WO2003063877A1 - Cefquinome composition for intra-mammary administration in cattle - Google Patents

Cefquinome composition for intra-mammary administration in cattle Download PDF

Info

Publication number
WO2003063877A1
WO2003063877A1 PCT/EP2003/000879 EP0300879W WO03063877A1 WO 2003063877 A1 WO2003063877 A1 WO 2003063877A1 EP 0300879 W EP0300879 W EP 0300879W WO 03063877 A1 WO03063877 A1 WO 03063877A1
Authority
WO
WIPO (PCT)
Prior art keywords
cefquinome
composition according
composition
oil
weight
Prior art date
Application number
PCT/EP2003/000879
Other languages
French (fr)
Inventor
Alan Banting
Sylvie Banting
Michel Duval
Original Assignee
Akzo Nobel N.V.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Akzo Nobel N.V. filed Critical Akzo Nobel N.V.
Publication of WO2003063877A1 publication Critical patent/WO2003063877A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0041—Mammary glands, e.g. breasts, udder; Intramammary administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • Infections may already be present in the udder at drying-off, or may gain access during the dry period and may be carried over into the subsequent lactation causing clinical or subclinical mastitis. Therefore the so-called dry cow treatments, that is during the approximate 4-week to 10 week period of time immediately preceding the delivery of a calf, have been performed widely.
  • British patent application GB A-132918 describes a dry cow formulation where the antibacterial agent is administered in the form of sustained release beadlets.
  • British patent application GB-A- 792545 describes an antibiotic preparation in which antibiotic particles are coated with an aluminium salt of a fatty acid and dispersed in oil to achieve a protracted effect.
  • US patent 3,912,806 describes a dry cow treatment that uses water insoluble granules (5-500 ⁇ in size) vehicle in an oily base in an aqueous medium.
  • European Patent EP 271306 discloses a dry cow treatment in the form of particles, were at least 65% by weight have a size in the range of 0-5 ⁇ , suspended in a hydrophobic oily vehicle gelled with aluminium stearate.
  • the PCT application WO 87/03876 discloses a dry cow treatment for Benzathine Cephalothin in an oily formulation comprising a hydrophobic oily vehicle, a gelling agent and a thickening agent.
  • US patent 4,172,138 disclosed a dry cow treatment containing a limited soluble penicillin salt and Neomycin in a slow release base (vegetable oil/ aluminium stearate).
  • the described dry cow formulations use antibacterial agents that are either not sufficiently active at the risk periods against some important mastitis pathogens as the so-called coliform bacteria ⁇ Escherichia coli, Enterobacter spp., Proteus spp., Aerobacter aerogenes, Klebsiella spp.) and some strains of Stapylococcus aureus, that are resistant to penicillin, or use a combination of two antibiotic ingredients to achieve the desired activity.
  • the incidence of coliform mastitis is about 4 times higher during dry period than during lactation and is elevated during the first 2 weeks after drying-off and 2 weeks prior to calving.
  • the occurrence of acute coliform mastitis is particularly increased due to the higher susceptibility of cows to infections because of decreased neutrophile function, delayed migration of neurophile cells into mammary gland and faster bacterial replication in the milk.
  • Combinations of two antibiotic ingredients are mainly used to broaden the antibiotic spectrum of the single compounds. This combination can however result in increased resistance development and undesired effects that are caused by pharmacological interactions and/or by local intolerance.
  • Cefquinome is effective against all major mastitis pathogens as Escherichia coli and other coliforms, Streptococcus uberis, Streptococcus agalactiae, Streptococcus dysgalactiae, and Stapylococcus aureus and coagulase-negative Staphylococci.
  • cefquinome for the use during the lactation of cows is available on the veterinary market (sold under the trademark Cobactan® LC by Intervet International b.v., Boxmeer, The Netherlands) containing 75 mg/8g of cefquinome sulphate that is proven to treat effectively acute and chronic mastitis during the milk lactation period.
  • Cobactan® LC by Intervet International b.v., Boxmeer, The Netherlands
  • An advantageous pharmaceutical composition for the dry cow treatment application would be one that is active against the major pathogens, non- irritant to the udder, and persists in the dry udder for as long as the risk of infection is present.
  • a therapeutic tissue level in the udder dry cow secretion above the minimum tissue concentration is reached.
  • the minimum concentration level, in the dry cow secretion that is considered to be efficacious, is determined by the MIC 90 (Minimum Inhibitory Concentration), i.e. 0.125 ⁇ g/mL for Streptococcus uberis and E.coli which are known to be the most common pathogens in mastitis in cattle at calving.
  • the veterinary composition according to the invention provides such a dry cow formulation that causes effective levels of the antibiotic in the udder of the dry cow that are suitable for the control of important mastitis pathogens over a sufficient time.
  • the present invention provides a veterinary composition for intramammary administration during the dry period, characterised in that it comprises cefquinome in a base, said base comprising an oil and colloidal silicon dioxide.
  • Colloidal silicon dioxide is submicroscopic fumed silica prepared by the vapour-phase hydrolysis of a silicon compound and is available e.g. as AEROSIL® of Degussa H ⁇ ls AG, Germany.
  • Colloidal silicon dioxide (AEROSIL®) is available as hydrophilic grade, hydrophobic grade and special AEROSIL grades.
  • the surface area of colloidal silicon dioxide - AEROSIL particles can be modified with organosilanes to change hydrophilic fumed silica into silica with predominantly hydrophobic characteristics.
  • hydrophobic grade AEROSIL e.g. AEROSIL R972, R974, R812; R812S, R202 and R805 grade, especially preferred is AEROSIL R972.
  • the colloidal silicon dioxide is present in an amount of 3 to 12 % by weight.
