(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)

(19) World Intellectual Property Organization International Bureau

(43) International Publication Date (10) International Publication Number 26 February 2009 (26.02.2009) PCT WO 2009/023943 Al

(51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 45/06 (2006.01) A61P 27/16 (2006.01) kind of national protection available): AE, AG, AL, AM, AO, AT,AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, (21) International Application Number: PCT/BR2008/000248 CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, (22) International Filing Date: 18 August 2008 (18.08.2008) IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, (25) Filing Language: English LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, (26) Publication Language: English RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY,TJ, (30) Priority Data: TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, PI 0703127-0 22 August 2007 (22.08.2007) BR ZW (71) Applicant (for all designated States except US): OURO FINO PARTICIPAς ό ES E EMPREENDIMENTOS (84) Designated States (unless otherwise indicated, for every LTDA [BR/BR]; Avenida Independencia, 3220 sala 04, kind of regional protection available): ARIPO (BW, GH, Alto da Boa Vista, Ribeirao Preto - Sp (BR). GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), (72) Inventors; and European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, (75) Inventors/Applicants (for US only): MASSARI, Jardel FR, GB, GR, HR, HU, IE, IS, IT, LT,LU, LV,MC, MT, NL, [BR/BR]; Av. Carlos Rateb Cury, 500, Condominio NO, PL, PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, Vila Vitόria, Country Village, Ribeirao Preto-SP (BR). CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). CORAUCCI NETO, Dolivar [BR/BR]; Rua Barao do Rio Branco, 221, Centra, Sertaozinho-SP (BR). Published: (74) Agent: ATEM E REMER ASSESSORIA E CONSUL- — with international search report TOIRA DE PROPRIEDADE INTELECTUAL LTDA.; — before the expiration of the time limit for amending the Praca Floriano, 19/28°andar, CEP 20031-050 Cinelandia, claims and to be republished in the event of receipt of Rio de Janeiro, RJ (BR). amendments

(54) Title: PHARMACEUTICAL ASSOCIATION, COMPOSITIONS FOR TOPICAL USE, FORMS OF DOSAGE AND METHOD OF TREATMENT OF ACUTE OR CHRONIC OTITIS IN PET ANIMALS

(57) Abstract: The present invention refers to a new pharmaceutical association comprising from the class of quinolones, azole antifungus, corticoid anti-inflammatory and local anesthesic from the class of amines. The pharmaceutical association of the present invention is particularly appropriate for the treatment of acute or chronic otitis in pet animals, caused by both bacteriae and fungi. The present invention also refers to compositions for topical use, as well as dosage forms comprising said pharmaceutical association, which are particularly appropriate for the treatment of acute or chronic otitis in cats and dogs. Description "PHARMACEUTICAL ASSOCIATION, COMPOSITIONS FOR TOPICAL USE, FORMS OF DOSAGE AND METHOD OF TREATMENT OF ACUTE OR CHRONIC OTITIS IN PET ANIMALS"

Field of the Invention The present invention refers to a new pharmaceutical association comprising quinolinone antibiotic, azole antifungic, corticoid anti-inflammatory and local amine anesthesics compounds. The pharmaceutical association of the present invention is particularly appropriate to the treatment of acute or chronic otitis in pet animals, caused both by bacteriae such as Staphylococcus intermedius, Staphylococcus aureus, Staphylococcus spp, Streptococcus spp, Streptococcus pyogenes, Proteus mirabilis, Proteus vulgaris, Proteus spp, Pseudomonas aeruginosa, Escherichia coli, Corynebacterium spp, among others such as fungi, e. g . Mallassezia pachydermatis (Pityrosporum cam's), Epidermophyton floccosum, Microsporum canis, Trichophyton rubrum, Trichophyton mentagrophytes, Candida spp and others. The present invention also refers to composition for topical use, as well as dosage forms comprising said pharmaceutical association, which are particularly appropriate to the treatment of acute or chronic otitis in cats and dogs.

