US 2010 00874O9A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0087409 A1 Freehauf et al. (43) Pub. Date: Apr. 8, 2010

(54) COMPOSITION COMPRISING AN (22) Filed: Jun. 2, 2009 ANTIBIOTIC AND ACORTICOSTEROD Related U.S. Application Data (60) Provisional application No. 61/057,940, filed on Jun. (75) Inventors: Keith A. Freehauf, Summit, NJ 2, 2008. (US); Jay Brumfield, Summit, NJ (US); Roger Tully, Mildenhall Publication Classification (GB) (51) Int. Cl. A6II 3/58 (2006.01) A6IP3L/00 (2006.01) Correspondence Address: SCHERING-PLOUGH CORPORATION (52) U.S. Cl...... S14/171 PATENT DEPARTMENT (K-6-1, 1990) (57) ABSTRACT 2000 GALLOPNGHILL ROAD This invention relates to compositions (e.g., otic composi KENILWORTH, NJ 07033-0530 (US) tions) comprising an antibiotic (generally a quinolone or naphthyridinone), corticosteroid, and organic acid (generally (73) Assignee: Intervet International BV. a fatty acid). This invention also relates to treatment methods using Such a composition, uses of such a composition to make medicaments, and therapeutic kits comprising Such a compo (21) Appl. No.: 12/476.783 sition. US 2010/0O87409 A1 Apr. 8, 2010

COMPOSITION COMPRISING AN the antibiotic comprises a quinolone (particularly a fluoro ANTIBOTC AND ACORTICOSTEROD quinolone, a salt of the fluoroquinolone, or a solvate of the fluoroquinolone or its salt). In other embodiments, the anti FIELD OF THE INVENTION biotic comprises a naphthyridinone (particularly a fluo ronaphthyridinone, a salt of the fluoronaphthyridinone, or a 0001. This invention relates to compositions comprising solvate of the fluoronaphthyridinone or its salt). an antibiotic (generally a quinolone or naphthyridinone), cor 0006. This invention also is directed, in part, to a method ticosteroid, and organic acid (generally a fatty acid). This for treating an infection in an animal by administering an invention also relates to treatment methods using Such a com above-described composition to the animal. position, uses of Such a composition to make medicaments, 0007. This invention also is directed, in part, to a use of an and therapeutic kits comprising Such a composition. above-described composition to prepare a medicament for treating an infection in an animal. BACKGROUND OF THE INVENTION 0008. This invention also is directed, in part, to a thera peutic kit. The kit comprises an above-described composition 0002 US Patent Application Publication No. 2006 and an additional component. The additional component may 0122159 discusses pharmaceutical formulations useful for be, for example, a diagnostic tool, an otic cleaning solution, treating infections in animals, particularly otic infections. an apparatus for cleaning an ear, instructions for administer The compositions are generally described as comprising a ing the composition to an animal, or a device for administer corticosteroid, antibiotic, and triazole. They include, for ing the composition to an animal. example, Suspensions comprising mometaSone furoate 0009. Further benefits of Applicants’ invention will be monohydrate, orbifloxacin, and posaconazole. A specific for apparent to one skilled in the art from reading this specifica mulation illustrated in US Patent Application Publication No. tion. 2006-0122159 is shown in Table 1: DETAILED DESCRIPTION OF PREFERRED TABLE 1. EMBODIMENTS 0010. This detailed description of preferred embodiments Formulation from Example 1 in US Patent is intended only to acquaint others skilled in the art with Appl. Publ. No. 2006-0122159 Applicants invention, its principles, and its practical appli Ingredient mg/g cation so that others skilled in the art may adapt and apply the Micronized Orbifloxacin 1O.O invention in its numerous forms, as they may be best Suited to Micronized Mometasone Furoate Monohydrate 1.O the requirements of a particular use. This detailed description Micronized Posaconazole 1.O and its specific examples, while indicating preferred embodi Mineral Oil USP (40 centistokes) 68S.O ments of this invention, are intended for purposes of illustra Plasticized Hydrocarbon Gel - Ointment Base quantity sufficient to tion only. This invention, therefore, is not limited to the pre (Plastibase (R) 50W, which is 5% polyethylene bring the total mass ferred embodiments described in this specification, and may and 95% mineral oil) to 1.g be variously modified. 0003) Applicants have observed an increase in at least one I. The Composition mometasone degradation product over time when the above 0011. The pharmaceutical composition of this invention formulation is stored at room temperature. Applicants have generally comprises a corticosteroid, an antibiotic, and an further observed that the orbifloxacin in the formulation organic acid. At the outset, it should be recognized that this accelerates the formation of the degradation product. The list of ingredients is not exhaustive. The composition, there formation of the degradation product generally can be mini fore, may (and generally will) contain additional ingredients. mized by storing the formulation at colder temperatures (e.g., These additional ingredients may include, for example, one 5° C.). There is, however, a need for a formulation that can or more additional corticosteroids, antibiotics, and/or organic remain stable at greater temperatures (e.g., room tempera acids. Also, as will be discussed in more detail below, the ture). This invention provides such a formulation. additional ingredients may comprise one or more other active ingredients. And, as will also be discussed below, the addi SUMMARY OF THE INVENTION tional ingredients may (and generally will) comprise one or more excipients. 0004 Briefly, this invention is generally directed to com 0012. In general, the composition may be in various forms, positions (e.g., Suspensions) that comprise a corticosteroid particularly non-Solid forms. For example, the composition and an antibiotic. These compositions generally are stable at may be in the form of a Suspension, Solution, emulsion, oint room temperature or greater (e.g., at 50° C.) over an extended ment, etc. In some embodiments, the composition is in the time (e.g., 5 months). Advantages of Such stable composi form of a Suspension. tions typically include, for example, elimination of the expense and manpower associated with refrigeration, elimi A. The Corticosteroid nation of the risk of product loss due to refrigeration failure, 0013 Corticosteroids are generally natural and synthetic and elimination of the risk of degraded product being admin analogues of hormones secreted by the hypothalamic-ante istered after inadvertent storage without refrigeration. rior pituitary-adrenocortical axis (also known as the pituitary 0005. This invention, therefore, is directed, in part, to a gland). Corticosteroids (particularly glucocorticoids) are pharmaceutical composition. The composition comprises a generally known to be potent anti-inflammatory agents. They corticosteroid, an antibiotic, and an organic acid. The organic also typically show antipruritic and vasoconstrictive activity. acid generally comprises a fatty acid that, in turn, comprises Various corticosteroids are, for example, used topically to from about 3 to about 18 carbon atoms, and has a melting treat corticosteroid-responsive dermatoses, such as psoriasis point of no greater than about 60°C. In some embodiments, and atopic dermatitis. US 2010/0O87409 A1 Apr. 8, 2010

0014 Examples of corticosteroids include the compounds shown in Table 2 (as well as salts of the compounds, and Solvates of the compounds and salts):