  • Cefquinome is the only fourth-generation cephalosporin developed for use in veterinary medicine. It is a semi-synthetic aminothiazolyl cephalosporin resembling cefotaxime, but with a bicyclic pyridinium group at the C-3 position (Isert et al, Seibert et al, 29 th Interscience Conference on Antimicrobial Agents and Chemotherapy Houston, Texas, 1989).
  • cefquinome when used herein includes pharmaceutically acceptable salts and esters thereof.
  • Cefquinome proved highly effective against the most commonly isolated mastitis pathogens, which were also the most important ones clinically (Streptococcus spp., Staphylococcus spp. and Enterobacteriaceae). Actinomyces pyogenes is also included in the spectrum of activity.
  • cephem acid addition salts have been proposed for the treatment of bacterial infections
  • all pharmaceutically acceptable cephem salts can be incorporated in the current formulation.
  • Preferred is cefquinome sulphate.
  • the base is selected so as to be non-toxic, veterinary acceptable, compatible with the antibacterial agent, and of a viscosity to permit administration, using a syringe at ambient temperature, whilst controlling the release characteristics of the finely divided drug particles.
  • the current invention provides a pharmaceutical composition for intramammary administration during the dry period comprising a pharmaceutically acceptable mineral oil or esters of fatty acids from natural origin or a mixture thereof that are suitable for carrying an anti- mastitis medicament and which have been found fully acceptable for intramammary infusion.
  • Mineral oils are mixtures of liquid hydrocarbons known in medicine as liquid paraffin, light liquid paraffin or petroleum, for example, those of the United States Pharmacopoeia (USP) or British Pharmacopoeia (BP).
  • USP United States Pharmacopoeia
  • BP British Pharmacopoeia
  • Esters of fatty acids that come from natural origin are conveniently prepared by the commercial fractionating of naturally occurring vegetable (e.g. coconut) oil to give mainly C 8-10 fatty acids followed by esterification of these acids with a chosen alcohol.
  • Fractionated vegetable oil having the desired composition is commercially available.
  • oils are Miglyol® 812 as capric/caprylic triglycerides and Miglyol® 840 as propylene glycol dicaprylate/caprate.
  • Miglyol 812 is Especially preferred.
  • composition according to the invention may comprise additionally a thickening agent that is selected from 12-hydroxy stearin or aluminium stearate or a combination thereof or a mixture with other thickening agents known in the art for intramammary formulations e.g. 12-hydroxystearin (Thixcin®), cellulose derivatives (e.g. ethylcellulose e.g. EC N50), beeswax, hydrogenated peanut or castor oil, hard or soft paraffin or metal salts of fatty acids.
  • Thixcin® cellulose derivatives
  • e.g. ethylcellulose e.g. EC N50 cellulose derivatives
  • beeswax hydrogenated peanut or castor oil
  • hard or soft paraffin or metal salts of fatty acids e.g. ethylcellulose e.g. EC N50
  • composition according to the present invention typically contains 4 to 6 % of cefquinome by weight and 3 to 12 % of the colloidal silicon dioxide in the oil.
  • the veterinary composition according to the current invention may further comprise additional pharmaceutical excipients known in the art.
  • additional pharmaceutical excipients are e.g. described in "Gennaro, Remington: The Science and Practice of Pharmacy” (20. Edition, 2000), incorporated by reference herein.
  • cefquinome sulphate at a particle size were at least 70 % of the cefquinome particle having a dimension below 5 ⁇ m is useful.
  • the particle size of cefquiniome that is used in the composition is below 50 ⁇ m, preferably below 20 ⁇ m, more preferably below 10 ⁇ m and most preferably below 5 ⁇ m. In a preferred embodiment 70% of the particles are in this most preferred range.
  • the colloidal silicon dioxide and optionally a thickening agent is added to the oily vehicle while stirring and heating to form the sterile base and the base is allowed to cool before adding the pre-sterile cefquinome.
  • High shear dispersion (HSD) utilising high intensity mills (e.g. by a Silverson mixer, rotor/stator Olsa, Becomix mixer) is used for proper dispersion of the active ingredient.
  • 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 mammary disorders in animals during the dry period.
  • the chosen formulation may be filled into the tube or syringe packs of the conventional type for intramammary administration, i.e. provided, with a cannula nozzle for insertion into the teat to allow extrusion directly into the mammary gland via the streak canal.
  • the veterinary composition according to the invention can be applied in general to all mammalian species that need treatment or prevention of bacterial infections of the mammary gland such as e.g. cattle, camel, buffalo, horses, goats, sheep, but especially to ruminants.
  • a single dose of the composition will normally contain 1 to 10 gram, preferably 3 to 8 gram of the composition.
  • Figure 1 Pharmacokinetics of cefquinome in dry cow secretions of healthy cows after a single intramammary administration of different cefquinome DC compositions
  • Formulation A 3 % ADS, 5% cefquinome in Liquid paraffin (w/w) Formulation D: 6 % AEROSIL, 5% cefquinome in Liquid paraffin (w/w) Formulation E and I: 6% ADS, 5% cefquinome in Miglyol 812 (w/w) Formulation F: 12 % AEROSIL, 5% cefquinome in Miglyol 812 (w/w) Formulation G: 6 % EC N50, 5% cefquinome in Miglyol 812 (w/w)
  • Formulation H 4 % EC N50, 5% cefquinome in Labrafil M1944CS (w/w)
  • Formulation K and K1 5% cefquinome in Plastibase (w/w)
  • the dose rate per quarter was 150 mg cefquinome.
  • Dry cow secretions were collected from each individual quarter at 1, 4, 7 and 14 days after treatment. Thereafter, samples were collected on a weekly basis until calving.
  • the cefquinome analysis was performed via a HPLC technique.
  • composition D and F/ F1 can be manufactured as described below.
  • Cefquinome as cefquinome sulphate (content 775 to 845 mg/g of cefquinome) (equivalent activity to) 5 g AEROSIL R972 6 g
  • composition was prepared as follows:
  • Miglyol 812 up to 100 g