Background of the Invention External otitis is an inflammation of soft tissue components in the external auditive passage. Said affection constitutes one of the most common and frustrating problems found in the medicine for small animals, since its treatment is difficult and has high recurrence probability. Otitis may be caused in a patient by various factors, which makes diagnostics and treatment become very difficult. Predisposing factors facilitate inflammation by allowing a favorable environment for the survival of perpetuating factors. As examples of predisposing factors, it could be mentioned the conformation of the auditive passage, humidity in the passage, ear hairs, race predisposition, immunodeficiency syndromes, endocrine unbalances, iatrogenic auditive traumatism and obstructing diseases. Perpetuating factors sustain and worse inflammatory processes, which routes include channel occlusion, secretion of irritating factors, pH changes in the passage and formation of an infection focus. Examples include bacterial infections caused by Staphylococcus intermedius, Proteus mirabilis, Pseudomonas aeruginosa, Corynebacterium spp and Escherichia co/i, and yeast infections caused by Malassezia pachydermatis. Typical signs as presented by animals suffering said disease are e . g. head shaking, ear itching and scrubbing, pain around the ears or the head, bad odor, behavior changes, etc. Initial otitis treatment, after an antibiogram is performed, includes the full cleaning of the external ear, control of the active inflammatory process and the use of commercial otological preparations, but said choice must be careful.

