|Title of Invention||
PHARMACEUTICAL FORMULATION COMPRISING AN ANTIBIOTIC, A TRIAZOLE AND A CORTICOSTERIOD
|Abstract||Abstract Disclosed are novel formulations for the treatment of otic infections in an animal comprising a triazole anti-fungal compound, a quinolone antibiotic and a corticosteroid such as mometasone furoate monohydrate.|
Background of the invention
All references cited herein are hereby incorporated in their entirety by reference. Qtorna;*® Otic Suspension contains Gentamicin Sulfate, USP, Betamethasone Valerate, USP and Clotrimazole, USP. Mornetamax© Otic Suspension contains Gentamicin Sulfate, USP, Clotrimazole, USP and Mometasone Furcate Wionohydrate.
A problem with these products exists with regards to the potential for ototoxicity due to the aminoglycosides that are often used in such products. Accordingly, there exists a need for new combination products for the treatment of infections in animals that do not suffer from these infirmities.
Summary of the Invention
Accordingly,.there-are disclosed pharmaceutical compositions for the
treatment of an infection in an animal comprising Orbiflcxacin or one of its pharmaceutical acceptable salts; an antifungally effective amount of the compound represented by the chemical structural formula I comprising:
Mometasone Furoate Monohydrate and at least one pharmaceutically acceptable carrier, wherein said composition is a suspension.
Also disclosed are pharmaceutical compositions for the treatment of an infection in an animal comprising Orbtfioxacin or one of its pharmaceutically
acceptable salts; an antifungally effective amount of a pharmaceutical^/ acceptable iriazoia compound, Mometasone Furoate Monohydrate and at least one pharmaceutically accaptabia carrier, wherein said composition is a suspension.
Detailed Description of the invention
Tha present invention is directed to a pharmaceutical composition for the treatment of an infection in an animal comprising Qrhifioxacin or one of its pharmaceutically acceptable salts; an antifungal!)' effective amount of tha compound represented by the chemical structural formula ! comprising:
Mometasone Furoate Monohydrate and a pharmaceutical acceptable carrier, wherein the composition is a suspension.
Mometasone Furoate Monohydrate is a synthetic steroid hormone in the glucocorticoid family. Glucocorticoid hormones are potent anti¬inflammatory agents. It aiso shows antipruritic and vasoconstrictive actions, it is used topically in the treatment of corticosteroid-responsive dermatoses such as psoriasis and atopic dermatitis. Mometasone Furoate, "the active component of ELOCON® lotion, cream, and ointment is an anti-inflammatory corticosteroid having the chemical name, 9,.21-Dichloro~11 (beta) ,17-dihydroxy-1 S(aipha)-methyipregna-1:4-diene-3.20-dione 17-(2 Furoate). It is practically insoluble in water; slightly soluble in methanol ethanol, and isopropanol; soluble in acetone and chloroform; and freely soluble in tetrahydrofuran. Its partition coefficient between octanoi and water is greater than 5000. Mometasone can exist in various hydrated; crystalline and
enantiomeric forms, e.g., as a Monohydrates. i his product is available from
Soherino-Ptauah "Corporation. Kanilworth, New Jersey. The
riiometasons Furoats wioriofrydrats may be present in amounts of about 0.01 to about 1 %, preferably about 0.1 %. Other corticosteroids for use in the present invention include Dexamethasone, Butoxicart, Rofieponide,
Betamethasone, Ruocinolone, Prednisone, Prednisolone, Loteprednof or Triamcinolone.
This invention further relates to stable formulations containing an antifungal))' effective amount of the micronized compound represented by the chemical structural formula (:
U.S. Patent No. 5,661,151 discloses the compound of formula I and its potent antifungal activity against a broad range of fungi such as Aspergillus, Candida, Cryptococcus, Fusarium, and other opportunistic fungi, U.S. Patent Nos. 5;S34,472 and 5,846,971, disclose oral pharmaceutical capsule compositions of the compound of structural formula i coated onto inert beads together with a binder. This product is available from Schering-Plough Corporation, Keniiworth, New Jersey. The Posaconazole may be present in amounts of about 0.01% to about 1%, preferabfy about 0.11%.
Other triazoie anti-fungal compounds for use in the present invention include Voriconazole, Ketoconazole, Fluconazole, Itraconazole, Saperconazoie, Neticonazole, Oxiconazoie, Isoconazole, Sulconazole, Tercanazole, Ttoconazoie, and/or the pharmaceutical^ acceptable salts thereof.
