FIELD OF THE INVENTION

[001] The invention provides compositions comprising ozenoxacin or any derivatives or salts thereof alone or with other agents for use in the treatment of dermatological diseases and conditions.

BACKGROUND OF THE INVENTION

[002] Antibacterial agents and retinoids are known to be effective in the treatment of skin disorders such as acne vulgaris. Antibacterial agents act by destroying P. acnes, the bacteria that causes acne condition. Retinoids allow the keratin plugs of microcomedones to be expelled, thus fewer lesions are able to rupture and cause papules, pustules and nodules of acne vulgaris. Most of the treatments developed thus far for the treatment of acne have a common disadvantage of severe adverse events during treatment such as erythema, irritation, burning, stinging, scaling and itching.

[003] The inventors of the present application have found that a combination of an antibacterial agent and a retinoid provides both the comedogenesis and the bacteriostatic effect in acne treatment. Ozenoxacin is a highly tolerable known antibacterial agent which in combination with a retinoid can provide safe and efficacious drug product for treatment of acne vulgaris.

SUMMARY OF THE INVENTION

[004] In some embodiments, this invention is directed to a composition comprising as active ingredients (i) ozenoxacin or any derivative or salt thereof, and at least one of (ii) a retinoid; (iii) a peroxide, or combinations thereof.

[005] In other embodiments, this invention provides a composition comprising (i) ozenoxacin or any derivative or salt thereof, and (ii) a retinoid.

[006] In other embodiments, this invention provides a composition comprising (i) ozenoxacin or any derivative or salt thereof, and (iii) a peroxide. [007] In some embodiments, the composition of this invention is for use in the treatment of a dermatological disease, disorder or symptom thereof.

[008] In some embodiment, this invention provides a method of treating a dermatological disease or disorder comprising topically applying a composition of this invention to an affected area of a subject in need thereof.

[009] In other embodiment, the dermatological disease, disorder or symptom is selected from acne, rosacea, infection, inflammation, pruritis, psoriasis, seborrhea, impetigo, herpes, contact and atopic dermatitis and any combination thereof.

[010] In some embodiment, this invention provides a method of treating rosacea comprising topically applying a composition comprising ozenoxacin or any derivative or salt thereof to an affected area of a subject in need thereof.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

[011] In the first aspect the invention provides a composition comprising as active ingredients (i) ozenoxacin or any derivative or salt thereof, and at least one of (ii) a retinoid; (iii) a peroxide, or combinations thereof.

[012] When referring to a "ozenoxacin or any derivative or salt thereof' it should be related to the dermatological antibacterial compound l-cyclopropyl-8-methyl-7-[5-methyl-6- (methylamino)-3-pyridinyl]-4-oxo-l,4-dihydro-3-quinolinecarb oxylic acid and any derivative or salt thereof, e.g. as described in US 6,335,447.

[013] In some embodiments the salts of basic groups include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, tartaric acid, formic acid, citric acid, trichloroacetic acid trifluoroacetic acid, methanesulfonic acid, benzenesulfonie acid, p-toluenesulfonie acid, mesitylenesulfonic acid and naphthalenesulfonic acid, and the like.

[014] In some embodiments the salts of acidic groups include, for example, salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and salts with nitrogen-containing organic bases such as trimethylamine, triefhylamine, tributylamine, pyridine, N.N-di methyianili ne, N-methylpiperidine, N~methylmorpholme, diethyl amine, dicyclohexyl amine, procain, dibenzylamme, N-benzyl-b- phenethyl amine, 1-ephenamine and N,N'-dibenzylethyienediamine, and the like.

[015] When referring to "retinoid" it should be understood to encompass any compound of a class of vitamers of vitamin A. In some embodiments, the retinoid is selected from tretinoin, isotretinoin, alitretinoin, etretinate, acitretin, tazarotene, adapalene, bexarotene or any combinations thereof.

[016] When referring to "peroxide " it should be understood to encompass a compound containing an oxygen single bond including, but not limited to the group consisting of benzoyl peroxide, carbamide peroxide or hydrogen peroxide or any combinations thereof.

[017] In some embodiments a composition of the invention comprises two active ingredients being (i) ozenoxacin or any derivative or salt thereof, and (ii) a retinoid.

[018] In other embodiments, a composition of the invention comprises two active ingredients being (i) ozenoxacin or any derivative or salt thereof, and (iii) a peroxide.

