GB2520065A

GB2520065A - Tulathromycin and nonsteroidal anti-inflammatory drug compositions

Info

Publication number: GB2520065A
Application number: GB1319762.9A
Authority: GB
Inventors: James Quinton Stewart Haughey
Original assignee: Norbrook Laboratories Ltd
Current assignee: Norbrook Laboratories Ltd
Priority date: 2013-11-08
Filing date: 2013-11-08
Publication date: 2015-05-13
Also published as: GB201319762D0; WO2015067959A1

Abstract

A composition comprises tulathromycin and at least one non-steroidal anti-inflammatory drug (NSAID). Preferably the tulathromycin is a mixture of tulathromycin A and B isomers which may be present in a ratio of 9:1 (isomer A:B). The following compositions have been exemplified tulathromycin and carprofen; tulathromycin and firocoxib; tulathromycin and flunixin meglumine; and tulathromycin and meloxicam. Preferably the composition is useful in the treatment of respiratory diseases in mammals, in particular, pigs and cattle.

Description

Tulathromycin and Nonsteroidal Anti-Inflammatory Drug Compositions

Technical Field

The present invention relates to novel compositions containing tulathrornyein and nonsteroidal anti-inflammatory drugs, pharmaceutical formulations comprising said compositions and their use for treatment and prevention of respiratoiy diseases in mammals.

Background Art

Non-steroidal anti-inflammatory drugs (NSATD) are a group of medicaments with analgesic, anti-inflammatory and antipyretic effects. NSATD are widely administered for the treatment of mild to severe pain. Among the most commonly used members of the NSAID class of drugs are aspirin, fluxinin, carprofen, firocoxib and meloxicam. See Peterson K, ci ci., "Drug Class Review: Nonsteroidal Antiinflammatory Drugs (NSAIDs)" (Orcgon Health and Science University, Portland, Oregon, US, 2010).

Macrolides are broad spectrum antibiotics formed by a largc lactonc ring that varies in size from 12 to 16 atoms. Macrolide antibiotics exhibit good activity against Gram-positive acrobes such as Streptococcus pneuinoniae and flaeinophilus injluenzae. See Zhancl G, ci al., Drugs 2001; 6 1(4):443-498. Their principal mechanism of action against pathogcns involves the direct inhibition of essential protein biosynthesis by selective binding to bacterial SOS ribosomal subunits.

hi addition to their antimicrobial ifinction, macrolidc antibiotics arc known to modulate immune cell thnctions. This class of antibiotics is known to influence the recruitment and infiltration of ncutrophils and to alter their ability to secrete histotoxic compounds and proinflammatory cytokines. See Ichikawa Y, ci al., Am. Rev. Respir. Dis.

1992; 146:196-203, Lee W, ci ci., Vet. Res. 2004; 35:213-224, Mikasa K, ci al., J. Antimicrob. Chemother. 1992; 30:339-348, Takeshita K, ci al., Drugs Exp. Clin. Res. 1989; 15:527-533 and Tsuchihashi Y, ci at, Antimicrob. Agents Chemother. 2002; 46:1101-1104. Recent findings also indicate that some macrolides may induce cellular death by apoptosis and block NF-icB signaling in T lymphocytes, macrophages or epithelial cells. Sec Aoshiba K, ci at, Antimicrob. Agents Chernother. 1995; 39:872-877, Buret A, c-cii., Can. J. Vet. Res. 2010; 74:1-10, Chin A, ci at, Antimicrob. Agents Chemother. 2000; 44:2465-2470, Chin A, ci at, Am. J. Vet. Res. 1998; 59:765-771, Lee W, ci at, Vet. Res. 2004; 35:213-224, LeivaM, dat, FEMS Immunol. Med. Microbiol. 2008; 53:343-350, Ou X, ci at, Respirology 2008; 13:63-72 and Wu L, ci al., Tnt. Immunopharmacol. 2009; 9:1105-1109. However, the precise mechanisms underlying the anti-inflammatory and proapoptotic activities of macrolides in neutrophils remain unclear.

