EP0250529A1 - Benzathine cephalothin, a process for its preparation and compositions containing it - Google Patents

Benzathine cephalothin, a process for its preparation and compositions containing it

Info

Publication number
EP0250529A1
EP0250529A1 EP19870900229 EP87900229A EP0250529A1 EP 0250529 A1 EP0250529 A1 EP 0250529A1 EP 19870900229 EP19870900229 EP 19870900229 EP 87900229 A EP87900229 A EP 87900229A EP 0250529 A1 EP0250529 A1 EP 0250529A1
Authority
EP
European Patent Office
Prior art keywords
cephalothin
oil
benzathine
composition
treatment
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP19870900229
Other languages
German (de)
French (fr)
Inventor
Maurice John Soulal
Clive James Moores
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Beecham Group PLC
Original Assignee
Beecham Group PLC
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 Beecham Group PLC filed Critical Beecham Group PLC
Publication of EP0250529A1 publication Critical patent/EP0250529A1/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic 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; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
    • C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group
    • C07D501/34—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group with the 7-amino radical acylated by carboxylic acids containing hetero rings
    • 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

Definitions

  • Benzathine cephalothin a process for its preparation and compositions containing it.
  • the present invention relates to a novel ⁇ lactam compound and the process for its production and to pharmaceutical composition containing the compound.
  • U.K. patent 982252 discloses heterocyclic substituted acyl derivatives of cephalosporin C including 7-(2-thienylacetamido)cephalosporanic acid, known as cephalothin.
  • cephalothin 7-(2-thienylacetamido)cephalosporanic acid
  • This compound particularly as its sodium salt, has become widely used for human patients as an antibacterial agent having potent activity against a broad spectrum of gram positive and gram negative bacteria.
  • cephalothin as an antibiotic is that it is an irritant when used intramuscularly.
  • benzathine cephalothin is as an antibacterial . It has been found however to be particularly effective in the treatment of mammary disorders, particularly in the treatment of bovine mastitis in dry cows. The compound has also been found to be surprisingly effective in the treatment of keratoconjunctivitis, and in particular bovine keratoconjunctivitis, which is a highly contageous disease of cattle caused by Moraxella bovis.
  • the present invention also provides a veterinary composition which comprises benzathine cephalothin and a veterinarily-acceptable carrier.
  • compositions suitably comprise a suspension of benzathine cephalothin in an aqueous medium or more preferably in a non-toxic veterinarily-acceptable oil.
  • an oily vehicle may comprise a mineral oil or a vegetable oil such as arachis oil, sesame oil, corn oil, cottonseed oil, soyabean oil, olive oil or a fractionated coconut oil.
  • a preferred vehicle is the fractionated coconut oil described in German OS 2635476. Suitable commercially available oils are Miglylol (Trade Mark) or Neobee (Trade Mark).
  • the active ingredient will normally represent 0.1 to 40%, more suitably 1 to 40% w/w. Particularly suitable ranges are 5 to 30% w/w.
  • the compound of the invention is used in the treatment or prophylaxis of bovine mastitis in dry cows it is normally provided in an oily formulation for intramammary use. Since slow release is required for tne therapy of dry cows a hydrophobic oily vehicle which has been strongly gelled with a gelling agent such as aluminium stearate may be used. Thickening agents such as 12-hydroxystearin, beeswax, hydrogenated peanut or castor oil or soft or hard paraffin may be used.
  • the composition may also contain pain relieving agents, corticosteroids and the like.
  • Surfactants such as Tween (Trade Mark), Span (Trade Mark) or Lanette wax may also be present. It may also be desirable to include an antioxidant such as butylated hydroxyanisole (Embanox - Trade Mark) in certain formulations.
  • the veterinary compositions for intramammary use are formulated as unit doses containing a therapeutically effective amount of benzathine cephalothin.
  • the preferred unit dose may contain 100 to 1000 mg more preferably 250 to 600 mg of benzathine cephalothin.
  • a typical dose is 500 mg.
  • a single dose of the composition will normally contain 1 to 20g of the formulated composition, preferably 2 to lOg. Typical formulations may contain 3g or 8g.
  • a single dose applied to the infected quarter may be effective. However one or more further doses may be applied depending on the length of the dry period.