[019] In some embodiments, said ozenoxacin or any derivative or salt thereof is in a solid particulate form (i.e. the ozenoxacin or any derivative or salt thereof is present in the composition in a non-dissolved form or substantially non-dissolved form). In other embodiments, said ozenoxacin or any derivative or salt thereof is dissolved in water.

[020] In some embodiments, said retinoid is in a solid particulate form (i.e. said retinoid is present in the composition in a non-dissolved form or substantially non-dissolved form).

[021] In other embodiments, said peroxide is in a solid particulate form (i.e. said peroxide is present in the composition in a non-dissolved form or substantially non-dissolved form).

[022] In some embodiments, at least one of said active ingredients is coated. In other embodiments at least one of said active ingredient is coated with a metal oxide layer.

[023] The term "coated by a metal oxide layer" or“ coated with a metal oxide layer’"’ used herein interchangeably should be understood to refer to the substantial or partial cover of the active ingredient by a metal oxide solid layer wherein said active ingredient is embedded, dispersed, entrapped, or encased, e.g. as a solid dispersion or molecular dispersion in said metal oxide layer. In some embodiments, said metal oxide is selected from silica, titania, alumina, zirconia, ZnO, and mixtures thereof. In further embodiments, said metal oxide is silica. [024] The term "coated form of the active ingredient” is meant that the active ingredient is embedded, dispersed, entrapped, or encased, e.g. as a solid dispersion or molecular dispersion in a polymeric carrier which may be an organic or inorganic carrier and which may serve as a matrix for dispersing the active ingredient or as encapsulated material coating said active ingredient (i.e. the active ingredient is present in a core or is a core material encapsulated by a shell composed of a polymeric material which may be an organic or inorganic polymer).

[025] In some embodiments, a composition of the invention comprises as active ingredients (i) ozenoxacin or any derivative or salt thereof, and (ii) a retinoid; wherein at least one of the active ingredients is coated with a metal oxide layer. In other embodiments, a composition of the invention comprises as active ingredients (i) ozenoxacin or any derivative or salt thereof, and (iii) a peroxide; wherein at least one of the active ingredients is coated with a metal oxide layer.

[026] In some other embodiments, at least one of said active ingredients is encapsulated within a microcapsule.

[027] The term“microcapsule”, as used herein, refers to a spherical microparticle consisting of a polymeric shell serving as a wall -forming material and encapsulated active agent located within the core of the microcapsule and partially also found in the shell matrix, but not on the outer surface of the shell. Microcapsules are distinct from microspheres, which consist of spherical homogeneous granules of the active substance dispersed in a polymer and are, in strict sense, spherically empty particles.

[028] In some embodiments, at least one active ingredient is encapsulated within a microcapsule. The term "encapsulated within a microcapsule" should be understood to refer to a microcapsule that is formed around the active ingredient of a composition of the invention wherein said active ingredient is embedded, dispersed, entrapped, or encased, e.g. as a solid dispersion or molecular dispersion in said microcapsule.

[029] In some embodiments, said microcapsules are prepared by deposition of metal oxide on the surface of a solid particulate matter of the active ingredient. In other embodiments said microcapsules are prepared by oil-in- water in situ polymerization encapsulation processes.

[030] In some embodiments, said microcapsule further comprises a phase changing material (PCM) in the core. The preparation of microcapsules under this embodiment can be found in WO 2011/080741 which is herein incorporated by reference. [031 ] The term "phase changing material" (PCM) is meant to encompass any substance capable of changing its state of matter (phase), or at least its viscosity, in accordance with the temperature it is exposed to. PCMs typically have a high heat of fusion which enables them to melt and solidify at certain temperatures, and are capable of storing and releasing large amounts of energy. Heat is absorbed or released when the PCM material changes from solid to liquid and vice versa. When PCMs reach the temperature at which they change phase or viscosity (for example their melting temperature), they absorb large amounts of heat at an almost constant temperature. The PCM continues to absorb heat without a significant raise in temperature until all the material is transformed to the liquid phase. When the ambient temperature around a liquid material falls, the PCM solidifies, releasing its stored latent heat. In accordance with an embodiment of the present invention a phase changing material is an organic material, and is characterized by the fact that at room temperature said PCM has a viscosity of between about 300cP to l,000,000cP (when measured under various conditions). In some embodiments the viscosity of said PCM at room temperature may be 300cP, 350cP, 400cP, 450cP, 500cP, 550cP, 600cP, 650cP, 700cP, 750cP, 800cP, 900cP, lOOOcP, 2000cP, 3000cP, 4000cP, 5000cP, 6000cP, 7000cP, 8000cP, 9000cP, l0,000cP, 20,000cP, 30,000cP, 40,000 cP, 50,000cP, 60,000 cP, 70,000cP, 80,000cP, 90,000cP, l00,000cP, 200,000cP, 300,000cP, 400,000cP, 500,000cP, 600,000cP, 700,000cP, 800,000cP, 900,000cP or l,000,000cP (when measured under various conditions).