Tulathromycin is a triamilide macrolide characterized by a IS-membered ring composed of 3 polar amine groups. This particular structure distinguishes it from other macrolides. See Evans N, Vet. Ther. 2005; 6:83-95. The drug is used in the treatment and IS prevention of respiratory diseases in cattle and swine. The therapeutic success of tulathromycin is partially attributed to its pharmacodynamic concentration in appropriate tissues and low inhibitory concentrations against various bacterial pathogens.

Tulathromycin also has a very high affinity for uptake within neutrophils and, to a lesser extent, macrophages, which helps target the delivery of the drug to infected tissues.

Compared to other antibiotics used in the treatment and prevention of bovine respiratory disease, tulathromycin has shown superior clinical efficacy and clears the infection and inflammation for reasons that remain not completely understood. Sec Nutsch R, ci al., Vet.

Ther. 2005; 6:167-179, Mount J, ci at, Can. J. Vet. Res. 2009; 73:49-57, Skogerboe T, ci al., Vet. Thcr. 2005; 6:180-196.

Sumtnaiy of the inveniton The present invention relates to a composition comprising tulathromycin and at least one nonsteroidal anti-inflammatory drug ("NSAID"). Surprisingly, the same antibiotic efficacy is attained when a lower than recommended amount of tulathromycin is used in the presence ofaNSAID. In addition to the obvious economic benefits of this composition, a lower tulathromycin have the further advantage of reducing the risk of developing antibiotic-resistant bacteria.

In a first aspect, the present invention is directed to a composition comprising tulathromycin and at least one NSAID.

hi a second aspect, the present invention refers to a pharmaceutical formulation comprising the composition of the first aspect and at least one pharmaceutically acceptable carrier, additive, adjuvant or vehicle.

In a third aspect, the present invention relates to a process for preparing the pharmaceutical formulation of the invention, which comprises mixing the composition of the first aspect and at least one pharmaceutically acceptable carrier, additive, adjuvant or vehicle.

In a fourth aspect, the present invention refers to a composition according to the first aspect or a pharmaceutical formulation according to the second aspect for its use as a medicament.

IS In a fifth aspect, the present invention is directed to a composition according to the first aspect or a pharmaceutical formulation according to the second aspect for its use in the treatment or prevention of respiratory diseases in mammals. Alternatively, the present invention is directed to the use of the composition according to the first aspect in the manufacture of a medicament for the treatment or prevention of a respiratory disease in mammals.

lii a sixth aspect, the present invention refers to a method of treating or preventing the inception of a respiratory disease in a subject, which comprises administering to the subject a therapeutically effective amount of the composition of the first aspect or the pharmaceutical formulation of the third aspect of the invention.

Description of the Embodiments

This invention relates to a novel composition that enables the administration of a lower yet effective dosage of tulathromycin to subjects suffering, or in risk of suffering, respiratory diseases. The components of the composition are tulathromycin and at least one NSAID. The NSATD can be an acetic acid derivative, an enolic acid derivative, a fenamic acid derivative, a propionic acid derivative, a salicylic acid derivative, a selective cyclooxigenase-2 inhibitor, a sulphoanilide compound or a pharmaceutically acceptable salt, isomer, enantiomer or tautomers thereof 1. Definitions The term "auxiliary" as used herein, means any component, other than the active substance(s) intentionally added to the formulation of a dosage form. Exemplary auxiliaries are acids (e.g. citric or tartaric acid), alcohols, a bicarbonate (e.g. sodium or potassium), binders, colorants, excipients, disintegrants, fillers, flavoring agents, flavor masking agents, foaming agents, lubricants, plaslizicers, pore-forming agents, sodium chloride, stabilizers, sugars and sweeteners. Some auxiliaries can serve multiple purposes (e.g. filler and disintegrant). See US Pharmacopoeia.

