WO1999062521A1 - Composition renfermant un acide carboxylique 7 beta-[2-(2- aminothiazol- 4-yl)-(z)-2- hydroxyiminoacetamido] -3-[(5-methyl- 1, 3, 4-thiadiazol- 2-yl)thiomethyl] - 3- cephem-4- pour traiter la mammite chez le betail - Google Patents

Composition renfermant un acide carboxylique 7 beta-[2-(2- aminothiazol- 4-yl)-(z)-2- hydroxyiminoacetamido] -3-[(5-methyl- 1, 3, 4-thiadiazol- 2-yl)thiomethyl] - 3- cephem-4- pour traiter la mammite chez le betail Download PDF

Info

Publication number
WO1999062521A1
WO1999062521A1 PCT/JP1999/002877 JP9902877W WO9962521A1 WO 1999062521 A1 WO1999062521 A1 WO 1999062521A1 JP 9902877 W JP9902877 W JP 9902877W WO 9962521 A1 WO9962521 A1 WO 9962521A1
Authority
WO
WIPO (PCT)
Prior art keywords
therapeutic
aminothiazol
thiomethyl
thiadiazol
methyl
Prior art date
Application number
PCT/JP1999/002877
Other languages
English (en)
Inventor
Yukishige Sassa
Toru Yamamoto
Sean Duffy
Original Assignee
Takeda Chemical Industries, Ltd.
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 Takeda Chemical Industries, Ltd. filed Critical Takeda Chemical Industries, Ltd.
Priority to AU39574/99A priority Critical patent/AU3957499A/en
Publication of WO1999062521A1 publication Critical patent/WO1999062521A1/fr

