NZ555774A

NZ555774A - Injectable veterinary composition comprising florfenicol, a pyrrolidone solvent and a cosolvent selected from diethyleneglycol monoethyl ether and / or tetrahydrofurfuryl alcohol polyethylene glycol ether

Info

Publication number: NZ555774A
Application number: NZ555774A
Authority: NZ
Inventors: Carole Barbot
Original assignee: Intervet Int Bv
Priority date: 2004-12-21
Filing date: 2005-12-20
Publication date: 2010-09-30
Also published as: ZA200705084B

Abstract

Disclosed is a composition for the treatment of microbial infection in an animal comprising florfenicol in a solvent system, wherein the solvent system comprises at least one ether selected from diethyleneglycol monoethyl ether and tetrahydrofurfuryl alcohol polyethylene glycol ether, and a pyrrolidone solvent (such as 2-pyrrolidone or N-methyl-2-pyrrolidone (NMP)). Also disclosed is a method of treating or preventing a microbial infection in a non-human animal comprising administering the composition as defined above to said non-human animal, thereby treating or preventing the microbial infection.

Description

<div class="application article clearfix" id="description"> P555774 1 Received at IPONZ on 12 August 2010 Injectable veterinary composition The current invention relates to a composition for the treatment of microbial infection in an animal. Bovine respiratory disease (BRD) has been one of the leading causes of economic 5 loss to both the dairy and beef industries throughout the world. Excessive mortality, reduced weight gains, and the cost of treatment and prevention have placed a heavy burden on the industry. For years, antimicrobial therapy has been the mainstay of BRD therapy. There are many effective antimicrobial agents currently available for the treatment of BRD e.g. Nuflor®, an injectable formulation of the broad- spectrum 10 antibiotic florfenicol. European patent No. 546018 discloses an injectable composition of florfenicol comprising 10 to 50% by weight of florfenicol; 10 to 65% by weight of a pyrrolidone solvent; 5 to 15% by weight of a viscosity reducing agent; and 5 to 40% by weight of polyethylene glycol. This formulation is however difficult to administer, especially 15 under cold whether conditions because the viscosity of the formulation becomes too high causing this poor syringeability. International patent application No. WO 92/04016 discloses a composition of florfenicol in a solvent system consisting essentially of aprotic polar solvents, e.g., N-methyl-2-pyrrolidone or 2-pyrrolidone. 20 International patent application No. WO 2004/014340 discloses a composition of 20% florfenicol in a solvent system comprising a mixture of a hydrophilic and a lipophilic solvent, e.g. laurocapram, a skin- penetration enhancer. United States patent application No. US 2004/0242546 disclose compositions of florfenicol comprising triacetin, dimethylamide and/or combinations thereof as a 25 carrier. It is an object of the present invention to provide alternative compositions with high concentration of florfenicol and related antibiotic compounds that can easily be loaded into and expelled from a syringe and provides after administration to an animal effective blood levels of the antibiotic compounds, or at least to provide the 30 public with a useful alternative. In one aspect, the invention comprises a composition for the treatment of microbial infection in an animal comprising florfenicol in a solvent system, wherein the solvent (followed by page 1a) 1a Received at IPONZ on 12 August 2010 system comprises at least one ether selected from diethyleneglycol monoethyl ether and tetrahydrofurfuryl alcohol polyethylene glycol ether, and a pyrrolidone solvent. In another aspect, the ether is diethyleneglycol monoethyl ether. In yet another aspect, the ether is present in an amount of 30% to 40% v/v. 5 In still another aspect, the florfenicol is present in an amount of 30% to 45% w/v. In even another aspect, the pyrrolidone solvent is selected from the group consisting of 2- pyrrolidone and N-methyl-2-pyrrolidone. In a further aspect, the ratio of the amount of pyrrolidone solvent to florfenicol is between 0.6 to 1.1. 10 In yet a further aspect, the composition comprises 1 to 89% v/v of an ether and 1 to 89% w/v of a pyrrolidone solvent. In still a further aspect, the invention comprises a composition according to any one of the preceding aspects consisting of Florfenicol 45 g N-methyl- 2- pyrrolidone (NMP) 35 g Diethylene glycol monoethylether ad100 ml 15 In even another aspect, the invention comprises a composition according to any one of the preceding aspects consisting of Florfenicol 45 g N-methyl- 2- pyrrolidone (NMP) 30 g Diethylene glycol monoethylether ad100 ml In one other aspect, the invention comprises the use of the composition according to any one of the preceding aspects for the manufacture of a medicament for the 20 treatment or prevention of a microbial infection in an animal. In yet one other aspect, the invention comprises a method of treating or preventing a microbial infection in a non-human animal comprising administering the composition according to any one of the preceding aspects to said non-human animal, thereby treating or preventing the microbial infection. 