The term "pharmaceutically acceptable salt" as used herein, refers o any salt of acidic or basic nature which may be formed with any of the compounds of the invention.

IS Examples of acidic salts include, but are not limited to, the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate salts. Examples of basic salts include, but are not limited, to the calcium, magnesium, sodium and potassium salts.

The terms "prevent", "preventing" and "prevention" as used herein, refer to inhibiting the inception, or decreasing the occurrence or recurrence, of a disease in a subject.

Prevention may be complete (e.g. the total absence of pathological cells in a subject) or partial. Prevention also refers to a reduced susceptibility to a clinical condition.

The term "subject" as used herein, refers to a mammalian, such as a human being, a non-human primate (e.g. chimpanzees and other apes and monkey species), a farm animal (e.g. cattle, sheep, pigs, goats and horses), a domestic mammal (e.g. dogs and cats), or a laboratory animal (e.g. rodents, such as mice, rats and guinea pigs. The term does not denote any particular age or sex.

The term "therapeutically effective amount" as used herein, refers to any amount of a composition or pharmaceutical formulation which, when administered to a subject: i) prevents the inception or recurrence or ii) causes the reduction or remission of the disease or codition against which the composition or formulation is effective.

The term "treat" or "treatment" as used herein, refers to the control of the progression of a disease after its clinical signs have appeared. Control of the disease progression is understood to mean the beneficial or desired clinical results that include, but are not limited to, reduction of the symptoms, reduction of the duration of the disease, stabilization of pathological states (specifically to avoid additional deterioration), delaying the progression of the disease, improving the pathological state, and remission (both partial and total). The control of progression of the disease also involves an extension of survival, compared with the expected survival if treatment is not applied.

The term "tulathromycin" as used herein, refers to (2R,3S,4R,SR,SR, I OR, II R, I 2S, I 3S, I 4/?)-I 3-[2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(propylamino)meth ylj-a-L-ribo-hexopyrano-syljoxyj-2-ethyl-3,4, I 0-trihydroxy-3,5,8, 10,12, I4-hexamethyl-II -[3,4,6-trideoxy-3-(dimethylamino)--D-xylo-hexopyranosyl]-oxyj-I -oxa-6-azacyclopenta IS decan-IS-one, CAS [217500-96-4], of molecular formula C41H,9N1012 and structural formula: HOfl OH OH? o2 0 6

I

OH

N H

Tulathromycin exists in two isomer forms: A and B. The product has been proved effective for the treatment and prevention of respiratory diseases caused by Mannhei in/a haernolydca, Paste-urella muitocida, Histoplillus somni and ?vlycoplasina bovis in caftle and Actinobacillus pleuropneumoniae, Pasteurella inultocida, Bordetella bronchiseptica, Haemophilus parasuis and Mycoplasma hyopneuinoniae in pigs.

2. Tulathromycin and nonsteroidal anti-inflammatory drugs compositions hi a first aspect, the present invention is directed to a composition comprising tulathromycin and at least one NSAID. Preferably, tulathromycin is about 95% (w/w) or less, and the NSAID is about 5% (w/w) or more, of the total composition weight. More preferably, tulathromycin is about 95% to about 50% w/w, and the NSAID is from about 5% to about 50% w/w, of the total composition weight. A composition wherein tulathromycin is from about 80% to about 60% w/w, and the NSAID is from about 20% to about 40% w/w, of the total composition weight is further preferred.