It is therefore clear that otitis in pet animals is a complex affection requiring some care in its treatment. Ciprofloxacin It is known from the specialized literature that ciprofloxacin is a fluoroquinolone antibiotic of second generation, bactericide for inhibiting the replication and transcription of the bacterial DNA. The advantages of using fluoroquinolones in anti-inflammatory treatments are related to their quick bactericidal action against a wide varity of clinically important bacterial microorganisms. Fluoroquinolones are powerful, well tolerated by animals and have been given through a variety of routes. They are mainly active for otitis of animals caused by the bacteriae Staphylococcus sp, Streptococcus sp, Proteus sp, Pseudomonas aeruginosa, Escherichia co/i, Corynebacterium spp and others. Literature mentions that, in assays with humans using ciprofloxacin, an efficacy of 77% has been obtained for the treatment of acute external otitis. In another experiment, the efficacy of ciprofloxacin as linked to dexametasone was higher than the use of ofloxacin, about 90% against 78% for clinical cure, and about 92% against 8 1.8% for microbiological cure. A four-day period was also observed to end otorrhea with the use of ciprofloxacin as associated to dexametasone, against a six day period with the use of ofloxacin. The joint administration of ciprofloxacin and improved results in cases of ostheitic and cholesteatomose forms, while chronical otitis requires the association of ciprofloxacin-based topical treatment with systemic antibiotic therapy. As opposed to first generation quinolones, the clinical administration of fluoroquinolones produces resistant mutants in a still relatively low frequency. No bacterial resistance to quinolones has been so far verified through plasmids. Ketoconazole is the reference antifungus imidazole and, as such, one of the most widely used compounds of the family of azoles worldwide. It is indicated for administration by topic and oral routes, and may be widely distributed throughout the skin and subskin tissue, which makes it become efficient for the treatment of surface or systemic skin infections by fungi. The main route for action of azole compounds is the inhibition of the enzyme lanostrel demethylase, which takes part in the biosynthesis of ergosterol, important for the integrity and maintainance of the function of fungus cell membrane. The alteration of fluidity and permeability of the cytoplasma membrane of the fungus reduces nutrient collection, causing the inhibition of fungus growth, originating morphological changes resulting in cell necrosis. Among the etiologic agents responsible for otitis in animals, yeasts from the genus Malassezia have been known for more than a century. In veterinary medicine, the species Malassezia pachydermatis is usually pointed out as responsible for external otitis in carnivorous pet animals and, more recently, by various forms of suffered by dogs with local or generalized skin diseases. There are also reports of isolation of other Malassezia species in the skin of cats. Therapeutical options as traditionally used for the treatment of Malassezia affections include a few azole derivatives, notably ketoconazole, itraconazole and enylconazole, chlorhexidine or selenium sulphate. Various works have already been performed to detect in vitro susceptibility of Malassezia pachydermatis against a few antifungus agents. Concerning local skin problems, topical treatment is usually sufficient, and the most widely used drugs in these cases are ketoconazole, chlorhexidine or selenium sulphate. In general cases, systemic treatment with ketoconazole or itraconazole is also required. Such treatments should last various weeks and may be linked to topical . The main advantage of systemic therapy is to eliminate yeasts as present in the skin and also in mucosae, considered by some authors as true reservoirs of said yeasts. Fluoroquinolone Fluoroquinolone (acetonide) is a medicine included in the group of corticoids or , for administration to the skin or mucous membranes, with high anti-inflammatory power. Topical route is a common method of administration, since it reaches high drug concentrations in the site of action, while reducing the risks of systemic side effects. Corticosteroids suffer just minimum absorption after being given on normal skin. There is a large regional anatomic variation in the penetration of corticosteroids and the solubility in the carrier represents important determination of the absorption of a topical . are able to block earlier manifestations of the inflammatory process, such as pain, heat and redness, up to later ones, such as tissue reparation and proliferation. Anti-inflammatory affect all types of inflammatory responses, be them caused by invading pathogens, physical or chemical stimulation or inadequate immunological reaction. However, the exact nature of the action of glucocorticoids in pet animals has not been fully explained. Effects of glucocorticoids involve interactions between steroids and intracell receivers, the latter ones found in nearly all tissues. After the interaction with the steroid, the receiver becomes "activated", i. e . its conformation is changed, so to expose a DNA fixation dominiun. Said complex starts or avoids the transcription of some given genes. Glucocorticoids inhibit many molecules linked to inflammation, such as cytokines, chemokines, metabolites of and adherence molecules. They inhibit microvascular dilatation, oedema and permeability increase, hyperalgesia and fibrin deposition. They reduce the initial migration of polymorphonuclear leukocites and later leakage of monocytes, also reducing the phagocitary activity. When topically applied, corticosteroids interact with receptor of dermal and intradermal cells. Said interaction induces peptides such as lipocurtains, which antagonize the action of A2 phospholipase, reducing the formation, release and action of endogenous chemical mediators of the inflammation. Such mediators include kinines, histamine, liposomal enzymes, and the complement system. Another effect contributing for the anti-inflammatory activity includes the stabilization of lisossomal and cell membranes, reduction of the number of Langerhans cells, inhibition of the movement of inflammatory cells, vessel constriction and antimitotic effect in various types of cells, including epidermal cells. The vast majority of anti-inflamatories so far available for veterinary medicine is composed by active principles not presenting selective activity in inflammatory processes of the auditive system. Lidocaine Lidocaine is a local anesthesic from the class of amides. It works at the central nervous system, cardiovascular system, respiratory tract, digestive tract, striated muscle fibers, urinary tract and reproductive tract. Lidocaine is a pharmaceutical with high affinity for body fats and adipose tissues. Lidocaine is linked to plasma proteins, mainly alpha 1-acid glycoprotein. Said link has been reported to be highly variable and the concentrations depend and may be higher in dogs with an inflammatory disease. Local anesthesics inhibit the generation and propagation of nervous impulses by blocking sodium channels, voltage-dependent in the nervous membrane. The most viable hypothesis is that the anesthesic enters the lipoprotein membrane and links itself to the receiving site at the sodium channel to avoid or forbid the ion movement. Currents as generated by sodium are reduced since the drug inhibits changes in channel conformation and therefore channels as linked to the drug no longer open. This delays the depolarization speed of the membrane, avoiding to reach the upper potential of the membrane. Blocking of sodium channels by most local anesthesics depend both on the voltage and frequency. Local anesthesics are able to block all nerves, thus their action is not limited to the loss of sensation, which is usually most desired, since motor loss also occurs. The disappearance of the nervous feature in response to local anesthesic blocking occurs in decreasing order, going through pain, heat, tact, deep pressure and finally motor function. Surface or topical anesthesia results when the local anesthesic is applied to the skin or mucosae to cause loss of sensitivity by paralysis of sensorial nervous terminations. Local anesthesics reduce the frequency and rate of depolarization by increasing the upper limit value and reducing the permeability of the membrane to sodium. The exact site of action of anesthesics is the external surface of the sodium channel, the internal surface (axoplasmatic side) of the sodium channel inside the nervous cell membrane where the anesthesic produces side pressure, and the constriction of the sodium channel and the axoplasmatic face of the sodium channel, and inside the cell membrane.