TABLE 2 Examples of Corticosteroids Examples of reported trade names for products containing the Corticosteroid corticosteroid Structure beclomethasone Beclovent (R) CH3 dipropionate QVAR (R) Vanceril

betamethasone Diprosone diproprionate Diprolene (R)

betamethasone Celestone (RM valerate Betnovate (R)

budesonide Entocort (REC Rhinocort Aqua (R) US 2010/0O87409 A1 Apr. 8, 2010

TABLE 2-continued

Examples of Corticosteroids Examples of reported trade names for products containing the Corticosteroid corticosteroid Structure

ciclesonide Alvesco (R) Omnaris (R)

deflazacort Calcort

dexamethasone Azium (R) Dexacort Decadron (R)

fluocinolone Derma-Smoothe, FS OH acetonide Retisert (R) US 2010/0O87409 A1 Apr. 8, 2010 4

TABLE 2-continued Examples of Corticosteroids Examples of reported trade names for products containing the Corticosteroid corticosteroid Structure

fluticaSone Flixotide propionate Flowent (R) Flixonase

f

fluticasone furoate Veramyst (R)

f

loteprednol Alrex (R) etabonate Lotemax (R)

Methylprednisolone Medro (R) US 2010/0O87409 A1 Apr. 8, 2010 5

TABLE 2-continued Examples of Corticosteroids Examples of reported trade names for products containing the Corticosteroid corticosteroid Structure prednisolone Prelone (R) Meti-Derm

prednisone DeltaSone Orasone (R) Meticorten

rofileponide

f

triamcinolone Nasacort (R) OH acetonide Tricortone US 2010/0O87409 A1 Apr. 8, 2010

In some embodiments, the corticosteroid in the composition Its chemical name is 9,21-dichloro-11 (beta),17-dihydroxy comprises a corticosteroid selected from the group consisting 16(alpha)-methylpregna-1,4-diene-320-dione 17-(2 of the compounds in Table 2, their salts, and solvates of the furoate). Mometasone furoate is, for example, the active com compounds and their salts. ponent of Elocon R. lotion, cream, and ointment, and is com 0015. In other embodiments, the corticosteroid comprises mercially available from Schering-Plough Corporation (Ken mometasone, a salt of mometaSone, or a solvate of mometa ilworth, N.J.). Sone or a mometasone salt. MometaSone is a synthetic glu 0017 Corticosteroids can exist in various enantiomeric cocorticoid, and corresponds in structure to: forms. They also can exist in various crystalline forms. For example, as indicated above, a Solvate of mometasone furoate may be used. In some embodiments, for example, the Solvate comprises a hydrate. This hydrate may be, for example, the monohydrate. 0018. In some embodiments, the corticosteroid comprises mometasone, mometaSone furoate, or a Solvate of mometa Sone or mometasone furoate (e.g., mometasone furoate monohydrate). 0019. In general, the total corticosteroid concentration in O the composition is sufficient for the corticosteroid to be thera 0016. In other embodiments, the corticosteroid comprises peutically effective at the dose in which the composition is a mometasone ester, a salt of a mometaSone ester, or a solvate administered. In some embodiments, the total concentration ofa mometaSone ester or mometaSone ester salt. In some Such of corticosteroid (e.g., mometasone, mometasone furoate, embodiments, the mometasone ester comprises mometaSone and/or Solvate of mometasone or mometaSone furoate) in the furoate. MometaSone furoate corresponds in structure to: composition is at least about 0.01% (by weight). In some such

embodiments, for example, the total concentration is from about 0.01 to about 1.0% (by weight).

B. The Antibiotic 0020. In some embodiments, the antibiotic comprises a quinolone. In general, the quinolone comprises a fluoroqui nolone, a salt of the fluoroquinolone, or a Solvate of the fluoroquinolone or its salt. Fluoroquinolone antibiotics include, for example, 6-fluoroquinolin-4(1H)-ones, salts of 6-fluoroquinolin-4(1H)-ones, and Solvates of 6-fluoroquino lin-4(1H)-ones and their salts. Examples of 6-fluoroquinolin 4(1H)-ones include those shown in Table 3:

TABLE 3

Examples of 6-Fluoroquinolin-4(1H)-ones

Examples of reported trade names for products containing the 6 6-Fluoroquinolin fluoroquinolin Structure

amifloxacin

OH US 2010/0O87409 A1 Apr. 8, 2010

TABLE 3-continued Examples of 6-Fluoroquinolin-4 (1H)-ones Examples of reported trade names for products containing the 6 6-Fluoroquinolin fluoroquinolin 4(1H)-one 4(1H)-one Structure balofloxacin O O

F OH

N N HC1 O NH H3 c.1 ciprofloxacin Cipro (R), Ciprobay, & O O Ciproxin

OH rur N

clinafloxacin O O

OH

N

C

HN

danofloxacin Advocin & Advocid O

OH

HC1 N

difloxacin Dicuiral (R) & Vetequinon

OH US 2010/0O87409 A1 Apr. 8, 2010

TABLE 3-continued Examples of 6-Fluoroquinolin-4(1H)-ones Examples of reported trade names for products containing the 6 6-Fluoroquinolin- fluoroquinolin 4(1H)-one 4(1H)-one Structure

enrofloxacin Baytril (R) O O

F OH r Nur N N CH3

feroxacin Megalone O O

F OH

N N H3 c1 N- F N F

flumequine Flubactin O O

F OH

N

CH3

garenoxacin O O

F H3C OH

N N /(' F F

gatifloxacin Tequin (R) & Zymar (R) O O

F OH

r N N HN HC1 O CH US 2010/0O87409 A1 Apr. 8, 2010

TABLE 3-continued

Examples of 6-Fluoroquinolin-4(1H)-ones

Examples of reported trade names for products containing the 6 6-Fluoroquinolin- fluoroquinolin 4(1H)-one 4(1H)-one Structure

grepafloxacin Raxar CH O O

F OH H3C itsur N N

ibafloxacin O O

F OH

HC N

CH

levofloxacin Levaquin (R), Gatigol, O O Tavanic, Lebact, Levox, & Cravit F OH

r N N N O HC1 - ~k.CH

lomefloxacin Maxaquin (R) O O

F OH

r N N HN F ls CH3 CH

marbofloxacin Marbocyl (R) & O O Zenequin

OH US 2010/0O87409 A1 Apr. 8, 2010 10

TABLE 3-continued

Examples of 6-Fluoroquinolin-4(1H)-ones

Examples of reported trade names for products containing the 6 6-Fluoroquinolin- fluoroquinolin 4(1H)-one 4(1H)-one Structure

moxifloxacin Avelox (R) & Vigamox (R) O O

F OH

N

O A. 'H. HC 1

nadifloxacin Acuatin, Nadoxia, & O O Nadixa F OH

N N

HO CH

norfloxacin Noroxin (R), Lexinor, O O Quinabic, & Janacin F OH

r N N

ofloxacin Floxin (R, Oxaldin, & O O Tarivid F OH

r N N HC1 CH3

orbifloxacin Orbax (R) & Victas F O O

F OH US 2010/0O87409 A1 Apr. 8, 2010 11

TABLE 3-continued Examples of 6-Fluoroquinolin-4(1H)-ones Examples of reported trade names for products containing the 6 6-Fluoroquinolin- fluoroquinolin 4(1H)-one 4(1H)-one Structure

paZufloxacin

pefloxacin

pradofloxacin

prulifloxacin

rufloxacin Uroflox US 2010/0O87409 A1 Apr. 8, 2010 12

TABLE 3-continued

Examples of 6-Fluoroquinolin-4(1H)-ones

Examples of reported trade names for products containing the 6 6-Fluoroquinolin fluoroquinolin 4(1H)-one 4(1H)-one Structure