In one embodiment of the first aspect of the invention, the composition comprises a mixture of the tulathromycin A and B isomers. More preferably, the isomers are present in the mixture in a ratio of about 9 to I of the tulathromycin isomer A form to the IS tulathromycin isomer B form. The tulathromycin compounds of the invention comprise the pharmaceutically acceptable salts, isomers, enantiomers and tautomers of the tulathromycin isomer A and B forms and the mixtures thereof In one embodiment, the nonsteroidal anti-inflammatory drug of the invention is an acetic acid derivative, an enolic acid derivative, a fenamic acid derivative, a propionic acid derivative, a salicylic acid derivative, a selective cyclooxigenase-2 inhibitor, a sulphoanilidc or a pharmaceutically acceptable salt, isomcr, enantiomcr or tautomcr thereof Preferably, the acetic acid derivative is aceclofcnac, acemetacin, benzofcnac, bromfenac, cinmetacin, clidenac, clopirac, diclofenac, ctodolac, fenclofcnac, fenclorac, fentiazac, fluxinin, flirafenac, ibufenac, indomcthacin, isoxepac, ketorolac, lonazolac, nabumctonc, oxaprozin, oxepinac, pirozolac, sulindac, tepoxalin, tolmetin, zomcpirac or a pharmaceutically acceptable salt, isomer, enantiomcr or tautomcr thereof. Prefcrably, the fenamic acid derivative is bucloxic acid, etofenamic acid, flufenamic acid, meclofenamic acid, mefenamic acid, piromidic acid, protizinic acid, tiaprofcnic acid, tolfcnamic acid or a pharmaceutically acceptable salt, isomer, enantiomer or tautomer thereof Preferably, the propionic acid derivative is bcnoxaprofen, butibufen, carprofen, cicloprofen, dexibuprofen, dexketoprofen, fenbufen, fenoprofen, flunoxaprofen, flurbiprofen, furaprofen, furobufen, ibuprofen, indoprofen, ketoprofen, loxoprofen, miroprofen, naproxen, oxaprozi, pirprofen, suprofen or a pharmaceutically acceptable salt, isomer, enantiomer or tautomer thereof Preferably, the salicylic acid derivative is acetylsalicylic acid, choline salicylate, diflunisal, magnesium salicylate, methylsalicylate, mesalamine, salicylamide, salsalate, sodium salicylate, sodium thiosalicylate, sulfasalazine or a pharmaceutically acceptable salt, isomer, enantiomcr or tautomer thereof Preferably, the selective cyclooxigenase-2 inhibitor is celecoxib, deracoxib, etoricoxib, firocoxib, lumiracoxib, paracetamol, parecoxib, phenylbutazone, robenacoxib, rofecoxib, valecoxib or a pharmaceutically acceptable salt, isomer, enantiomer or tautomer thereof Preferably, the sulphoanilide is nimesulide.

Preferably, the enolic acid derivative is droxicam, isoxicam, lornoxicam, meloxicam, piroxicam, tecnoxicam or a pharmaceutically acceptable salt, isomer, enantiomer or tautomer thereof More prefeTably, the enolic acid derivative is meloxicam or a pharmaceutically acceptable salt, isomer, enantiomer or tautomer thereof Any compound referred to herein is intended to repTesent such specific compound as well as certain variations or forms of it. Tn particular, compounds referred to herein may IS have asymmetric centers and therefore exist in different enantiomeric or diastereomeric forms. Thus, any given compound referred to herein is intended to represent any one of a racemate, one or more enantiomeric forms, one or more diastereomeric forms, and mixtures thereof Likewise, stereoisomerism or geometric isomerism about the double bond is also possible, therefore in some cases the molecule could exist as trans and cis isomers. If the molecule contains several double bonds, each double bond will have its own stereoisomerism, that could be the same as, or different to, the stereoisomcrism of the other doublc bonds of the moleculc. Furthermore, compounds referred to herein may exist as atropisomers. All the stereoisoniers including enantiomers, diastereoisomers, geometric isomers and atropisomers of the compounds referred to hercin, and mixtures thcreof, are considered within the scope of the present invention.

Furthermore, any compound referred to herein may exist as tautomers. Specifically, the term tautomer refers to one of two or more structural isomers of a compound that exist in equilibrium and are readily converted from one isomeric form to another. Common tautomeric pairs include, but are not limited to, amine-imine, amide-imidic acid, keto-enol, and lactam-lactim.