25 (followed by page 1b) P555774 1b Received at IPONZ on 12 August 2010 The present disclosure includes a composition for the treatment of microbial infection in an animal comprising an antibiotic compound selected from the group of chloramphenicol, thiamphenicol and florfenicol in a solvent system, characterized in (followed by page 2) P555774 2 Received at IPONZ on 12 August 2010 that the solvent system comprises an aliphatic ether alcohol and a pyrrolidone solvent. The compositions of the present disclosure comprise at least one antibiotic compound selected from the group of chloramphenicol, thiamphenicol and florfenicol. 5 Fluorine-containing analogs of antibiotics chloramphenicol and thiamphenicol have been shown to have antibiotic activity, both against organisms sensitive to and resistant to chloramphenicol and thiamphenicol. See Schafer, T. W. et al., "Novel Fluorine-Containing Analogs of chloramphenicol and thiamphenicol: Antibacterial and Biological Properties," in CURRENT CHEMOTHERAPY AND INFECTIOUS 10 DISEASE P ROCEEDINGS OF THE 11™ ICC AND THE 19™ ICAA AMERICAN SOCIETY OF MICROBIOLOGY 1980, 444-446. Examples of such compounds, and methods for their manufacture, are described and claimed in U.S. Pat. No.4,235,892. The medical profession has become increasingly concerned about the transference of bacterial resistance to humans when antibiotics useful in treating humans are 15 administered to livestock. Because the chloramphenicol group of antibiotics is infrequently used now to treat humans, its derivatives are particularly appropriate for veterinary use. Of particular interest are the 3-fluoro, 3-deoxy derivatives. A preferred antibiotic compound is florfenicol (D-(threo) -1-p- methylsulfonyl phenyl-2-dichloroacetamido-3-fluoro-1-propanol). Florfenicol is the active ingredient in the 20 commercial product Nuflor®, that is marketed by Schering-Plough Animal Health. US Patent no. 4,235,892, describes the compound and a processes for making said compound. This patent is incorporated herein by reference. Another preferred antibiotic compound is D-(threo)-1-p-methylsulfonyl phenyl-2-difluoroacetamido-3-fluoro-1-propanol. Processes for the manufacture of these 25 preferred antibiotic compounds, and intermediates useful in such processes, are described in U.S. Pat. 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 5,663,361. Another preferred antibiotic is thiamphenicol. The concentration of florfenicol or other antibiotic compound typically is from 10% to 30 60% w/v; with the preferred level between 20 % and 50% w/v. Especially preferred is a composition, comprising 30 to 45% w/v of florfenicol. P555774 3 Received at IPONZ on 12 August 2010 The solvent system in the composition according to the present disclosure comprises an aliphatic ether alcohol and a pyrrolidone solvent. The composition for the treatment of microbial infection in an animal comprises preferably in the solvent system 1 to 89 % v/v of an aliphatic ether alcohol and 1 to 89 % w/v of a pyrrolidone 5 solvent. Preferred in accordance with the present disclosure are compositions in which the aliphatic ether alcohol is an ether of 1, 2- ethanediol oligo- or polymers. Especially preferred in accordance with the present disclosure are compositions in which the carrier is a terminal mono-ether of 1,2 -ethanediol oligo- or polymers. 10 As carrier a pharmaceutical^ acceptable C^s alkyl or tetrahydrofurfuryl di- or partial-ether of a low molecular weight mono- or poly-oxy-alkanediol is useful. Suitable components are, e.g. di- or partial-, especially partial-, -ethers of mono- or poly-, especially mono- or di-, -oxy- alkanediols comprising from 2 to 12, especially 4 carbon atoms. Preferably the mono- or poly-oxy-alkanediol moiety is straight-15 chained. Especially suitable for use in accordance with the disclosure are di- or partial-ethers of formula I R, ~[0~(CH2)2 ]x -OR2 (I) wherein Ri is C1-5 alkyl or tetrahydrofurfuryl, 20 R2 is hydrogen, Ci_5 alkyl or tetrahydrofurfuryl, and x is an integer of from 1 to 6, especially from 1 to 4, most especially about 2. Particularly preferred for use in accordance with the disclosure are partial ethers as defined above, e.g. products of formula I, wherein R2 is hydrogen. C1-5 alkyl moieties in the above defined ethers may be branched or straight chain, 25 e.g. including methyl, ethyl, n-propyl, i- propyl, n-butyl and t-butyl groups. Such ethers are known products and commercially available or may be produced analogously to the known products. Especially preferred products of formula I for use in relation to the present disclosure are those known and commercially available under the trade name Transcutol. 