[032] In one embodiment, the phase changing material is selected from natural or synthetic paraffins (e.g. having a molecular formula of C _n H2 _n+ 2, wherein h=10-100), Cio-Cioo alkane, Cio- Cioo alkene (having at least one double bond), Cio-Cioo alkyne (having at least one triple bond), waxes, aliphatic alcohols (e.g. having a molecular formula of CH3(CH2) _n OH n=10-100) and fatty acids (e.g. having a molecular formula of CH3(CH2) _n COOH n= 10-100), or any combination thereof.

[033] In some embodiments said phase changing material is at least one natural or synthetic paraffin. In some embodiments said at least one phase changing material is a Cio-Cioo aliphatic alcohol (in other embodiments Cio, C20, C30, C40, C50, C60, C70, Cso, C90 to C100 aliphatic alcohol). In further embodiments said at least one phase changing material is a Cio-Cioo aliphatic fatty acid (in other embodiments Cio, C20, C30, C40, C50, C60, C70, Cso, C90 to C100 aliphatic fatty acid). [034] In one embodiment said PCMs are liquified (or at least become substantially or partially liquified, pliable or semi-solid) at a temperature range of between about 35 °C to about 60°C, more preferably in a temperature range of between about 35°C to about 45°C.

[035] Examples of the phase changing materials include, but are not limited to: Carnauba wax (m.p. 82-86°C), Beeswax pure (m.p. 6l-65°C), Beeswax white pure, (m.p. 6l-65°C), Beeswax bleached technical (m.p. 6l-65°C), Montan wax bleached (m.p. 80-86°C), Montan wax bleached, partially saponified (m.p. 99-l05°C), Montanic acid (m.p. 8 l-87°C), Hydrocarbon wax synthetic (m.p. 106-1 l4°C), Microcrystalline wax (m.p. 89-95°C), Microcrystalline wax (m.p. 76-82°C), Hardwax partially saponified (m.p. l04-l09°C), Beeswax yellow (m.p. 6l-66°C), Polishing Wax (m.p.78-84°C), Castor wax (m.p. 83-89°C), Microwax (m.p. 89-95 °C), Microwax (m.p. 80-86°C), Microwax (m.p. 76-82°C), Ozokerite (m.p. 72-79°C), Microcrystalline wax, plastic (m.p. 76- 82°C), Microcrystalline wax, soft (m.p. 74-80°C), Wax blend (m.p. 62-68°C), Polyolefin wax (m.p. 65-75°C), Lanolin, Shellac, Bayberry wax (m.p. 45°C), Candelilla wax (m.p. 67-79°C), Ouricury wax, Rice bran wax (m.p. 77 - 86°C), Soy candle (wax), Paraffin (m.p. 47 - 64°C), Chinese wax, and any combinations thereof.

[036] According to another embodiment of the present invention, the coated form of the active ingredient may be in form of a polymeric microsponge where the active ingredient is adsorbed or entrapped in said microsponge as described for example in US Pat. No. 4,690,825; US Pat. No. 5,145,675, US Pat. No. 5,879,716 and US Pat. No. 5,955,109, incorporated herein by reference in their entirety.

[037] In other embodiments a microparticle of the invention may also be prepared by a process as disclosed in co-owned PCT application, publication number WO 2007/015243, the content of which is incorporated herein by reference in its entirety.

[038] In other embodiments an encapsulated microcapsule of the invention may also be prepared by a process as disclosed in US Pat. No. 6,932,984, US pat. No. 9,682,031 and PCT application, publication number WO 2007/023495 which are incorporated herein by reference in their entirety.

These references disclose a method for microencapsulation of substances by solvent removal method using non -chlorinated solvents.