  • the formulation would suitably be administered to the cow by means of an intramammary syringe, a tube or by other suitable packs which contain a unit dose of the formulation.
  • a syringe is provided with a cannula nozzle for insertion into the teat to allow extrusion of the formulation directly into the mammary gland via the streak canal.
  • the present invention also provides a method of treatment or prophylaxis of mammary disorders in animals which method comprises the intramammary administration of an effective amount of a composition of benzathine cephalothin and an aqueous or oily vehicle.
  • compositions of the present invention for the treatment of kevatoconjunctivitis contain benzathine cephalothin in an oily vehicle.
  • the oily vehicle is a mineral oil base, preferably liquid paraffin containing 0 to 5% by weight of composition of aluminium stearate and from 0 to 2% by weight of composition of stearic acid.
  • the oily vehicle may comprise a vegetable oil such as arachis oil or a fractionated coconut oil such as Miglylol or Neobee.
  • a suitable dose unit is typically between 20 and 200 mg of benzathine cephalothin.
  • benzathine cephalothin For the treatment of cattle a dose of about 150 mg of benzathine cephalothin is appropriate but a smaller dose, for example 50 mg may be sufficient for the treatment of keratoconjunctivitis in domestic animals such as cats and dogs. Frequently a single application of the formulation will oe sufficient. However severe infections may require more than one application.
  • the present invention further provides a method of treatment of keratoconjunctivitis in animals which comprises administering to the animal by topical instillation an effective amount of a composition of benzathine cephalothin and a veterinarily acceptable oil as carrier.
  • a composition of benzathine cephalothin and a veterinarily acceptable oil as carrier are in common use.
  • the container is a sealed aluminium tube or a polyethylene syringe.
  • the present invention also provides a process for the preparation of benzathine cephalothin which process comprises reacting solution of a compound of the formula (II).
  • R x is hydrogen or a carboxy protecting group, with a solution of N, -dibenzylethylenediamine or a salt thereof.
  • the reactants may be dissolved in any suitable aqueous or non-aqueous solvent. Particularly high yields are obtained by reacting cephalothin (free acid) with N, -dibenzylethylenediamine (free base) in a non-aqueous solvent.
  • a preferred solvent is acetone or methanol.
  • Veterinary compositions of the present invention may be prepared by mixing benzathine cephalothin with the vehicle and with any other components of the formulation. The process may suitably be carried out as follows:-
  • the formulation is then packed in an appropriate form for administration, eg. syringe or tube.
  • the polymorphic form is readily determined by IR spectroscopy.
  • Cephalothin (free acid) (3.05g; 0.007 mole) was dissolved in acetone (50cm 3 ) and with stirring added to a solution of N,N-dibenzylethylenediamine (free base) (0.84g; 0.0035 mole) in acetone (50cm 3 ).
  • a gelatinous precipitate immediately appeared which was removed by filtration, after vigorous stirring for 30 minutes, washed well with acetone (50cm 3 ) and dried at 35° for 24 hours.
  • Cephalothin (free acid) (3.05g? 0.007 mole) was dissolved in methanol (50cm 3 ) and with stirring added a solution of N,N-dibenzylethyleneddiamine (free base) (0.084g; 0.0035 mole) in methanol (50cm 3 ). The product precipitated immediately and stirring was continued for 30 minutes. The product was filtered off, washed well with methanol and dried at 35° for 24 hours.
  • the composition was prepared as follows.
  • the suspension was filled as 3g doses into intramammary syringes.
  • a gel of the mineral oil base was formed by dissolving the aluminium stearate and stearic acid in the heated liquid paraffin. After cooling the benzathine cephalothin was incorporated by high shear stirring and the weight adjusted to 500g with further liquid paraffin.
  • the suspension was filled as 8g doses into intramammary syringes.
  • the homogenous composition was prepared as described in Example 3.
  • the suspension was then packaged into 1 ml polyethylene syringes on aluminium tubes. This constitutes a single dose form containing 125mg of benzathine cephalothin suitable for treatment of bovine infectious kerataconjunctivitis.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Céphalotine de benzathine destinée à être utilisée dans le traitement des infections bactériennes chez l'animal et notamment dans le traitement ou la prophylaxie de troubles mammaires et de la kératoconjonctivite.Benzathine cephalotin intended to be used in the treatment of bacterial infections in animals and in particular in the treatment or prophylaxis of breast disorders and keratoconjunctivitis.

