26
62.7 0.1% + BPO at 5% TPA 0.01% + Adapalene at 11.00 3.03 59.0 0.1%
+ BPO at 10%
[0077] Conclusion:
[0078] After a single topical application of the positive control
CD0153 (0.01%) diluted in TPA solution, a decrease of 92% of the
ear thickness was observed.
[0079] 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).
[0080] Adapalene alone has a low anti-inflammatory effect, reducing
the TPA-induced ear edema by 13%.
[0081] 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).
[0082] Adapalene at 0.1% increase the anti-inflammatory effect
obtained with BPO whatever tested doses.
[0083] Lower doses of BPO will be used to attempt to show a dose
related effect for the association.
[0084] These results show a potential synergistic anti-inflammatory
effect of the combination compared to the compounds singly
applied.
[0085] Each patent, patent application, publication, text and
literature article/report cited or indicated herein is hereby
expressly incorporated by reference.
[0086] 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.
* * * * *