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A veterinary composition for intramammary administration for the treatment and prevention of mammary disorders during the dry period, comprising cefquinome in an oil/colloidal silicon dioxide base.

Description

CEFQUINOME COMPOSITION FOR INTRA-MAMMARY ADMINISTRATION IN CATTLE
The present invention is concerned with a veterinary composition for the prophylaxis and treatment of mastitis, especially during the dry period.
Inflammations of the bovine mammary gland are one of the major problems of agricultural dairy production. Despite preventive care by selective breeding, milking technology and hygiene measures, it is often impossible to prevent infections, most of which are caused by bacterial pathogens.
Infections may already be present in the udder at drying-off, or may gain access during the dry period and may be carried over into the subsequent lactation causing clinical or subclinical mastitis. Therefore the so- called dry cow treatments, that is during the approximate 4-week to 10 week period of time immediately preceding the delivery of a calf, have been performed widely.
The infusion of antibacterial agents into each quarter immediately after the last milking of the lactation, in order to treat existing infections and to afford prophylaxis against new infections has been practised for many years.
In the prior art various methods and compositions for dry cow treatment have been proposed. Present products available are formulations of medicaments in aqueous, glycerol, or vegetable-oil type vehicles. For more prolonged release of medicaments in the udder, mineral oil and vegetable oil with gelling agents such as aluminium stearate and emulsifier-type agents are used.
British patent application GB A-132918 describes a dry cow formulation where the antibacterial agent is administered in the form of sustained release beadlets.
British patent application GB-A- 792545 describes an antibiotic preparation in which antibiotic particles are coated with an aluminium salt of a fatty acid and dispersed in oil to achieve a protracted effect. US patent 3,912,806 describes a dry cow treatment that uses water insoluble granules (5-500 μ in size) vehicle in an oily base in an aqueous medium.
European Patent EP 271306 discloses a dry cow treatment in the form of particles, were at least 65% by weight have a size in the range of 0-5μ, suspended in a hydrophobic oily vehicle gelled with aluminium stearate.
The PCT application WO 87/03876 discloses a dry cow treatment for Benzathine Cephalothin in an oily formulation comprising a hydrophobic oily vehicle, a gelling agent and a thickening agent.
US patent 4,172,138 disclosed a dry cow treatment containing a limited soluble penicillin salt and Neomycin in a slow release base (vegetable oil/ aluminium stearate).
The described dry cow formulations use antibacterial agents that are either not sufficiently active at the risk periods against some important mastitis pathogens as the so-called coliform bacteria {Escherichia coli, Enterobacter spp., Proteus spp., Aerobacter aerogenes, Klebsiella spp.) and some strains of Stapylococcus aureus, that are resistant to penicillin, or use a combination of two antibiotic ingredients to achieve the desired activity.
The incidence of coliform mastitis is about 4 times higher during dry period than during lactation and is elevated during the first 2 weeks after drying-off and 2 weeks prior to calving. In the peri-parturient phase, the occurrence of acute coliform mastitis is particularly increased due to the higher susceptibility of cows to infections because of decreased neutrophile function, delayed migration of neurophile cells into mammary gland and faster bacterial replication in the milk.
Combinations of two antibiotic ingredients are mainly used to broaden the antibiotic spectrum of the single compounds. This combination can however result in increased resistance development and undesired effects that are caused by pharmacological interactions and/or by local intolerance.
Furthermore the manufacturing process for a composition comprising only one active ingredient is simpler and reduces the cost.
Therefore a dry cow product with only one antibiotic ingredient with a good local tolerance, a sufficient broad spectrum and duration of activity would be desired.
A known broad spectrum antibiotic is Cefquinome. Cefquinome is effective against all major mastitis pathogens as Escherichia coli and other coliforms, Streptococcus uberis, Streptococcus agalactiae, Streptococcus dysgalactiae, and Stapylococcus aureus and coagulase-negative Staphylococci.
An intramammary preparation of cefquinome for the use during the lactation of cows is available on the veterinary market (sold under the trademark Cobactan® LC by Intervet International b.v., Boxmeer, The Netherlands) containing 75 mg/8g of cefquinome sulphate that is proven to treat effectively acute and chronic mastitis during the milk lactation period. However, a dry cow treatment for cefquinome has not yet been allied in practice in the veterinary market.
Although various dry cow formulations have been proposed in prior art they did not deliver a suitable duration of antibiotic concentration in the udder for the treatment of subclinical mastitis and the prevention of new infections with mastitis pathogens during the dry period in combination with cefquinome.