Orbifloxacin Is a ootent synthetic broad-spectrum antibacterial aaeni classified as a quinoione carbolic acid derivatives. it is safe and effective for the management of diseases in dogs and cats associated with bacteria susceptible to Orbifteacin. Quinotones and derivatives, thereof useful in the practice of the present invention include, but are not limited to, Orbifezacin, Ciprofloxacin. Dancfe-acln, Eno:~acin, Grepafbxscin, Levofloxacin, Lometaeacin. Nalidixic acid, Norfloxacin, Ofloxacin, Soariteacih, Marfaofiaxacin, Enrofoxacin, Ibataacin, Garenoxacin, T-3S1 1M1, T-3511 W*4, T3S11M6, Gatifeacin, Gemifteacin, Wioxiiteacin, Difiaxacin, Rufbxacin, Pradofloxacin and Trovafioxacin mesylate and'or metabolites thereof. Other quinoiones useful in the practice of the present invention are described in WO 96/16055 published May 30, 1995; U.S. Pat Wo, 5,104,356 issued Apr. 14, 1932; U.S. Pat. Wo. 5,496,947 issued Mar. 5, 1996; U.S. Pat No. 5,498,515 issued Mar. 12,1996; U.S. Pat Wo. 5:770,5-97 issued Jun. 23, 1998; U.S. Pat. -Wo. 5,840,333 issued Wov. 24, 1998: U.S. Pal. Ho. 5,672,500 issued Sep, 30, 1997; U.S. Pat Wo. 5,491,139 issued Feb. 13, 1996; U.S. Pat Wo. 5.530,115 * ' issued Jun. 25: 1995; and U.S. Pat Wo. 5346,133 issued Jul. 8; 1997.. all incorporated by reference herein.
The quinoione compounds useful in the practice of im present invention comprise from about 0.01 % to about 30% by weight of the pharmaceutical compositions of the present invention. Preferably, the quinoione compounds usefu! in the practice of the present invention comprise from about 0.1% to about 10% by weight of the pharmaceutical compositions of the present invention. More preferably, the quinoione compounds useful in the practice of the present invention comprise from about 0.5% to 5% by weight of the pharmaceutical compositions of the present invention.
The Orbifioxacin may be present in amounts of about 0.1% to about 10%, preferably about 1%.
Fluorine-containing analogs of antibiotics chloramphenicol and thiamphenicoi have been shown to have antibiotic activity, both against organisms sensitive to and resistant to chloramphenicol and thiamphenicoi. See Schafer, T.W. et a/., "Novel Fluorine-Containing Analogs of Chloramphenicol and Thiamphenicoi: Antibacterial and Biological Properties," in CURRENT CHEMOTHERAPY AND INFECTIOUS DISEASE PROCEEDINGS OF THE 1 1TH
ICC AND THE 1 9TH ICAAC AMERICAN SOCIETY OF MICROBIOLOGY 1 330, 444-445.
Examples of such compounds, and methods ior their manufacture, are described and claimed in U.S. Patent Kb. 4.235,852. The medical profession has become increasingly concerned about the transference of bacteria! resistance to humans when antibiotics useful in treating humans are
administered to livestook.Because the chloramphenicol group of antibiotics is
infrequently used now to treat humans, its derivatives are particularly appropriate tor veterinary use. Of particular interest are the S-fiuoro, 3-deo^y derivatives.
wherein R is a member selected from the group consisting of methyl or ethyl or a habgenated derivative thereof, dihalogenodeuteriomethyl, 1-hafogeno-1-deuterioethyL l,2-dihabgeno-1-deuterioethyL azidomethyl and methyisuSfonyimethyi;
each of Xand X' is a member independently selected from the group consisting of N02, SO2R1, SORi, SRi, SONH2, S02NH2, SONHRl5 S02NHR1s CORi, ORi, Ri, CN, halogen, hydrogen, phenyl, and phenyl substituted by halogen, N02j R1t ORi, P02Ri, CONHRi, NHR1, NRiR2l CON^Ffe or OCOR-M wherein each of R1 and R2 is a member independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, butyl, t-butyl, isobutyi and phenyl;
and Z is hydrogen or an aoyi group of a ftydrocarboncarboxyite acid (prefarabfy a hydrocarbondicarbO/ryiic acid) having up to 1S carbon atoms or an acyl aroup of an amino- hvdrocarboncarbascviic acid havino UD to 12 carbon atoms; and the pharmaceutically acceptable safe of said acyl groups.