3. P/iarnzaceutical!bnnulations In another aspect, the present invention relates to a pharmaceutical formulation comprising a composition of tulathromycin and at least one NSATD, a pharmaceutically acceptable salt, isomer, enantiomer or tautomer thereof, and at least a pharmaceutically acceptable carrier, additive, adjuvant or vehicle. The tulathromycin and N SAID compositions of the invention may be formulated for their simultaneous, separate or sequential administration, with at least one pharmaceutically acceptable carrier, additive, adjuvant or vehicle. Therefore, these compositions may be administered: i) as part of the same pharmaceutical formulation, the two active ingredients being then administered always simultaneously or ii) as two units, each unit with one of the active ingredients and making possible their simultaneous, sequential or separate administration.

Preferably, tulathromycin and the NSAID are administered simultaneously in the same pharmaceutical formulation.

In another embodiment, tulathromycin is independently administered from the NSAID (i.e. in two units) but at the same time. An example of this dosage regime would be the administration of the tulathromycin and firocoxib composition.

The auxiliary materials of the pharmaceutical formulations can be carriers, excipients, support materials, lubricants, fillers, solvents, diluents, colorants, and flavor conditioners such as sugars, antioxidants or agglutinants. In the case of suppositories, this may imply waxes or fafty acid esters or preservatives, emulsifiers or carriers for parenteral application. The selection of those auxiliary materials and the amounts to be used will depend on the form of application of the pharmaceutical formulation. Examples of auxiliaries that may be used according to the invention include, but are not limited to, glycerol triaeetate, monothioglyeerol, polyethylene glyeol, propylene glycol and water.

The pharmaceutical formulations according to the invention can be adapted to any form of administration, such as the subcutaneous, intramuscular, intra-articular, intraperitoneal, intravenous, pulmonary, nasal, percutaneous or oral administration.

Suitable formulations for oral administration include, but are not limited to, tablets, capsules, chewing gums, granules, drops, syrups, pastes, feed premixes, gels or boluses.

Suitable preparations for parenteral administration are solutions, suspensions, reconstitutable dry preparations or sprays. Preferably, the pharmaceutical formulation is suitable for intramuscular or subcutaneous injection. The formulations of the invention may be produced following methods known in the art. See Gunnar A, Ed., "Remington: The Science and Practice of Pharmacy" 20th ed. (Lippincott Williams & Wilkins, Philadelphia, PA, US, 2003).

4. Use of compositions and formulations for the treatment or prevention of respiratoly diseases In another aspect, the present invention refers to the use of a composition or a pharmaceutical formulation according to the invention for the treatment and prevention of respiratory diseases. In a particular embodiment, said respiratory diseases are mediated by bacterial pathogens of the Xfannheimia spp, Pasteurelia spp, f-Jistophiius spp, Mycoplasma spp, Actinobacillus spp, Bordetella spp, and Haemophilus spp. Alternatively, the present invention refers to a method for treating or preventing a respiratory disease in a subject, which comprises administering to the subject a therapeutically effective amount of a composition or pharmaceutical formulation of the invention. Preferably, the subject is cattle or a pig.

Preferably, the composition or formulation of the invention is administered once by injection. The subcutaneous route of administration is preferred for cattle. The intramuscular route is the preferred way of delivery for pigs.

This invention is farther illustrated by the following examples which should not be construed as limiting. The contents of all documents cited throughout this application are incorporated herein in their entirety by reference.

General procedures I. Tulathromycin, carprq/èn, flux/nm meglummne and meloxicam compositions Liquid formulations containing the composition of tulathromycin with carprofen, fluxinin meglumine and meloxicam are prepared by adding the active ingredients to a monothioglycerol, propylene glycol and water vehicle as described in the art to achieve the concentrations of the examples.

2. Tulathromycin and firocoxib composition An aqueous formulation of tulathromycin is prepared by adding the active ingredient to a monothioglycerol, propylene glycol and water vehicle as described in the art. A non-aqueous formulation of firocoxib is prepared by adding the active ingredient to a glycerol triacetate and polyethylene glycol vehicle as described in the art. The aqueous and non-aqueous formulations are administered separately.