An advantageous pharmaceutical composition for the dry cow treatment application would be one that is active against the major pathogens, non- irritant to the udder, and persists in the dry udder for as long as the risk of infection is present. During the effective period a therapeutic tissue level in the udder dry cow secretion above the minimum tissue concentration is reached. The minimum concentration level, in the dry cow secretion that is considered to be efficacious, is determined by the MIC90 (Minimum Inhibitory Concentration), i.e. 0.125 μg/mL for Streptococcus uberis and E.coli which are known to be the most common pathogens in mastitis in cattle at calving.
Therefore there is a need for a dry cow formulation that provides the desired product profile with only one broad spectrum antibiotic and overcomes these drawbacks.
The veterinary composition according to the invention provides such a dry cow formulation that causes effective levels of the antibiotic in the udder of the dry cow that are suitable for the control of important mastitis pathogens over a sufficient time.
The present invention provides a veterinary composition for intramammary administration during the dry period, characterised in that it comprises cefquinome in a base, said base comprising an oil and colloidal silicon dioxide.
Colloidal silicon dioxide is submicroscopic fumed silica prepared by the vapour-phase hydrolysis of a silicon compound and is available e.g. as AEROSIL® of Degussa Hϋls AG, Germany. Colloidal silicon dioxide (AEROSIL®) is available as hydrophilic grade, hydrophobic grade and special AEROSIL grades. The surface area of colloidal silicon dioxide - AEROSIL particles can be modified with organosilanes to change hydrophilic fumed silica into silica with predominantly hydrophobic characteristics. Preferred is hydrophobic grade AEROSIL, e.g. AEROSIL R972, R974, R812; R812S, R202 and R805 grade, especially preferred is AEROSIL R972. Preferably the colloidal silicon dioxide is present in an amount of 3 to 12 % by weight. Cefquinome is the only fourth-generation cephalosporin developed for use in veterinary medicine. It is a semi-synthetic aminothiazolyl cephalosporin resembling cefotaxime, but with a bicyclic pyridinium group at the C-3 position (Isert et al, Seibert et al, 29th Interscience Conference on Antimicrobial Agents and Chemotherapy Houston, Texas, 1989).
The term "cefquinome" when used herein includes pharmaceutically acceptable salts and esters thereof.
The fourth generation cephalosporins possess favourable chemotherapeutic properties, i.e. a broad spectrum activity against a wide range of gram positive and gram negative organisms that are important in human and veterinary medicine and low rates of adverse effects (Limbert et al, Antimicrob Agents Chemotherap 35, 14-19, 1991, Caprille et al; J. Vet. Pharmacol. Ther. H, 1-32, 1988)). Cefquinome is described to be stable against chromosomally and plasmid encoded β-lactamases.
Cefquinome proved highly effective against the most commonly isolated mastitis pathogens, which were also the most important ones clinically (Streptococcus spp., Staphylococcus spp. and Enterobacteriaceae). Actinomyces pyogenes is also included in the spectrum of activity.
Various crystalline cephem acid addition salts have been proposed for the treatment of bacterial infections In general all pharmaceutically acceptable cephem salts can be incorporated in the current formulation. Preferred is cefquinome sulphate.
The current invention discloses in pharmaceutical composition comprising 1 to 10 % by weight of cefquinome. Preferably the pharmaceutical composition comprises 2 to 8%, most preferred 4 to 6 % by weight of cefquinome.
The base is selected so as to be non-toxic, veterinary acceptable, compatible with the antibacterial agent, and of a viscosity to permit administration, using a syringe at ambient temperature, whilst controlling the release characteristics of the finely divided drug particles.
In a preferred embodiment, the current invention provides a pharmaceutical composition for intramammary administration during the dry period comprising a pharmaceutically acceptable mineral oil or esters of fatty acids from natural origin or a mixture thereof that are suitable for carrying an anti- mastitis medicament and which have been found fully acceptable for intramammary infusion.
Mineral oils are mixtures of liquid hydrocarbons known in medicine as liquid paraffin, light liquid paraffin or petroleum, for example, those of the United States Pharmacopoeia (USP) or British Pharmacopoeia (BP).
Especially good results have been achieved with liquid paraffin. Liquid paraffin, a mineral oil is a mixture of liquid saturated hydrocarbons that is obtained from petroleum.
Esters of fatty acids that come from natural origin are conveniently prepared by the commercial fractionating of naturally occurring vegetable (e.g. coconut) oil to give mainly C 8-10 fatty acids followed by esterification of these acids with a chosen alcohol. Fractionated vegetable oil having the desired composition is commercially available. Examples of such oils are Miglyol® 812 as capric/caprylic triglycerides and Miglyol® 840 as propylene glycol dicaprylate/caprate. Especially preferred is Miglyol 812.
The composition according to the invention may comprise additionally a thickening agent that is selected from 12-hydroxy stearin or aluminium stearate or a combination thereof or a mixture with other thickening agents known in the art for intramammary formulations e.g. 12-hydroxystearin (Thixcin®), cellulose derivatives (e.g. ethylcellulose e.g. EC N50), beeswax, hydrogenated peanut or castor oil, hard or soft paraffin or metal salts of fatty acids. By "by weight" in this patent application it is meant a percentage by weight of the total composition.
Preferably the composition according to the present invention typically contains 4 to 6 % of cefquinome by weight and 3 to 12 % of the colloidal silicon dioxide in the oil.