[039] In other embodiments an encapsulated microcapsule of the invention may also be prepared by a Sol-Gel process, thus isolating the active ingredient from the environments. In some embodiments, the microcapsules are formed using a sol-gel process as disclosed in the following documents (herein incorporated by reference): US patent Nos. 6,303,149, 6,238,650, 6,468,509, 6,436,375, US2005037087, US2002064541, and International publication Nos. WO 00/09652, WO00/72806, WO 01/80823, WO 03/03497, WO 03/039510, WO00/71084, W005/009604, and WO04/81222, disclose sol-gel microcapsules and methods for their preparation; EP 0 934 773 and U.S. Pat. No. 6,337,089 teach microcapsules containing core material and a capsule wall made of organopolysiloxane, and their production; EP0941 761 and U.S. Pat. No. 6,251,313 also teach the preparation of microcapsules having shell walls of organopolysiloxane; U.S. Pat. No. 4,931 ,362 describes a method of forming microcapsules or micromatrix bodies having an interior water- immiscible liquid phase containing an active, water-immiscible ingredient. Microcapsules prepared by a sol-gel process are also disclosed in GB2416524, US6,855,335, W003/066209; which are all incorporated herein by reference in their entirety.

[040] In other embodiments, microcapsules are formed by the encapsulation process disclosed in the following publications (herein incorporated by reference): US 7,629,394, US 9,205,395, US 2015/0328615, US 2014/0186630. Controlled release microcapsules: IN01958CH2007, IN02080CH2007, US 4,235,872, US4670250, EP 0248531, US 4,970,031, US 5,238,714, W01993/21764, US 5,575,987, WO 1994/20075, US 2004/137031 , US 2006/003014, US 2010/180464. which are all incorporated herein by reference in their entirety.

[041] In some embodiments, the encapsulated benzoyl peroxide (E-BPO) is prepared as described in US patent publication 2010-0016443, and the encapsulated All Trans Retinoic Acid (E-ATRA) is prepared as described in US patent publication US 2012/0202695.

[042] In some embodiments, a composition of the invention comprises as active ingredients (i) ozenoxacin or any derivative or salt thereof, and (ii) a retinoid; wherein at least one of the active ingredients is encapsulated within a microcapsule. In other embodiments, a composition of the invention comprises as active ingredients (i) ozenoxacin or any derivative or salt thereof, and (iii) a peroxide; wherein at least one of the active ingredients is encapsulated within a microcapsule.

[043] In some embodiments, said ozenoxacin or any derivative or salt thereof comprises at least

0.2% w/w of the composition. In other embodiments, said ozenoxacin or any derivative or salt thereof comprises between about 0.2% w/w to about 5%w/w of the composition. In another embodiment, the ozenoxacin or any derivative or salt thereof comprises between about 0.2% w/w to about l%w/w of the composition. In another embodiment, the ozenoxacin or any derivative or salt thereof comprises between about 0.2% w/w to about 2%w/w of the composition. In another embodiment, the ozenoxacin or any derivative or salt thereof comprises between about 0.2% w/w to about 3%w/w of the composition. In another embodiment, the ozenoxacin or any derivative or salt thereof comprises between about 0.2% w/w to about 4%w/w of the composition. In another embodiment, the ozenoxacin or any derivative or salt thereof comprises between about 1 % w/w to about 5% w/w of the composition.

[044] In further embodiments, said retinoid comprises at least 0.01 %w/w of the composition. In other embodiments, said retinoid comprises between about 0.01 %w/w to about l%w/w of the composition. In other embodiments, said retinoid comprises between about 0.01 %w/w to about 0.05%w/w of the composition. In other embodiments, said retinoid comprises between about

0.03%w/w to about l %w/w of the composition. In some embodiments, the retinoid is selected from tretinoin, isotretinoin, alitretinoin, etretinate, acitretin, tazarotene, adapalene, bexarotene or any combinations thereof.

[045] In other embodiments, said peroxide comprises at least l%w/w of the composition. In further embodiments, said peroxide comprises between about l%w/w to about l5%w/w of the composition. In further embodiments, said peroxide comprises between about l%w/w to about 5%w/w of the composition. In further embodiments, said peroxide comprises between about 5%w/w to about l0%w/w of the composition. In further embodiments, said peroxide comprises between about 3%w/w to about l0%w/w of the composition. In some embodiments, the peroxide is selected from benzoyl peroxide, carbamide peroxide or hydrogen peroxide or any combinations thereof.

[046] In some embodiments, the composition of this invention is stable for a period between 2 weeks to about 2 years at room temperature. In some embodiment, the composition of this invention is stable for a period between 2 weeks to about 2 years at ambient conditions.