included among the habgenated groups contemplated for the moiety R
in Formula ! ars the mono-, di- and tri-fiuoro, the mono-, di- and tri-chbro-, the
mono- and dl-bromo-, and the iodo-msthyi groups as well as the mono- and
di-fiuoro-, the mono- and dl-chloro-. the mono- and di-bromo-, and the iodo
ethyl groups wherein the halogen substituents are preferably on the carbon
alpha to the carbonyl function. Also included are mixed dihabgenoaifcyi
groups in which both halogens ars preferably bonded to the carbon alpha to
the carbonyl groups, e.g., groups such as fiuorochbro-, fiuorobromo-; and
chbrobromo-methyl and -ethyl, as well as trihalogen-methyl groups such as
dichiorofiuoro- and difiuorochbromethyl.
Also included among the compounds of Formula I ars the ester derivatives, e.g. 1 -hydrocarboncarbcxyiates of Formula I wherein Z is an acyl group of a hydrocarboncarbcxyiic acid having up to 16 carbon atoms that may be saturated, unsaturated, straight chain or branched chain, aliphatic, cyclic, cyclic-aliphatic, aromatic, aryi-aiiphatic, or alkyl-aromatic and may be substituted by hydroxy, alkoxy containing from 1 to 5 carbon atoms, carbcxyl, N02, NHRi, NR1R2, SRi, SOR1, or halogen, wherein R1 and R2 are as defined above.
Other antibacterialty active ester derivatives of Formula 1 are those wherein Z is an acyl group of an amino acid containing up to 12 carbon atoms that may be saturated, unsaturated, straight chain, branched chain or cyclic, that may contain aromatic groups and that may be substituted by hydroxyl groups.
Preferred ester derivatives include those derived from dibasic hydrocarboncarboxylates, e.g. the 1-succinate and 1-palmitate esters, which provide water soluble, pharmaceutically acceptable cationic salts, e.g. the sodium or potassium salts as well as salts with amine, e.g. trimethyiamine.
Also preferred are ester derivatives of amino acids that provide water soluble, pharmaceutical^' acceptable acid addition salts with mineral or organic sods, e.g. the hydrochloric, or sulfuric acid, or succinic acid addition salts.
As used herein the term "pharmaceutical acceptable salts11 thus includes salts wherein the acidic hydrogen in the dibasic hydrocarboncarboscyiats esters of this invention is replaced with a cation (e.g. sodium D-(thrao}-1 -p-nitrophenyf-2-dichloroacetamido-3-fiuoro-1 -propyl hemisuccinais) as wall as salts wherein the acidic hydrogen forms an acid addition salt with an amine (ag, D-(threo}-1-p-nitrophenyf-2-dichbroacetamido-3-fluoro-t-propyl hemisuccinate M-trimethylamine salt). Also included are the acid addition salts formed between mineral or oraanic acids and the amine in the amino acid esters of the compounds of Formula I (ag. D-(thrao)-1-p-nitrophanyl-2-dichloroacetamido-3-fiuoro-1 -propyl gfycinate hydrochloride).
Among the pharmaceutical^' acceptable cationic salts of the dibasic hydrocarboncarboxyiate esters included in Formula l are salts of alkali and alkaline earth metals (e.gv sodium, potassium, calcium, aluminum) and salts with an amine such as thalkylamines, procaine, dibenzylamins, N-banzyi-beta-phenethylamine, N,N'-dibenzylethylenediamine, N-(lower}alkyipiperidines (e.g. N-ethyipiperidine), and N-methyl giucamine.
Preferably R is a habgenated derivative of methyl or ethyl, Z is a hydrogen, X is phenyl, COR-i or S02Ri, Ri is methyl and X1 is hydrogen. Most preferably R is CHCI2 or CHF,.
A preferred antibiotic. compound is florfenicoi (D-(threo)-l-p-methylsulfonyl phenyl-2-dich!oroacetamido-3-fluoro-1-propano[). Another preferred antibiotic compound is D-(threo)-1 -p-methylsulfonyl phenyl-2-difluoroacetamido-3-ffuoro-1-propanol. Processes for the manufacture of these preferred antibiotic compounds, and intermediates useful in such processes, are described in U.S. Patent Nos. 4:311,857; 4,582,918; 4,973,750; 4,876,352: 5,227,494; 4,743,700; 5,567,844;"' 5,105,009; 5,382,673; 5,352,832; and 5,663,351.
Also preffered antibiotics ars tetracyclines. Particularly preferred is chbrotatracydine and G-yLatraoyoiins.
Also for use in the prasant indention are compounds such as Arnosdciliin, Ampbiiiin, Ampbiiiin Trihydrate. Ampiciliin Sodium, Apabilfin, Aspoxbilfin, Aziaciliin, Bacampbiliin, GarbsnbiiEin, Garbanbillin Sodium,
Dicioxaciliin, Dbbxasiliirt Sodium, Fiucbxaciliin, Hetaciliin, Lanampbiliin, Meciiiinam, KAatampbiliiri, kriaihbiliin, Wiezbciliin, hiafciliin, Mafciliin Sodium, Qxaciliin, Panbilib Acid, Penicillin G, Penicillin G Benzathine, Penicillin G Potassium, Penbiliin G Sodium, Panbiliin V, Phenethiciliin, Phanethbiliin Potassium, Piperacillin, Piparaciliin Sodium, Prvampbiiiin, Suibenbiliin, Suitambiliin, Taiarnpbiliin, Tbaroillin, Cefaclor, Gefadroxii, Gefadroxil Wionohydrate, Gatamandota: Getamandoie Lithium, Gefarnandoie Nanfate, Cefamandoie Sodium, Gefazafiur, Gafazadona, Gefazoiin, Gefazoiin Sodium. Cefciidine, Gefdinir, Cafapims. Gefetamet Gsfbdms: Cefiuprenam, Cafmanoxima, Gefmetazoie Sodium, Gafodizima. Gafonbid. Cafoparszone. Cafoperazons Sodium, Ceforanids. Cefoseiis, Cefotaxime, Gafotaxima Sodium, Cefotiam, Cefozopran, Cefpimizoie, Cafpimizoie Sodium, Cefpiramide, Cefpirome, Cefpodcxime, CefproziK Cefquinome, Cefroxadine, Cefsulodin, Cafsuiodin Sodium Hydrate, Ceftazidime, Ceftazidime Pentahydrate, Ceftezoie, Geftibuten, Ceftiolene, Caftizoximer Ceftriaxone, Ceftriaxone Disodium Salt, Ceftriaxone Sodium, Cefuroxime, Cefuzonam, Cephacetrile, Cephalexin, Cephaioridine, Cephalosporin C, Caphabthin. Cephaiothin Sodium, Cephapirin, Gephapirin Sodium, Cephradina. Loracarbaf, Cefbuperazone, Cefoxitin, Cefoxitin Sodium, Cefmincx. Cafmetazote, Cefotetan, either alone or in combination with Beta Lactamase inhibitors such as Clavulanic Acid. Potassium Clavuianate, Sulbactam Lodopenbiflanb acid, 6-Bromopenbillanic acid, Olivanb acids, and Tazobactam.
Also for use in the present invention are macroiide antimitotics such as Azithromycin, Brefeldin, Clarithromycin, Erythromycin, Erythromycin Estoiate, Erythromycin Ethyl Succinate, Erythromycin Stearate,. Josamycin, Kitasamycin and Tulathromycin.
Another preferred antibiotic compound is Tilmbosin. Tilmbosin is a macroiide antibiotic that is chemically defined as 20-dihydro-2D-deoxy-20-(Gis-3r5-dimsthylpiparidin-1-yf)-desmycosin and. which is- reportedly disclosed in U.S. Pat. Ho. 4,820,695. Also disclosed in U.S. Pat Kb. 4,820,695 is an injectable, aqueous formulation comprising 50% (by volume) propylene glycol. 4% (by volume) benzyl alcohol, and 50 to 500 mg'mi of active ingredient. Tilmbosin may be present as the base or as a phosphate. Tiimicosin has-been found to be useful in treatment of respiratory infections, particularly Pasteurelia haemotyiba infections in cattle when administered by injection over a 4 day treatment period.
Another suitable antibiotic for use in the present invention is Tulathromycin. Tulathromycin has the following chemical structure:
Tulathromycin may be identified as 1-Oxa-S-azacyclopentadecan-15-one, 13-[[2,6-dideoxy-3-C-methl-4-3-0-methyl-4-C-[(propylamino)methy-a-L" ribo-hexopyranosyi}oxy}-2-ethy!-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyi-11-[[3,4,6-trideoxy-3-(dimethylamino)-[3-D-xylo-hexopyranosyI]oxy]- (2R. 3S, 4R, 5RT 8R, 10R, 11R, 12S, 13S, 14R). Tulathromycin may be prepared in accordance with the procedures set forth in U.S. Publication No.
2Q03/0084S39 A1, which is incorporated by reference in fe entirety. Tuiaihromycin may be presant in injectable dosage forms- at concentration levels raining from about 5.0% to about 70% by weight Tulsathromycin is
WW = w «-'
most desirably administered in dosages ranging from about' Q.2 mg per kg body weight per day (mg/kg/day) to about 200 mg/kg'day in single or divided
doses (i.e.,from 1 to 4 dosses per day) and more preferably 1.25,2.5 or 5
mo/ka ones or twice weekly, aithouah variations will necessarily occur
w" w ■ ' *■ ■■
depending upon the species, weight and condition of the subject being treated. Tutathromycin may be present in injectable dosage forms at concentration levels ranging from about 5.0% to about 70% by weight.
There are five reasons why this otic product that is intended for use in companion animais is novel. The fluoroquinolone antibiotic (Orhificxacin) has not been used in this type of product previously (although it is available in Member States in tablet form for the treatment of urinary tract infections in docs). Moreover, the usual antibiotic in this class of medicines Is aentamicin (or other aminoglycosides) which have been associated with an increased incidence of deafness, particularly in dogs. Hence. this product can be expected to have better safety profile.
The anti-inflammatory drug preferably is Mometasone. it is the first in class of corticosteroids. Thus, this product is expected to safer than other topical corticosteroid preparations currently used in veterinary medicine.
The antifungal drug preferably is posaconazols: a drug with 10-400x the antifungal activity of traditional antifungal compounds used in veterinary medicine such as clotrimazole, miconazole, nystatin. It will be the first use of a triazole antifungal in veterinary medicine. The combination for this proposed otic product is new. The product requires only one application per day. In summary, the justification for use of the centralized procedure is:
• Novel antibiotic in an otic preparation with none of the ototoxicity of the aminoglycosides often used in such products;
• Novel, corticosteroid, with a better safety profile when compared other corticosteroids used in otic preparations;
• Potent triazole anti-fungal drug;
Movel combination of the three drugs described above; : Single daily application.
Other inert ingredients can be added to the present composition, as desired. Such irrarediants include presen/atives, chelating aaents, antioxidants and stabilizers. Exemplary preservatives include methyl p. hydroxybenzoaie (methyiparaben) and propyl p-hydroxybanzoate (propylparaben). Exemplary chelating agents include edetaie sodium. Exemplary antioxidants include butyiated hydroryanisois and sodium monothioglycaroL
In order to prepare the suspension compositions of the present invention, the vehicie(s) or a portion of the vehicle(s), are added to the compounding, vessel, followed by the remaining sxcipients and the actives. Additives, such as those listed above, may also be included in the vessel and - mixed-into the formulation (the order of addition is not critical .
The compositions may be administered once daily or divided into multiple doses. Often only one dose will be sufficient to treat the infection! 'in some circumstances one dose followed by a second dose 43 hours later will be required to treat the animal. Alternatively, the medication may be administered once daily for up to 7 days. The precise dose will depend on the stage and severity of the infection, the susceptibility of the infecting organism to the composition, and the individual characteristics of the animal species being treated, as will be appreciated by one of ordinary skill in the art.
As stated hereinabove, pharmaoeutically-acceptabie excipients include, but are not limited to, resins, fillers, binders, lubricants, solvents, glidants, disintegrants, co-solvents, surfactants, preservatives, buffer systems, pharmaceutical-grade dyes or pigments, and viscosity enhancing agents.
Preferred buffer systems include, but are not limited to, NaOH, acetic, boric, carbonic, phosphoric, succinic, malalo tartaric, citric, benzoic, lactic, glyceric, gluconic, glutaric and glutamic acids and their sodium, potassium and ammonium salts. The pharmaceutical composition of the present invention generally contain from 0.1% to 20% buffer systems.
Preferred, surfactants include, but are not limited to. poN/o;::veinvlene sorbitan fatty acid esters, polyoxyethylene monoallyl ethers, sucross monoestars and ianoiin asters and others, alkyl sulfate salts, sodium, potassium, and ammonium salts of fatty acids.
Preferred preservatives include, but are not limited to, phenol, alkyl
phenyiphenol benzoic acid and the salts thereof, chbrobutanol, benzyl alcohol, thimarosal phenyimercuric acetate and nitrate, nitromersoL benzalkonium chloride, cetyipyridinium chloride, methy! paraben, and propyl paraben. Particularly preferred is sorbic acid. The compositions of the present invention generally include from 0.01% to 5% preservatives.
Preferred viscosity enhancing agents include, but are not limited to, methyiceliuiose, sodium carboxymethylceiiuiose, hydroxypropyl-methybeliuiose, hydroxypropybeliubse, sodium alginate, carbomer, povidone, acacia, guar gunv xanthan gum and tragacanth. Particularly
preferred are methyiceliuiose. carbomer. xanthan aum. auar cum. oovidone. sodium carhoxymethybeliubss, and magnesium aluminum silicate....
Compositions of the present invention include 0.1 % to 5% viscosity agents.
A particularly preferred thickening agent is Plastibase SOW: It is available from Bristol-Myers Squibb, Plastibase® SOW contains 5% polyethylene in 95% mineral oil. Polyethylene is an inert hydrocarbon with a high molecular weight and high melting point. It is used as a thickening agent to increase the viscosity of the mineral oil. Other preferred thickening agents include carboxyvinyl polymers, carrageenan, hydroxyethyl cellulose, iappnite and water soluble salts of cellulose ethers such as sodium carboxymethylceiiuiose and sodium carboxymethyl hydroxyethyl cellulose. Natural gums such as gum karaya, xanthan gum, gum arabic5-a-nd gum tragacanth can aiso be used. Colloidal magnesium aluminum siiicate or finely divided silica can be used as part of the thickening agent to further improve texture.
Liquid pharmaceutical compositions generally include a tiquid carrier such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil.
Physiological saints solution, or glycols such as ethylene glycol, propylene glycol or polyethylene glycol may be included. Such compositions and preparations generally contain at least 0.1 wt % of the compound.
A preferred class of thickening or gelling or suspending agents includes a class of hornopolymers of acrylic acid crossiinked with an alleyl ether of pentaerythroyl or an ethyl of sucrose or carbomers. carbomers are
commercially available from B.F. Goodrich as the GarbopoS® series. Particularly preferred Garbopois include Carbopol 934, 940, 941, 956, and mixtures thereof. Copolymers of iactide and glycoiide monomers, the copolymer having the molecular weight in the range of from about 1,000 to about 120,000 (number average), are useful for delivery of actives. These polymers are described in U.S. Pat No. 5,198,220, issued Mar. 30,1993 and U.S. Pat. No. 5242,510, issued Sep. 7, 1933, both to Damani, and U.S. Pat. No.-4,443,430. to Mattel, issued Apr. 17, 1934.
Thickening aaents in an amount from about. 0.1 % to about 1-5%, preferably from about 2% to about 10%. more preferably from about 4% to about 3%, by weight of the total composition, can be used. Higher concentrations can be used for sachets, non-abrasive eels and subainalvai
' W WW"
.The compositions of the present invention may optionally contain lactose, mannttoi, sorbitol, tribasic calcium phosphate, dibasic calcium phosphate, compressible sugar, starch, calcium sulfate, dextro and microcrystamine cellulose, magnesium stearate, stearic acid, talc, colloidal silicon dicxide, starch, sodium starch glycolate. crospovidone, croscarmebse sodium, and microcrystaiiine cellulose, acacia, tragacanth, hydroxypropylceiluicse, pregelantinized starch, gelatin. povidone, ethyiceilulose, hydroxypropylceiluicse, hydroxypropylmethylcellulose, and methyicelluiose.
The present invention is more particularly described in the following example which are intended as illustrative only since numerous modifications and variations therein will be apparent to those skilled in the art.
The actual amount of Orbifloxacin is to be determined based on assay arid moisture content of the lot "to be used. The actual amount of Mometasone Furoate Monohydrate is to be determined based on assay and moisture content of the lot to be used. The actual amount of Posaconazoie is to be determined based on assay and moisture content of the bi to be used. ™" The formulation may be prepared as known to one of ordinary skill in the art.
Although certain presently preferred embodiments of the invention have been described herein, it will be apparent to those skilled in the art to which the invention pertains that variations and modifications of the described embodiments may be made without departing from the spirit and scope of the invention. Accordingly, it is intended that the invention be limited only to the extent required by the appended claims and the applicable rules of law.
1, A pharmaceutical composition for the treatment of an otic infection in an animal comprising Orbifloxaacin or one of its pharmaceutical^/ acceptable 5 salts; an antifungal!/ effective amount of a pharmaceutical!/ acceptable
pharmaceutical!/ acceptable carrier, wherein said composition is a suspension.