Description

Benzathine cephalothin, a process for its preparation and compositions containing it.
The present invention relates to a novel β lactam compound and the process for its production and to pharmaceutical composition containing the compound.
U.K. patent 982252 discloses heterocyclic substituted acyl derivatives of cephalosporin C including 7-(2-thienylacetamido)cephalosporanic acid, known as cephalothin. This compound, particularly as its sodium salt, has become widely used for human patients as an antibacterial agent having potent activity against a broad spectrum of gram positive and gram negative bacteria. One disadvantage of cephalothin as an antibiotic is that it is an irritant when used intramuscularly.
We have now found a novel salt of cephalothin which has particular utility in the treatment of bacterial infection in animals.
According to the present invention there is provided a compound of formula I:
Hereinafter the compound of formula I will be referred to by its trivial name benzathine cephalothin.
The major utility of benzathine cephalothin is as an antibacterial . It has been found however to be particularly effective in the treatment of mammary disorders, particularly in the treatment of bovine mastitis in dry cows. The compound has also been found to be surprisingly effective in the treatment of keratoconjunctivitis, and in particular bovine keratoconjunctivitis, which is a highly contageous disease of cattle caused by Moraxella bovis.
Thus the present invention also provides a veterinary composition which comprises benzathine cephalothin and a veterinarily-acceptable carrier.
The compositions suitably comprise a suspension of benzathine cephalothin in an aqueous medium or more preferably in a non-toxic veterinarily-acceptable oil. When an oily vehicle is employed it may comprise a mineral oil or a vegetable oil such as arachis oil, sesame oil, corn oil, cottonseed oil, soyabean oil, olive oil or a fractionated coconut oil. A preferred vehicle is the fractionated coconut oil described in German OS 2635476. Suitable commercially available oils are Miglylol (Trade Mark) or Neobee (Trade Mark).
In compositions in accordance with this aspect of the invention the active ingredient will normally represent 0.1 to 40%, more suitably 1 to 40% w/w. Particularly suitable ranges are 5 to 30% w/w. When the compound of the invention is used in the treatment or prophylaxis of bovine mastitis in dry cows it is normally provided in an oily formulation for intramammary use. Since slow release is required for tne therapy of dry cows a hydrophobic oily vehicle which has been strongly gelled with a gelling agent such as aluminium stearate may be used. Thickening agents such as 12-hydroxystearin, beeswax, hydrogenated peanut or castor oil or soft or hard paraffin may be used.
The composition may also contain pain relieving agents, corticosteroids and the like. Surfactants such as Tween (Trade Mark), Span (Trade Mark) or Lanette wax may also be present. It may also be desirable to include an antioxidant such as butylated hydroxyanisole (Embanox - Trade Mark) in certain formulations.
Preferably the veterinary compositions for intramammary use are formulated as unit doses containing a therapeutically effective amount of benzathine cephalothin. For use in the dry cow the preferred unit dose may contain 100 to 1000 mg more preferably 250 to 600 mg of benzathine cephalothin. A typical dose is 500 mg.
A single dose of the composition will normally contain 1 to 20g of the formulated composition, preferably 2 to lOg. Typical formulations may contain 3g or 8g.
In the treatment of mastitis in dry cows a single dose applied to the infected quarter may be effective. However one or more further doses may be applied depending on the length of the dry period. The formulation would suitably be administered to the cow by means of an intramammary syringe, a tube or by other suitable packs which contain a unit dose of the formulation. Such a syringe is provided with a cannula nozzle for insertion into the teat to allow extrusion of the formulation directly into the mammary gland via the streak canal.