[047] In some embodiments, the composition of this invention is stable for at least 3 months when the composition is stored at room temperature. In other embodiments the composition of this invention is stable for a period of between about 3 months to about 2 years when it is stored at room temperature. [048] In some embodiments, the composition of this invention comprising ozenoxacin or any derivative or salt thereof, and a peroxide, is stable for at least one year under refrigeration conditions.

In some embodiments, the composition of this invention comprising ozenoxacin or any derivative or salt thereof, a peroxide and a retinoid, is stable for at least one year under refrigeration conditions.

[049] The term“table” as used herein refers to the ability of the composition to maintain said at least one active ingredient within said composition, with a maximal degradation of between about 0 to 5% of said active agent, for a set period of time under conditions of temperature and RH.

[050] The term“ room temperature” refers herein to a temperature between 20-25°C.

[051 ] The present invention also relates to pharmaceutical compositions comprising the defined active ingredients in admixture with pharmaceutically acceptable auxiliaries, and optionally other therapeutic agents. The auxiliaries must be“acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof.

[052] Pharmaceutical compositions include those suitable for topical (including transdermal, buccal and sublingual, vaginal, anal) administration or administration via an implant or dermatological or topical patch. The compositions may be prepared by any method well known in the art of pharmacy. Such methods include the step of bringing in association compounds used in the invention or combinations thereof with any auxiliary agent. The auxiliary agent(s), also named accessory ingredient(s), include those conventional in the art, such as carriers, fillers, binders, diluents, disintegrants, lubricants, colorants, flavouring agents, anti-oxidants, and wetting agents.

[053] The invention further includes a pharmaceutical composition, as hereinbefore described, in combination with packaging material, including instructions for the use of the composition for a use as hereinbefore described.

[054] For transdermal, topical or dermatological administration, e.g. gels, patches or sprays can be contemplated. Compositions or formulations suitable for pulmonary administration e.g. by nasal inhalation include fine dusts or mists which may be generated by means of metered dose pressurized aerosols, nebulisers or insufflators. [055] The exact dose and regimen of administration of the composition will necessarily be dependent upon the therapeutic or nutritional effect to be achieved and may vary with the particular formula, the route of administration, and the age and condition of the individual subject to whom the composition is to be administered.

[056] In some embodiments, a composition of the invention is formulated to a dermatological composition.

[057] Topical therapies can be delivered in various vehicles, which include powders, liquids, combinations of liquid and oil. The vehicle influences a therapy’s effectiveness and may itself cause adverse effects (e.g., contact or irritant dermatitis). Generally, aqueous and alcohol-based preparations are drying because the liquid evaporates and are used in acute inflammatory conditions. Powders are also drying. Oil-based preparations are moisturizing and are preferred for chronic inflammation. Vehicle selection is guided by location of application, cosmetic effects, and convenience.

[058] Inert powders may be mixed with active agents to deliver therapy. They are prescribed for lesions in moist or intertriginous areas. Liquid vehicles include baths and soaks, foams, solutions, lotions and gels. Baths and soaks are used when therapy must be applied to large areas, such as with extensive contact dermatitis or atopic dermatitis. Foams are alcohol- or emollient-based aerosolized preparations. They tend to be rapidly absorbed and may be favored in hair-bearing areas of the body. Solutions are ingredients dissolved in a solvent, usually ethyl alcohol, propylene glycol, polyethylene glycol, or water. Solutions are convenient to apply (especially to the scalp for disorders such as psoriasis or seborrhea) but tend to be drying. Two common solutions are Burow solution and Domeboro solution. Lotions are water-based emulsions. They are easily applied to hairy skin. Lotions cool and dry acute inflammatory and exudative lesions, such as contact dermatitis, tinea pedis, and tinea cruris. Gels are ingredients suspended in a solvent thickened with polymers. Gels are often more effective for controlled release of topical agents. They are often used in acne, rosacea, and psoriasis of the scalp. Combinations include creams, ointments. Combination vehicles usually contain oil and water but may also contain propylene or polyethylene glycol. Creams are semi-solid emulsions of oil and water. They are used for moisturizing and cooling and when exudation is present. They vanish when rubbed into skin. Ointments are oil based with little if any water. Ointments are optimal lubricants and increase drug penetration because of their occlusive nature; a given concentration of drug is typically more potent in an ointment. They are used for lichenified lesions and lesions with thick crusts or heaped- up scales, including psoriasis and lichen simplex chronicus. Ointments are less irritating than creams for erosions or ulcers. They are usually best applied after bathing or dampening the skin with water. Dressings protect open lesions, facilitate healing, increase drug absorption, and protect the patient’s clothing.