30 P555774 4 Received at IPONZ on 12 August 2010 Transcutol (CAS no. 31692-85-0) is the compound diethyleneglycol monoethyl ether of formula I, wherein Ri =C2 H5, R2 =H and x=2. Products for use in accordance with the present disclosure are those known and commercially available, e.g. under the trade name Transcutol® from Gattefosse, (St Priest, France), in particular the 5 product Transcutol® P and HP. Synonym names for transcutol are: 1-Hydroxy-3,6-dioxaoctane, 2-(2'-Ethoxyethoxy) ethanol, 2-(2-Ethoxyethoxy) ethanol, 2-(2-Ethoxyethyoxy) ethanol, 3,6-Dioxa-1-octanol, 3,6-Dioxa-1-oktanol, 3,6-Dioxaoctan-1-ol, Aethyldiaethylenglycol, APV, Carbitol , Carbitol cellosolve, Carbitol solvent, DEGEE, DEGMEE, Diethylene glycol 10 ethyl ether, Diethylene glycol monoethyl ether, Diglycol monoethyl ether, Dioxitol, Dowanol, Dowanol 17, Dowanol DE, Ektasolve DE, Ethanol, 2,2'-oxybis-, monoethyl ether, Ethanol, 2-(2-ethoxyethoxy)-, Ether monoethylique du diethylene glycol, Ethoxy diglycol, Ethoxydiglycol, Ethyl carbitol, Ethyl diethylene glycol, Ethyl digol, Ethyldiethylene glycol, Ethyl carbitol. 15 Glycofurol (CAS No. 57-55-6), also known as tetrahydrofurfuryl alcohol polyethylene glycol ether or a-(tetrahydrofuranyl)-oo- hydroxypoly(oxy-1,2-ethanediyl) has the formula I wherein Ri = [CHEM-3] R2 =H and x has an average value of from 1 to 2. It has an average molecular weight of ca. 190; a b.p. of from ca. 80-100. degree. C. (at 40N/m2), a density of ca. 1.070-1.090 g/cm3 (at 20° C.); a hydroxy value of ca. 20 300-400; a refractive index of ca. 1.4545 (sodium D line, 589 mm) (at 40° C.); and a viscosity of ca. 8-18 mN s/m2 (at 20°). (c.f. "Handbook of Pharmaceutical Excip ients, published by American Pharmaceutical Association/ The Pharmaceutical Society of Great Britain (1986), p. 127 and Fiedler, "Lexikon der Hilfstoffe", 3rd edition (1989), p. 577.) 25 The precise properties of Glycofurol vary according to relative purity. Thus lower quality grades contain significant amounts of tetrahydrofurfuryl alcohol and other impurities. Synonym names for gylcofurol are: Glycofurol 75; tetraglycol; Poly(oxy-1,2-ethanediyl), a-(tetrahydrofuranyl)-oo-hydroxy- (9CI). Tetraglycol is also used as a 30 synonym for tetrahydrofurfuryl alcohol. The amount of aliphatic ether alcohol present in the compositions of the present disclosure is from 1 to 89% v/v, in one embodiment preferably from 15 to 25 %, in another embodiment from 1 to 89% v/v , 20 to 50% v/v, 25 to 45% v/v and especially preferred 30 to 40 % v/v. P555774 5 Received at IPONZ on 12 August 2010 Suitable pyrrolidone solvents for the composition according to the present disclosure are especially 2-pyrrolidone and N-methyl-2- pyrrolidone. The preferred solvent is N-methyl-2-pyrrolidone. Examples of compounds suitable for use in accordance with the present disclosure are those known and commercially available, e.g. under the 5 trade name Pharmasolv® from International Specialty Products, (Wayne, New Jersey, U.S.A.). Particularly suitable is the product Polysolv® V. The amount of pyrrolidone solvent in the compositions of the present disclosure may comprise from 1 to 89 % w/v, preferably 20 to 50% w/v. Especially preferred are compositions, comprising 30 % w/v to 40 % of the pyrrolidone solvent. 10 The ratio between the amount of pyrrolidone solvent and the amount of florfenicol is between 0.6 and 1.1, especially preferred is a ratio between 0.7 and 0.9. The composition according to the current disclosure may further comprise additional pharmaceutical excipients known in the art. Such pharmaceutical excipients are e.g. described in "Gennaro, Remington: The Science and Practice of Pharmacy", (20. 15 Edition, 2000), incorporated by reference herein. Such ingredients include preservatives, chelating agents, antioxidants and stabilizers. Exemplary preservatives include methyl p-hydroxybenzoate (methylparaben) and propyl p-hydroxybenzoate (propylparaben). Exemplary chelating agents include edetate sodium. Exemplary antioxidants include butylated hydroxyanisole and sodium 20 monothioglycerol. The composition contemplated herein can, if desired, include more than one pharmacologically active ingredient. In order to prepare the composition of the present disclosure, the vehicle(s) or a portion of the vehicle(s), are added to the compounding vessel, followed by the 25 remaining excipients and the actives. The mixture is mixed until all solids are dissolved. Additional solvent to bring the composition to final volume may be added if needed. 