3. Statistical analysis P values are determined based on a chi-square analysis and by comparing the results obtained for each tulathromycin and tulathromycin-NSAIID compositions and their respective placebo vehicle.

Example I

Effectiveness oft/ic tuiathroniycin and A/SAID compositions for the treatment bovine respiratoty diseases Nasopharyngcal swabs wcrc collectcd from calves aged 4 to 11 months old and weighing 150 to 320 kg. The samples were analyzed for the presence of Mannheiinia haeinolyeica, Pasleureila muilocida, Thslophztus SOintit and Mycopiasma spp pathogens.

Calves positive for any of the pathogcns and having a rectal temperature of? 40 °C were enrolled in the assay.

Tulathromycin and the tulathromycin and NSAID compositions were administered as a singlc dosage at a ratio of 2.4 mL of solution per 100 kg of body weight. Saline solution at an equivalent volume of 0.025 mL/kg of body weight was used as placebo. The solutions were administered subcutaneously in the neck at day 0. See Table 1.

The treatment success was determined on day 14. A treatment was classified as successful if it the subject survived through day 14 without being classified as a treatment failure. A calf was classified as a treatment failure if it had a rectal temperature of? 40 °C on any of days 3-14.

Table 1

Percentage Assay Active ingredients Treated Cured cured p value 1 Placebo 33 8 24.2% _________ 2 Tulathromycin 100 mg/mL 35 27 77.1% p<.Ol 3 Tulatlirornycin 90 rng/mL 38 28 72.5% p<.Ol _______ Carprofen 50 mg/mL _________ __________ ____________ __________ 4 Tulathromycin 80 mg/nth 34 23 67.6% p<.Ol _______ Carprofen 55 mg/mL _________ __________ ____________ __________ Tulathromycin 90 mg/nt 36 22 61.1% p<.Ol _______ Firocoxib 20 mg/mL _________ __________ ____________ __________ 6 Tulathromycin 80 mg/mL 32 18 56.2% p<.Ol ______ Firocoxib 22.5 mg/niL ________ _________ ___________ _________ 7 Tulathromycin 90 mg/mL 33 24 72.7% p<.OI _______ Fluxinin meglumine 50 mg/mL _________ __________ ____________ __________ 8 Tulathromycin 80 mg/nt 35 23 65.7% p<.Ol ______ Fluxinin meglumine 55 mg/mL ________ ________ __________ ________ 9 Tulathromycin 90 mg/mL 38 28 76.3% p<.Ol Meloxicam 20 mg/mL ________ _________ ___________ _________ tO Tulathromycin 80 mg/mL 35 24 68.6% p<.OI ______ Meloxicam 22.5 mg/mL ________ _________ ___________ _________

Example 2

Effectiveness of the tulathromycin and NSAID compositions/br the treatment porcine respiratory diseases Nasopharyngeal swabs were collected from pigs aged 6 to 24 weeks of age and weighing tO to 62.7 kg. The samples were analyzed for the presence of Ac/inohacilius pleuropneumoniae, Pasteurella multocida, Bordeteila bronchiseptica and Haemophiius parasuis pathogens. Pigs positive for any of the pathogens and having a rectal temperature of? 40°C were enrolled in the assay.

IS Tulathromycin and the tulathromycin and NSAID compositions were administered as a single dosage at a ratio of 0.25 mL of solution per 10 kg of body weight. Saline solution at an equivalent volume of 0.025 nt/kg of body wcight was uscd as placebo. Thc solutions wcrc administered by intramuscular injection at day 0. See Table 2.

The treatment success was determined on day 7. A treatment was classified as successful if it thc subjcct survived through day 7 and had a rectal temperature of < 40 °C.