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

Definitions

  • the present invention relates to an agent adapted to provide long-lasting antibacterial activity in milk following administration into the udder of livestock, thus finding application in the field of veterinary medicine.
  • JP-A-334386/1992 describes a long-acting antibacterial composition comprising 7j3-[2-(2- aminothiazol-4-yl) - ( Z) -2-hydroxyiminoacetamido] -3- [ (5- methyl-1,3,4-thiadiazol-2-yl)thiomethyl] -3-cephem-4- carboxylic acid or a pharmacologically acceptable salt thereof .
  • the present invention relates to: (1) a therapeutic or prophylactic agent for mastitis in livestock which comprises 7 - [2-(2-aminothiazol-4-yl)- (Z)-2-hydroxyiminoa ⁇ etamido] -3- [ (5-methyl-1,3,4- thiadiazol-2-yl)thiomethyl] -3- ⁇ ephem-4-carboxylic acid or a pharmacologically acceptable salt thereof, (2) the therapeutic or prophylactic agent as described in (1) above, wherein at least 90% of particles of 7 ⁇ - [ 2- (2-aminothiazol-4-yl) - (Z) -2-hydroxyimlnoacetamido] -3- [ (5-methyl-l,3,4-thiadiazol-2-yl)thiomethyl] -3-cephem-4- oarboxylic acid or a pharmacologically acceptable salt thereof have a diameter of 50 m or less,
  • the carrier is one or more components selected from the group consisting of mineral oil, vegetable oil, soft white paraffin, hydrogenated vegetable oil, medium-chain fatty acid triglyceride and medium-chain fatty acid propylene glyool diester,
  • the therapeutic or prophylactic agent as described in (1) above which comprises 0.05 weight % to 50 weight % of
  • the therapeutic or prophylactic agent as described in (1) above which is a single administration type
  • (8) a method for treatment or prevention of mastitis of a livestock which comprises infusing effective amount of 7 ⁇ - [2- (2-aminothiazol-4-yl) - (Z) -2-hydroxyiminoacetamido] - 3- [ ( 5-methyl-1 ,3,4-thiadiazol-2-yl)thiomethyl] -3-cephem- 4- ⁇ arboxyli ⁇ acid or a pharmacologically acceptable salt thereof into the udder of livestock, and
  • Fig. 1 is a diagrammatic representation of the time courses of concentration of Compound (I) in milk following infusion of the compositions according to Examples into the udders of cows.
  • Fig. 2 is a diagrammatic representation of the therapeutic efficacy of the composition of the present invention in bovine mastitis as compared with the reference drug. The evaluation is based on the number of bacteria in milk.
  • Mastitis is an inflammatory disease of the mammary tissues which arises from growth of invading bacteria in the udder and causes troubles such as deterioration of the quality of milk.
  • Compound (I) which is used for a therapeutic or prophylactic agent of mastitis of the present invention is represented by the formula:
  • the pharmacologically acceptable salt of Compound (I) includes the salts with inorganic bases, salts with organic bases , salts with inorganic acids and salts with organic acids .
  • the inorganic base forming such a salt includes alkali metals (e.g. sodium, potassium, etc.), alkaline earth metals (e.g. calcium, magnesium, etc.) and the organic base includes but is not limited to trimethylamine, triethylamine, pyridine, picoline, N,N' -dibenzylethylenediamine, ethanolamine, diethanolamine, trishydroxymethylaminomethane, and dicyclohexylamine.
  • the inorganic acid includes but is not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid
  • the organic acid includes but is not limited to formic acid, acetic acid, trifluoroa ⁇ eti ⁇ acid, oxalic acid, tartari ⁇ acid, fumaric acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.
  • the salt with a base i.e. the salt with an inorganic base or the salt with an organic base
  • the salt with an acid i.e.
  • the salt with an inorganic acid or the salt with an organic acid means the salt involving the amlno group of Compound (I). Particularly preferred is the salt with an alkali metal such as sodium.
  • Compound (I) or a pharmacologically acceptable salt thereof can be produced typically by the process described in Example 16 of JP-A-11713/1985, or any process analogous thereto .
  • the antimastitis composition viz. medicinal composition for treatment or prevention of mastitis.
  • the antimastitis composition may contain, in addition to Compound (I) or a pharmacologically acceptable salt thereof, one or more (preferably one to three) other active ingredients (e.g. antimicrobial agents such as benzylpenicillin, erythromy ⁇ in, lin ⁇ omy ⁇ in, etc.).
  • active ingredients e.g. antimicrobial agents such as benzylpenicillin, erythromy ⁇ in, lin ⁇ omy ⁇ in, etc.
  • the antimastitis composition according to the invention may contain a carrier which is acceptable for animal use.
  • the carrier mentioned above includes but is not limited to mineral oil (e.g. liquid paraffin), vegetable oil (e.g. peanut oil, sesame oil, cottonseed oil, soybean oil, olive oil, etc.), soft white paraffin, hydrogenated vegetable oil(e.g. hydrogenated castor oil), medium-chain fatty acid triglyceride, and medium-chain fatty acid propylene glycol diester.
  • the medium-chain fatty acid constituting said medium-chain fatty acid triglyceride may be any of straight-chain fatty acids containing 4-14 carbon atoms.
  • the medium-chain fatty acid triglyceride may for example be capryli ⁇ / ⁇ apri ⁇ triglyceride.
  • the medium-chain fatty acid constituting said propylene glycol medium-chain fatty acid diester includes straight-chain fatty acids containing 4-14 carbon atoms.
  • the propylene glycol medium-chain fatty acid diester may for example be propylene glycol dicaprylate/dicaprate.
  • a typical combination may consist of soft white paraffin and liquid paraffin (1 part by weight: 10 parts by weight - 10 parts by weight : 1 part by weight) or hydrogenated castor oil and peanut oil (1 part by weight: 100 parts by weight - 100 parts by weight : 1 part by weight) .
  • the content of Compound (I) or its pharmacologically acceptable salt in the whole composition may be 0.05-50 weight % and preferably 0.1-20 weight %.
  • the content of the carrier based on the whole composition may be 50-99.95 weight % and preferably 80-99.9 weight %.