Especially good results were achieved with a composition containing 5 % of cefquinome sulphate and 6-12 % of AEROSIL R972 and in liquid paraffin or Miglyol® 812.
The veterinary composition according to the current invention 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. Edition, 2000), incorporated by reference herein.
It has been observed that the release period and/or the amount of cefquinome released can be increased by the use of an antibacterial agent in the form of very finely divided particles. Therefore cefquinome sulphate at a particle size were at least 70 % of the cefquinome particle having a dimension below 5 μm is useful.
Preferably the particle size of cefquiniome that is used in the composition is below 50 μm, preferably below 20 μm, more preferably below 10 μm and most preferably below 5 μm. In a preferred embodiment 70% of the particles are in this most preferred range.
A desired reduction of particle size of the cephalosporin can be generally achieved by micronisation by an air jet mill or alternatively by milling the crystals of non- micronised cephalosporin in e.g. a high-energy hammer mill or by milling of the suspension (wet milling). Preferably the cefquinome will be used in a micronised form. The current invention furthermore provides a process for preparing an veterinary composition as claimed in any of the preceding claims comprising the steps of mixing the oil and the colloidal silicon dioxide to create the base and suspending the cefquinome in said base.
The colloidal silicon dioxide and optionally a thickening agent is added to the oily vehicle while stirring and heating to form the sterile base and the base is allowed to cool before adding the pre-sterile cefquinome. High shear dispersion (HSD) utilising high intensity mills (e.g. by a Silverson mixer, rotor/stator Olsa, Becomix mixer) is used for proper dispersion of the active ingredient.
A detailed description of a preferred embodiment of the manufacturing process according to the invention is provided in example 1.
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 mammary disorders in animals during the dry period.
The chosen formulation may be filled into the tube or syringe packs of the conventional type for intramammary administration, i.e. provided, with a cannula nozzle for insertion into the teat to allow extrusion directly into the mammary gland via the streak canal.
The veterinary composition according to the invention can be applied in general to all mammalian species that need treatment or prevention of bacterial infections of the mammary gland such as e.g. cattle, camel, buffalo, horses, goats, sheep, but especially to ruminants.
A single dose of the composition will normally contain 1 to 10 gram, preferably 3 to 8 gram of the composition. Brief description of the figures:
Figure 1: Pharmacokinetics of cefquinome in dry cow secretions of healthy cows after a single intramammary administration of different cefquinome DC compositions
Examples:
Example 1
Pharmacokinetics of cefquinome in dry cow secretions of healthy cows after a single intramammary administration of different cefquinome DC compositions
Material and Methods: The following cefquinome formulations were tested
Formulation A: 3 % ADS, 5% cefquinome in Liquid paraffin (w/w) Formulation D: 6 % AEROSIL, 5% cefquinome in Liquid paraffin (w/w) Formulation E and I: 6% ADS, 5% cefquinome in Miglyol 812 (w/w) Formulation F: 12 % AEROSIL, 5% cefquinome in Miglyol 812 (w/w) Formulation G: 6 % EC N50, 5% cefquinome in Miglyol 812 (w/w)
Formulation H: 4 % EC N50, 5% cefquinome in Labrafil M1944CS (w/w) Formulation K and K1 : 5% cefquinome in Plastibase (w/w)
Each animal received 4 different formulations, i.e. one formulation per udder quarter. The dose rate per quarter was 150 mg cefquinome. Dry cow secretions were collected from each individual quarter at 1, 4, 7 and 14 days after treatment. Thereafter, samples were collected on a weekly basis until calving. The cefquinome analysis was performed via a HPLC technique.
Results:
The local administration of 9 different cefquinome formulations into the udders of healthy dairy cows at drying off did not cause any localized symptoms or systemic side effects throughout the complete dry cow- and post calving period. Formulations D and F showed cefquinome concentrations above MIC for important mastitis pathogens for more than 29 days and therefore the most interesting persistence profile
Detailed results of the cefquinome concentrations in dry cow secretions and milk samples are graphically illustrated in Figure 1.
The composition D and F/ F1 can be manufactured as described below.
Manufacture of Composition D
Cefquinome as cefquinome sulphate (content 775 to 845 mg/g of cefquinome) (equivalent activity to) 5 g AEROSIL R972 6 g
Liquid paraffin up to 100 g
The composition was prepared as follows:
1. Disperse 30 g of AEROSIL R972 in 439.17 g of liquid paraffin under continuous stirring. 2. Heat-sterilize the base and allow it to cool.
3. Add 30.83 g of cefquinome sulphate (cefquinome content 811 mg/g) under high shear dispersion with a Silverson mixer (15 to 20min).
4. Fill the suspension as 3 g doses into intramammary syringes.
Manufacture of Composition F
Cefquinome 5 g
AEROSIL R972 12 g
Miglyol 812 up to 100 g
Disperse 60 g of AEROSIL R972 in 409.17g of Miglyol 812 under continuous stirring. Add 30.83g of cefquinome sulphate under high shear dispersion.
Manufacture of Composition F1
Cefquinome 5 g
AEROSIL R972 6 g Miglyol 812 up to 100 g
Disperse 30 g of AEROSIL R972 in 439.17g of Miglyol 812 under continuous stirring. Add 30.83g of cefquinome sulphate under high shear dispersion.