Table 2

________ ______________________________________ ___________ ____________ _______________ ____________

Percentage Assay Active ingredients Treated Cured cured p value 11 Placebo 49 23 469% ________ 12 Tulathromycin 100 mg/nt 41 29 707% p<.Ol 13 Tulathromycin 90 mg/mt 42 28 667% p<.Ol _______ Carprofen 50 mg/mI. _________ __________ ____________ __________ 14 Tulathromycin 80 mg/mL 46 28 608% p<.Ol _______ Carprofen 55 mg/mL _________ __________ ____________ __________ Tulathromycin 90 mg/mL 47 28 596% p<.Ol ______ Firocoxib 20 mg/niL ________ _________ ___________ _________ 16 Tulathromycin 80 mg/mL 44 23 523% p<.Ol ______ Firocoxib 22.5 mg/mL ________ _________ ___________ _________ 17 Tulathromycin 90 mg/nt 45 30 66.7% p<.Ol ______ Fluxinin meglumine 50 mg/mL ________ _________ ___________ ________ 18 Tulathromycin 8Omg/mL 44 26 59.1% p<.Ol Fluxinin meglumine 55 mg/niL __________ ___________ _____________ __________ 19 Tulathromycin 90 mg/mL 43 30 69.7% p<.Ol ______ Meloxicam 20 mg/mL ________ _________ ___________ _________ Tulathromycin 80 mg/mt 49 30 61.2% p<.Ol _______ Meloxicam 22.5 mg/nt _________ __________ ____________ __________

Example 3

Effectiveness of the tulathromycin and VSAID compositions in the prevention of bovine respiratoy diseases Calves exposed to pathogens associated to bovine respiratory diseases were recruited and distributed randomly among the different treatment groups. The subjects aged 4 to 11 months old and weighed 150 to 320 kg.

Tulathromycin and the tulathromycin and meloxicam compositions were administered as a single dosage at a ratio of 2.4 mL of solution per 100 kg of body weight. Saline solution at an equivalent volume of 0.025 mL/kg of body weight was used as placebo. The solutions were administered subcutaneously in the neck at day 0. See Table 3.

The treatment failure was determined on days 1-14. A treatment was classified as a failure if it the subject developed a rectal temperature of? 40 °C on any of days 1-14.

Table 3

Percentage Assay Active ingredients Treated Failures failures p value 21 Placebo 104 60 582% ________ 22 Tulathromycin 100 mglmL 139 IS 108% p<.Ol 23 Tulathromycin 90 mgimL 134 15 111% p<.Ol Meloxicam 20 mg/rnL ________ _________ ___________ _________ 24 Tulathromycin 80 mglmL 141 17 12.1% p<.Ol _______ Meloxicam 22.5 mg/mL _________ __________ ____________ _________ The results above suggest that a when a NSAID is co-administered with tulathromycin, a lower antibiotic dosage can be used and still be efficacious in the treatment and prevention of respiratory diseases caused by of Mannheiniia spp, Pasteurel/a spp, His! op hi/us spp, Mycoplasma spp, Actinobacillus spp, Bordetella spp and T-Taeinophiius spp pathogcns in catfic and pigs.