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 of the present disclosure exhibit desirable properties which are 30 useful characteristics for the administration of relatively high concentrations of florfenicol or other antibiotic compounds. The compositions are physically and chemically stable. The compositions have desirable viscosity characteristics which P555774 6 Received at IPONZ on 12 August 2010 allows for good syringeability over a wide temperature range and ease of processing, such as good flow rate through sterilizing filter membranes. By syringeable it is meant that the suspension can be withdrawn easily from an ampoule/ vial into a syringe with a 16 to 18 gauge needle and subsequently injected 5 from such a syringe through the 16 to 18 gauge needle intramuscularly (im) or subcutaneously (sc). The composition according to the disclosure shows better syringeability than compositions currently available. The rheological properties and syringeability of prior art formulation and compositions according to the present disclosure are shown in 10 Tables 1 and 2. Experiments 1 and 2 show the pharmacokinetic evaluation of compositions according to the invention after i.m. and s.c. administration to cattle. The compositions according to the present disclosure are particularly useful for cattle and other bovids, swine, and other large mammals. In addition to the treatment of bovine respiratory disease, the compositions of this 15 disclosure are also suitable for the treatment of infectious diseases such as swine respiratory disease, footrot, acute mastitis, pinkeye (infectious keratoconjunctivitis), acute pneumonia, metritis and enteritis. The dosage regimen for treatment of such diseases would be as described above. The compositions according to the present disclosure will generally be administered 20 to cattle at 1 mg to 100 mg of the antibiotic compound(s) per kilogram of body weight. Preferably the compositions of the present disclosure will be administered to bovines at 20 mg to 50 mg of the antibiotic compound(s) per kilogram of body weight. More preferably the dose will be 40 mg/kg of the antibiotic compound and is administered once subcutaneously. Also preferable is the administration of two doses 25 of 20 mg/kg administered at time 0 and 48 hours post initial administration. The compositions according to the present disclosure will generally be administered to swine at a dose of 15 mg to 100 mg of the antibiotic compound per kilogram of body weight. Preferably, the compositions of the present disclosure will be administered to swine at 20 mg to 50 mg of the antibiotic compound per kilogram of 30 body weight. 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, P555774 7 Received at IPONZ on 12 August 2010 one dose followed by a second dose 48 hours later will be required to treat the animal. An "effective amount" is the dose required to alleviate a particular symptom of an infection, infestation or disease or to protect an animal against infections, infestations 5 or diseases. 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. The following examples describe in detail particular embodiments of the invention. 10 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 range and scope of the invention. P555774 WO 2006/067138 8 PCT/EP2005/056950 EXAMPLE 1 An injectable solution (Formulation A) is prepared from the following: Ingredients Weight/ml Florfenicol 45 g N-methyl- 2- pyrrolidone (NMP) 30 g Diethylene glycol monoethylether ad 100 ml The solution is prepared according to the following procedure: N-methyl-2-5 pyrrolidone and diethylene glycol monoethylether are mixed well and then florfenicol is dissolved in the mixture and the clear solution is sterilized by filtration. EXAMPLE 2 An injectable solution (Formulation B) is prepared from the following: Ingredients Weight/ml Florfenicol 45 g N-methyl- 2- pyrrolidone (NMP) 30 g Glycofurol ad 100 ml 10 The solution is prepared according to the following procedure: N-methyl-2-pyrrolidone and glycofurol are mixed well and then florfenicol is dissolved in the mixture and the clear solution is sterilized by filtration. WO 2006/067138 P555774 9 PCT/EP2005/056950 EXAMPLE 3 An injectable solution (Formulation C) is prepared according to the process shown in Example 1: Ingredients Weight/ml Florfenicol 40 g N-methyl- 2- pyrrolidone (NMP) 30 g Diethylene glycol monoethylether ad 100 ml 5 EXAMPLE 4 An injectable solution (Formulation D) is prepared according to the process shown in Example 2: Ingredients