Claims

Claims
A veterinary composition for intramammary administration during the dry period, characterised in that it comprises cefquinome in a base, said base comprising an oil and colloidal silicon dioxide.
The composition according to claim 1 , characterised in that the colloidal silicon dioxide is preferably a hydrophobic colloidal silicon dioxide, most preferably AEROSIL® R972.
The composition according to claims 1 to 2, characterised in that it comprises the colloidal silicon dioxide in an amount of 3 to 12 % by weight.
The composition according to any of claims 1 to 3, characterised in that the cefquinome is cefquinome sulphate.
The composition according to any of claims 1 to 4, characterised in that it comprises 1 to 10 % by weight of cefquinome, preferably 2 to 8% by weight, most preferred 4 to 6% by weight of cefquinome.
A composition according to any of claims 1 to 5, characterised in that it comprises cefquinome at a particle size were at least 70% of the particle have a dimension below 5μm.
The composition according to any of claims 1 to 6, characterised in that the oil is a pharmaceutically acceptable mineral oil or an ester of fatty acids from natural origin or a mixture thereof.
The composition according to claim 7, characterised in that the mineral oil is liquid paraffin. The composition according to claim 7, characterised in that the ester of fatty acids from natural origin is Miglyol® 812.
The composition according to any of claims 1 to 9, characterised in that the composition additionally comprises a thickening agent.
The composition according to any if claims 1 to 10, characterised in that it comprises 4 to 6 % by weight of cefquinome sulphate, 3 to 12 % by weight of AEROSIL® R972V in oil.
A process for preparing an veterinary composition as claimed in any of the preceding claims comprising the steps of mixing the oil and the colloidal silicon dioxide and optionally an additional thickening agent to create the base and suspending the cefquinome in the base.
The use of a veterinary composition according to any of the preceding claims for the manufacture of a medicament for the treatment or prevention of mammary disorders in animals during the dry period
PCT/EP2003/000879 2002-02-01 2003-01-28 Cefquinome composition for intra-mammary administration in cattle WO2003063877A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP02075464 2002-02-01
EP02075464.4 2002-02-01

Publications (1)

Publication Number Publication Date
WO2003063877A1 true WO2003063877A1 (en) 2003-08-07

Family

ID=27635869

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2003/000879 WO2003063877A1 (en) 2002-02-01 2003-01-28 Cefquinome composition for intra-mammary administration in cattle

Country Status (2)

Country Link
AR (1) AR038245A1 (en)
WO (1) WO2003063877A1 (en)

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004037265A1 (en) * 2002-10-25 2004-05-06 Akzo Nobel N.V. Prolonged release pharmaceutical composition
US6911441B2 (en) 2002-12-16 2005-06-28 Akzo Nobel N.V. Prolonged release pharmaceutical composition
WO2008025773A1 (en) * 2006-08-30 2008-03-06 Intervet International B.V. Pharmaceutical compositions comprising cefquinome
DE102007055341A1 (en) 2007-11-19 2009-05-20 Bayer Animal Health Gmbh Stabilization of oily suspensions containing hydrophobic silicas
WO2011009827A1 (en) 2009-07-20 2011-01-27 Intervet International B.V. Method of making cefquinome particles
WO2012095439A1 (en) * 2011-01-12 2012-07-19 Intervet International B.V. Use of liquid medium exchange by cross flow filtration in the preparation of drug suspensions
WO2012095438A1 (en) 2011-01-12 2012-07-19 Intervet International B.V. Particles and suspensions of cephalosporin antibiotics
EP2596783A1 (en) * 2011-11-22 2013-05-29 Viktor Lvovich Limonov Pharmaceutical composition for the preparation of infusion solutions of antimicrobial preparations, its production process
WO2013129944A1 (en) * 2012-02-27 2013-09-06 Bayer New Zealand Limited Controlled release compositions and their methods of use
CN104546703A (en) * 2013-12-10 2015-04-29 中国农业科学院饲料研究所 Cefquinome sulfate breast injection for dairy cow in lactation period and preparation method thereof
CN104840420A (en) * 2014-11-18 2015-08-19 中国农业科学院饲料研究所 Cefquinome sulfate uterine injectant for milk cows and preparation method of cefquinome sulfate uterine injectant
CN104873462A (en) * 2014-11-18 2015-09-02 中国农业科学院饲料研究所 Cefquinome-sulfate breast injection agent for dry period of dairy cows and preparation method thereof
CN105796491A (en) * 2016-03-30 2016-07-27 佛山市南海东方澳龙制药有限公司 Composition, application of composition, and preparation comprising composition
CN106344509A (en) * 2016-10-26 2017-01-25 成都乾坤动物药业股份有限公司 Cefquinome sulfate oil suspension and preparation method thereof
AU2015261543B2 (en) * 2012-02-27 2017-09-28 Elanco New Zealand Controlled release compositions and their methods of use
WO2020053189A1 (en) * 2018-09-14 2020-03-19 Institut Dr. Rilling Healthcare Gmbh Combustible and edible composition of medium-chain triglycerides and silicic acid
CN114869850A (en) * 2022-06-20 2022-08-09 山东晟阳生物工程有限公司 Cefquinome sulfate injection

