(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 2 December 2010 (02.12.2010) WO 2010/136585 A2 (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 47/32 (2006.01) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, (21) International Application Number: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, PCT/EP2010/057469 DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (22) International Filing Date: HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, 28 May 2010 (28.05.2010) KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (25) Filing Language: English NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, (26) Publication Language: English SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 61/213,322 29 May 2009 (29.05.2009) US (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (71) Applicant (for all designated States except US): GAL- GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, DERMA RESEARCH & DEVELOPMENT [FR/FR]; ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, 2400 Route des Colles, Les Templiers, F-06410 Biot TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (FR). EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, (72) Inventor; and SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, (75) Inventor/Applicant (for US only): VILLARD, GW, ML, MR, NE, SN, TD, TG). Christophe [FR/FR]; 6 11, chemin de Ia Martourette, F-06530 Le Tignet (FR). Published: (74) Agent: ALLAB, Myriam; L'Oreal, D.I.P.I., 25-29 Quai — without international search report and to be republished Aulagnier, F-92665 Asnieres-Sur-Seine (FR). upon receipt of that report (Rule 48.2(gf) (54) Title: COMBINATION OF ADRENERGIC RECEPTOR AGONIST - 1 OR -2, PREFERABLY BRIMONIDINE WITH FILLERS, PREFERABLYHYALURONIC ACID (57) Abstract: The present invention provides a combination of quantity of adrenergic receptor agonist α- 1 or α- 2, and preferably product known as brimonidine with fillers and preferably with hyaluronic acid for decreasing skin or cutaneous reactions. COMBINATION OF ADRENERGIC RECEPTOR AGONIST α-1 OR α-2, PREFERABLY BRIMONIDINE WITH FILLERS, PREFERABLYHYALURONICACID. The present invention is in the surgical and dermatological domain. The present invention provides a combination of quantity of adrenergic receptor agonist α- 1 or α-2, and preferably product known as brimonidine with fillers and preferably with hyaluronic acid for decreasing skin or cutaneous reactions. Superficial bruising and, to a lesser extent, bleeding are not uncommon consequences (reported on average, about one-third of the time) of many aesthetic procedures, including dermal fillers, botulinum toxins and laser resurfacing. More significant bruising occurs with surgical procedures such as liposuction, breast augmentations/lifts, face lifts and tummy tucks. The management of secondary immediate reactions due to subcutaneous or intradermic injection of fillers with vascular damages or vascular breaking wall inducing ecchymosis, bruising, leakage of blood components having immediate action on inflammation setting up, redness and oedema, are of particular interest. Although bruising and bleeding, as well as redness and erythema are not generally considered a big problem, most physicians prepare their patients for this possibility by alerting them to it prior to the procedure. Particularly, physicians often caution against using aspirin or other anticoagulant drugs before and after the procedure, extensively use ice packs immediately after the procedure and quite commonly recommend Arnica, an herb used to promote healing. This kind of drawbacks may discourage some patients and particularly towards aesthetic procedures. In particular with regards to the consequences of Bruising/Bleeding, Physicians report that one of the most significant concerns for patients is the amount of "downtime" and when bruising occurs, patients prefer to stay home rather than return to work and social activities Therefore, there is a need for alleviating bruising/bleeding that occur during aesthetic or surgical procedures especially when fillers are injected. The present invention is based on the demonstration by the Applicant that the topical application/ administration of an adrenergic receptor agonist together with aesthetic or surgical procedure, for instance filler injection, reduces the occurrence of skin/ cutaneous reactions. The present invention provides a combination either an association of quantity of adrenergic receptor agonist α- 1 or α-2, and preferably product known as brimonidine with fillers and preferably with hyaluronic acid. Said combination is topically administrated to an individual in need. The present invention provides the use in an individual in need, of a quantity of adrenergic receptor agonist α- 1 or α-2, and preferably product known as brimonidine in combination or association with fillers and preferably with hyaluronic acid. More specifically, the invention provides the use in an individual in need, of a quantity of adrenergic receptor agonist α- 1 or α-2, in combination or association with fillers intended for decreasing of alleviating cutaneous reactions. In particular embodiment, the quantity of adrenergic receptor agonist α- 1 or α-2, in combination or association with fillers are intended to be applied to the skin simultaneously or one after the other, in any order, or in a sequential order and more specifically the skin application of a quantity of adrenergic receptor agonist α- 1 or α-2, in combination or association with fillers is 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. In preferred embodiments, the adrenergic receptor agonist α- 1 or α-2 is brimonidine combination or association with filler(s) or the filler(s) in combination or association with adrenergic receptor agonist α- 1 or α-2 and preferably brimonidine, is hyaluronic acid. In a most preferred embodiment the cutaneous reactions are selected from the following: bruising, bleeding, ecchymosis, erythema, oedema, necrosis, ulceration, swelling and/or inflammation. The present invention provides a kit of part combining or associating a quantity of adrenergic receptor antagonist α- 1 or α-2, and preferably product known as brimonidine with fillers and preferably with hyaluronic acid. Said quantity of adrenergic receptor antagonist α- 1 or α-2 is in a form of a topical composition or formulation. The invention provides also a method for diminishing or decreasing or avoid bruising and, to a lesser extent, bleeding and particularly in aesthetic procedures, including dermal fillers and preferably hyaluronic acid, Botulinum toxin and laser resurfacing, by providing to an individual in need thereof a quantity of adrenergic receptor agonist α- 1 or α-2, and preferably product known as brimonidine. In another embodiment, the invention provides a method for alleviating or decreasing cutaneous reactions and particularly in aesthetic procedures, including injection of dermal fillers and preferably hyaluronic acid, Botulinum toxin and laser resurfacing, by providing to an individual in need thereof a quantity of adrenergic receptor agonist α- 1 or α-2, and preferably product known as brimonidine. In a most preferred embodiment the cutaneous reactions are selected from the following: bruising, bleeding, ecchymosis, erythema, oedema, necrosis, ulceration, swelling and/or inflammation. The expression "association" of adrenergic receptor antagonist or salts thereof with fillers means that the two active principles are formulated separately; or adrenergic receptor antagonist (preferably brimonidine) or the salts thereof is thus present in a first composition, while the fillers (preferably hyaluronic acid) is/are present in a second composition. In the context of the invention "combination" and "association" are interchangeable. Thus, according to a another embodiment of the invention, the pharmaceutical composition is in the form of a composition A comprising adrenergic receptor antagonist, intended to be applied concomitantly with a composition B comprising the filler(s). Preferably, composition A and composition B are presented in the form of a kit, allowing concomitant 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). The expression "concomitant" application means that the compositions are intended 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 precedes the application of the pharmaceutical composition A), 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 provides a method for diminishing or decreasing or avoiding bruising and, to a lesser extent, bleeding