Patent application title: COMBINATIONS OF ADAPALENE AND BENZOYL PEROXIDE FOR TREATING ACNE LESIONS
Marie-Line Abou-Chacra Vernet (Nice, FR)
Denis Gross (Callian, FR)
Christian Loesche (Valbonne, FR)
Michel Poncet (Mougins, FR)
Galderma Research & Development
IPC8 Class: AA61K31327FI
Class name: Carboxylic acid, percarboxylic acid, or salt thereof (e.g., peracetic acid, etc.) benzene ring nonionically bonded polycyclo ring system
Publication date: 2012-03-08
Patent application number: 20120059063
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.
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.
CROSS-REFERENCE TO EARLIER APPLICATIONS
 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. §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
 1. Technical Field of the Invention
 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 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.
 2. Description of Background and/or Related and/or Prior Art
 Adapalene is marketed under the trademark Differin® 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.
 WO 03/055 472 moreover describes stable pharmaceutical compositions comprising adapalene and benzoyl peroxide (BPO).
 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
 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.
 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.
 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.
 Preferably, the acne lesions are of inflammatory and/or non-inflammatory type.
 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.
 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.
 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.
 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.
 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
 FIGS. 1-3 are graphs showing the change in the number of lesions over time, upon treatment either according to the invention or not;
 FIG. 4 is a graph showing the degree of success over time of treatment according to the invention or not; and
 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
 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.
 The term "pharmaceutically acceptable medium" means a medium that is compatible with the skin, mucous membranes and the integuments.
 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.
 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).
 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.
 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.
 The present invention thus also features compositions 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 being suited to be applied concomitantly to the skin, mucous membranes and/or the integuments.
 Compositions A and B are preferably useful for a single cutaneous topical application per day.
 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.
 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.
 All the percentages are indicated by weight relative to the total weight of the composition.
 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.
 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.
 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.
 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.
 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.
 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.
 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.
 Preferably, the pharmaceutical compositions combining adapalene and BPO, or the pharmaceutical compositions A and/or B, are gels.
 The pharmaceutical compositions of the invention may contain inert additives or combinations of these additives, such as:
 wetting agents;
 texture enhancers;
 preservatives such as para-hydroxybenzoic acid esters;
 humidity regulators;
 pH regulators;
 osmotic pressure modifiers;
 UV-A and UV-B screening agents; and
 antioxidants, such as a-tocopherol, butylhydroxyanisole or butylhydroxytoluene, superoxide dismutase, ubiquinol, or certain metal-chelating agents.
 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.
 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.
 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.
 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;
 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.
 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.
 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.
 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.
 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%.
 According to another embodiment, this 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.
 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.
 Preferably, the container comprises two compartments, and each of these compartments comprises either composition A or composition B.
 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.
 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.
 The container may be at least partly made of thermoplastic material. Examples of thermoplastic materials include polypropylene and polyethylene.
 Alternatively, the container is made of a non-thermoplastic material, especially of glass or metal (or alloy).
 The container may have rigid walls or deformable walls, especially in the form of a tube or a tube bottle.
 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.
 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.
Clinical Study Results
 A clinical study for confirmation of efficacy was performed for a topical gel combining adapalene+benzoyl peroxide (BPO).
 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.
 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.
 All the treatments were applied once a day for 12 weeks, to 517 patients suffering from acne.
 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.
 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).
 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.
 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:
 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.
 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).
 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.
Evaluation of the Anti-Inflammatory in Ear Oedema Model on Balb/c Mice
 The study was carried out with 45 (5 par groups) female 9 weeks aged Balb/c ByJlc mice.
 The Edema was induced by a single application of 20 μl of TPA dissolved in acetone at 0.01%.
 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).
 The treatments activity was measured by inflammation evaluation with ear thickness at T+6hours.
 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%
 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.
 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).
 Adapalene alone has a low anti-inflammatory effect, reducing the TPA-induced ear edema by 13%.
 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).
 Adapalene at 0.1% increases the anti-inflammatory effect obtained with BPO whatever the tested doses.
 Lower doses of BPO will be used to attempt to show a dose related effect for the association.
 These results show a potential synergistic anti-inflammatory effect of the combination compared to the compounds singly applied.
 Each patent, patent application, publication, text and literature article/report cited or indicated herein is hereby expressly incorporated by reference in its entirety.
 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.
Patent applications by Christian Loesche, Valbonne FR
Patent applications by Denis Gross, Callian FR
Patent applications by Marie-Line Abou-Chacra Vernet, Nice FR
Patent applications by Michel Poncet, Mougins FR
Patent applications by Galderma Research & Development
Patent applications in class Polycyclo ring system
Patent applications in all subclasses Polycyclo ring system