Thus the present invention also provides a method of treatment or prophylaxis of mammary disorders in animals which method comprises the intramammary administration of an effective amount of a composition of benzathine cephalothin and an aqueous or oily vehicle.
Suitably compositions of the present invention for the treatment of kevatoconjunctivitis contain benzathine cephalothin in an oily vehicle.
Suitably the oily vehicle is a mineral oil base, preferably liquid paraffin containing 0 to 5% by weight of composition of aluminium stearate and from 0 to 2% by weight of composition of stearic acid. Alternatively the oily vehicle may comprise a vegetable oil such as arachis oil or a fractionated coconut oil such as Miglylol or Neobee.
The dosage regime will vary with the size of the sufferer. A suitable dose unit is typically between 20 and 200 mg of benzathine cephalothin. For the treatment of cattle a dose of about 150 mg of benzathine cephalothin is appropriate but a smaller dose, for example 50 mg may be sufficient for the treatment of keratoconjunctivitis in domestic animals such as cats and dogs. Frequently a single application of the formulation will oe sufficient. However severe infections may require more than one application.
Thus the present invention further provides a method of treatment of keratoconjunctivitis in animals which comprises administering to the animal by topical instillation an effective amount of a composition of benzathine cephalothin and a veterinarily acceptable oil as carrier. A number of suitable containers for instillation of a formulation onto an infected eye are in common use. Preferably the container is a sealed aluminium tube or a polyethylene syringe.
The present invention also provides a process for the preparation of benzathine cephalothin which process comprises reacting solution of a compound of the formula (II).
wherein Rx is hydrogen or a carboxy protecting group, with a solution of N, -dibenzylethylenediamine or a salt thereof. The reactants may be dissolved in any suitable aqueous or non-aqueous solvent. Particularly high yields are obtained by reacting cephalothin (free acid) with N, -dibenzylethylenediamine (free base) in a non-aqueous solvent. A preferred solvent is acetone or methanol. Veterinary compositions of the present invention may be prepared by mixing benzathine cephalothin with the vehicle and with any other components of the formulation. The process may suitably be carried out as follows:-
(a) the oil is heated, the gelling or thickening agent is mixed in and the oil allowed to cool,
(b) the powdered active ingredient is mixed into the base with stirring and
(c) high shear mixing equipment is used to produce a fine monogenous dispension.
The formulation is then packed in an appropriate form for administration, eg. syringe or tube.
The following Examples illustrate the invention.
Example 1
Sodium cephalothin (16.8g; 0.04 mole) was dissolved in water (150cm3), diluted with acetone (150cm3) and filtered. To the vigorously stirred solution was added a filtered solution of N,N-dibenzylethylenediamine diacetate (7.2g; 0.02 mole) in water (70cm3). The product precipitated immediately as a white gelatinous solid. The mixture was stirrred for 30 minutes and the precipitate removed by filtration. The filter cake was slurry washed in water (300cm3)for 1 hour, filtered off and dried at 35° for 24 hours.
Yield = 17.9g (86.9% of theory)
Analysis
% Benzathine (f.b.) = 23.2 (Theory = 23.3%) % Cephalothin (f.a.) = 77.8 (Theory = 76.7%)
Example 2
Sodium cephalothin (4.2; 0.01 mole) was dissolved in water (40cm3) and diluted with methanol (40cm3). To this stirred solution was added a filtered solution of N,N-dibenzylethylenediamine diacetate (1.8g; 0.005 mole), in water (20cm3). The salt precipitated out immediately. The mixture was stirred vigorously for 30 minutes and the product removed by filtration. The ' 'filter cake' ' was washed well with water (80cm3) and dried at 35° for 24 hours.
Yield = 4.3g (83.3% of theory)
Analysis
% Benzathine (f.b) = 23.8 (Theory = 23.3%) % Cephalothin (f.a.) = 75.6 (Theory = 76.7%)
Example 3
Sodium cephalothin (4.2g; 0.01 mole) was dissolved in water (40cm3) and with good stirring added a filtered solution of N,N-dibenzylethylenediamine diacetate (1.8g; 0.005 mole) in water (20cm3). The salt precipitated immediately and after stirring for 30 minutes was removed by filtration and slurry washed in water (100cm3), washed with acetone (100cm3) and dried at 35° for 24 hours.
Yield = 4.1g (79.5% of theory)
Analysis
% Benzathine (f.b.) - 24.0 (Theory = 23.2%) % Cephalothin (f.a) = 76.1 (Theory = 76.7%)
Example 4
Sodium cephalothin (84g; 0.2 mole) was dissolved in water(420 cm3) at ambient temperature and filtered. Benzathine diacetate (36g; 0.1 mole) was dissolved in water (360 cm3) at ambient temperature, filtered, and slowly added to the vigorously stirred sodium cephalothin solution. When the addition was complete acetone (390 cm3) was added to facilitate stirring. Stirring was continued for 30 minutes to ensue homogeneity. The product was removed by filtration and washed free of sodium acetate by reslurrying in 50% aqueous acetone. The filter-bed was washed with acetone to aid drying and the product dried in a fan oven at 35° for 48 hours (Note 4).
Yield = 100.5g (97% of theory)
Analysis (Typical)
Cephalothin content by hplc 78.18%
Benzathine content by hplc 24.6% Acetone 0.1%
Water 0.1%
Acetate 0.3%
The polymorphic form is readily determined by IR spectroscopy.
Example 5
Cephalothin (free acid) (3.05g; 0.007 mole) was dissolved in acetone (50cm3) and with stirring added to a solution of N,N-dibenzylethylenediamine (free base) (0.84g; 0.0035 mole) in acetone (50cm3). A gelatinous precipitate immediately appeared which was removed by filtration, after vigorous stirring for 30 minutes, washed well with acetone (50cm3) and dried at 35° for 24 hours.
Yield = 3.55g (97% of theory)
Example 6
Cephalothin (free acid) (3.05g? 0.007 mole) was dissolved in methanol (50cm3) and with stirring added a solution of N,N-dibenzylethyleneddiamine (free base) (0.084g; 0.0035 mole) in methanol (50cm3). The product precipitated immediately and stirring was continued for 30 minutes. The product was filtered off, washed well with methanol and dried at 35° for 24 hours.
Yield = 3.6g (99% Of theory)
Example 7
g % benzathine cephalothin 83.3 16.667 12-nydroxystearin (Thixcin R) 20 4. 0 colloidal silica (Aerosil R972) 5 1 .0 butylated hydroxyanisole (Embanox) .1 0.02
arachis oil to 500 100
The composition was prepared as follows.
20g of Thixcin R O.lg of Embanox and 5g of colloidal silica were dissolved in dried Arachis oil by heating to above 150°C for one hour and stirring and then allowing to cool. 83.3g of benzathine cephalothin was then incorporated into this thickened base by high shear stirring and the weight adjusted to 500g by the addition of further Arachis oil.
The suspension was filled as 3g doses into intramammary syringes.
Example 8
9 % benzathine cephalothin 83.3 16.667 aluminium stearate 15.35 3.069 liquid paraffin 480.61 96.122 stearic acid 4.04 0.808
A gel of the mineral oil base was formed by dissolving the aluminium stearate and stearic acid in the heated liquid paraffin. After cooling the benzathine cephalothin was incorporated by high shear stirring and the weight adjusted to 500g with further liquid paraffin.
The suspension was filled as 8g doses into intramammary syringes.
Example 9
An ointment formulation was aseptically prepared from
% w/w of composition benzathine cephalothin 16.67 liquid paraffin BP ) mineral 80.10 aluminium stearate ) oil 2.56 stearic acid BPC ) base 0.67
The homogenous composition was prepared as described in Example 3.
The suspension was then packaged into 1 ml polyethylene syringes on aluminium tubes. This constitutes a single dose form containing 125mg of benzathine cephalothin suitable for treatment of bovine infectious kerataconjunctivitis.