  • the antimastitis composition of the present invention may additionally contain various auxiliary ingredients such as a stabilizer, adispersant, an analgesic, a corti ⁇ osteroid, and/or an antioxidant.
  • auxiliary ingredients such as a stabilizer, adispersant, an analgesic, a corti ⁇ osteroid, and/or an antioxidant.
  • the composition can be provided in the form of, for example, a solution, a suspension, an emulsion, or an ointment.
  • an oil-based suspension, an emulsion, or an ointment is preferred.
  • Such dosage forms can be manufactured by mixing Compound (I) or its pharmacologically acceptable salt with said carrier and optional ingredients in the per se known manner.
  • a suspension can be produced by mixing Compound (I) or its pharmacologically acceptable salt with a suspending medium carrier.
  • the antimastitis composition of the present invention is preferably manufactured under sterile conditions.
  • Such an antimastitis composition can be manufactured using Compound (I) or its pharmacologically acceptable salt and a carrier, both preferably sterilized beforehand, by the sterile procedure.
  • a mixture of Compound (I) or a pharmacologically acceptable salt thereof and a carrier may be sterilized with ethylene oxide gas or by 7 -ray irradiation.
  • Compound (I) or its salt has a marked influence on the diffusability of the particles in milk. Therefore, Compound (I) or its salt is micronized or pulverized by means of, for example, a hammer mill, jet mill, or colloid mill to the extent that at least 90% of the particles will be not greater than 50 fl m, preferably not greater than 15 p. m, in diameter. This pulverization procedure may be applied to a mixture of Compound (I) or its salt and a carrier.
  • the antimastitis composition of the present invention can be used as a safe drug of low toxicity.
  • the recipient animal includes but is not limited to cows, sows, ewes, she-goats, and mares. Particularly, the composition is effective in prevention and treatment of bovine mastitis (in cows) .
  • the antimastitis composition of the present invention is generally provided as aseptically filled into unit-dose containers, for example syringes, in the amount of 1-20 g, preferably 2-10 g, per container.
  • the unit dose may be 10-500 mg, preferably 50-200 mg, as Compound (I) or a pharmacologically acceptable salt thereof.
  • one container equivalent per udder i.e. 10-500 mg of Compound (I) or its pharmacologically acceptable salt per udder, is infused (or injected) into the udder of the livestock to be treated.
  • the infusion frequency and administration period may be once dally for 1-7 days but generally only one administration (i.e. a single administration) provides a satisfactory therapeutic or prophylactic effect.
  • the antimastitis composition of the present invention is preferably administered during the lactation period, whether before or after onset of mastitis, but can be administered during the dry (non-lactating) period.
  • Compound (I) inclusive of its pharmacologically acceptable salt has excellent antibacterial activity against various bacteria causing bovine mastitis, particularly Staphylooo ⁇ cus aureus. streptococci, Corynebacterium spp., Escherichia ⁇ oli, and Krebsiella spp. [Examples]
  • Compound (I) was pulverized to the extent that at least 90% of the particles were not greater than 15
  • a carrier comprising soft white paraffin and liquid paraffin.
  • the resulting suspension was distributed into syringes, 3 g per syringe.
  • the recipe per syringe was as follows .
  • Compound (I) was pulverized to the extent that at least 90% of the particles were not greater than 15 p, m in diameter and admixed with a carrier comprising hydrogenated castor oil and peanut oil.
  • the resulting suspension was distributed into syringes, 3 g per syringe.
  • the recipe per syringe was as follows.
  • the antimastitis compositions obtained in Examples 1 and 2 were respectively infused into the udders of cows and the concentration of the drug in milk was serially determined.
  • Test animals Eight lactating Friesian dairy cows (3-11 years old, body weights 500-650 kg) were used.
  • the antimastitis compositions obtained in Examples 1 and 2 were respectively infused once into the udders of 4 test cows, one syringe equivalent per quarter.
  • Determination of concentration of Compound (I) in milk After infusion of each composition, 20 ml of milk was serially collected and the concentration of compound (I) in each milk sample was determined by high-performance liquid chromatography.
  • Test animals Eight lactatlng Friesian dairy cows (3-12 years old, body weights 500-700 kg) were used. Treatment: The each quarter of the udder of test cows were randomly assigned to the following treatments, respectively.
  • Treatment A A composition containing 100 mg of Compound (I) as obtained in Example 1 was infused once.
  • Treatment B A commercial composition containing 450 mg of cefazolin (oily suspension) was infused once.
  • Treatment C A commercial composition containing 150 mg of cefazolin (oily suspension) was infused once daily for 3 days .
  • Treatment D Drug-free control
  • Inoculation with infective bacteria and administration of drugs A wild strain of Staphyloco ⁇ cus aureus was cultured in broth at 30-35 * C for 16 hours and the culture was diluted with saline to a density of about 100 CFU (colony forming units)/0.2 ml. The diluted bacterial suspension was used to inoculate all quarters of the udders of test cows. 0.2 ml per quarter. In 5 cows, definite symptoms were observed after 48 hours and therefore the respective treatments were carried out at this point of time. In the remaining 3 animals, no definite symptoms were found at that time. Therefore, a booster inoculum, 0.5 ml per quarter, was given and the respective treatments were carried out at points of time when definite symptoms were noted.
  • CFU colony forming units
  • the antimastitis composition of the present invention is capable of producing outstanding therapeutic and prophylactic effects on mere single administration (infusion into the milk cistern) before or after onset of mastitis in animals because Compound (I) or its pharmacologically acceptable salt is retained in high concentration in the milk for many hours .

