Pharmaceutical compositions comprising cefquinome

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ABSTRACT:Pharmaceutical composition for intrauterine application of cefquinome in a base comprising a medium chain triglyceride, a thickener and macrogol cetostearyl ether and its use for the treatment of metritis in mammalian animals.

Furthermore the current invention provides the use of the pharmaceutical composition according to the current invention for the manufacture of a medicament for the treatment or prevention of metritis, especially acute metritis in mammalian animals, especially in cows after parturition.

Example 6 shows a pharmacokinetic study after intrauterine administration of the composition according to the invention.

The composition according to the invention proved highly effective against the most commonly isolated metritis pathogens, (E. coli, A. pyogenes, Prevotella spp., Fusobacterium spp.).

To be efficacious in the control of a pathogen, an antibiotic should be 5 present at a minimum concentration level in tissues or biological fluids, which is characterized by its MIC (Minimum Inhibitory Concentration) against a pathogen. The minimum concentration level, in the lochia and endometrium of postpartum cows that is considered to be efficacious, is determined by the MICs of cefquinome against the different pathogens.

As shown in example 6, after intrauterine administration of the pharmaceutical composition according to the invention during the effective period a therapeutic efficient level in the lochia and endometrium above the MIC for the different pathogens was reached.

Example 7 shows another pharmacokinetic study after intrauterine administration of the composition according to the invention compared with a known cefquinome sulphate formulation for intramammary administration in lactating cows. This Cobactan LC formulation contains 75 mg Cefquinome sulphate in a paraffinum liquidum base.

These experiments show that the intra-uterine formulation according to the invention provides higher plasma concentrations and prolonged concentrations in lochia that are helpful in achieving the therapeutic effect of the composition. Hence, example 7 shows that a topical formulation developed for other body cavities (udder) is less suitable for intrauterine administration.

The veterinary composition according to the invention can be applied in general to all mammalian species that need treatment or prevention of metritis and bacterial infections of the uterus such as e.g. pigs, cattle, camel, buffalo, horses, goats, sheep, and companion animals such as cats, dogs, but especially to cows.

The chosen formulation may be filled into the tube or syringe packs of the conventional type for intrauterine administration, i.e. connected to a catheter for insertion to allow extrusion directly into the uterus via the cervical canal.

A single dose of the composition will normally contain 1 to 50 gram, preferably 15 to 35 gram of the composition.

The particular amount of composition required for a particular treatment will vary, depending upon the species, age and weight of the host animal being treated, the particular disease to be guarded against, or treated, as well as the specific antimicrobial agent selected for the treatment, the route and the frequency of administration. For example the dose of cefquinome sulphate for the treatment of acute metritis in post partum cows is 900 mg of cefquinome for intrauterine administration.

Examples Example 1: Preparation of a cefquinome sulphate composition (100 kg) 3.60 kg Cefquinome as sulphate 1.11 kg Macrogol cetostearyl ether -12 0.47 kg Macrogol cetostearyl ether- 20 0.79 kg Hydrogenated castor oil up to 100 kg Medium chain triglycerides The manufacturing process encompasses the following steps:

1. The base of macrogol cetostearyl ether - 12 , macrogol cetostearyl ether - 20, hydrogenated castor oil is weighted and mixed in medium chain triglycerides, and homogenized under heating 2. the cefquinome sulphate is suspended under homogenisation 3. the product is filled in syringes.

Example 2: Preparation of cefquinome sulphate composition (100 kg) 3.60 kg Cefquinome as sulphate 2.22 kg Macrogol cetostearyl ether -12 0.94 kg Macrogol cetostearyl ether- 20 0.79 kg Hydrogenated castor oil up to 100 kg Medium chain triglycerides The composition is manufactured as disclosed in Example 1 Example 3: Preparation of cefquinome sulphate composition (100 kg) 3.60 kg Cefquinome as sulphate 1.66 kg Macrogol cetostearyl ether -12 0.70 kg Macrogol cetostearyl ether- 20 0.79 kg Hydrogenated castor oil up to 100 kg Medium chain triglycerides The composition is manufactured as disclosed in Example 1 Example 4: Preparation of a cefquinome sulphate composition (100 kg) 3.60 kg Cefquinome as sulphate 1.57 kg Macrogol cetostearyl ether -12 0.79 kg Hydrogenated castor oil up to 100 kg Medium chain triglycerides The manufacturing process encompasses the following steps:

4. The base of macrogol cetostearyl ether and hydrogenated castor oil is weighted and mixed in medium chain triglycerides, and homogenized under heating 5. the cefquinome sulphate is suspended under homogenisation 6. the product is filled in syringes.

Example 5: Preparation of a cefquinome sulphate composition (100 kg) 3.60 kg Cefquinome as sulphate 1.57 kg Macrogol cetostearyl ether -20 0.79 kg Hydrogenated castor oil up to 100 kg Medium chain triglycerides The composition is manufactured as disclosed in Example 4 Example 6: In vivo pharmacokinetic study Two pharmacokinetic studies were performed, during which plasma, lochia, and endometrium cefquinome concentrations after administration of a composition according to the invention (Examplel) were measured.

In parallel, bacteria isolated from field cases of acute metritis were tested against cefquinome to determine MIC's.

Cefquinome concentrations from the pharmacokinetic studies were compared to MIC's of cefquinome against acute metritis pathogens.

Material and methods:

One to six days after calving, fourteen healthy cows received an intra-uterine administration of 900mg cefquinome in a composition of example 1.

Lochia samples and endometrium biopsies were collected at 7, 24, 48, and 72 hours after treatment. Blood samples were collected just before treatment, and then for up to 48 hours after treatment.

Cefquinome concentrations in lochia and endometrium were determined with validated microbiological assays. Cefquinome concentrations in plasma were determined with a validated HPLC assay.

The strains used to determine the MIC's were isolated between 2000 to 2005, from cows with acute metritis from different European countries (France, Germany, Hungary and Netherlands). Strains were collected by intra-uterine swabbing, before any treatment.

The pathogens identified were used to determine cefquinome MIC's, using standard broth micro-dilution or agar dilution techniques.