Claims

Claims
1. Benzathine cephalothin which is the compound of formula (I):
( I )
2. A veterinary composition which comprises benzathine cephalothin and a veterinarily acceptable carrier.
3. A veterinary composition as claimed in claim 2, comprising from 0.1 to 40% w/w of benzathine cephalothin.
4. A veterinary composition as claimed in claim 2 or claim 3, comprising a suspension of benzathine cephalothin in an aqueous medium or in a non-toxic veterinarily acceptable oil.
5. A veterinary composition as claimed in claim 4, wherein the non-toxic veterinarily acceptable oil is a mineral oil or a vegetable oil.
6. A veterinary composition as claimed in claim 5, wherein the mineral oil is liquid paraffin containing 0 to 5% by weight of composition of aluminium stearate and from 0 to 2% by weight of composition of stearic acid.
SUBSTITUTE SHEET
7. A veterinary composition as claimed in claim 5, wherein the vegetable oil is arachis oil, sesame oil, corn oil, cottonseed oil, soyabean oil, olive oil or a fractionated coconut oil.
8. A process for the preparation of a compound as claimed in claim 1, which process comprises reacting a solution of a compound of formula (II).
COOR (ID
with a solution of N,N-di-benzylethylenediamine or a salt thereof.
9. A method of treatment or prophylaxis of mammary disorders in animals, which method comprises the intramammary administration of an effective amount of a composition of benzathine cephalothin and an aqueous or oily vehicle.
10. A method of treatment of keratoconjunctivitis in animals, which comprises administering to the animal by topical installation, an effective amount of a composition of benzathine cephalothin and a veterinarily acceptable oil as carrier.
11. The use of benzathine cephalothin for the manufacture of a medicament for the treatment or prophylaxis of mammary disorders in animals.
12. The use of benzathine cephalothin for the manufacture of a medicament for the treatment of keratoconjunctivitis in animals.
SUBSTITUTE SHξET
EP19870900229 1985-12-23 1986-12-22 Benzathine cephalothin, a process for its preparation and compositions containing it Withdrawn EP0250529A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB858531609A GB8531609D0 (en) 1985-12-23 1985-12-23 Compounds
GB8531609 1985-12-23

Publications (1)

Publication Number Publication Date
EP0250529A1 true EP0250529A1 (en) 1988-01-07

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ID=10590167

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Country Status (3)

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EP (1) EP0250529A1 (en)
GB (1) GB8531609D0 (en)
WO (1) WO1987003876A1 (en)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ZA942070B (en) * 1993-03-25 1995-01-31 Smithkline Beecham Corp Benzathine salt of cefonicid
US5705496A (en) * 1994-03-24 1998-01-06 Smithkline Beecham Corporation Crystalline benzathine salt of cefonicid and its preparation
WO2003063877A1 (en) * 2002-02-01 2003-08-07 Akzo Nobel N.V. Cefquinome composition for intra-mammary administration in cattle
WO2004032899A1 (en) * 2002-10-08 2004-04-22 Orchid Chemicals & Pharmaceuticals Ltd. Antibiotic formulation for intramammary administration in milking animals
AU2003279302B2 (en) * 2002-10-25 2008-10-16 Intervet International B.V. Prolonged release pharmaceutical composition
US6911441B2 (en) 2002-12-16 2005-06-28 Akzo Nobel N.V. Prolonged release pharmaceutical composition
US7842791B2 (en) 2002-12-19 2010-11-30 Nancy Jean Britten Dispersible pharmaceutical compositions
AU2015261543C1 (en) * 2012-02-27 2022-10-13 Elanco New Zealand Controlled release compositions and their methods of use
AU2013201147A1 (en) * 2012-02-27 2013-09-12 Bayer New Zealand Limited Controlled release compositions and their methods of use

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3129224A (en) * 1962-11-23 1964-04-14 Smith Kline French Lab Antimicrobial 3-methyl-7-aminodecepha-losporanic acid derivatives
ES425601A1 (en) * 1974-04-23 1976-06-16 Lafarquim Procedure for the obtaining of insoluble or small soluble cefalexine sales. (Machine-translation by Google Translate, not legally binding)
ES469096A1 (en) * 1978-04-24 1978-11-16 Antibioticos Sa Salts of DELTA <3>-cephem compounds with low water-solubility

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8703876A1 *

Also Published As

Publication number Publication date
WO1987003876A1 (en) 1987-07-02
GB8531609D0 (en) 1986-02-05

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