WO2000061149A1

WO2000061149A1 - Long-acting antibacterial composition

Info

Publication number: WO2000061149A1
Application number: PCT/JP2000/002227
Authority: WO
Inventors: Kazuhiro Awai; Toru Yamamoto; Sean Duffy
Original assignee: Takeda Schering-Plough Animal Health K.K.
Priority date: 1999-04-07
Filing date: 2000-04-06
Publication date: 2000-10-19
Also published as: GB9907916D0; AU3671100A

Abstract

The present invention relates to a long-acting antibacterial composition which comprises 7 β-[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, a gelling agent and a carrier. The composition of the present invention exhibits therapeutic and prophylactic effects by mere single administration (intramuscular or subcutaneous injection) before or after onset of infectious diseases in livestock because 7 β-[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 is retained in high concentration in plasma for a lot of hours.

Description

DESCRIPTION

Long-Acting Antibacterial Composition

[Technical Field]

The present invention relates to an agent exhibiting long-lasting antibacterial activity in blood following intramuscular or subcutaneous administration to livestock, thus finding application in the field of veterinary medicine. [Background Art]

It has been pointed out that the therapeutic efficacy of β -lactam antibiotics is closely related to the time period during which its focal concentration remains over minimal inhibitory concentration (MIC) . Any drug that is able to maintain an effective concentration in the affected tissue for many hours not only provides for good therapeutic efficacy but allows its administration frequency and dosage to be reduced, leading to conservation of drug expenditures. For the therapy or prophylaxis of infectious diseases for livestock, intramuscular or subcutaneous injection of various β -lactam drugs has been practiced, and the usual dosing schedule is once a day for 3 days.

JP-A-334386/1992 describes a long-acting antibacterial composition comprising 7 j3-[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. There is a demand for development of an improved therapeutic drug for infectious diseases in livestock which would be effective with reduced and fewer doses . [Disclosure of Invention]

The inventors of the present invention did much research for satisfying the above demand and found that an administration of a composition comprising 7 /3-[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, a gelling agent and a carrier to livestock provides outstandingly sustained activity in blood. The present invention has been developed on the basis of the above finding.

Namely, the present invention relates to: (1) a long-acting antibacterial composition which comprises 7 j3 -[2-(2-aminothiazol-4-yl)-(Z)-2- hydroxyiminoacetamido] -3- [ ( 5-methyl-l , 3 , 4-thiadiazol-2- yl) thiomethyl] -3-cephem-4-carboxylic acid or a pharmacologically acceptable salt thereof, a gelling agent and a carrier, (2) the long-acting antibacterial composition as described in (1) above, wherein the gelling agent is an aluminum salt of a fatty acid,

(3) the long-acting antibacterial composition as described in ( 1 ) above , wherein the gelling agent is aluminum distearate,

(4) the long-acting antibacterial composition as described in (1) above, wherein the carrier is one or more components selected from the group consisting of mineral oil, vegetable oil, medium-chain fatty acid triglyceride and medium-chain fatty acid propylene glycol diester,

(5) the long-acting antibacterial composition as described in (1) above, which further comprises lecithin or a phospholipid,

(6) the long-acting antibacterial composition as described in (5) above, wherein the content of phosphatidylcholine in the lecithin or phospholipid is 20 % weight by volume or more,

(7) the long-acting antibacterial composition as described in (1) above, which comprises 2 % weight by volume to 60 % weight by volume of 7 β - [ 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 to the total composition,

(8) the long-acting antibacterial composition as described in (1) above, which comprises 0.05 % weight by volume to 5 % weight by volume of the gelling agent to the total composition,

(9) the long-acting antibacterial composition as described in (5) above, which comprises 0.05 % weight by volume to 8 % weight by volume of lecithin or phospholipid to the total composition,

(10) the long-acting antibacterial composition as described in (9) above, wherein the lecithin or phospholipid is phosphatidylcholine ,

(11) the long-acting antibacterial composition as described in (1) above, wherein at least 90% of particles of 7 β - [ 2- ( 2-aminothiazol-4-yl) - ( Z ) -2-hydroxyiminoacetamido] -3- [ ( 5-methyl-l , 3 , 4-thiadiazol-2-yl) thiomethyl] -3-cephem-4- carboxylic acid or a pharmacologically acceptable salt thereof have a diameter of 25 Mm or less, (12) a method for treatment or prevention of an infectious disease of livestock which comprises injecting effective amount of a composition which comprises 7 /3-[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, a gelling agent and a carrier to said livestock,

(13) the method as described in (12) above, wherein the dose of 7 /3 -[2-(2-aminothiazol-4-yl)-(Z)-2- hydroxyiminoacetamido] -3- [ ( 5-methyl-l , 3 , 4-thiadiazol-2- yl) thiomethyl ] -3-cephem-4-carboxylic acid or a pharmacologically acceptable salt thereof is 1 mg to 30 mg per kg bodyweight , and

(14) use of 7 β - [2-(2-aminothiazol-4-yl) -(Z)-2- hydroxyiminoacetamido] -3- [ ( 5-methyl-l , 3 , 4-thiadiazol-2- yl) thiomethyl] -3-cephem-4-carboxylic acid or a pharmacologically acceptable salt thereof for preparing the long-acting antibacterial composition as described in (1) above .

[Brief Description of the Drawing]

Fig. 1 is a diagrammatic representation of the time courses of concentration of 7 β - [2- ( 2-aminothiazol-4- yl) - (Z) -2-hydroxyiminoacetamido] -3- [ (5-methyl-l, 3,4- thiadiazol-2-yl) thiomethyl] -3-cephem-4-carboxylic acid in plasma following intramuscular injection of the composition according to Example 1 to cattle. [Best Mode for Carrying Out the Invention]

7 β -[2-(2-aminothiazol-4-yl)-(Z)-2- hydroxyiminoacetamido] -3- [ ( 5-methyl-l , 3 , 4-thiadiazol-2- yl) thiomethyl] -3-cephem-4-carboxylic acid (hereinafter sometimes referred to as "Compound (I)") which is used for a long-acting antibacterial composition 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.) and 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, and the organic acid includes but is not limited to formic acid, acetic acid. trifluoroacetic acid, oxalic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. Among these salts, the salt with a base (i.e. the salt with an inorganic base or the salt with an organic base) means the salt involving the carboxylic group of Compound (I) and 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 amino 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 method described in Example 16 of JP-A-11713/1985 , or any method analogous thereto. The long-acting antibacterial composition according to the present invention contains, in addition to Compound (I) or a pharmacologically acceptable salt thereof, a gelling agent and a carrier.

The gelling agent as mentioned above includes but is not limited to an aluminum salt of a fatty acid such as stearic acid. The gelling agent is typically aluminum monostearate, aluminum distearate or aluminum tristearate, or a mixture thereof. Especially preferred is aluminum distearate.

The carrier as 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. ) , 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. Thus, the medium-chain fatty acid triglyceride may for example be caprylic/capric 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. Thus, the propylene glycol medium-chain fatty acid diester may for example be propylene glycol dicaprylate/dicaprate. Those carriers can be used each alone or in combination of 2 or more (preferably not more than 3) species. The carrier is preferably vegetable oil such as sesame oil.

The long-acting antibacterial composition according to the present invention may further contain lecithin or a phospholipid. The lecithin includes soybean lecithin or egg lecithin.

Deoiled lecithin or lecithin fraction or deoiled lecithin fraction may be used. Preferable lecithin includes EPIKURON®

100 (soybean lecithin, deoiled), EPIKURON® 130 (soybean lecithin, deoiled), EPIKURON® 135F (soybean lecithin fraction) or EPIKURON® 145V (soybean lecithin fraction, deoiled) . The above-mentioned lecithin can be used as the mixture of two or more kinds of lecithin.

The phospholipid includes phosphatidyl choline (e.g. dilauroylphosphatidyl choline, dimyristoylphosphatidyl choline, dipalmitoylphosphatidyl choline, distearoylphosphatidyl choline, dioleoylphosphatidyl choline, etc.), phosphatidyl serine (e.g. dilauroylphosphatidyl serine, dimyristoylphosphatidyl serine, dipalmitoylphosphatidyl serine, distearoylphosphatidyl serine, dioleoylphosphatidyl serine, etc.), phosphatidyl ethanolamine (e.g. dilauroylphosphatidyl ethanolamine , dimyristoylphosphatidyl ethanolamine , dipalmitoylphosphatidyl ethanolamine , distearoylphosphatidyl ethanolamine, dioleoylphosphatidyl ethanolamine, etc.), phosphatidyl inositol (e.g. dilauroylphosphatidyl inositol, dimyristoylphosphatidyl inositol, dipalmitoylphosphatidyl inositol, distearoylphosphatidyl inositol, dioleoylphosphatidyl inositol, etc.), phosphatidic acid (e.g. dilauroylphosphatidic acid, dimyristoylphosphatidic acid. dipalmitoylphosphatidic acid, distearoylphosphatidic acid, dioleoylphosphatidic acid, etc.), or phosphatidyl glycerol (e.g. dilauroylphosphatidyl glycerol, dimyristoylphosphatidyl glycerol, dipalmitoylphosphatidyl glycerol, distearoylphosphatidyl glycerol, dioleoylphosphatidyl glycerol, etc.). The above-mentioned phospholipid can be used as the mixture of two or more kinds of phospolipid.

The content of phosphatidylcholine in such a lecithin or phospholipid may have an influence on the duration of antibacterial activity in blood. The lecithin or phospholipid, whose content of phosphatidylcholine is 20 % weight by volume or more (20-100 % weight by volume), preferably 30 % weight by volume or more (30-100 % weight by volume) , more preferably 35 % weight by volume or more (35-100 % weight by volume), may be used in the present invention.

The long-acting antibacterial composition of the present invention 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, tylosin, etc.). Moreover, the antibacterial composition may additionally contain various auxiliary ingredients such as a stabilizer, a dispersant such as trisodium citrate, an analgesic, a corticosteroid, an antioxidant, and/or a preservative .

The content of Compound ( I ) in the whole composition may be 2-60 % weight by volume and preferably 4-40 % weight by volume. The content of the gelling agent in the whole composition may be 0.05-5 % weight by volume and preferably 0.1-2 % weight by volume.

The content of carrier in the whole composition may be 35-97.95 % weight by volume and preferably 58-95.9 % weight by volume.

The content of lecithin or phospholipid in the whole composition may be 0.05-8 % weight by volume and preferably 0.1-4 % weight by volume.

Referring to the dosage form, the composition can be provided in the form of , for example, a solution, a suspension, or an emulsion. Among them, an oil-based suspension is preferred.

Such dosage forms can be manufactured by mixing Compound (I) or its pharmacologically acceptable salt with said gelling agent, carrier and optional ingredients in the per se known manner. For example, a suspension can be produced by mixing Compound (I) or its pharmacologically acceptable salt with a vehicle comprising a gelling agent, a carrier and optional ingredients. It is optional to first mix a gelling agent, a carrier and optional ingredients and then add Compound (I) or its pharmacologically acceptable salt or to mix all of the ingredients together in one operation. The lecithin or phospholipid may be added in any step in the per se known manner.

The long-acting antibacterial composition of the present invention is preferably manufactured under sterile conditions. Such an antibacterial composition can be manufactured using Compound (I) or its pharmacologically acceptable salt and a vehicle comprising a gelling agent, a carrier and optional ingredients, both preferably sterilized beforehand, by the sterile procedure. Moreover, a mixture of Compound ( I ) or its pharmacologically acceptable salt thereof, a gelling agent, a carrier and optional ingredients may be sterilized with ethylene oxide gas or by

T -ray irradiation. The inventors of the present invention have further discovered that the particle diameter of Compound ( I ) or its salt has an influence on the duration of the antibacterial activity in blood. 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 are not greater than 25 m, preferably not greater than 5 m, in diameter. This pulverization procedure may be applied to a mixture of Compound (I) or its salt, a gelling agent, a carrier and optional ingredients. The long-acting antibacterial composition of the present invention can be used as a safe drug of low toxicity. The recipient animal includes livestock such as cattle, cows, pigs, chicken, sheep and horses and companion animals such as dogs and cats. The composition is effective in prevention and treatment of infectious diseases (e.g. respiratory disease) in livestock and companion animals, particularly bovine and swine respiratory disease.

The long-acting antibacterial composition of the present invention is generally provided as aseptically filled into vials, for example glass vials, in the amount of 20-500 ml per vial. Usually, the long-acting antibacterial composition is injected intramuscularly or subcutaneously to livestock at a dose of 1 mg to 30 mg, preferably 2 mg to 20 mg, as Compound (I) or its pharmacologically acceptable salt per kg bodyweight . Generally only one administration (i.e. a single administration) provides a satisfactory therapeutic or prophylactic effect. The antibacterial composition of the present invention is administered before or after onset of the infectious diseases.

Compound (I) inclusive of its pharmacologically acceptable salt has excellent antibacterial activity against various bacteria causing bovine respiratory disease, particularly Pasteurella haemolytica and Pasteurella multocida, and various bacteria causing swine respiratory disease, particularly Actinobacillus pleuropneumoniae. The following example and test example illustrate the present invention in further detail, but it is understood that those are by no means limitative of the scope of the invention. [ Example 1 ] Compound (I) was pulverized to the extent that at least and admixed with a vehicle comprising aluminium distearate, lecithin (EPIKURON®135F)and sesame oil. The lecithin, in which the content of phosphatidylcholine was not less than 35 % weight by volume, was used. The resulting suspension was distributed in glass vials. The recipe per vial was as follows .

Compound (I) 10% w/v

Lecithin 2% w/v

Base* ad 100% volume (*Base: Aluminium distearate 0.25% w/w

Sesame oil ad 100% w/w)

The constitution per vial was as follows. Compound (I) 10% w/v

Lecithin 2% w/v Aluminium distearate 0.21% w/v

Sesame oil ad 100% volume

The effectiveness of the present invention is now explained in terms of the measured concentrations of Compound (I) in plasma following intramuscular injection of the antibacterial composition of Example 1 to cattle. [Test Example 1]

The antibacterial composition obtained in Example 1 was intramuscularly injected to cattle and the concentration of the drug in plasma was serially determined. Test animals: Four beef type cattle, at least 8 weeks of age and weighing between 200 and 400 kg were used. Treatment: The antibacterial composition obtained in Example 1 was intramuscularly injected once into the rump of each test animal at a dose of 5 mg of Compound ( I ) per kg bodyweight . Determination of concentration of Compound (I) in plasma: After injection of the composition, 10 ml of blood was serially collected from cattle for 56 hours. Plasma was collected from each blood sample and the concentration of Compound (I) in plasma was determined by high-performance liquid chromatography.

The results are presented in Fig.l. In this experiment, single administration at a dose rate of 5 mg of Compound (I) per kg body weight resulted in a maximum concentration in plasma of more than 1 \1 g/ml and, moreover, concentration over the minimal inhibitory concentration (MIC) against Pasteurella haemolytica (0.05 fi g/ml) were maintained for at least 56 hours. The results indicate that the concentration of Compound (I) in plasma is high and sustained for a long time. [Industrial Applicability] The antibacterial composition of the present invention exhibits therapeutic and prophylactic effects on mere single administration (intramuscular injection) before or after onset of infectious diseases in livestock because Compound (I) or its pharmacologically acceptable salt is retained in high concentration in plasma for a lot of hours.

Claims

1. A long-acting antibacterial composition which comprises 7 j3 -[2-(2-aminothiazol-4-yl)-(Z)-2- hydroxyiminoacetamido] -3- [ ( 5-methyl-l , 3 , 4-thiadiazol-2- yl) thiomethyl] -3-cephem-4-carboxylic acid or a pharmacologically acceptable salt thereof, a gelling agent and a carrier.

2. The long-acting antibacterial composition as claimed in claim 1 , wherein the gelling agent is an aluminum salt of a fatty acid.

3. The long-acting antibacterial composition as claimed in claim 1, wherein the gelling agent is aluminum distearate.

4. The long-acting antibacterial composition as claimed in claim 1, wherein the carrier is one or more components selected from the group consisting of mineral oil, vegetable oil, medium-chain fatty acid triglyceride and medium-chain fatty acid propylene glycol diester.

5. The long-acting antibacterial composition as claimed in claim 1, which further comprises lecithin or a phospholipid.

6. The long-acting antibacterial composition as claimed in claim 5 , wherein the content of phosphatidylcholine in the lecithin or phospholipid is 20 % weight by volume or more.

7. The long-acting antibacterial composition as claimed in claim 1, which comprises 2 % weight by volume to 60 % weight by volume of 7 β - [2- (2-aminothiazol-4-yl) - ( Z) -2- hydroxyiminoacetamido] -3- [ (5-methyl-l , 3 , 4-thiadiazol-2- yl) thiomethyl] -3-cephem-4-carboxylic acid or a pharmacologically acceptable salt thereof to the total composition.

8. The long-acting antibacterial composition as claimed in claim 1, which comprises 0.05 % weight by volume to 5 % weight by volume of the gelling agent to the total composition.

9. The long-acting antibacterial composition as claimed in claim 5, which comprises 0.05 % weight by volume to 8 % weight by volume of lecithin or phospholipid to the total composition.

10. The long-acting antibacterial composition as claimed in claim 9 , wherein the lecithin or phospholipid is phosphatidylcholine .

11. The long-acting antibacterial composition as claimed in claim 1, wherein at least 90% of particles of 7 j3-[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 have a diameter of 25 m or less.

12. A method for treatment or prevention of an infectious disease of livestock which comprises injecting effective amount of a composition which comprises 7 β-[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, a gelling agent and a carrier to said livestock.

13. The method as claimed in claim 12, wherein the dose of

7 β -[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 is 1 mg to 30 mg per kg bodyweight . hydroxyiminoacetamido] -3- [ (5-methyl-l, 3, 4-thiadiazol-2- yl) thiomethyl] -3-cephem-4-carboxylic acid or a pharmacologically acceptable salt thereof for preparing the long-acting antibacterial composition as claimed in claim 1.