Brief Description of the Invention Therefore, considering the complexity of otitis in pet animals and the background as reported above, the object of the present invention is to provide a new pharmaceutical association comprising one or more from the class of quinolones, azole antifungus, corticoid anti-inflammatory and local anesthesic from the class of amines compounds, so to effectively cure said disease. Another object of the present invention is to provide new compositions for topical administration, intended to the treatment of acute or chronic otitis in pet animals, particularly cats and dogs, mainly caused by the bacteriae Staphylococcus intermedius, Staphylococcus aureus, Staphylococcus spp, Streptococcus spp, Streptococcus pyogenes, Proteus mirabilis, Proteus vulgaris, Proteus spp, Pseudomonas aeruginosa, Escherichia coli, Corynebacterium spp, among others, and by fungi such as Mallassezia pachydermatis (Pityrosporum cam's), Epidermophyton floccosum, Microsporum canis, Trichophyton rubrum, Trichophyton mentagrophytes, Candida spp and others. Another particular object of the present invention is to provide new dosage forms for the topical administration of said compositions, as well as a method of treatment of acute or chronic otitis in pet animals, particularly cats and dogs.

Detailed Description of the Invention These and other objects are reached by a new pharmaceutical association comprising one or more antibiotic compounds from the class of quinolones, azole antifungus, corticoid anti-inflammatory and local anesthesic from the class of amines. Said association is particularly intended for the topical treatment of acute or chronic otitis in pet animals, notably cats and dogs, caused by bacteriae such as Staphylococcus intermedius, Staphylococcus aureus, Staphylococcus spp, Streptococcus spp, Streptococcus pyogenes, Proteus mirabilis, Proteus vulgaris, Proteus spp, Pseudomonas aeruginosa, Escherichia coli, Corynebacterium spp and others, as well as fungi, such as Mallassezia pachydermatis {Pityrosporum cam's), Epidermophyton floccosum, Microsporum canis, Trichophyton rubrum, Trichophyton mentagrophytes, Candida spp and others. Antibiotics making part of the pharmaceutical association of the present invention are one or more from those pertaining to the group comprising ciprofloxacin, nalidixic acid, pyromidic acid, cynoxacin, rosoxacin, pipemidic acid, pefloxacin, ofloxacin, fleroxacin, enoxacin, difloxacin, amifloxacin, irloxacin, rufloxacin, lomefloxacin, norfloxacin, levofloxacin, trovafloxacin, temafloxacin, tosufloxacin, sparfloxacin, clinafloxacin and their respective pharmaceutically acceptable salts. Preferably, the antibiotic is chosen from the group comprising ciprofloxacin, norfloxacin, levofloxacin, trovafloxacin and their pharmaceutically acceptable salts. Still more preferably, the antibiotic is ciprofloxacin and its pharmaceutically acceptable salts. Salts from the pharmaceutically acceptable antibiotic compounds of the present invention are preferably hydrochlorides and lactates. As azole antifungus agent of the association of the present invention, it may be selected one or more among compounds of the group ketoconazole, imidazole, clotrimazole, econazole, myconazole, enylconazole, itraconazole, fluconazole, voriconazole, posaconazole, tioconazole, oxyconazole, isoconazole, bifonazole, sulconazole and ravuconazole. Preferably, the azole antifungus agent is selected from the group comprising ketoconazole, imidazole, clotrimazole, econazole, myconazole, enylconazole, itraconazole and fluconazole. Even more preferably, the azole antifungus compound is ketoconazole. The corticoid anti-inflammatory of the pharmaceutical association of the present invention is chosen from the group comprising one or more from , chlobetasol, , , halobetasole, , , , betametasone, , , , deoxymetasone, , diflucortolone, fluandrenolone, fluchlorolone, , flucinolone, , butyl, , fluprepnidene, halcinonide, halobetasol, , , , , tiamcinolone and their respective acceptable pharmaceutical salts. Other corticosteroids which may integrate the pharmaceutical association of the present invention refer to the group comprising alclometasone dipropionate, amcinonide, beclometasone dipropionate, betametasone dipropionate, betametasone valerate, budesonide, chlobetasol propionate, , desonide, deoxymetasone, difluorasone diacetate, , fluandrenolone, fluchlorolone, , fluocinolone valerate, fluocinonide, , fluocortolone hexanoate, fluocortolone pivalate, acetate, halcinonide, halobetasole propionate, , hydrocortisone aceptonate, , methylprednisolone aceponate, mometasone furoate, prednicarbate, thiamcinolone acetonide. Preferably, the corticoid anti-inflammatory of the present invention is selected