KR101458611B1 - Composition of the combined antibiotics for veterinary applications - Google Patents

Abstract

The present invention relates to a complex antibiotic composition for animals containing florfenicol, tylosine and dexamethasone as main components, which comprises florfenicol, tylosin or a veterinarily acceptable salt thereof , Dexamethasone or a veterinarily acceptable salt thereof, and an excipient include glycerol foams, butylhydroxytoluene, butylhydroxyanisole and 1-methylpyrrolidone.
The present invention relates to a composition which contains a high concentration of flouropenicol, has a low viscosity, an excellent scanning ability and is excellent in stability of the entire composition, and can be injected without recrystallization of an active ingredient.

Description

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The present invention relates to a complex antibiotic composition for animals, and more particularly, to a composition containing a high concentration of florfenicol, a low viscosity, a high sphericity Which is excellent in stability of the whole composition and can be injected without recrystallization of the active ingredient.

Florfenicol is a substance with D- (threo) -1-p-methylsulfonylphenyl-2-dichloroacetamide-3-fluoro-1-propanol structure, It is an antibacterial agent and is known to be useful for veterinary purposes. Fluorupenicol has low solubility in water and is difficult to prepare as a injectable composition and has low solubility among many pharmaceutically acceptable organic solvents such as 1,2-propanediol, glycerin, benzyl alcohol and the like.

When treating large animals such as cows, pigs and the like, it is sometimes preferable to administer a composition containing a high concentration of florfenicol.

In this case, the composition of the conventional patent No. 104340 (Application No. 93-700553, Publication No. 96-5705) comprises 10 to 50% by weight of florphenicol, 10 to 65% by weight of pyrrolidone, 10 to 65% by weight of ethanol or propylene glycol (Centipoise) consisting of 5 to 15% by weight of polyethylene glycol (PEG) and 5 to 40% by weight of polyethylene glycol (PEG) is known, but the viscosity was so high that it was difficult for the user to inject into large numbers of animals on farms. In addition, Chinese patent No. 1582909 A (published on February 23, 2005) discloses a combination of florfenicol: tyrosine at a weight ratio of 1: 1.5 to 1: 6, Korean Patent No. 0756164 (published on September 5, 2007) discloses a composition comprising dexamethasone in water in a combination of florfenicol: tyrosine in a weight ratio of 2: 1, In domestic patent No. 0748252 (published on Aug. 10, 2007), 15 to 30% by weight of florpenicol, 2 to 8% by weight of tyrosine and 0.01 to 0.5% by weight of dexamethasone are mixed with 30 to 70% by weight of dimethylsulfoxide, To 20% by weight of water and 5 to 10% by weight of water are known, It is preferable that the injection is usually 20 cp (centipoise) or less, and more preferably 10 cp (centipoise). In addition, there is known a composition containing an emulsion type florfenicol containing a hydrophilic solvent, an oil and a surfactant, but it has a disadvantage in that stability is deteriorated when stored for a long period of time. Particularly in the case of a composition containing a high concentration of florfenicol, It is necessary to improve stability of the preparation such as precipitation due to lowering of solubility. Tylosine is a macrolide antibiotic and is known to be effective against several bacteria including streptococcus bacteria and bacteria of Staphylococcus aureus. To treat or prevent various diseases of various animals such as swine flu, dog colitis, etc. Has been used. These tiles have a drawback that the storage stability is poor due to the low water content of the tiles during the storage of the new injections by the tiles, while the gins are easy to prepare with the injection solutions because of the high water solubility. One of the main components of the present invention, dexamethasone, is also widely known as a drug having antiinflammatory, analgesic and antiallergic action.

The present invention relates to a combination antibiotic for animals comprising a high concentration of florfenicol, tylosin or a veterinarily acceptable salt thereof, dexamethasone or a veterinarily acceptable salt thereof, to an animal antibiotic for glycerol, butylhydroxytoluene, butylhydroxyanisole , 1-methylpyrrolidone, etc., it was possible to obtain excellent injections having high stability and high stability of florpenicol, tylosin and dexamethasone with low viscosity and excellent scanning ability.

Accordingly, it is an object of the present invention to provide a composite antibiotic composition for animals which has a low viscosity of less than 10 centipoise (cp), excellent scanning ability, excellent storage stability, and no crystallization of active ingredient.

The present invention relates to a pharmaceutical composition comprising 10 to 40% by weight of florfenicol, 2 to 10% by weight of tylosin or veterinarily acceptable salt thereof, 0.01 to 0.5% by weight of dexamethasone or veterinarily acceptable salt thereof, 20 to 40% 0.01 to 0.1% by weight of butylhydroxytoluene, 0.1 to 2% by weight of butylhydroxyanisole and 40 to 70% by weight of 1-methylpyrrolidone.

Particularly, a preferred composition is a composition comprising 200 mg / ml of flouropenicol, 58.9 mg / ml of tylosin tartaric acid, 0.5 mg / ml of dexamethasone acetate, 200 to 400 mg / ml of glycerol, 0.2 mg / ml of butylhydroxytoluene, Roxanisole 5-10 mg / ml and 1-methylpyrrolidone 400-700 mg / ml.

The present invention also relates to a method for producing a polyurethane foam, which comprises mixing 20 to 40% by weight of glycerol foam and 40 to 70% by weight of 1-methylpyrrolidone, adding 10 to 40% 2 to 10% by weight of a pharmaceutically acceptable salt, 0.01 to 0.5% by weight of dexamethasone or a veterinarily acceptable salt thereof, 0.01 to 0.1% by weight of butylhydroxytoluene and 0.1 to 2% by weight of butylhydroxyanisole are dissolved And a method for producing the obtained complex antibiotic composition for animals.

Particularly, a preferable composition is prepared by mixing 200-400 mg / ml of glycerol foam and 400-700 mg / ml of 1-methylpyrrolidone, adding 200 mg / ml of florpenicol to dissolve the tiles, And then adding and dissolving 58.9 mg / ml of rosin tartaric acid, 0.5 mg / ml of dexamethasone acetate, 0.2 mg / ml of butylhydroxytoluene and 5 to 10 mg / ml of butylhydroxyanisole.

More preferably, the present invention provides a injectable composition characterized in that the composition has a viscosity of 1 to 10 cP (centipoise).

It is an object of the present invention to provide a composite antibiotic composition for animals having excellent scanning ability and storage stability.

The injectable composition of the present invention preferably contains 10 to 40% by weight, based on the total weight of flourpenicol, one of the active ingredients. When the amount is less than 10% by weight, there is a problem in that the injection is too large in order to obtain a sufficient effect when injected into a target animal, and when it exceeds 40% by weight, it is difficult to prepare an excellent injecting agent such as recrystallization. It is preferable that the injectable composition of the present invention contains 2 to 10% by weight, based on the weight of the composition, of ginsenoside or a veterinarily acceptable salt thereof, which is one of the active ingredients. The ginseng or the veterinarily acceptable salt thereof as a tile is highly hydrophilic and is liable to dissolve in water, while the florphenicol is hydrophilic and hardly soluble in the dissolution of water, alcohol and the like. Therefore, when the content is out of the above range, the content of other components increases or decreases, making it difficult to produce injections in which both flouropenicol and tile are dissolved, and the viscosity may increase.

The injectable composition of the present invention may further comprise an anti-inflammatory agent dexamethasone or a veterinarily acceptable salt thereof, preferably 0.01 to 0.5% by weight, based on the total weight, of dexamethasone or a veterinarily acceptable salt thereof .

The term " veterinarily acceptable salt " referred to in the present invention includes, but is not limited to, acetate salts, benzenesulfonate salts, benzoate salts, bicarbonate salts, bitartrate salts, camsylate salts, carbonate salts, chloride salts, But are not limited to, iodide, citrate, dihydrochloride, edetate, eddylate, esrate, esylate, fumarate, glucosate, gluconate, glutamate, Salts of maleates, maleate salts, mandelate salts, mesylate salts, methylsulfate salts, nitrate salts, phosphate / diphosphate salts, salicylate salts, stearate salts, succinate salts, Salts, and the like. However, the veterinarily acceptable salts within the scope of not impairing the object of the present invention include May be used.

In the present invention, 20 to 40% by weight of glycerol foam, 40 to 70% by weight of 1-methylpyrrolidone, or a mixture thereof is used as the main flouropenic solvent. When 20 wt% or less of glycerol foam is used, the browning of the injection solution occurs. When the glycerol foam is used in an amount of 40 wt% or more, the viscosity is increased and the use of the injection solution is inconvenient. In the case of 1-methylpyrrolidone, viscosity is increased when it is used in an amount of 40% by weight or less, and it is not preferable in view of browning of an injection solution and stability of a preparation when it is used in an amount of 70% by weight or more.

Glycerol formal and 1-methyl-2-pyrollidone have low viscosity compared to solvents such as propylene glycol and polyethylene glycol which have been used mainly to dissolve florfenicol, Fluprenicol, tylosin, and flurofenicol are highly stable and excellent injections with high flourfenicol solubility can be made.

As an antioxidant mentioned in the present invention, excellent injections can be obtained when 0.01 to 0.1% by weight of butylhydroxytoluene and 0.1 to 2% by weight of butylhydroxyanisole are administered.

As described above, the present invention provides a polyvinyl alcohol having a low viscosity of 1 to 10 cP (centipoise) using glycerol foam, 1-methylpyrrolidone, butylhydroxytoluene and butylhydroxyanisole, There is a feature that it is possible to provide an excellent antibiotic pharmaceutical composition for animals containing florfenicol, tylosin and dexamethasone excellent in stability of the composition and capable of injecting without recrystallization of the active ingredient.

Fig. 1 is a table of results obtained by extrapolating the content of the composition of Example 3 for 6 months (Fig. 1A: florphenicol, Fig. 1B: tylosin, Fig. 1C: dexamethasone acetate)
FIG. 2 is an enlarged photograph of the flouropenicol raw material (FIG. 2A) and the composition of Example 3 (FIG. 2B).

Example  Manufacture of 1 to 6 and Comparative Example  1-5

Compositions for injection were prepared in the compositions shown in Table 1-2 below. Specifically, glycerol foam and 1-methylpyrrolidone were mixed in a beaker, and then flouropenicol was added to completely dissolve the mixture. Add tartaric acid, dexamethasone acetate, butylhydroxytoluene, and butylhydroxyanisole as tiles in this order to complete dissolution. The mixture was filtered with 1-methylpyrrolidone and pre-sterilized sterile filter paper to obtain a composition of Example.

In the case of the comparative example, the main solvent is added to the beaker, and florpenicol, terephthalic acid, and dexamethasone acetate are added and completely dissolved. And the mixture was filtered with a sterile filter paper previously sterilized to obtain a comparative composition.

Ingredients (unit mg / ml) Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Florphenicol 200 200 200 200 200 200 New tartaric acid as a tile 58.9 58.9 58.9 58.9 58.9 58.9 Dexamethasone acetate 0.5 0.5 0.5 0.5 0.5 0.5 Glycerol foam 200 250 300 350 375 400 Butylhydroxytoluene 0.2 0.2 0.2 0.2 0.2 0.2 Butylhydroxyanisole 5 10 5 10 5 10 1-Methylpyrrolidone 700 570 520 470 445 400

Ingredients (unit mg / ml) Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Florphenicol 200 200 200 200 200 New tartaric acid as a tile 58.9 58.9 58.9 58.9 58.9 Dexamethasone acetate 0.5 0.5 0.5 0.5 0.5 Dimethylsulfoxide 330 330 270 240 700 Transcuttle - 530 560 590 - Polyethylene glycol 200 - - - - 110 Polyethylene glycol 400 530 - - - -

Experimental Example 1: Measurement of Viscosity

The viscosity was measured by using a capillary viscometer (Canon fence type) to compare the fall time with the standard. The results are shown in Table 3 below.

Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Comparative Example 1 Comparative Example 2 Viscosity 6.5 cP 6.8 cP 7.0 cP 7.6 cP 7.9 cP 8.1 cP 18.2 cP 17.6 cP

As shown in Table 3, the present invention can provide a composition for injection which has lower viscosity than the composition of the Comparative Example.

Experimental Example 2: Measurement of scanning ability

0.5 ml of the composition of the above Examples and Comparative Examples was taken and filled in a polypropylene syringe having a diameter of 23 mm with a needle of 18 gauge and 4 cm length and prepared as a syringe sample. The scanning ability of each sample was measured at room temperature using a modeling instrument (Model-215EC) and a digital push pull gage (Model-Rx series) manufactured by AIKOH ENGINEER, and the results are shown in Table 4 below.

Example Feeding capacity (kgf) Example Feeding capacity (kgf) Comparative Example Feeding capacity (kgf) Comparative Example Feeding capacity (kgf) One 1.2 5 1.7 One 9.6 5 6.5 2 1.3 6 1.9 2 8.0 3 1.5 3 8.3 4 1.6 4 8.7

As shown in Table 4, it was confirmed that the composition of the present invention was excellent in the scanning ability as compared with the composition of the comparative example. As a result, it is not stiff at the time of injection of the composition, so that it can be smoothly injected, and the effort of the injector can be alleviated when injecting into a large number of animals.

Experimental Example 3: Evaluation of stability of injectable composition

In order to confirm the stability of the prepared composition according to storage, the composition for injection prepared in Comparative Examples and Examples was stored for 6 months at a temperature of 40 ± 2 ° C. and a relative humidity of 75 ± 5% , Tylosin and dexamethasone content were determined by high performance liquid chromatography (HPLC). The HPLC was performed on a Waters 510 series HPLC system (Waters), column: Cosmosil 5C18-AR-II (4.6 x 150 mm), 5 쨉 m (Nacalai Tesque), mobile phase: Florfenicol (Acetonitrile: Water: : 3), Tylosine (0.85 m / l sodium perchlorate: Acetonitrile = 600: 400 adjusted to pH 2.5 with dilute hydrochloric acid), Dexamethasone acetate (Methanol: 0.05 M Phosphate Buffer = 52: 48), Wavelength: Florfenicol (224 nm) Tylosine (280 nm), Dexamethasone acetate (254 nm), flow rate: 1.0 ml / min, and injection volume: 20 ㎕ were measured. The changes in florfenicol, tylosin and dexamethasone acetate contents 6.

As shown in Tables 5 and 6, it was confirmed that the present invention can stably exist without decreasing the content during storage at accelerated 6 months compared with the comparative composition.

FIG. 1 is a table showing the results of measurement of the product of Example 3 according to the statistical analysis method (extrapolation method) of the stability test guidelines such as veterinary drugs.

Experimental Example 4: Properties of the injectable composition (precipitation-visual observation, microscopic observation)

The composition of the above-prepared example was placed in a 10 ml vial and stored at room temperature for 6 months. Observation of the precipitation (visual observation, microscopic observation) and the like were shown in Table 7.

Storage period
(Room temperature) Example 1
(Precipitation) Example 2
(Precipitation) Example 3
(Precipitation) Example 4
(Precipitation) Example 5
(Precipitation) Example 6
(Precipitation) Early Visual observation Light yellow liquid Visual observation Light yellow liquid Visual observation Light yellow liquid Visual observation Light yellow liquid Visual observation Light yellow liquid Visual observation Light yellow liquid Microscopic observation No sediment Microscopic observation No sediment Microscopic observation No sediment Microscopic observation No sediment Microscopic observation No sediment Microscopic observation No sediment 3 months Visual observation Light yellow liquid Visual observation Light yellow liquid Visual observation Light yellow liquid Visual observation Light yellow liquid Visual observation Light yellow liquid Visual observation Light yellow liquid Microscopic observation No sediment Microscopic observation No sediment Microscopic observation No sediment Microscopic observation No sediment Microscopic observation No sediment Microscopic observation No sediment 6 months Visual observation Light yellow liquid Visual observation Light yellow liquid Visual observation Light yellow liquid Visual observation Light yellow liquid Visual observation Light yellow liquid Visual observation Light yellow liquid Microscopic observation No sediment Microscopic observation No sediment Microscopic observation No sediment Microscopic observation No sediment Microscopic observation No sediment Microscopic observation No sediment

As shown in Table 7, precipitation (visual observation, microscopic observation) and the like were not observed in all of the examples of the present invention.

2, the florphenicol raw material having a high solubility at a high concentration and the product of Example 3 were enlarged by 700 times using a microscope (manufacturer: SamSween Scientific, model name: Microscopy MSB-80T, CCD Camera SC-150). As a result, Indicating that the florphenicol was completely dissolved.

Claims (4)

Wherein the composition contains 10 to 40% by weight of florfenicol, 2 to 10% by weight of tylosin or veterinarily acceptable salt thereof, and 0.01 to 0.5% by weight of dexamethasone or veterinarily acceptable salt thereof, 40 to 65% by weight of 1-methylpyrrolidone, 0.01 to 0.1% by weight of butylhydroxytoluene, 0.1 to 2% by weight of butylhydroxyanisole, and 40 to 65% by weight of 1-methylpyrrolidone. delete After 20 to 40% by weight of glycerol foam and 40 to 65% by weight of 1-methylpyrrolidone are mixed, 10 to 40% by weight of florpenicol is dissolved in the solution, An animal composite obtained by adding 2 to 10% by weight of a salt, 0.01 to 0.5% by weight of dexamethasone or a veterinarily acceptable salt thereof, 0.01 to 0.1% by weight of butylhydroxytoluene and 0.1 to 2% by weight of butylhydroxyanisole A method for preparing an antibiotic composition.
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