Sarafloxacin Floxasol, Saraflox, O O Sarafin F OH

r N N

F

Sitafloxacin O O

F OH

N N

C HN w

spairfloxacin Zagam NH2 O O

F OH H3C, r N N itsu F ÖH,

temafloxacin Omniflox O O US 2010/0O87409 A1 Apr. 8, 2010

Other examples of 6-fluoroquinolin-4(1H)-ones include those shown in Table 4: TABLE 4-continued

TABLE 4 Additional Examples of 6-Fluoroquinolin-4(1H)-ones

Additional Examples of 6-Fluoroquinolin-4(1H)-ones O O

F O O OH F OH N N r N F A itsu CH3 HN

O O

O O F F OH NH M N N r N C itsu /\ HN

NH2 O O F OH r N itsu F

NH2 O O F OH

N N

HN

O O

F OH

N N

HC-/ US 2010/0O87409 A1 Apr. 8, 2010 14

moxifloxacin, norfloxacin, pefloxacin, pradofloxacin, sita TABLE 4-continued floxacin, sparfloxacin, and temafloxacin; salts of Such 6-fluo roquinolin-4(1H)-ones; and Solvates of Such 6-fluoroquino Additional Examples of 6-Fluoroquinolin-4(1H)-ones lin-4(1H)-ones and their salts. O O 0023. In some embodiments, the antibiotic comprises an antibiotic selected from the group consisting of danofloxacin, F difloxacin, enrofloxacin, and Sarafloxacin; salts of Such OH 6-fluoroquinolin-4(1H)-ones; and solvates of such 6-fluoro quinolin-4(1H)-ones and their salts H3C N 0024. In some embodiments, the antibiotic comprises an antibiotic selected from the group consisting the 6-fluoro quinolin-4(1H)-ones shown in Table 4, salts of such 6-fluo CH3 roquinolin-4(1H)-ones, and Solvates of Such 6-fluoroquino O O lin-4(1H)-ones and their salts. 0025. In some embodiments, the antibiotic comprises F orbifloxacin, a salt of orbifloxacin, or a solvate of orbifloxacin OH or an orbifloxacin salt. Orbifloxacin is a known synthetic potent and broad-spectrum antibacterial agent safe and effec N N tive for management of diseases, particularly in dogs and cats. 0026. In some embodiments, the antibiotic comprises a | l 6-fluoroquinolin-4(1H)-one that comprises three rings fused CH3 together. In some Such embodiments, for example, the anti HN biotic comprises an antibiotic selected from the group con sisting offlumequine, ibafloxacin, levofloxacin, nadifloxacin, ofloxacin, paZufloxacin, prulifloxacin, and rufloxacin; salts of Such 6-fluoroquinolin-4(1H)-ones; and Solvates of Such See Chu et al., “Minireview: Structure-Activity Relationships 6-fluoroquinolin-4(1H)-one and their salts. In other embodi ments, the antibiotic comprises marbofloxacin, a salt of mar of the Fluoroquinolones.” Antimicrobial Agents and Chemo bofloxacin, or a solvate of marbofloxacin or a marbofloxacin therapy, 33(2), pp. 131-135 (February 1989). salt. 0021. In some embodiments, the antibiotic comprises an 0027. In other embodiments, the antibiotic comprises a antibiotic selected from the group consisting of the 6-fluoro naphthyridinone. In general, the naphthyridinone comprises a quinolin-4(1H)-ones shown in Table 3, salts of such 6-fluo fluoronaphthyridinone, a salt of the fluoronaphthyridinone, or roquinolin-4(1H)-ones, and Solvates of Such 6-fluoroquino a solvate of the fluoronaphthyridinone or its salt. Fluoronaph lin-4(1H)-ones and their salts. thyridinone antibiotics include, for example, 6-fluoro-1.8- 0022. In some embodiments, the antibiotic comprises an naphthyridin-4(1H)-ones, salts of 6-fluoro-1,8-naphthyridin antibiotic selected from the group consisting of amifloxacin, 4(1H)-ones, and solvates of 6-fluoro-1,8-naphthyridin-4 balofloxacin, ciprofloxacin, clinafloxacin, fleroxacin, (1H)-ones and their salts. Examples of 6-fluoro-1.8- garenoxacin, gatifloxacin, grepafloxacin, lomefloxacin, naphthyridin-4(1H)-ones include those shown in Table 5:

TABLE 5

Examples of 6-Fluoro-1,8-naphthyridin-4(1H)-ones

Examples of reported trade names for products containing 6-Fluoro-1.8- the 6-fluoro-1,8- naphthyridin- naphthyridin 4(1H)-one 4(1H)-one Structure

enoxacin Penetrex & Enroxi O O

F 21 OH N N N US 2010/0O87409 A1 Apr. 8, 2010 15

TABLE 5-continued Examples of 6-Fluoro-1.8-naphthyridin-4 (1H)-ones Examples of reported trade names for products containing 6-Fluoro-1,8- the 6-fluoro-1.8- naphthyridin- naphthyridin 4(1H)-one 4(1H)-one Structure gemifloxacin Factive O O

F 21 OH

HC-O Sa N N N NF A HN

tOSufloxacin O O

F 21 OH N N N N HN F

F

trovafloxacin Trovan O O

0028. In some embodiments, the antibiotic comprises an 0030. Other examples of 6-fluoro-1,8-naphthyridin-4 antibiotic selected from the group consisting of the 6-fluoro- (1H)-ones include: O O 1.8-naphthyridin-4(1H)-ones shown in Table 5, salts of such 6-fluoro-1,8-naphthyridin-4(1H)-ones, and solvates of such F 21 OH 6-fluoro-1,8-naphthyridin-4(1H)-ones and their salts. 0029. In some embodiments, the antibiotic comprises an 2. s antibiotic selected from the group consisting of enoxacin, N gemifloxacin, toSufloxacin, and trovafloxacin; salts of Such HN ne-HCl, 6-fluoro-1,8-naphthyridin-4(1H)-ones; and solvates of such CH 6-fluoro-1,8-naphthyridin-4(1H)-ones and their salts. 3 US 2010/0O87409 A1 Apr. 8, 2010

See Chu et al., Antimicrobial Agents and Chemotherapy, at p. prises lauric acid (which has 14 carbon atoms). In still other 132. In some embodiments, the antibiotic comprises this embodiments, the fatty acid comprises oleic acid (which has compound, a salt of it, or a Solvate of it or its salt. 18 carbon atoms). It should be recognized that the composi 0031. In general, the antibiotic concentration in the com tion can comprise more than one type of fatty acid. For position is sufficient for the antibiotic to be therapeutically example, in Some such embodiments, the composition com effective at the dose in which the composition is adminis prises both oleic acid and lauric acid. tered. In some embodiments, the antibiotic concentration in 0036. In general, the fatty acid concentration in the com the composition (i.e., the total concentration of all antibiotics position is sufficient to effectively to reduce (and preferably in the composition) is at least about 0.01% (by weight). In substantially or completely inhibit) the production of at least some embodiments, the concentration is from about 0.01 to one corticosteroid (e.g., mometasone or mometaSone furoate) about 30% (by weight), from about 0.1 to about 10% (by degradation product over at least 1 month, at least 2 months, weight), or from about 0.5 to about 5% (by weight). or at least 5 months while being stored in high density poly ethylene (“HDPE) plastic bottles with low density polyeth C. The Organic Acid ylene (“LDPE) caps at a temperature of at least 15° C., at 0032. The organic acid generally comprises a fatty acid. least 20° C., at least 25°C., at least 40°C., or least at 50° C. The fatty acid preferably comprises at least about 3 carbon In some embodiments, the fatty acid concentration is at least atoms. In some embodiments, for example, the fatty acid about 0.01% (by weight). In some such embodiments, for comprises from about 3 to about 18 carbon atoms. In other example, the concentration is from about 0.01 to about 5.0% embodiments, the fatty acid comprises from about 4 to about (by weight). In other embodiments, the concentration is from 18 carbon atoms. In still other embodiments, the fatty acid about 0.1 to about 2.0% (by weight). In some embodiments, comprises from about 7 to about 18 carbon atoms. the composition comprises oleic acid, and the oleic acid con 0033. The fatty acid may be a naturally-occurring fatty centration in the composition is from about 0.1 to about 2.0% acid or a synthetic acid. It also may be saturated or unsatur (by weight). In other embodiments, the composition com ated. In some embodiments, the fatty acid comprises an prises lauric acid, and the lauric acid concentration is from unbranched aliphatic chain that comprises at least about 4 about 0.1 to about 1.0% (by weight). carbon atoms, and is either saturated or unsaturated. Prefer ably, the fatty acid has a melting point that is no greater than D. Additional Ingredients in the Composition about 60° C. 0037. As noted above, the composition of this invention 0034) The fatty acid preferably dissolves or is miscible in may (and generally will) comprise other ingredients. Those a vehicle present in the composition attemperatures in which ingredients may be, for example, one or more other active the composition is used. The fatty acid also preferably dis ingredients and/or one or more excipients. Solves or is miscible in a vehicle present in the composition at i. Other Active Ingredients temperatures in which the composition is stored. Thus, for 0038. It is contemplated that a variety of active ingredients example, in Some embodiments wherein the composition is a may be incorporated into the composition of this invention in Suspension comprising a mineral oil vehicle, the fatty acid is addition to the corticosteroid and antibiotic. Any Such active miscible in mineral oil at room temperature (i.e., from about ingredient preferably is suitable for the context in which the 20 to about 25°C.). In such embodiments, the fatty acid also composition is being used, and not significantly detrimental is preferably miscible in mineral oil at cooler or warmer to the corticosteroid and antibiotic activities. temperatures in which the composition may be used or stored. 0039. In some embodiments the composition comprises 0035. In some embodiments, the fatty acid comprises pro an antifungal. In some such embodiments, for example, the pionic acid (which has 3 carbon atoms). In other embodi antifungal comprises an imidazole, a salt of an imidazole, or ments, the fatty acid comprises myristic acid (which has 14 a solvate of an imidazole or its salt. Imidazoles include, for carbon atoms). In other embodiments, the fatty acid com example, those shown in Table 6:

TABLE 6 Examples of Antifungal Inidazoles Examples of reported trade names for products containing Imidazole the imidazole Structure clotrimazole Canesten (R), MyCelex (R), Lotrimin (R), Lotrimin AF(R), Agisten, Clotrimaderm, & Clotrimazole-Teva N/ C US 2010/0O87409 A1 Apr. 8, 2010

TABLE 6-continued Examples of Antifungal Imidazoles Examples of reported trade names for products containing Imidazole the imidazole Structure econazole Spectazole (R) C Cy N

O

C

C SOCO3ZOIt Travogen -Y C

O

C C C

ketoconazole NiZoral (R) CH3 r -NO C Nu

myconazole Monistat (R) C C Cy N

O

C

C US 2010/0O87409 A1 Apr. 8, 2010

TABLE 6-continued Examples of Antifungal Imidazoles Examples of reported trade names for products containing Imidazole the imidazole Structure neticonazole Atolant ( N ) N CH 21 S 1. 3

oxiconazole Oxistat (R) l N C

O 2 n N

C C C

Sertaconazole Ertaczo (R) \- 1

C

O C

S

C Sulconazole Exelderm (R) O)pN

S

C C C tioconazole Vagistat (R) eY C

NS O S le C C US 2010/0O87409 A1 Apr. 8, 2010

In some embodiments, the antifungal comprises an antifungal selected from the group consisting of the imidazoles shown in Table 6, salts of such imidazoles, and solvates of such imida Zoles and their salts. 0040. In other embodiments, the antifungal comprises a triazole, a salt of a triazole, or a solvate of a triazole or its salt. Triazoles include, for example, those shown in Table 7:

TABLE 7

Examples of Antifungal Triazoles

Examples of reported trade names for products containing Triazole the triazole Structure

fluconazole Diflucan (R) & Trican

itraconazole Sporanox (R) C

C

Na \U/ N 1NN N / N O X-ch H3C

posaconazole Noxafil (R) N CH3 US 2010/0O87409 A1 Apr. 8, 2010 20

TABLE 7-continued

Examples of Antifungal Triazoles Examples of reported trade names for products containing Triazole the triazole Structure

Saperconazole F /N N

N

F O O

O

Nur N HC O X N N H3C \ 2 N

terconazole Terazo (R) CH3 SN y

C O O ''

7 N C e

Voriconazole Vfend (R) a\ US 2010/0O87409 A1 Apr. 8, 2010 21

In some embodiments, the antifungal comprises an antifungal flucloxacillin, hetacillin, lenampicillin, mecillinam, selected from the group consisting of the triazoles shown in metampicillin, methicillin, mezlocillin, nafcillin, nafcillin Table 7, salts of such triazoles, and solvates of such triazoles Sodium, oxacillin, penicillic acid, penicillin G, penicillin G and their salts. benzathine, penicillin G potassium, penicillin G Sodium, 0041. In some embodiments, the antifungal comprises penicillin V, phenethicillin, phenethicillin potassium, pip posaconazole, a salt of posaconazole, or a solvate of posa eracillin, piperacillin Sodium, pivampicillin, Sulbenicillin, conazole or its salt. In some Such embodiments, for example, Sultamicillin, talampicillin, ticarcillin, cefaclor, cefadroxil, the antibiotic comprises posaconazole. Posaconazole is cefadroxil monohydrate, cefamandole, cefamandole known to have antifungal activity against a broad range of lithium, cefamandole nanfate, cefamandole Sodium, fungi, including Aspergillis, Candida, Cryptococcus, cefazaflur, cefaZedone, cefazolin, cefazolin Sodium, cefcli Fusarium, and other opportunistic fungi. Discussions relat dine, cefdinir, cefepime, cefetamet, cefixime, cefluprenam, ing to posaconazole may be found in, for example, U.S. Pat. cefimenoXime, cefimetazole Sodium, cefodizime, cefonicid, Nos. 5,661,151; 5,834,472; and 5,846,971. cefoperaZone, cefoperaZone sodium, ceforanide, cefoselis, 0042. In some embodiments, the antifungal comprises cefotaxime, cefotaxime sodium, cefotiam, cefoZopran, nystatin, a salt of nyStatin, or a Solvate of nyStatin oranyStatin ce?pimizole, cefpimizole Sodium, cefpiramide, cefpirome, salt. NyStatin corresponds in structure to: cefpodoxime, cefprozil, cefiguinome, cefroxadine, cefsu

HO 'OH

0043. In general, the concentration of antifungal agent in lodin, cefsulodin Sodium hydrate, ceftazidime, ceftazidime the composition is sufficient for the antifungal agent to be pentahydrate, ceftezole, ceftibuten, ceftiolene, cefti therapeutically effective at the dose in which the composition Zoxime, ceftriaxone, ceftriaxone disodium salt, ceftriax is administered. When more than one antifungal agent is one sodium, cefuroxime, cefuZonam, cephacetrile, cephal present in the composition, the total concentration of all the exin, cephaloridine, cephalosporin C, cephalothin, antifungal agents is Sufficient for the combined antifungal cephalothin Sodium, cephapirin, cephapirin Sodium, ceph agents to be therapeutically effective at the dose in which the radine, loracarbef, cefbuperaZone, cefoxitin, cefoxitin composition is administered. In some embodiments, the con centration of antifungal agent in the composition (i.e., the Sodium, cefiminox, cefimetazole, cefotetan, either alone or total concentration of all antifungal agents in the composi in combination with B-lactamase inhibitors. Such as clavu tion) is at least about 0.01% (by weight). In some such lanic acid, potassium clavulanate, Sulbactam Iodopenicil embodiments, for example, the concentration is from about lanic acid, 6-bromopenicillanic acid, olivanic acids, and 0.01 to about 1.0% (by weight). taZobactam. 0044. In some embodiments, the composition comprises 004.8 D. Macrollide antibitiotics, such as azithromycin, one or more antibiotics (in addition to the quinolone or naph brefeldin, clarithromycin, erythromycin, erythromycin thyridinone antibiotic(s)). Such antibiotics may include, for estolate, erythromycin ethyl succinate, erythromycin Stear example, the following antibiotics (as well as their salts, their ate, josamycin, kitasamycin, tulathromycin, and tilmi Solvates, and Solvates of their salts): COS1. 0045 A. Chloramphenicol, thiamphenicol, and fluorine 0049. In some embodiments, the composition comprises containing analogs of chloramphenicol and thiamphenicol one or more anti-inflammatory ingredients in addition to the (e.g., florfenicol or D-(threo)-1-p-methylsulfonyl phenyl corticosteroid(s). Such anti-inflammatory ingredients may 2-difluoroacetamido-3-fluoro-1-propanol). include, for example, one or more non-steroidal anti-inflam 0046 B. Tetracyclines, such as chlorotetracycline and matory drugs ("NSAIDs). NSAIDs include, for example, Oxytetracycline. salicylates, arylalkanoic acids, 2-arylpropionic acids (or 0047 C. Amoxicillin, amplicillin, amplicillin trihydrate, “profens”), N-arylanthranilic acids, pyrazolidine derivatives, ampicillin Sodium, apalcillin, aspoxicillin, azlocillin, oxicams, COX-2 inhibitors, sulphonanilides, and licofelone. bacampicillin, carbenicillin, carbenicillin Sodium, In some embodiments, the NSAID comprises aspirin, ibupro carfecillin, carindacillin, ciclacillin, cloxacillin Sodium, fen, or naproxen. Anti-inflammatory ingredients also may cloxacillin benzathine, dicloxacillin, dicloxacillin Sodium, include, for example, antihistamines. Antihistamines include, US 2010/0O87409 A1 Apr. 8, 2010 22 for example, H-receptor agonists, H-receptor agonists, 1,000 to about 120,000 (number average). These polymers H-receptor agonists, H-receptor agonists, mast cell stabi are described in U.S. Pat. Nos. 5,198,220; 5,242,910; and lizers, and vitamin C. 4,443,430. ii. Excipients 0053 Contemplated surfactants include, for example, 0050 Contemplated excipients in the compositions of this polyoxyethylene Sorbitan fatty acid esters; polyoxyethylene invention include, for example, liquid vehicles, viscosity monoalkyl ethers; Sucrose monoesters; lanolin esters and enhancing agents, Surfactants, preservatives, stabilizers, res ethers; alkylsulfate salts; and Sodium, potassium, and ammo ins, fillers, binders, lubricants, glidants, disintegrants, co nium salts of fatty acids. Solvents, and pharmaceutical-grade dyes or pigments. 0054 Contemplated preservatives include, for example, phenol; alkyl esters of parahydroxybenzoic acid (e.g., methyl 0051. In some embodiments, the compositions of this p-hydroxybenzoate (or “methylparaben) and propyl p-hy invention are in the form of a Suspension. Such compositions droxybenzoate (or “propylparaben”)); sorbic acid; o-phe generally include a liquid vehicle (or “carrier') such as water, nylphenol benzoic acid and the salts thereof; chlorobutanol: petroleum, animal oils, vegetable oils, mineral oil, or syn benzyl alcohol; thimerosal; phenylmercuric acetate and thetic oil. Physiological saline solution, or glycols (e.g., eth nitrate; nitromersol, benzalkonium chloride; and cetylpyri ylene glycol, propylene glycol, or polyethylene glycol) also dinium chloride. A particularly contemplated preservative is may be included. In some embodiments, the liquid vehicle sorbic acid. To the extent a composition of this invention comprises mineral oil. comprises a preservative, the preservative concentration in 0052 Compositions of this invention typically include the composition generally is no greater than about 5% (by one or more viscosity-enhancing agents (or “thickening weight). In some embodiments, for example, the preservative agents'). The concentration of the Viscosity-enhancing agent concentration is from about 0.01 to about 5% (by weight). in the composition is generally at least about 0.1% (by 0055 Contemplated stabilizers include, for example, weight). For example, in Some embodiments, the concentra chelating agents, such as edetate Sodium. Contemplated Sta tion is from about 0.1 to about 15% (by weight). In some such bilizers also include, for example, antioxidants, such as buty embodiments, for example, the concentration is from about lated hydroxyanisole and sodium monothioglycerol. 0.1 to about 5%. In other embodiments, the concentration is 0056 Contemplated binders include, for example, gelatin, from about 2 to about 10% (by weight), or from about 4 to about 8% (by weight). In some embodiments, the viscosity acacia, and carboxymethyl cellulose. enhancing agent comprises polyethylene. Polyethylene is an 0057 Contemplated lubricants include, for example, inert hydrocarbon with a high molecular weight and high magnesium Stearate, Stearic acid, and talc. melting point. It may be used as a thickening agent to increase 0.058 Contemplated disintegrants include, for example, the Viscosity of for example, a mineral oil vehicle. In some corn Starch and alginic acid. embodiments, polyethylene is introduced into the composi 0059) Other inert ingredients may generally be added to tion in the form of Plastibase.R. 50W (commercially available the composition as desired. It is contemplated that these may from Bristol-Myers Squibb). Plastibase.R. 50W contains 5% include, for example, lactose, mannitol, Sorbitol, calcium car polyethylene in 95% mineral oil. Other contemplated viscos bonate, Sodium carbonate, tribasic calcium phosphate, diba ity-enhancing agents also (or alternatively) may be used. In sic calcium phosphate, Sodium phosphate, kaolin, compress Some embodiments, for example, the Viscosity-enhancing ible Sugar, starch, calcium sulfate, dextro or microcrystalline agent comprises, for example, methylcellulose, sodium car cellulose, colloidal silicon dioxide, Starch, Sodium starch gly boxymethylcellulose, hydroxypropyl-methylcellulose, colate, crospovidone, croScarmelose sodium, microcrystal hydroxypropylcellulose, sodium alginate, carbomer, povi line cellulose, tragacanth, hydroxypropylcellulose, pregelan done, acacia, guar gum, Xanthan gum, or tragacanth. In other tinized starch, poVidone, ethylcellulose, embodiments, the viscosity-enhancing agent comprises hydroxypropylcellulose, hydroxypropylmethylcellulose, and methylcellulose, carbomer, Xanthan gum, guar gum, povi methylcellulose. done, Sodium carboxymethylcellulose, or magnesium alumi E. Salts num silicate. In other embodiments, the viscosity-enhancing agent comprises carboxyvinyl polymers; carrageenan; 0060. As noted above, many compounds present in the hydroxyethyl cellulose; laponite; and water soluble salts of composition of this invention may be in the form of a salt. For cellulose ethers. Such as Sodium carboxymethylcellulose and example, many of the above-described antibiotics, corticos sodium carboxymethyl hydroxyethyl cellulose. In still other teroids, and antifungals may be in the form of a salt. A salt embodiments, the viscosity-enhancing agent comprises natu may be advantageous due to one or more of its physical ral gums, such as gum karaya, Xanthan gum, gum arabic, and properties. Such as pharmaceutical stability in differing tem gum tragacanth. In still yet other embodiments, the Viscosity peratures and humidities; crystalline properties; and/or a enhancing agent comprises colloidal magnesium aluminum desirable solubility in water, oil, or other solvent. Acid and silicate or finely divided silica, which can be used as part of base salts typically can be formed by, for example, mixing a the thickening agent to further improve texture. In still yet compound with an acid or base, respectively, using various further embodiments, the Viscosity-enhancing agent com known methods in the art. In general, when the composition prises homopolymers of acrylic acid crosslinked with an alkyl of this invention is intended to be administered in vivo (i.e., to ether of pentaerythritol or an alkyl ether of sucrose, or car an animal) for a therapeutic benefit, all the salts in the com bomers. Carbomers are commercially available from B.F. position preferably are pharmaceutically acceptable. Goodrich as the CarbopolR series. In some embodiments, the 0061 An acid addition salt typically can be prepared by carbomer is Carbopol R. 934, 940, 941, 956, or a mixture reacting a free base compound with an approximately sto thereof. Copolymers of lactide and glycolide monomers may ichiometric amount of an inorganic or organic acid. Examples be useful for delivery of actives, particularly where the of often suitable inorganic acids for making pharmaceutically copolymer has a molecular weight in the range of from about acceptable salts include hydrochloric, hydrobromic, US 2010/0O87409 A1 Apr. 8, 2010

hydroiodic, nitric, carbonic, Sulfuric, and phosphoric acid. are suitable to treat non-mammals, such as birds (e.g., tur Examples of often Suitable organic acids for making pharma keys, chickens, etc.) and fish (e.g., salmon, trout, koi, etc.). ceutically acceptable salts generally include, for example, 0065. In general, the compositions of this invention are aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, administered in a dosage form that provides a therapeutically carboxylic, and Sulfonic classes of organic acids. Specific effective amount of the composition (and particularly the examples of often Suitable organic acids include cholic, Sor active ingredients) to the infection site. For an anti-inflam bic, lauric, acetic, trifluoroacetic, formic, propionic, succinic, matory (e.g., a corticosteroid, Such as mometasone furoate glycolic, gluconic, digluconic, lactic, malic, tartaric acid, cit monohydrate), a “therapeutically effective amount” is an ric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, amount that is sufficient to ameliorate, Suppress, or eradicate glutamic, aryl carboxylic acid (e.g., benzoic), anthranilic target inflammation, or effect antipruritic or vasoconstrictive acid, mesylic, Stearic, Salicylic, p-hydroxybenzoic, pheny action in a target tissue. For an anti-infective (e.g., an antibi lacetic, mandelic, embonic (pamoic), alkylsulfonic (e.g., otic or antifungal), a “therapeutically effective amount' is an ethanesulfonic), arylsulfonic (e.g., benzenesulfonic), pan amount that is sufficient to ameliorate, Suppress, or eradicate tothenic, 2-hydroxyethanesulfonic, Sulfanilic, cyclohexy a target pathogen infection. In some embodiments, a suffi laminosulfonic, B-hydroxybutyric, galactaric, galacturonic, cient amount of the composition is administered to achieve an adipic, alginic, butyric, camphoric, camphorsulfonic, cyclo antibiotic concentration that is at least equal to the MIC pentanepropionic, dodecylsulfic, glycoheptanoic, glycero level (minimum inhibitory concentration, i.e., the concentra phosphic, heptanoic, hexanoic, nicotinic, 2-naphthale tion that inhibits the growth of 90% of the target pathogen) of Sulfonic, oxalic, palmoic, pectinic, 3-phenylpropionic, picric, the antibiotic for a target pathogen. To the extent the compo pivalic, thiocyanic, tosylic, and undecanoic acid. sition comprises multiple active ingredients having combined 0062. In general, a base addition salt can be prepared by effects on a desired target tissue or pathogen, the amount of reacting a free acid compound with an approximately sto each ingredient that constitutes a “therapeutically effective ichiometric amount of an inorganic or organic base. amount' is the amount that, when combined with the other Examples of base addition salts may include, for example, active ingredients, causes the desired effect on the target metallic salts and organic salts. Metallic salts, for example, tissue or pathogen. include alkali metal (group Ia) salts, alkaline earth metal 0066. It is contemplated that the compositions of this (group IIa) salts, and other physiologically acceptable metal invention may be administered rectally, vaginally, via inha salts. Such salts may be made from aluminum, calcium, lation (e.g., via a mist or aerosol), transdermally (e.g., via a lithium, magnesium, potassium, sodium, and zinc. For transdermal patch), or parenterally (e.g., Subcutaneous injec example, a free acid compound may be mixed with sodium tion, intravenous injection, intramuscular injection, etc.). It hydroxide to form Suchabase addition salt. Organic salts may also is contemplated that the compositions may be adminis be made from amines, such as trimethylamine, diethylamine, tered orally. For example, the composition may be added to N,N'-dibenzylethylenediamine, chloroprocaine, ethanola the intended animal recipient's feed, either directly or as part mine, diethanolamine, ethylenediamine, meglumine (N-me of a premix, or as a separate dosage form. thylglucamine), and procaine. Basic nitrogen-containing 0067. In some embodiments, a composition of this inven groups may be quaternized with agents such as C-C-alkyl tion is used to treat an otic infection. In some Such embodi halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bro ments, the otic infection is in a dog. In other embodiments, the mides, and iodides), dialkyl Sulfates (e.g., dimethyl, diethyl, otic infection is in a cat. When used to treat anotic infection, dibuytl, and diamyl Sulfates), long chain halides (e.g., decyl the composition of this invention is typically administered to lauryl, myristyl, and Stearyl chlorides, bromides, and the animals infected ear(s). Although a single daily dose is iodides), arylalkyl halides (e.g., benzyl and phenethyl bro preferred, it is contemplated that the composition can be mides), and others. administered in multiple daily doses. In many instances, one II. Preparation of the Compositions of this Invention dose is sufficient to treat the infection, particularly when the 0063. The compositions of this invention generally may be composition comprises, for example, mometasone furoate prepared using, for example, techniques well-known in the monohydrate, orbifloxacin, and posaconazole. In some cir art. Typically, any vehicle(s) to be used in the composition (or cumstances, however, it may be desirable (or necessary) to a portion of Such vehicle(s)) is/are added to a compounding administer a second dose at, for example, 48 hours after the vessel, followed by the remaining excipients, the actives, and first dose to completely treat the animal (or ensure that the the fatty acid. In general, the order in which the components treatment is complete). In other instances, the composition are added to the vessel is not critical. may be administered daily for up to 7 days (or more). III. Treatment Methods. Using a Composition of this Inven 0068 Determining the proper dosage is generally within tion the skill in the art. The precise dose will depend on various 0064 Compositions of this invention may generally be factors. These factors may include, for example, the type used to treat infections in animals. It is contemplated that the (e.g., species and breed), age, size, sex, diet, activity, and composition may be used to treat a range of animals, espe condition of the intended recipient; pharmacological consid cially mammals. Such mammals include, for example, erations, such as the activity, efficacy, pharmacokinetic, and humans. Other mammals include, for example, farm or live toxicology profiles of the particular composition adminis Stock mammals (e.g., Swine, bovines, sheep, goats, etc.). tered; and whether the composition is being administered as laboratory mammals (e.g., mice, rats, jirds, etc.), companion part of a combination therapy with one or more active ingre mammals (e.g., dogs, cats, equines, etc.), and wild and Zoo dients. For example, in some embodiments wherein a com mammals (e.g., buffalo, deer, etc.). In some embodiments, the position of this invention is used to treat an otic infection in a compositions are used to treat canines (e.g., dogs). In other dog, the dose is from about 1 to about 10 drops. In other embodiments, the compositions are used to treat felines (e.g., embodiments wherein a composition of this invention is used domestic cats). It is contemplated that the compositions also to treat an otic infection in a dog, the dose is from about 25 to US 2010/0O87409 A1 Apr. 8, 2010 24 about 500 mg. In some such embodiments, for example, the least one mometasone degradation product in a Suspension dose is from about 25 to about 250 mg. comprising mometaSone furoate monohydrate in combina IV. Therapeutic Kits tion with orbifloxacin. In this experiment, the Suspension had 0069. This invention also is directed to kits that are, for the composition shown in Table 8: example, Suitable for use in performing the treatment meth ods described above. In general. Such a kit will comprise a TABLE 8 therapeutically effective amount of a composition of this invention, and an additional component(s). The additional Suspension Comprising a MometaSone Compound component(s) may be, for example, one or more of the fol and a Fluoroquinolone Antibiotic lowing: a diagnostic tool, instructions for administering the Component Concentration (mg/g) composition, or an apparatus for administering the composi Micronized Orbifloxacin 1O.O tion (e.g., a syringe or Squeeze bottle). In some embodiments Micronized Mometasone Furoate 1.O for otic treatments, the kit may comprise a composition of this Monohydrate Micronized Posaconazole 1.O invention in combination with, for example, an apparatus for Mineral Oil 68S.O cleaning an ear and/or an ear-cleaning solution. Examples of Plasticized Hydrocarbon Gel --- quantity sufficient to bring the contemplated apparatuses for cleaning an ear include clean Ointment Base (Plasticbase 50W) total mass to 1 g (after any ing cloths (e.g., dry cloths or alcohol pads) or a powered ear addition of oleic acid or lauric acid) cleaner (such as the Auriflush(R) System sold by Schering Plough Corp.). Examples of contemplated ear-cleaning solu tions include Virbac Animal Health’s Cerulytic(R) Solution The Suspension was separated into Sub-lots. Each Sub-lot was (comprising propylene glycol dicaprylate/dicaprate, benzyl combined with oleic acid to achieve a specific oleic acid alcohol, fragrance, and butylated hydroxytoluene), Pfizer Inc. concentration (at 0.1%, 0.2%, 0.5%, 1.0%, or 2.0%), com 's Oti-Clens(R Solution (comprising propylene glycol-malic bined with lauric acid to achieve a specific lauric acid con acid, benzoic acid, and salicylic acid), Vet Solutions Ear centration (0.1%, 0.2%, 0.5%, or 1.0%), or combined with no Cleaning Solution (comprising propylene glycol, aloe Vera oleic or lauric acid (i.e., the controls). The sub-lots were gel, Sd alcohol 40-2, lactic acid, glycerin, dioctyl sodium packaged into 7.5 g HDPE plastic bottles with LDPE caps, SulfoSuccinate, Salicylic acid, fragrance, benzoic acid, and and then placed on stability storage in the upright position. To benzyl alcohol), and IVX Animal Health’s OtiRinse(R) Solu tion (comprising dioctyl sodium sulfosuccinate, salicylic avoid introducing any contaminants from labels, none of the acid, lactic acid, benzoic acid, and aloe Vera). packages contained a commercial label. Each of the bottles was stored under one of the following set of conditions (a) a EXAMPLES temperature of 40°C. and a relative humidity of 75%, or (b) 0070 The following examples are merely illustrative, and 50° C. under ambient conditions. not limiting to the remainder of this disclosure in any way. (0072 Samples were evaluated with HPLC at the begin Example 1 ning of the experiment, and then at the 1-month, 2-month, and Stabilization of a Suspension Using Oleic Acid or 5-month time points afterward to determine the concentration Lauric Acid of the mometasone degradation product. The observed con 0071. The purpose of this experiment was to demonstrate centrations of the mometasone degradation product are that oleic acid or lauric acid can reduce the formation of at shown in Table 9:

TABLE 9

Mometasone Degradation Product Concentration Observed Over Time Under Different Conditions and Different Oleic Acid and Lauric Acid Concentrations

Time Points (months) and Conditions

1 1 2 2 5 5 40° C. 50° C. 40° C. 50° C. 40° C. 50° C. Acid Added Initial 75% RH. Ambient 75% RH. Ambient 75% RH. Ambient

Control (none) ND O.35% O.26% O.46% O.30% O.60% O.25% 0.1% Oleic Acid ND ND ND ND ND ND ND 0.2% Oleic Acid ND ND ND ND ND ND ND 0.5% Oleic Acid ND ND ND ND ND ND ND 1.0% Oleic Acid ND ND ND ND ND ND ND 2.0% Oleic Acid ND ND ND ND ND ND ND 0.1% Lauric Acid ND ND ND ND ND ND ND 0.2% Lauric Acid ND ND ND ND ND ND ND 0.5% Lauric Acid ND ND ND ND ND ND ND 1.0% Lauric Acid ND ND ND ND ND ND ND US 2010/0O87409 A1 Apr. 8, 2010

In Table 9, “ND” means none detected. As can be seen, the (0078. The above detaileddescription of preferredembodi presence of both acids at all the tested levels inhibited the ments is intended only to acquaint others skilled in the art formation of the mometasone degradation product for up to 5 with the invention, its principles, and its practical application months at 40° C. and 75% relative humidity, and at 50° C. so that others skilled in the art may adapt and apply the under ambient conditions. Applicants also did not observe invention in its numerous forms, as they may be best Suited to any changes in the physical appearance of the samples, and the requirements of a particular use. This invention, therefore, did not detect any new degradation products as a result of the is not limited to the above embodiments, and may be vari oleic acid or lauric acid being added. ously modified. Example 2 We claim: 1. A pharmaceutical composition, wherein: An Illustrative Otic Formulation Comprising Oleic the composition comprises: Acid a corticosteroid, 0073. The following Table 10 illustrates a composition of an antibiotic, and this invention comprising oleic acid. a fatty acid; the antibiotic comprises: TABLE 10 a fluoroquinolone, a salt of the fluoroquinolone, or a solvate of the fluoroquinolone or its salt, or Illustrative otic Formulation Comprising Oleic Acid a fluoronaphthyridinone, a salt of the fluoronaphthyri Component Concentration (mg/g) dinone, or a solvate of the fluoronaphthyridinone or its salt; Micronized Orbifloxacin 1O.O Micronized Mometasome Furoate 1.O the fatty acid: Monohydrate comprises from about 3 to about 18 carbon atoms, and Micronized Posaconazole 1.O has a melting point of no greater than about 60° C. Mineral Oil 68S.O 2. A composition according to claim 1, wherein the com Oleic Acid 2O Plasticized Hydrocarbon Gel --- quantity Sufficient to bring position is in the form of a suspension. Ointment Base (Plasticbase 50W) the total mass to 1 g 3. A composition according to claim 1, wherein the corti costeroid comprises mometasone, mometaSone furoate, or a Solvate of mometaSone or mometasone furoate. 4. A composition according to claim 3, wherein the corti Example 3 costeroid comprises mometasone furoate monohydrate. An Illustrative Otic Formulation Comprising Lauric 5. A composition according to claim 1, wherein the antibi Acid otic comprises a 6-fluoroquinolin-4(1H)-one, a salt of the 6-fluoroquinolin-4(1H)-one, or a solvate of the 6-fluoro 0074 The following Table 11 illustrates a composition of quinolin-4(1H)-one or its salt. this invention comprising lauric acid. 6. A composition according to claim 5, wherein the 6-fluo roquinolin-4(1H)-one comprises a 6-fluoroquinolin-4(1H)- TABLE 11 one selected from the group consisting of amifloxacin, balo Illustrative otic Formulation Comprising Oleic Acid floxacin, ciprofloxacin, clinafloxacin, fleroxacin, garenoxacin, gatifloxacin, grepafloxacin, lomefloxacin, Component Concentration (mg/g) moxifloxacin, norfloxacin, pefloxacin, pradofloxacin, sita Micronized Orbifloxacin 1O.O floxacin, sparfloxacin, temafloxacin, danofloxacin, difloxa Micronized Mometasome Furoate 1.O cin, enrofloxacin, Sarafloxacin, flumequine, ibafloxacin, Monohydrate levofloxacin, nadifloxacin, ofloxacin, paZufloxacin, pruli Micronized Posaconazole 1.O Mineral Oil 68S.O floxacin, rufloxacin, and marbofloxacin. Lauric Acid 2O 7. A composition according to claim 5, wherein the 6-fluo Plasticized Hydrocarbon Gel --- quantity Sufficient to bring roquinolin-4(1H)-one comprises orbifloxacin. Ointment Base (Plasticbase 50W) the total mass to 1 g 8. A composition according to claim 1, wherein the com position further comprises an antifungal agent. 0075. The words “comprise”, “comprises', and “compris 9. A composition according to claim 8, wherein the anti ing are to be interpreted inclusively rather than exclusively. fungal agent comprises a triazole, a salt of triazole, or a This interpretation is intended to be the same as the interpre solvate of the triazole or its salt. tation that these words are given under United States patent 10. A composition according to claim 9, wherein the tria law. Zole comprises a triazole selected from the group consisting 0076. The term “pharmaceutically acceptable' is used of fluconazole, itraconazole, Saperconazole, terconazole, and adjectivally to mean that the modified noun is appropriate for Voriconazole. use in a pharmaceutical product. When it is used, for example, 11. A composition according to claim 9, wherein the tria to describe a salt or excipient, it characterizes the salt or Zole comprises posaconazole. excipient as being compatible with the other ingredients of 12. A composition according to claim 1, wherein the fatty the composition, and not deleterious to the intended recipient acid comprises lauric acid. animal to the extent that the deleterious effect(s) outweighs 13. A composition according to claim 1, wherein the fatty the benefit(s) of the salt or excipient. acid comprises oleic acid. 0077 All references cited in this patent are incorporated 14. A composition according to claim 1, wherein the com by reference into this patent. position further comprises mineral oil. US 2010/0087409 A1 Apr. 8, 2010 26

15. A method for treating an infection in an animal, a diagnostic tool, wherein the method comprises administering a composition an otic cleaning solution, according to any one of claims 1 to 14 to the animal. 16. A method according to claim 15, wherein the infection an apparatus for cleaning an ear, comprises an otic infection in a dog. instructions for administering the composition to an ani 17. A therapeutic kit, wherein the kit comprises: mal, and a composition according to any one of claims 1 to 14, and a device for administering the composition to an animal. an additional component selected from the group consist ing of: ck c. c. : :