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (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

La présente invention concerne un agent permettant de prévenir ou de traiter la mammite chez le bétail, cet agent renfermant un acide carboxylique 7 β-[2-(2-aminothiazol-4-yl)-(Z)-2-hydroxyiminoacétamido]-3-[(5-méthyl-1,3,4-thiadiazol-2-yl)thiométhyl]-3-cephem-4, ou un sel pharmaceutiquement acceptable de celui-ci. L'agent de la présente invention est capable de produire d'excellents effets thérapeutiques et prophylactiques par une simple administration (infusion dans la citerne), avant ou après que la mammite se soit déclarée chez le bétail, l'acide carboxylique 7 β-[2-(2-aminothiazol-4-yl)-(Z)-2-hydroxyiminoacétamido]-3-[(5-méthyl-1,3,4-thiadiazol-2-yl)thiométhyl]-3-cephem-4, ou le sel pharmaceutiquement acceptable de celui-ci, restant présent à une teneur élevée dans le lait pendant de nombreuses heures.
PCT/JP1999/002877 1998-06-01 1999-05-31 Composition renfermant un acide carboxylique 7 beta-[2-(2- aminothiazol- 4-yl)-(z)-2- hydroxyiminoacetamido] -3-[(5-methyl- 1, 3, 4-thiadiazol- 2-yl)thiomethyl] - 3- cephem-4- pour traiter la mammite chez le betail WO1999062521A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU39574/99A AU3957499A (en) 1998-06-01 1999-05-31 Composition comprising 7beta-[2-(2- aminothiazol- 4-yl)-(z)-2- hydroxyiminoacetamido] -3-[(5-methyl- 1, 3, 4-thiadiazol- 2-yl)thiomethyl] -3- cephem-4- carboxilic acid for treating mastitis for livestock

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9811687.4A GB9811687D0 (en) 1998-06-01 1998-06-01 Therapeutic or prophylatic agent of mastitis for livestock
GB9811687.4 1998-06-01

Publications (1)

Publication Number Publication Date
WO1999062521A1 true WO1999062521A1 (fr) 1999-12-09

Family

ID=10832981

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1999/002877 WO1999062521A1 (fr) 1998-06-01 1999-05-31 Composition renfermant un acide carboxylique 7 beta-[2-(2- aminothiazol- 4-yl)-(z)-2- hydroxyiminoacetamido] -3-[(5-methyl- 1, 3, 4-thiadiazol- 2-yl)thiomethyl] - 3- cephem-4- pour traiter la mammite chez le betail

Country Status (3)

Country Link
AU (1) AU3957499A (fr)
GB (1) GB9811687D0 (fr)
WO (1) WO1999062521A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000061149A1 (fr) * 1999-04-07 2000-10-19 Takeda Schering-Plough Animal Health K.K. Composition antibacterienne a action prolongee