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3252859A (en) * 1962-10-24 1966-05-24 Masti Kure Company Inc Colloidal silica-oil composition and method of using same
GB2087236A (en) * 1980-11-17 1982-05-26 Leo Pharm Prod Ltd Pharmaceutical preparations containing a 6 beta -halopenicillanic acid
WO1987003876A1 (en) * 1985-12-23 1987-07-02 Beecham Group P.L.C. Benzathine cephalothin, a process for its preparation and compositions containing it

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3252859A (en) * 1962-10-24 1966-05-24 Masti Kure Company Inc Colloidal silica-oil composition and method of using same
GB2087236A (en) * 1980-11-17 1982-05-26 Leo Pharm Prod Ltd Pharmaceutical preparations containing a 6 beta -halopenicillanic acid
WO1987003876A1 (en) * 1985-12-23 1987-07-02 Beecham Group P.L.C. Benzathine cephalothin, a process for its preparation and compositions containing it

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SHPIGEL NY ET AL: "Efficacy of cefquinome for treatment of cows with mastitis induced using Escherichia coli", JOURNAL OF DAIRY SCIENCE, vol. 80, no. 2, - 1997, S00N34, pages 318 - 323, XP000105696 *

Cited By (44)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004037265A1 (en) * 2002-10-25 2004-05-06 Akzo Nobel N.V. Prolonged release pharmaceutical composition
JP2006510607A (en) * 2002-10-25 2006-03-30 アクゾ・ノベル・エヌ・ベー Sustained release pharmaceutical composition
US6911441B2 (en) 2002-12-16 2005-06-28 Akzo Nobel N.V. Prolonged release pharmaceutical composition
WO2008025773A1 (en) * 2006-08-30 2008-03-06 Intervet International B.V. Pharmaceutical compositions comprising cefquinome
DE102007055341A1 (en) 2007-11-19 2009-05-20 Bayer Animal Health Gmbh Stabilization of oily suspensions containing hydrophobic silicas
US9095511B2 (en) 2007-11-19 2015-08-04 Bayer Intellectual Property Gmbh Stabilization of oily suspensions comprising hydrophobic silicas
TWI400243B (en) * 2009-07-20 2013-07-01 Intervet Int Bv Method of making cefquinome particles
JP2012533596A (en) * 2009-07-20 2012-12-27 インターベツト・インターナシヨナル・ベー・ベー Method for producing cefquinome particles
JP2016047827A (en) * 2009-07-20 2016-04-07 インターベット インターナショナル ベー． フェー． Method of producing cefquinome particles
CN102471350A (en) * 2009-07-20 2012-05-23 英特维特国际股份有限公司 Process for the manufacture of cefquinome particles
CN102471350B (en) * 2009-07-20 2015-05-06 英特维特国际股份有限公司 Method of making cefquinome particles
WO2011009827A1 (en) 2009-07-20 2011-01-27 Intervet International B.V. Method of making cefquinome particles
AU2010275302B2 (en) * 2009-07-20 2014-10-09 Intervet International B.V Method of making cefquinome particles
WO2012095439A1 (en) * 2011-01-12 2012-07-19 Intervet International B.V. Use of liquid medium exchange by cross flow filtration in the preparation of drug suspensions
WO2012095438A1 (en) 2011-01-12 2012-07-19 Intervet International B.V. Particles and suspensions of cephalosporin antibiotics
US9066864B2 (en) 2011-01-12 2015-06-30 Intervet Inc. Use of liquid medium exchange by cross flow filtration in the preparation of drug suspensions
JP2014502624A (en) * 2011-01-12 2014-02-03 インターベツト・インターナシヨナル・ベー・ベー Use of liquid medium exchange with cross-flow filtration in the preparation of drug suspensions
CN103126995A (en) * 2011-11-22 2013-06-05 维克托历沃维奇·利莫诺夫 Pharmaceutical composition for the preparation of antibacterial preparation infusion and its preparation method (variation)
EP2596783A1 (en) * 2011-11-22 2013-05-29 Viktor Lvovich Limonov Pharmaceutical composition for the preparation of infusion solutions of antimicrobial preparations, its production process
CN107913250B (en) * 2011-11-22 2021-01-22 维克托历沃维奇·利莫诺夫 Pharmaceutical composition for preparing infusion solution of antibacterial agent and preparation method (variation form) thereof
CN107913250A (en) * 2011-11-22 2018-04-17 维克托历沃维奇·利莫诺夫 Pharmaceutical composition for the preparation of antibacterial preparation infusion and its preparation method (variation)
AU2012211402B2 (en) * 2011-11-22 2013-12-05 Viktor Lvovich Limonov Pharmaceutical composition for the preparation of infusion solutions of antimicrobial preparations, its' production process
CN103126995B8 (en) * 2011-11-22 2018-04-06 维克托历沃维奇·利莫诺夫 Pharmaceutical composition for preparing infusion solution of antibacterial agent and preparation method (variation form) thereof
US9889158B2 (en) 2011-11-22 2018-02-13 Viktor Lvovich Limonov Pharmaceutical composition for the preparation of infusion solutions of antimicrobial preparations, its production process (variations)
US9844566B2 (en) 2011-11-22 2017-12-19 Viktor Lvovich Limonov Pharmaceutical composition for the preparation of infusion solutions of antimicrobial preparations, its production process (variations)
CN110604819A (en) * 2012-02-27 2019-12-24 拜耳新西兰有限公司 Controlled release compositions and methods of use thereof
WO2013129944A1 (en) * 2012-02-27 2013-09-06 Bayer New Zealand Limited Controlled release compositions and their methods of use
AU2015261543C1 (en) * 2012-02-27 2022-10-13 Elanco New Zealand Controlled release compositions and their methods of use
US10828311B2 (en) 2012-02-27 2020-11-10 Bayer New Zealand Limited Controlled release compositions and their methods of use
US20150045337A1 (en) * 2012-02-27 2015-02-12 Bayer New Zealand Ltd Controlled release compositions and their methods of use
RU2627429C2 (en) * 2012-02-27 2017-08-08 Байер Нью Зиленд Лимитед Compositions with controlled release and methods of their use
AU2015261543B2 (en) * 2012-02-27 2017-09-28 Elanco New Zealand Controlled release compositions and their methods of use
CN104244983A (en) * 2012-02-27 2014-12-24 拜耳新西兰有限公司 Controlled release compositions and their methods of use
CN104546703B (en) * 2013-12-10 2017-06-23 中国农业科学院饲料研究所 A kind of Lactation of Dairy Cow phase is with Cefquinome sulfate breast injection and preparation method thereof
CN104546703A (en) * 2013-12-10 2015-04-29 中国农业科学院饲料研究所 Cefquinome sulfate breast injection for dairy cow in lactation period and preparation method thereof
CN104840420A (en) * 2014-11-18 2015-08-19 中国农业科学院饲料研究所 Cefquinome sulfate uterine injectant for milk cows and preparation method of cefquinome sulfate uterine injectant
CN104873462A (en) * 2014-11-18 2015-09-02 中国农业科学院饲料研究所 Cefquinome-sulfate breast injection agent for dry period of dairy cows and preparation method thereof
CN104873462B (en) * 2014-11-18 2017-04-05 中国农业科学院饲料研究所 A kind of milch cow dry breast phase Cefquinome sulfate breast injection and preparation method thereof
CN105796491A (en) * 2016-03-30 2016-07-27 佛山市南海东方澳龙制药有限公司 Composition, application of composition, and preparation comprising composition
CN106344509A (en) * 2016-10-26 2017-01-25 成都乾坤动物药业股份有限公司 Cefquinome sulfate oil suspension and preparation method thereof
WO2020053189A1 (en) * 2018-09-14 2020-03-19 Institut Dr. Rilling Healthcare Gmbh Combustible and edible composition of medium-chain triglycerides and silicic acid
US12233040B2 (en) 2018-09-14 2025-02-25 Institut Dr. Rilling Healthcare Gmbh Combustible and edible composition of medium-chain triglycerides and silicic acid
CN114869850A (en) * 2022-06-20 2022-08-09 山东晟阳生物工程有限公司 Cefquinome sulfate injection
CN114869850B (en) * 2022-06-20 2023-04-28 山东晟阳生物工程有限公司 Cefquinome sulfate injection