10 2. The composition according to claim 1, wherein the wimetasone Furcate yonohydrate is present in an amount of at feast about 0.01%.
3. The oomoosition according to claim i, wherein the orbifloxacin is present in an amount of at least about 0.1 %.
4. The composition according to claim 1, wherein the antifungally effective amount of a pharmaceutically acceptable triazoie compound is present in an amount of at least about 0-01%.
20 5. The composition according to claim 4. wherein the antifungal!'/ effective amount of a pharmaceutical!}' acceptable triazoie compound is Posaconazoie
5. A pharmaceutical composition for the treatment of an infection in an
animal comprising Orbifloxacin or one of its pharmaceutical acceptable
25 salts; an antifungally effective amount of the compound represented by the chemical structural formula I comprising:
Mometasons Furoate Wionohydrate and at least oris pharmaceutical!}' acceptable carrier, wherein said composition is a suspension.
7. The composition according to claim 6, wherein the Mometasone
Furoate Mionohydrate is present in an amount of at least about 0:01 %.
3. The composition according to claim 6, wherein the Orbifioxacin is present in an amount of at least about 0.1 %.
9. The composition according to claim 6, wherein the antifungally effective
amount of a pharmaceutically acceptable triazole compound is present in an
amount of at least about 0.01%.
10. A pharmaceutical composition for the treatment of an infection in an
animal comprising an antibiotic or one of its pharmaceutically acceptable
salts; an antifungal effective amount of a pharmaceutically acceptable
triazole compound, a corticosterold and at least one pharmaceutically
acceptable carrier,, wherein said composition is a suspension.
11. The composition according to claim 10, wherein the corticosterold is
selected from the group consisting of Mometasone, Mometasone Furoate,
Mometasone Furcate Monohydrata, Daxamethasona Butoxicart Rotteponide, Budasonids, Dsfiazacorl Giciesonids, Fiuticasans. Becbmethasone, Latepradnol, Triamcinolone Betamethasone, Ruocinobna; Prednisone, Prednisolone and/or pharmaceutically acceptable sails thereof.
12. The composition according to claim 10, wherein the corticosteroid is K/bmetasons Furcate Wibnohydrate and wherein the wiometasone Furoate Monohydrate is present in an amount of at is at about 0.01%.
13. The composition according to claim 10. wherein the antibiotic is a quinoline antibiotic and wherein the quinoline antibiotic is present in an
amount of at least about 0,1 %.
14. The composition according to claim 10. wherein the quinoline antibiotic is selected from the group consisting of Orbifioxacin, Ciprofloxacin. Danofloxacin, Enoxacin, Grepafbxacin, Levofioxacin, Lomefbxacin, Nalidixic acid, Norfloxacin, Ofloxacin, Sparfloxacin, Marbofioxacln, lbafioxacinr Garenoxacin, T-3811M1. T-3811M4, T3311 MS, Gatrfioxacin, Gemrficxacin, Moxiflcxacin. Difloxacin, Rufloxacin, Pradofloxacin and Trovafloxacin mesylate and/or metabolites thereof.
15. The composition according to claim 14, wherein said quinoline antibiotic is Orbifioxacin.
16. The composition according to claim 10, wherein the antifungal effective amount of a pharmaceutical^ acceptable triazole compound is present in an amount of at least about 0.01%.
17. The composition according to claim 10, wherein the antifungal effective amount of a pharmaceutically acceptable triazole compound is selected from the group consisting of Voriconazole, Ketoconazole, Fluconazole, Itraconazole, Saperconazoie, Netbonazoie, Oxbonazoie, isoconazole, Subonazole, Tbconazoie and/or the pharmaceutically acceptable salts thereof.
18. The composition according to claim 17. wherein the antifungally effective amount of a pharmaceutically acceptable triazole compound is
19. The composition according to claim 10. wherein the antibiotic is-
salected from the group consisting of Amoxicillin, Ampiciiiin. Ampiciiiin
Trihydrate, Ampiciiiin Sodium, Apabcilin, Aspcxbiliin, Aziocillin.. Bacampiciliin.