[059] Nonocclusive dressings include gauze dressings. They maximally allow air to reach the wound, which is often preferred in healing, and allow the lesion to dry. Nonocclusive dressings wetted with solution, usually saline, are used to help cleanse and debride thickened or crusted lesions. The dressings are applied wet and removed after the solution has evaporated (wet-to-dry dressings); materials from the skin then adhere to the dressing. Occlusive dressings increase the absorption and effectiveness of topical therapy. Most common are transparent films such as polyethylene (plastic household wrap) or flexible, transparent, semi-permeable dressings. Hydrocolloid dressings can be applied with a gauze cover in patients with cutaneous ulceration. Zinc oxide gelatin (Unna paste boot) is an effective occlusive dressing for patients with stasis dermatitis and ulcers. Plastic tape impregnated with flurandrenolide, a corticosteroid, can be used for isolated or recalcitrant lesions. Occlusive dressings applied over topical corticosteroids to increase absorption are sometimes used to treat psoriasis, atopic dermatitis, skin lesions resulting from systemic lupus erythematosus, and chronic hand dermatitis, among other conditions. Other occlusive dressings are used to protect and help heal open wounds, such as burns.

[060] In some embodiments, said dermatological composition is selected from a gel, cream, foam, lotion, ointment, paste, patch, liniment, paint, aerosol, suppository and any combination thereof.

[061] In another one of its aspects the invention provides a composition as defined herein above for use in the treatment of a dermatological disease, disorder or symptom thereof. In some embodiments, the treatment comprises once daily or twice daily topical administration of the composition of the present invention to a subject in need thereof. In some embodiments, the treatment is for a period of time of up to 12 weeks.

[062] In some embodiments, co-administration of the active agents/ingredients exhibits an additive and/or synergistic effect during or following the treatment. [063] In some embodiments, co-administration of the active ingredients may be made either by administration of a single combination composition, or alternatively by separate administration of a first composition comprising (i) ozenoxacin or any derivative or salt thereof, and (ii) one or both of a peroxide and a retinoid.

[064] In some embodiments, this invention provides a dual chamber dispenser, having a first chamber charged with a first composition comprising ozenoxacin or any derivative or salt thereof, and a second chamber charged with a second composition comprising at least one of (ii) a retinoid; (iii) a peroxide, or combinations thereof, wherein the two compositions are mixed before applying on the skin of a patient in need thereof, thus administering a combination product. In another embodiment, at least one active ingredient is coated/encapsulated.

[065] In some embodiments, this invention provides a dual chamber dispenser, having a first chamber charged with a first composition comprising ozenoxacin or any derivative or salt thereof, and a second chamber charged with a second composition comprising at a retinoid, wherein the two compositions are mixed before applying on the skin of a patient in need thereof, thus administering a combination product. In another embodiment, at least one active ingredient is coated/encapsulated.

[066] In some embodiments, this invention provides a dual chamber dispenser, having a first chamber charged with a first composition comprising ozenoxacin or any derivative or salt thereof, and a second chamber charged with a second composition comprising at a peroxide, wherein the two compositions are mixed before applying on the skin of a patient in need thereof, thus administering a combination product. In another embodiment, at least one active ingredient is coated/encapsulated.

[067] In some embodiments, this invention provides a dual chamber dispenser, having a first chamber charged with a first composition comprising ozenoxacin or any derivative or salt thereof, and a second chamber charged with In some embodiments, this invention provides a dual chamber dispenser, having a first chamber charged with a first composition comprising ozenoxacin or any derivative or salt thereof, and a second chamber charged with a second composition comprising at a retinoid and a peroxide, wherein optionally at least one or both of the retinoid and peroxide is coated/encapsulated, wherein the two compositions are mixed before applying on the skin of a patient in need thereof, thus administering a combination product.

[068] The term "treatment" as used herein means the management and care of a patient for the purpose of combating a disease, disorder or condition. The term is intended to include the delaying of the progression of the disease, disorder or condition, the alleviation or relief of symptoms and complications, and/or the cure or elimination of the disease, disorder or condition.