from the group comprising fluocinolone, chlobetasol, diflucortolone, halcinonide, halobetasol, betametasone, budesonide, flumetasone, hydrocortisone, methylprednisolone and thiamcinolone. Even more preferably, the corticoid anti-inflammatory is fluocinolone. Pharmaceutically acceptable salts from corticoid anti-inflammatory compounds are prefereably hydrochlorides. As anesthesical compounds, the pharmaceutical association of the present invention comprises one or more as selected from the group comprising lidocaine, procaine, chlorprocaine, tetracaine, benzocaine, mepivacaine, prilocaine, ropivacaine, bupivacaine, etidocaine and their corresponding pharmaceutically acceptable salts. Lidocaine and its pharmaceutically acceptable salts, such as hydrochloride, sodium salt and carbonate, notably hydrochloride, are preferable as the anesthesic of the present invention. Compositions for topical use object of the present invention typically comprise as their active ingredients, in percentage by weight, 0.03 to 3.0% of antibiotic from the class of quinolones, 0.1 to 10.0% of azole antifungus, 0.002 to 0.20% of corticoid anti-inflammatory and 0.2 to 20.0% of local anesthesic from the class of amines, and pharmaceutically acceptable excipients. Particularly preferred are the compositions comprising the active ingredients, in percentuals by weight, 0.03 to 3.0% of ciprofloxacin, 0.1 to 10.0% of ketoconazol, 0.002 to 0.20% of fluocinolone and 0.2 to 20.0% lidocaine. Even more particularly, compositions for topical use of the present invention comprise, in percentage by weight, 0.03 to 3.0% of ciprofloxacin hydrochloride, 0.1 to 10.0% of ketoconazole, 0.002 to 0.20% of fluocinolone hydrochloride and 0.2 to 20.0% of lidocaine hydrochloride. Compositions for topical use of the present invention additionally comprise excipients in appropriate quantities to formulate the active ingredients. Said excipients should be generally pharmaceutically acceptable and include, among others, thickening agents, carries and coloring agents. As examples of pharmaceutically acceptable thickening agents which may be used in the compositions of the present invention, we mention the group consisting of polyvinylpyrrolidone 9OK, polyvinylpyrrolidone K-12, polyvinylpyrrolidone K-17, polyvinylpyrrolidone K-30, polyvinylpyrrolidone/vinyl acetate (6:4), hydroxyethylcellulose, methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, carboxyvinyl polymers or carbomers, polyacrylates, natural or synthetic gums, alginates, clays, polyoxyethylene glycols, gelatin, xanthan, pectins and pectates. Examples of carriers which may be used are one or more compounds from the group consisting of glycerin, , mineral oil, water, isopropyl alcohol, ethyl alcohol, glyceroformol, polyethylene glycols of various molecular weights, hexylene glycol, and vegetal oils of soy, canola, peanuts, corn, cotton or sesame. Examples of coloring agents for use in the present invention may be selected from the group consisting of amaranthus red, sunset yellow, sunset yellow 6 (Cl 15985), tartrazin yellow 5 (Cl 19140), shining blue 1 (Cl 42090), indigotin blue 2 (Cl 70015), patent blue 5 (Cl 42051), Bordeaux red 2 (Cl 16185), erythrosin red 3 (Cl 45430), azorubin red 5 (Cl 14720), ponceaux red 6 4R (Cl 16255), allura red 40 (Cl 16035), pigments of iron oxide and titanium dioxide. Furthermore, the invention refers to dosage forms for the pharmaceutical association and compositions of the present invention. Said dosage forms should guarantee the efficacy of the topical treatment of acute or chronic otitis in pet animals, particularly cats and dogs. Thus, preferably, dosage forms of the present invention should comprise enough quantity of active ingredients to supply to the animal dosages of 0.001 to 10.0 mg/kg of body weight of antibiotic from the class of quinolones, 0.001 to 20.0 mg/kg of body weight of azole antifungus, 0.0001 to 10 mg/kg of body weight of corticoid anti-inflammatory and 0.001 to 20.0 mg/kg of body weight of local anesthesic from the class of amines. More preferably, dosage forms of the present invention comprise enough quantity of active ingredients to supply to the animal dosages of 0.001 to 10.0 mg/kg of body weight of ciprofloxacin, 0.001 to 20.0 mg/kg of body weight of ketoconazole, 0.0001 to 10 mg/kg of body weight of fluocinolone and 0.001 to 20.0 mg/kg of body weight of lidocaine. Especially preferred are the dosage forms comprising sufficient quantity of active ingredients to supply the animal with dosages of 0.045 mg/kg of body weight of ciprofloxacin hydrochloride, 0.1 5 mg/kg of body weight of ketoconazole, 0.003 mg/kg of body weight of fluocinolone hydrochloride and 0.30 mg/kg of body weight of lidocaine hydrochloride.

Examples The present invention will be disclosed with reference to the examples that follow, which show various forms of embodiment of the invention, but not imposing any limit or restriction to the scope as defined by the set of claims. Various products based on the association object of the present invention have been formulated, comprising active ingredients under the corresponding quantities as detailed below, based on 100 grams of product. Table 1

Compound (A): ciprofloxacin (hydrochloride) Compound (B): ketoconazol Compound (C): fluocinolone hydrochloride Compound (D): lidocaine hydrochloride Formulations above was for topical administration on the external auditive passage, after its cleaning to remove all earwax excess and other dirts, under preferable dosages of four drops for dogs and three drops for cats, during seven to ten consecutive days. The treatment was not interrupted before 48 hours after symptoms disappear, which usually occured after between ten and twenty days of treatment. Claims "PHARMACEUTICAL ASSOCIATION, COMPOSITIONS FOR TOPICAL USE, FORMS OF DOSAGE AND METHOD OF TREATMENT OF ACUTE OR CHRONIC OTITIS IN PET ANIMALS"

1. PHARMACEUTICAL ASSOCIATION particularly appropriate to the treatment of acute or chronic otitis in pet animals, notably cats and dogs, which comprises antibiotic from the class of quinolones, azole antifungus, corticoid anti-inflammatory and local anesthesic from the class of amines compounds. 2. PHARMACEUTICAL ASSOCIATION of claim 1 wherein the antibiotic is one or more from the group comprising ciprofloxacin, nalidixic acid, pyromidic acid, cinoxacin, rosoxacin, pipemidic acid, pefloxacin, ofloxacin, fleroxacin, enoxacin, difloxacin, amyfloxacin, irloxacin, rufloxacin, lomefloxacin, norfloxacin, levofloxacin, trovafloxacin, temafloxacin, tosufloxacin, sparfloxacin, clinafloxacin and its pharmaceutically acceptable salts. 3. PHARMACEUTICAL ASSOCIATION of claim 2 wherein the antibiotic is ciprofloxacin or its pharmaceutically acceptable hydrochlorides or lactates. 4 . PHARMACEUTICAL ASSOCIATION of claim 1 wherein the azole antifungus is selected from one or more from the compounds from the group of ketoconazole, imidazole, clotrimazole, econazole, , enylconazole, itraconazole, fluconazole, voriconazole, posaconazole, tioconazole, oxyconazole, isoconazole, bifonazole, sulconazole and ravuconazole. 5. PHARMACEUTICAL ASSOCIATION of claim 4 wherein the azole antifungus is ketoconazole. 6. PHARMACEUTICAL ASSOCIATION of claim 1 wherein the corticoid anti-inflammatory is chosen from the group comprising one or more from fluocinolone acetonide, chlobetasol, diflucortolone, halcinonide, halobetasole, alclometasone, amcinonide, beclometasone, betametasone, budesonide, clobetasone, desonide, deoxymetasone, diflorasone, diflucortolone, fluandrenolone, fluchlorolone, flumetasone, flucinolone, fluocinonide, fluocortin butyl, fluocortolone, fluprepnidene, halcinonide, halobetasol, hydrocortisone, methylprednisolone, mometasone, prednicarbate, thiamcinolone and their corresponding acceptable pharmaceutical salts. 7. PHARMACEUTICAL ASSOCIATION of claim 1 wherein the corticoid anti-inflammatory is chosen from the group comprising one or more from alclometasone dipropionate, amcinonide, beclometasone dipropionate, metametasone dipropionate, betametasone valerate, budesonide, chlobetasol propionate, clobetasone butyrate, desonide, deoxymetasone, difluorasone diacetate, diflucortolone valerate, fluandrenolone, fluchlorolone, flumetasone pivalate, fluocinolone valerate, fluocinonide, fluocortin butyl, fluocortolone hexanoate, fluocortolone pivalate, , halcinonide, halobetasol propionate, hydrocortisone butyrate, hydrocortisone aceptonate, hydrocortisone acetate, methylprednisolone aceponate, mometasone furoate, prednicarbate, thiamcinolone acetonide.

8 . PHARMACEUTICAL ASSOCIATION of claim 6 wherein the corticoid anti-inflammatory is fluocinolone hydrochloride.

9 . PHARMACEUTICAL ASSOCIATION of claim 1 wherein the anesthesic is one or more as selected from the group comprising lidocaine, procaine, chloroprocaine, tetracaine, benzocaine, mepivacaine, prilocaine, ropivacaine, bupivacaine, etidocaine and their corresponding pharmaceutical acceptable salts. 10. PHARMACEUTICAL ASSOCIATION of claim 9 wherein the anesthesic is lidocaine hydrochloride, sodium salt or carbonate, preferably lidocaine hydrochloride. 11. COMPOSITIONS FOR TOPICAL USE for the treatment of acute or chronic otitis in pet animals, notably cats and dogs, which comprises as active ingredients, in percentage by weight, 0.03 to 3.0% of antibiotic from the class of quinolones, 0.1 to 10.0% of azole antifungus, 0.002 to 0.20% of corticoid anti¬ inflammatory and 0.2 to 20.0% of local anesthesic from the class of amines, their pharmaceutically acceptable salts and pharmaceutically acceptable excipients. 12. COMPOSITIONS FOR TOPICAL USE of claim 11 wherein the antibiotics from the class of quinolones, azole antifungus, corticoid anti-inflammatories and local anesthesics from the class of amines are those defined by any of claims 2 to 10. 13. COMPOSITIONS FOR TOPICAL USE of claim 11 which comprises as active ingredients, in percentual by weight, 0.03 to 3.0% of ciprofloxacin, 0.1 to 10.0% of ketoconazol, 0.002 to 0.20% of fluocinolone and 0.2 to 20.0% of lidocaine. 14. COMPOSITIONS FOR TOPICAL USE of claim 11 which comprises as active ingredients, in percentual by weight, 0.03 to 3.0% of ciprofloxacin hydrochloride, 0.1 to 10.0% of ketoconazole, 0.002 to 0.20% of fluocinolone hydrochloride and 0.2 to 20.0% of lidocaine hydrochloride. 15. DOSAGE FORMS, for the treatment of acute or chronic otitis in pet animals, notably cats and dogs, which comprises sufficient quantity to supply the animal with 0.001 to 10.0 mg/kg of body weight of antibiotic from the class of quinolones, 0.001 to 20.0 mg/kg of body weight of azole antifungus, 0.0001 to 10 mg/kg of body weight of corticoid anti-inflammatory and 0.001 to 20.0 mg/kg of body weight of local anesthesic from the class of amines. 16. DOSAGE FORMS of claim 15, wherein the antibiotics from the class of quinolones, azole antifungus, corticoid anti-inflammatories and local anesthesics from the class of amines are those as defined by any of claims 2 to 10. 17. DOSAGE FORMS of claim 15 which comprises sufficient quantity of active ingredients to supply the animal with 0.001 to 10.0 mg/kg of body weight of ciprofloxacin, 0.001 to 20.0 mg/kg of body weight of ketoconazol, 0.0001 to 10 mg/kg of body weight of fluocinolone and 0.001 to 20.0 mg/kg of body weight of lidocaine. 18. DOSAGE FORMS of claim 15 which comprises sufficient quantity of active ingredients to supply the animal with 0.045 mg/kg of body weight of ciprofloxacin hydrochloride, 0.1 5 mg/kg of body weight of ketoconazole, 0.003 mg/kg of body weight of fluocinolone hydrochloride and 0.30 mg/kg of body weight of lidocaine hydrochloride. 19. METHOD TO THE TREATMENT OF ACUTE OR CHRONIC OTITIS IN PET ANIMALS, notably cats and dogs, which comprises the application of an efficient quantity of the pharmaceutical association as defined by any of claims 1 to 10. A. CLASSIFICATION OF SUBJECT MATTER IPC8: A61K 45/06 (2006.01); A61P 27/16 (2006.01) According to International Patent Classification (IPC) or to both national classification and IPC B. FIELDS SEARCHED

Minimum documentation searched (classification system followed by classification symbols) IPC8: A61K

Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched

Electronic data base consulted during the international search (name of data base and, where practicable, search terms used) WPI, EPODOC, TXTE, medline, embase, xpesp

C. DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of document, with indication where appropriate, of the relevant passages Relevant to claim No.

X WO 2005/055921 A2 (EILAT E.) 23 June 2005 (23.06.2005) 1-14,19 page 24, lines 5-8; claims 1,9,15,18,19,21

X US 2007/054844 A 1 (LANE) 8 March 2007 (08.03.2007) 1-14,19 paragraph [0025]; claims 1-3, 10,11

WO 2005/032528 A2 (QTM LLC) 14 April 2005 (14.04.2005) 1-14,19 claims

Further documents are listed in the continuation of Box C. See patent family annex.

* Special categories of cited documents: "T" later document published after the international filing date or "A" document defining the general state of the art which is not considered priority date and not in conflict with the application but cited to be of particular relevance to understand the principle or theory underlying the invention "E" earlier application or patent but published on or after the international "X" document of particular relevance; the claimed invention filing date cannot be considered novel or cannot be considered to involve "L" document which may throw doubts on priority claim(s) or which is an inventive step when the document is taken alone cited to establish the publication date of another citation or other "Y" document of particular relevance; the claimed invention special reason (as specified) cannot be considered to involve an inventive step when the "O" document referring to an oral disclosure, use, exhibition or other document is combined with one or more other such means documents, such combination being obvious to a person "P" document published prior to the international filing date but later than skilled in the art the priority date claimed "&" document member of the same patent family

Date of the actual completion of the international search Date of mailing of the international search report 11 December 2008 (11.12.2008) 23 December 2008 (23.12.2008)

Name and mailing address of the ISA/ A T Authorized officer Austrian Patent Office KRENN M. Dresdner Straβe 87, A-1200 Vienna

Facsimile No. +43 / 1 / 534 24 / 535 Telephone No. +43 / 1 / 534 24 / 435

Form PCT/ISA/210 (second sheet) (January 2004) C (Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.

WO 2006/020689 A 1 (SCHERING-PLOUGH LTD.) 1-14,19 23 February 2006 (23.02.2006) claims

Form PCT/ISA/210 (continuation of second sheet (I)) (January 2004) | Continuation of first sheet

Continuation No. II:

Observations where certain claims were found unsearchable

(Continuation of item 2 of first sheet)

This international search report has not been established in respect of certain claims under Article 17(2)(a) for the following reasons:

Claims Nos.: 19 because they relate to subject matter not required to be searched by this Authority, namely:

Although claim 19 refers to a method of treatment of the human/animal body by therapy, a search has been carried out and bases on the alleged effect of the composition.

Claims Nos.: 15-18 because they relate to parts of the international application that do not comply with the prescribed requirements to such an extent that no meaningful international search can be carried out, specifically:

A dose regime is not an appropriate feature to characterize a dosage form.

Form PCT/ISA/210 (continuation of first sheet (I)) (January 2004) Patent document cited Publication Patent family Publication in search report date members) date

WO 2005055921 US Al 2008075670 2008-03-27 EP A2 1699431 2006-09-13 CA Al 2548892 2005-06-23 WO A2 2005055921 2005-06-23

US A 2007054844 WO A2 2008036292 2008-03-27 US Al 2007078116 2007-04-05 US Al 2007054844 2007-03-08 EP A2 1754481 2007-02-21 EP A2 1715858 2006-11-02 EP A2 1658070 2006-05-24

WO A 2005032528 US Al 2007078116 2007-04-05 US Al 2007054844 2007-03-08 EP A2 1754481 2007-02-21 EP A2 1715858 2006-11-02 EP A2 1658070 2006-05-24 WO A2 2005077360 2005-08-25

WO A 2006020689 RU A 2007108875 2008-09-20 BR A PI0514098 2008-05-27 JP T 2008509913T 2008-04-03 CW A 101039668 2007-09-19 KR A 20070041571 2007-04-18 EP Al 1776109 2007-04-25

FormPCr/ISA/210 (patent family annex) (July 1998; reprint January 2004)