Claims

Claims 1. A composition comprising tulathromycin and at least onc nonstcroidal anti-inflammatory drug.
2. The composition according to claim 1 wherein tulathromycin is from about 95% to about 50% w/w or the nonsteroidal anti-inflammatory drug is from about 5% to about 50% w/w based on the total weight of the composition.
3. The composition according to claim I wherein tulathromycin is from about 80% to about 60% w/w or the nonsteroidal anti-inflammatory drug is from about 20% to about 40% w/w based on the total weight of the composition.
4. The composition according to any preceding claim, wherein tulathromycin is a mixture of the tulathromycin A and B isomers.
5. The composition according to claim 4, wherein the isomers are present in the mixture in a ratio of about 9 to I of the tulathromycin isomer A form to the tulathromycin isomer B form.
6. The composition according to any preceding claim wherein the nonsteroidal anti-inflammatory drug is an acctic acid derivative, an cnolic acid dcrivativc, a fcnamic acid dcrivativc, a propionic acid derivative, a salicylic acid dcrivativc, a selective cyclooxigcnasc-2 inhibitor and a sulphoanilidc.
7. The composition according to any onc of claims 1 to 6 whcrcin thc acctic acid dcrivativc is accclofcnac, accmctacin, aclofcnac, bcnzofcnac, bromfcnac, cimiictacin, clidcnac, clopirac, diclofenac, ctodolac, fcnclofcnac, fcnclorac, fcntiazac, fluxinin, ftirafcnac, ibufcnac, indomcthacin, isoxcpac, ketorolac, lonazolac, nabumctonc, oxaprozin, oxcpinac, pirozolac, sulindac, tenclofenac, tepoxalin, tiopinac, tolmetin, zidometacin, zomepirac or a pharmaceutically acceptablc salt, isomer, cnantiomcr or tautomcr thcrcof
8. The composition according to any one of claims I to 6 wherein the fenamic acid derivative is bucloxic acid, etofenamic acid, flufenamic acid, meclofenamic acid, mefenamic acid, niflumic, piromidic acid, protizinic acid, tiaprofenic acid, tolfenamic acid or a pharmaceutically acceptable salt, isomer, enantiomer or tautomer thereof
9. The composition according to any one of claims 1 to 6 wherein thc propionic acid derivative is alminoprofen, benoxaprofen, butibufen, carprofen, cicloprofen, dexibuprofen, dexketoprofen, fenbufen, fenoprofen, flunoxaprofen, fluprofen, flurbiprofen, furaprofen, furobufen, ibuprofen, indoprofen, ketoprofen, loxoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, surprofen, tioxaprofen or a pharmaceutically acceptable salt, isomer, enantiomer or tautomer thereof
10. The composition according to any one of claims I to 6 wherein the salicylic acid derivative is acetylsalicylic acid, choline salicylate, difiunisal, flufenisal, magnesium salicylate, methylsalicylate, mesalamine, salicylamide, salsalate, sodium salicylate, sodium thiosalicylate, sulfasalazine or a pharmaceutically IS acceptable salt, isomer, enantiomer or tautomer thereof I. The composition according to any one of claims I to 6 wherein the selective cyclooxigenase-2 inhibitor is celecoxib, deracoxib, etoricoxib, firocoxib, lumiracoxib, paracetamol, parecoxib, phenylbutazone, robenacoxib, rofecoxib, valecoxib or a pharmaceutically acceptable salt, isomer, enantiomer or tautomer thereof 12. The composition according to any one of claims 1 to 6 wherein the sulphoanilide is nimesulide.13. The composition according to any one of claims 1 to 6 wherein the enolic acid derivative is droxicam, isoxicam, lornoxicam, meloxicam, piroxicam, sudoxicam, tecnoxicam a pharmaceutically acceptable salt, isomer, enantiomer or tautomcr thereof.14. A pharmaceutical formulation comprising the composition according to any one of claims 1 to 13 or a pharmaceutically acceptable salt, isomer, enantiomer or tautomer thereof, and at least a pharmaceutically acceptable carrier, additive, adjuvant or vehicle.IS. The composition according to any one of claims I to 13 or the pharmaceutical formulation according to claim 14 for use as a medicament.16. The composition according to any one of claims I to 13 or the pharmaceutical formulation according to claim 14 for use in the treatment or prevention of a respiratory disease in mammals.17. Usc of the composition according to any one of claims 1 to 13 in the manufacture of a medicament for the treatment or prevention of a respiratory disease in a mammal.18. A method for treating or preventing a respiratory disease in a subject, which comprises administering to the subject a therapeutically effective amount of the composition according to any one of claims 1 to 13 or the pharmaceutical formulation according to claim 14.19. The method of claim 18 wherein the subject is cattle.20. The method of claim 18 wherein the subject is a pig.