Weight/ml Florfenicol 40 g N-methyl- 2- pyrrolidone (NMP) 30 g Glycofurol ad 100 ml EXAMPLE 5 10 An injectable solution (Formulation E) is prepared according to the process shown in Example 2: Ingredients Weight/ml Florfenicol 45 g N-methyl- 2- pyrrolidone (NMP) 37 g Glycofurol ad 100 ml P555774 WO 2006/067138 10 PCT/EP2005/056950 EXAMPLE 6 An injectable solution (Formulation F) is prepared according to the process shown in Example 1: Ingredients Weight/ml Florfenicol 30 g N-methyl- 2- pyrrolidone (NMP) 30 g Diethylene glycol monoethylether ad 100 ml 5 EXAMPLE 7 An injectable solution (Formulation G) is prepared according to the process shown in Example 1: Ingredients Weight/ml Florfenicol 45 g N-methyl- 2- pyrrolidone (NMP) 35 g Diethylene glycol monoethylether ad 100 ml WO 2006/067138 P555774 11 PCT/EP2005/056950 Table 1a): Comparison of rheological profile of florfenicol compositions under various temperature conditions Composition Formulation A Formulation B Reference prior art formulation Florfenicol (g) 45 45 30 NMP (g) 30 30 25 Propylene glycol 15 Macrogol 300 ad 100 ml Glycofurol ad 100 ml Transcutol ad 100 ml Specific gravity 1.157 1.196 1.167 Rheological profile - at room temperature viscosity (Pa.s) 0.043 0.089 0.11 yield point (Pa) -0.12 0.051 0.215 - after 5°C storage viscosity (Pa.s) 0.032 0.31 0.57 yield point (Pa) 1.01 0.96 0.96 - after -18°C storage viscosity (Pa.s) 0.20 0.47 0.47 yield point (Pa) 0.9 0.89 0.91 WO 2006/067138 P555774 12 PCT/EP2005/056950 Table 1 b) Syringeability of florfenicol compositions under various temperature conditions Composition Formulation A Formulation B Reference prior art formulation Syringeability (1.5 mm) -at room temperature suction time (sec) 7.3 11.6 14.0 emptying time (sec) 3.3 4.0 5.6 - after 5°C storage suction time (sec) 12.3 18.3 20.3 emptying time (sec) 3.3 4.3 5.3 - after -18°C storage suction time (sec) 9.0 15.3 19.6 emptying time (sec) 3.3 4.3 5.0 WO 2006/067138 P555774 13 PCT/EP2005/056950 Table 2: Comparison of rheological profile and syringeability of florfenicol compositions Composition Formulation C Formulation D Reference prior art formulation Florfenicol (g) 40 40 30 NMP (g) 30 30 25 Propylene glycol 15 Macrogol 300 ad 100 ml Glycofurol ad 100 ml Transcutol ad 100 ml Specific gravity 1.14 1.181 1.167 Rheological profile - at room temperature viscosity (Pa.s) 0.0094 0.013 0.11 yield point (Pa) 1.1 1.08 0.215 Syringeability (1.5 mm) -at room temperature suction time (sec) 6.3 9.3 14.0 emptying time (sec) 2.6 4.3 5.6 WO 2006/067138 P555774 14 PCT/EP2005/056950 Experiment 1 Formulations A and B and the reference prior art formulation were administered subcutaneously at a dose of 40 mg/kg florfenicol to cattle of 206 to 279 kg BW. Formulation A was tested in a cross over design (6 animals treated with Formulation 5 A followed by reference prior art formulation 29 days later and 6 animals treated vice versa). The pharmacokinetic profile of B was investigated in a single treatment design (n = 6). Florfenicol concentrations in plasma samples taken prior to and 1, 2, 4, 6, 8, 10, 24, 48, 72, 96, 120, 144 and 288 hours following each treatment were determined by HPLC and pharmacokinetic parameters were calculated: 10 Table 3: Summary of pharmacokinetic parameters Test item n T max [h] C max [pg/mL] AUC [h*|jg/mL] ;Formulation A ;12 ;6.83 ;1.43 ;116.63 ;Formulation B ;6 ;6 ;1.61 ;122.07 ;Reference prior art formulation ;12 ;6.67 ;2.12 ;127.77 ;Experiment 2 ;In Experiment 2 pharmacokinetic parameters of the Formulations A E and F were evaluated compared to a reference prior art formulation ;15 Groups of 6 cattle (3 heifers and 3 bulls) of 186 - 241 kg bodyweight (BW) were treated either subcutaneously at dose of 1 x 40 mg florfenicol / kg BW or intramuscularly at a dose of 2 x 20 mg florfenicol / kg BW at a 48 hour interval. ;Florfenicol concentrations in plasma samples taken prior to and 1, 2, 4, 6, 8, 10, 24, 48, 72, 96, 120, 144 and 288 hours following each treatment were determined by 20 HPLC and pharmacokinetic parameters were calculated: ;WO 2006/067138 ;P555774 ;15 ;PCT/EP2005/056950 ;Table 4: Mean values of pharmacokinetic parameters after treatment with Formulations A, E and F compared to a reference prior art formulation ;Treatment (n = 6) ;Tmax [h] ;Cmax [M9 / mL] ;AUC (O-LOQ) [|jg / mL*h] Subcutaneous treatment at a dose of 40 mg florfenicol / kg BW Formulation A 5.67 3.22 163.12 Formulation F 4.33 4.03 191.83 Formulation E 4.17 4.39 167.53 Reference prior art formulation 3.83 4.05 209.64 Intramuscular treatment at a dose of 2 x 20 mg florfenicol / kg BW Formulation A 6 2.03 100.16 Formulation F 4 3.02 111.01 Reference prior art formulation 3 2.95 91.38 P555774 Received at IPONZ on 12 August 2010 16 </div>