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH04334386A (ja) * 1991-05-08 1992-11-20 Takeda Chem Ind Ltd 持続性抗菌剤

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH04334386A (ja) * 1991-05-08 1992-11-20 Takeda Chem Ind Ltd 持続性抗菌剤

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
D.H. KLAUBERT: "New cephalosporins in development pipelines", EXPERT OPINON ON INVESTIGATIONAL DRUGS, vol. 3, no. 2, 1994, pages 133 - 144, XP002116215 *
DATABASE WPI Section Ch Week 9301, Derwent World Patents Index; Class B02, AN 93-005535, XP002116217 *
Y. INAMOTO: "Studies on beta-lactam antibiotics. XIX. Structure-activity relationships of cephalosporins having a thiadiazolylthiomethyl group at the C-3 side chain.", J. ANTIBIOT., vol. 44, no. 5, 1991, pages 507 - 516, XP002116216 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000061149A1 (fr) * 1999-04-07 2000-10-19 Takeda Schering-Plough Animal Health K.K. Composition antibacterienne a action prolongee

Also Published As

Publication number Publication date
AU3957499A (en) 1999-12-20
GB9811687D0 (en) 1998-07-29

Similar Documents

Publication Publication Date Title
JP6779619B2 (ja) 乳房炎をはじめとする微生物感染を処置する方法
JPH09509677A (ja) 茶エキスまたはその活性フラクションおよびβ−ラクタム抗生物質を含む抗菌剤
JP2006510607A (ja) 持続放出性医薬組成物
WO2021006317A1 (fr) Nouvel agent thérapeutique contre une maladie causée par prototheca
JPS61286382A (ja) 雌の哺乳動物における子宮内膜炎の治療用組成物
Crispie et al. The lantibiotic lacticin 3147 produced in a milk-based medium improves the efficacy of a bismuth-based teat seal in cattle deliberately infected with Staphylococcus aureus
WO1999062521A1 (fr) Composition renfermant un acide carboxylique 7 beta-[2-(2- aminothiazol- 4-yl)-(z)-2- hydroxyiminoacetamido] -3-[(5-methyl- 1, 3, 4-thiadiazol- 2-yl)thiomethyl] - 3- cephem-4- pour traiter la mammite chez le betail
US5120711A (en) Synergistically active veterinary compositions and process for preparing same
EP1945223B1 (fr) Compositions de cefquinome et procédés d'utilisation de celles-ci
KR102203849B1 (ko) 동물용 복합 항생제 조성물
EP0548558A2 (fr) Compositions contenant des tensioactifs comme agents de potentialisation pour le traitement des maladies chez les mammifères
US4610993A (en) Use of selected pyridine-N-oxide disulfide compounds to treat or prevent bovine mastitis
RU2762088C1 (ru) Способ лечения мастита у коров
AU2018222615B2 (en) Combinations of lysobactin and aminoglycosides against diseases caused by Gram-positive and Gram-negative bacteria in non-human animals
WO2000061149A1 (fr) Composition antibacterienne a action prolongee
JP2001511451A (ja) 家畜乳房炎の治療のためのリファマイシン誘導体の使用
RU2741764C2 (ru) Лизобактин для применения для лечения коровьего мастита
KR20240060261A (ko) Prrs 기저질환이 있는 자돈의 연쇄상구균의 치료를 위한 효과적인 천연항생제의 발굴과 적용
JP2019522052A (ja) 抗細菌組成物
Pyörälä et al. Efficacy of enrofloxacin in the treatment of bovine clinical mastitis
IE930944A1 (en) Veterinary compositions for the treatment of mastitis
HU204698B (en) Process for producing pharmaceutical composition suitable for treating mammitis and other staphylococcus infection

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AL AM AU AZ BA BB BG BR BY CA CN CU CZ EE GD GE HR HU ID IL IN IS JP KG KR KZ LC LK LR LT LV MD MG MK MN MX NO NZ PL RO RU SG SI SK SL TJ TM TR TT UA US UZ VN YU ZA

AL Designated countries for regional patents

Kind code of ref document: A1

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

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
122 Ep: pct application non-entry in european phase