[069] Topical dermatologic treatments include cleansing agents, absorbent dressings (eg, hydrocolloid patches or powder) and super-absorbent powders, anti-infective agents, anti- inflammatory agents, astringents (drying agents that precipitate protein and shrink and contract the skin), emollients (skin hydrators and softeners), keratolytics (agents that soften, loosen, and facilitate exfoliation of the squamous cells of the epidermis).

[070] When referring to a "dermatological disease , disorder or symptom thereof' any type of disease, disorder or any symptoms thereof that is being expressed on the skin or any mucosal membrane (including any parts of the external and internal skin of a subject, hair, nails, mucosal membranes and so forth) of a subject.

[071] In some embodiments, said dermatological disease, disorder or symptom is selected from acne, rosacea, infection, inflammation, pruritis, psoriasis, seborrhea, impetigo, herpes, contact and atopic dermatitis and any combination thereof. In further embodiments, said dermatological disease, disorder or symptom is acne.

[072] In another aspect the invention provides a method of treating a dermatological disease or disorder comprising topically applying a composition as defined herein above. In some embodiments, the composition of the present invention is applied once daily or twice daily. In some embodiments, the composition of the present invention is applied once daily or twice daily for a period of time of up to 12 weeks.

[073] The invention further provides a composition comprising ozenoxacin or any derivative or salt thereof, for use in the treatment of rosacea and any symptom thereof.

[074] In some embodiments, said composition further comprising benzoyl peroxide optionally in an encapsulated form.

[075] In another aspect the invention provides a method of treating rosacea and any symptom thereof comprising topically applying a composition comprising ozenoxacin or any derivative or salt thereof to an affected area of a subject in need thereof. EXPERIMENTAL SECTION

Example 1. Cream formulation of ozenoxacin and tretinoin.

[076] Preparation of cream formulation of ozenoxacin 2% and tretinoin 0.1 %: Oil Phase: 720.0 grams of Cyclomethicone 5-N, 540.0 grams of Cetyl Alcohol, 360.0 grams of Polyoxyl 100 Stearate, 540.0 grams of Glyceryl Monosterate and 18.0 grams of tretinoin are mixed at 70° C. Water phase: 18.0 grams of Ethylendiaminetetraacetate Disodium salt are dissolved in 14,000 grams of water. 720.0 grams of glycerin (99.5%) and 360.0 grams of ozenoxacin are added to the solution. After the solution is heated to 70°C., 72.0 grams of Carbopol 980 NF are added and the resulting mixture is homogenized at 3300 rpm for 10 minutes to ensure that all materials completely melts and dissolves. 76.5 grams of sodium hydroxide (20%) are then added and the mixture is stirred under high shear for 10 minutes at no less than 70°C. The oil phase is added to the water phase under high shear at 70°C, and the resulting emulsion is homogenized at 3300 rpm for 10 minutes. 72.0 grams of Citric Acid are added. The emulsion is cooled to 35° C. and the pH of the cream is adjusted to 5 using HC1 5N solution. Water is added until the total weight of the cream reaches 18 kilograms.

Example 2. Gel formulation of ozenoxacin and adapalene.

[077] Preparation of gel formulation of ozenoxacin 2% and adapalene 0.3%: 20.0 grams of PVP (Plasdone K-29/30) and 80 grams of water are mixed to prepare 100 grams of 20% poly vinylpyrrolidone (PVP) solution. 850.0 grams of Glycerin (99.5%) and 14,000 grams of water are mixed and stirred for 10 minutes at 2800 rpm. 212.5 grams of Natrosol (250HHX) and 42.5 grams of Klucel (HF Pharm) are added, and the resulted gel is homogenized at 8400 rpm for at least 70 minutes until it was free of lumps. 100 grams of PVP (20%), 360.0 grams of ozenoxacin and 54.0 grams of m i cron i zed adapalene are added to the gel under high shear. The pH of the gel is adjusted to 5 using HC1 5N. Water was added to complete the total weight of the mixture to 18 ozenoxacin are added to the solution kilograms, and the mixture was finally mixed until homogeneity. Example 3.

[078] The cream and the gel, as described in Examples 1 and 2, are tested on patients with moderate to severe acne vulgaris. The parameters evaluated in this study are: IGA (investigator global assessment) and number of inflammatory and non-inflammatory lesions. The success criteria in IGA is 2-grade improvement and patients with clear or almost clear conditions, and the reduction of lesions count.