Claims

<div class="application article clearfix printTableText" id="claims"> Claims

1. A composition for the treatment of microbial infection in an animal comprising florfenicol in a solvent system, wherein the solvent system comprises at least one ether selected from diethyleneglycol monoethyl ether and tetrahydrofurfuryl alcohol 5 polyethylene glycol ether, and a pyrrolidone solvent.

2. The composition according to claim 1, wherein the ether is diethyleneglycol monoethyl ether.

3. The composition according to claim 1 or claim 2 wherein the ether is present in an amount of 30% to 40% v/v. 10

4. The composition according to any one of claims 1 to 3 wherein the florfenicol is present in an amount of 30% to 45% w/v.

5. The composition according to any one of claims 1 to 4 wherein the pyrrolidone solvent is selected from the group consisting of 2- pyrrolidone and N-methyl-2-pyrrolidone. 15

6. The composition according to any one of claims 1 to 5 wherein the ratio of the amount of pyrrolidone solvent to florfenicol is between 0.6 to 1.1.

7. The composition according to any one of claims 1 to 6 wherein it comprises 1 to 89% v/v of an ether and 1 to 89% w/v of a pyrrolidone solvent.

8. The composition according to any one of claims 1 to 7 consisting of Florfenicol 45 g N-methyl- 2- pyrrolidone (NMP) 35 g Diethylene glycol monoethylether ad 100 ml 20

9. The composition according to any one of claims 1 to 7 consisting of Florfenicol N-methyl- 2- pyrrolidone (NMP) Diethylene glycol monoethylether 45 g 30 g ad100 ml Received at IPONZ on 12 August 2010 17

10. Use of the composition according to any one of claims 1 to 9 for the manufacture of a medicament for the treatment or prevention of a microbial infection in an animal.

11. A method of treating or preventing a microbial infection in a non-human animal comprising administering the composition according to any one of claims 1 to 9 to said non-human animal, thereby treating or preventing the microbial infection.

12. The composition according to any one of claims 1 to 9 substantially as described herein with reference to any one of the Examples or Figures thereof.

13. The use according to claim 10 substantially as described herein with reference to any one of the Examples or Figures thereof.

14. The method according to claim 11 substantially as described herein with reference to any one of the Examples or Figures thereof. </div>