Carbenicillin, CarbenicilEin Sodium. Carreciilin, Carindacillin. Cbiaciliin,
Cloxaciliin Sodium, Cioxacillin Benzathine, Dbtaxacilfin, Dicioxaciliin Sodium,
Fiucloxacillin, Hetacillin, Lenampbillin, Mecillinam, Metampicillin, MethiciHin,
Mezlocillin, Nafciliin, Nafcillin Sodium, Oxacillin, Peniciliic Acid, Peniciliin G:
Penicillin G Benzathine, Peniciliin G Potassium, Penicillin G Sodium, Penicillin
V, Phenethiciiiin, Phenethiciiiin Potassium, Piperacillin, Piperacillin Sodium, Pivampiciilin, SuEbenbiSIin, Suttamiciliin, Talampiciliin, Ticarcillin, Cefaclor, Cefadroxil, Cefadrcxil Monohydrate, Cefamandoie, Cefamandole Lithium, Cefamandoie Nanfate, Cefamandole Sodium, Cefazafiur, Cefazedone, Cefazoiin, Cefazoiin Sodium, Cefciidine, Cefdinir, Cefepime, Cefetamet Cefixime, Cefiuprenam, Cefmenoxime, Cefmetazole Sodium, Cefodizime, Cefonicid, Cefoperazone, Cefoperazone Sodium, Ceforanide, Cefosefis, Cefotaxime, Cefotaxime Sodium, Cefotiam, Cefozopran, Cefpimizole, Cefpimizole Sodium, Cefpiramide, Cefpirome, Cefpodoxime, CefproziL Cefquinome, Cefroxadine, Cefsubdin, Cefsulodin Sodium Hydrate, Ceftazidime, Ceftazidime Pentahydrate, Ceftezole, Ceftibuten, Ceftiolene,
Caftizoxime Ceftriaxone, Ceftriaxone Disodium Salt, Ceftriaxone Sodium, Cefuroxirne. Csfuzonarn. Cephaoetrils. Cephalexin. Cephaloridine, Cephalosporin C; Cephalothin, Cephalothin Sodium, Gephapirin, Cephapirin Sodium, Gephradine, Loraoarbef. Gefbuperazone, Cefoxitin, Cefoxitin Sodium, Germinox, Cermatazole, Cefotetan, either alone or in combination with Beta Lactamase inhibitors such .as Glavuianic Acid Potassium Glavulanats, Sulbactam Lodopenicilianic acid, S-Bromopenicilianic acid, Qiivanic acids, and Tszohactam.
20. Ths composition according to claim 10. wherein tha antibiotic is
selected from tha group consisting of antibitiotics such as Azithromycin.
Brefeldin, Clarithromycin. Erythromycin, Erythromycin Estoiate,Erythromycin Ethyl Succinate. Erythromycin Stearate. Josamycin, Kitasamycin and
21. The composition according to claim 10. wherein the antibiotic is
selected from the group consisting of 3-fiuoro, 3-deoxy derivatives.
wherein R is a member selected from the group consisting of methyl or ethyl or a hatogenated derivative thereof, dihalogenodeuteriomethyl, 1-halogeno-l-deuterioethyi, 1,2-dihalogeno-l-deuterioethyi, azidomethyl and methyisuifonyimeth.yl;
each of X and X1 is a member indeoendently selected from the croup consisting of MO2, S02R1 SOR-t! SR1, SOWH2: S02NH2,SOWHR1,SO2WHR1 ODR1, OR-;. R1,OH, halogen, hydrogen, phenyl, and phenyl substituted by halogen, NO2, R1, OR1, P02R1, CONHR1, NHR1, NR1R2 COWR1R2 or GCOR1, therein each of Ri and R2 is a member independently selected, from the group consistinn of methyl,ethyl,n-propyl,isopropyl, butyl, t-butyl, Isobutyl and phenyl;
and Z Is hydrogen or an acyl group of a hydrocarboncarboxylic acid (preferably a hydrocarbondicarboryiic acid) having up to 16 carbon atoms or an acyi group of an amino- hydrocarboncarboxylic acid having up to 12 carbon atoms; and the pharmaceutically acceptable salts of said acyl groups.
22. The composition according to claim 21, wherein the antibiotic is
23. The composition according to claim 10., wherein the antibiotic is
24. The composition according to claim 10, wherein the antibiotic is
Dated this 13 day of February 2007
|Indian Patent Application Number||622/CHENP/2007|
|PG Journal Number||53/2010|
|Date of Filing||13-Feb-2007|
|Name of Patentee||SCHERING-PLOUGH LTD|
|Applicant Address||WEYSTRASSE 20, P O BOX, CH-6000 LUCERNE 6,|
|PCT International Classification Number||A61K31/538|
|PCT International Application Number||PCT/US05/28379|
|PCT International Filing date||2005-08-10|