Also Published As

Publication number Publication date
AR038245A1 (en) 2005-01-05

Similar Documents

Publication Publication Date Title
WO2003063877A1 (en) Cefquinome composition for intra-mammary administration in cattle
CN100355457C (en) Dispersible pharmaceutical compositions
US10098840B2 (en) Nanoparticulate composition containing antibiotics for intramammary administration in animals
TWI262084B (en) Dispersible formulation of an anti-inflammatory agent
US6001870A (en) Nasopharynx administration of mupirocin for prophylactic treatment of recurrent otitis media
RU2319508C2 (en) Dispersible preparation of antiinflammation agent
US6156792A (en) Calcium mupirocin non-aqueous nasal spray for otitis media or for recurrent acute bacterial sinusitis
MXPA05010019A (en) Dispersible pharmaceutical composition for treatment of mastitis and otic disorders.
JP7705985B2 (en) Novel Use of Glucocorticoids for the Treatment of Epithelial Microbial Infections of Fluid-Containing Organs with Natural External Orifices in Mammals - Patent application
KR102100271B1 (en) Controlled release compositions and their methods of use
IE62876B1 (en) Veterinary treatment
AU2024278169A1 (en) Controlled Release Compositions and their Methods of Use
NZ607636A (en) Controlled release compositions and their methods of use
NZ607636B2 (en) Controlled Release Compositions and Their Methods of Use
HK1081457B (en) Dispersible pharmaceutical compositions

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AU BA BB BG BR BZ CA CN CO CR CU CZ DM DZ EC EE GD GE HR HU ID IL IN IS JP KP KR LC LK LR LT LV MA MD MG MK MN MX NO NZ OM PH PL RO RU SD SG SK TN TR TT UA US UZ VN YU ZA ZM

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP