KR101564538B1 - Composition of the combined antibiotics for veterinary applications - Google Patents

Abstract

The present invention relates to a composition of combined antibiotics for veterinary application, which contains florfenicol, tylosine, and dexamethasone as main ingredients. The composition according to the present invention comprises: florfenicol, tylosine, or a veterinarily acceptable salt thereof; dexamethasone or a veterinarily acceptable salt thereof; and glycerol formal, butylhydroxytoluene, butylhydroxyanisole, 1-methyl pyrrolidone, dimethylacetamide, and propylene carbonate as a diluting agent. The present invention relates to an excellent composition which contains high levels of florfenicol but has a low viscosity, and prevent a syringe barrel from being cloudy in the case of injecting with a continuous injector. In addition, the composition facilitates injection by greatly alleviating pain of a target animal, and has excellent medicine stability of the overall composition, thereby being able to be injected without recrystallization of an active ingredient.

Description

≪ Desc / Clms Page number 1 > Composition of the combined antibiotics for veterinary applications &

The present invention relates to a composite antibiotic composition for animals, and more particularly, to a composition containing a high concentration of florphenicol and having a low viscosity by using a combination of ginsenoside and florfenicol as a tile known as a macrolide antibiotic, The present invention relates to an excellent composition which can be injected without the recrystallization of an active ingredient because the syringe barrel does not become cloudy and the pain to the target animal is greatly alleviated to facilitate injection and stability of the whole preparation.

Florfenicol is a substance with D- (threo) -1-p-methylsulfonylphenyl-2-dichloroacetamide-3-fluoro-1-propanol structure, 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. In addition, when the continuous syringe is scanned, the syringe barrel is scattered and the expensive continuous syringe can not be used. 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.

Tylosin is a macrolide antibiotic substance known to be effective against various bacteria such as streptococcus bacteria and bacteria of Staphylococcus aureus. Therefore, in order to treat or prevent various diseases of various animals such as swine flu and dog colitis, 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.

Generally, it is preferable to prepare the florfenicol and tile so that the concentration of the injectable preparation is 20 cp (centipoise) or less, more preferably 10 cp (centipoise) It is said.

In addition, a flourfenicol-containing composition for use in an emulsion type using a hydrophilic solvent, an oil and a surfactant is known, 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 flourpenicol in a high- It is necessary to improve stability of the preparation such as precipitation due to lowering of solubility. As a method for improving this, there is the following patented technology recently introduced.

First, 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 5 (Centipoise) consisted of about 15% to 15% by weight of polyethylene glycol (PEG) and about 5 to 40% by weight of polyethylene glycol (PEG), but the viscosity was so high that it was difficult for the user to inject into large 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. In domestic patent No. 1352867 (published on Apr. 21, 2014), 10 to 40% by weight of florpenicol, 2 to 10% by weight of tyrosine, 0.01 to 0.5% by weight of dexamethasone, 1 to 20% by weight of glycerol foam, 0.01 to 0.1% by weight of butylhydroxyanisole, 0.1 to 2% by weight of butylhydroxyanisole, and 50 to 80% by weight of 1-methylpyrrolidone are known. Pain and pain relief in viscous and infused injections was improved. However, there is a disadvantage in that it is not possible to use expensive continuous syringes such as a syringe barrel that is sprayed on the farm when a large number of animals are injected with a continuous syringe.

The present invention relates to a combination antibiotic for animals comprising a high concentration of florfenicol, a tylosin or veterinarily acceptable salt, dexamethasone or a veterinarily acceptable salt, to glycerol foam, butylhydroxytoluene, butylhydroxyanisole, 1 - Low viscosity using a mixture of methylpyrrolidone, dimethylacetamide, propylene carbonate, etc., and easy to inject because the syringe barrel does not become cloudy when injected with a continuous syringe. Stability of florfenicol, tylosin and dexamethasone Can be made with excellent solubility of fluorfenicol.

Accordingly, the present invention provides a method for preparing a pharmaceutical composition which is low in viscosity, does not cause syringe barrel to become cloudy when injected by a continuous syringe, and is easy to inject by greatly alleviating pain to a target animal, It is an object of the present invention to provide a composite antibiotic composition for animals.

The present invention relates to a pharmaceutical composition comprising 10 to 40% by weight of florfenicol, 2 to 10% by weight of a tylosin or veterinarily acceptable salt, 0.01 to 0.5% by weight of dexamethasone or veterinarily acceptable salt, 1 to 30% by weight of glycerol, The present invention relates to a process for producing a polymer comprising the steps of: 0.01 to 0.1% by weight of butylhydroxytoluene; 0.1 to 2% by weight of butylhydroxyanisole; 1 to 20% by weight of 1-methylpyrrolidone; 1 to 30% by weight of dimethylacetamide; Or a pharmaceutically acceptable salt thereof.

Particularly preferred compositions are those comprising 300 mg / ml of flouropenicol, 84.4 mg / ml of tylosin tartaric acid, 0.75 mg / ml of dexamethasone acetate, 100 to 150 mg / ml of glycerol foams, 0.2 mg / ml of butylhydroxytoluene, Wherein the composition is an antibiotic composition for animals comprising 1 to 5 mg / ml of Roxanisol, 50 to 70 mg / ml of 1-methylpyrrolidone, 100 to 150 mg / ml of dimethylacetamide and 340 to 450 mg / ml of propylene carbonate .

The present invention also relates to a method for producing a flourephenol compound, which comprises mixing 1 to 30% by weight of glycerol foam, 1 to 20% by weight of 1-methylpyrrolidone, 1 to 30% by weight of dimethylacetamide, and 25 to 60% by weight of propylene carbonate, By weight of a tylosin or veterinarily acceptable salt thereof and from 0.01 to 0.5% by weight of dexamethasone or veterinarily acceptable salt thereof, from 0.01 to 0.1% by weight of butylhydroxytoluene, And 0.1 to 2% by weight of a sol is added to the mixture to dissolve the antibiotic composition.

Particularly, a preferable production method is a method of mixing 100 to 150 mg / ml of glycerol, 50 to 70 mg / ml of 1-methylpyrrolidone, 100 to 150 mg / ml of dimethylacetamide and 340 to 450 mg / ml of propylene carbonate After that, 300 mg / ml of florfenicol, 84.4 mg / ml of tile acyl tartaric acid, 0.75 mg / ml of dexamethasone acetate, 0.2 mg / ml of butylhydroxytoluene and 1 to 5 mg / ml of butylhydroxyanisole were dissolved and dissolved And a method for producing the obtained complex antibiotic composition for animals.

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

In the present invention, it is an object of the present invention to provide a composition of a preparation which is easy to inject and which is stable by preventing the syringe barrel from being scattered during injection by the continuous syringe and greatly alleviating the pain to the subject animal.

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 a tile or a veterinarily acceptable salt, which is one of the active ingredients. Shin or a veterinarily acceptable salt thereof as a tile has a high hydrophilicity and is easy to dissolve in water. On the other hand, the florphenicol has low hydrophilicity and is difficult to dissolve in 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 Or it can be used.

In the present invention, a mixture of 1 to 30% by weight of glycerol foam, 1 to 20% by weight of 1-methylpyrrolidone, 1 to 30% by weight of dimethylacetamide and 25 to 60% by weight of propylene carbonate as a dissolution aid use. When the glycerol foam is used in an amount of 1% by weight or less, browning of the injection solution occurs. When the glycerol foam is used in an amount of 30% by weight or more, the viscosity becomes high. In the case of 1-methylpyrrolidone, the viscosity is increased and precipitation occurs when it is used in an amount of 1% by weight or less, and the solubility is increased when it is used in an amount of 20% by weight or more. In addition, precipitation occurs at 25 wt% or less of propylene carbonate, and precipitation occurs even when 60 wt% or more of the propylene carbonate is used, which is not preferable from the standpoint of stability.

The glycerol formal, 1-methyl-2-pyrollidone, dimethylacetamide, and propylene carbonate used in the present invention are conventionally used to dissolve florphenicol The viscosity is low as compared with a solvent such as propylene glycol or polyethylene glycol which is mainly used, the syringe barrel does not become cloudy when injected by a continuous syringe, the pain to the target animal is greatly alleviated, Nicole, a tylosin-containing formulation, was superior in stability and was able to make excellent injections with high flourfenicol solubility.

As an antioxidant mentioned in the present invention, excellent injections were obtained when 0.01 to 0.1 wt% of butylhydroxytoluene and 0.1 to 2 wt% of butylhydroxyanisol were administered.

The compound antibiotic composition for animals of the present invention can be formulated into an animal injectable solution, a liquid preparation, an injectable preparation or the like.

As described above, the present invention uses propylene carbonate as a solubilizing agent, using butylhydroxytoluene, butylhydroxyanisole or the like as a further additive, using glycerol foam, 1-methylpyrrolidone, or dimethylacetamide as a solubilizing agent The viscosity of the composition is low and the syringe barrel does not become cloudy when injected by the continuous syringe. In addition, the pain to the target animal is greatly alleviated and the injection is easy, and the preparation stability of the whole composition is excellent, Lt; RTI ID = 0.0 > florfenicol, tylosin, < / RTI > and dexamethasone,

Fig. 1 is a photograph of the state of a syringe barrel taken after the composition of Example 2 was injected by a continuous syringe. (Fig. 1A: Example 2 was continuously washed with water after washing, Fig. 1B: Was filled with 2 ml and washed with water after 4 hours.)
Fig. 2 is a photograph of the state of a syringe barrel taken after the composition of Comparative Example 1 was injected by a continuous syringe. (Fig. 2A: Comparative Example 1 was continuously washed and washed with water. Fig. 2B: Was filled with 2 ml and washed with water after 4 hours.)
Fig. 3 is a photograph showing the images of Example 2 and Comparative Example 3; Fig. (Fig. 3A: properties of Example 2 after 6 months at room temperature, and Fig. 3B: Properties of Comparative Example 3 that were initially precipitated).
FIG. 4A is a photograph of the shape of a continuous syringe (Model-HSW ECO-Matic 2 ml LL with bottle attachment) of HENKE SASS WOLF (Germany).

Example  1 to 3 and Comparative Example  1-3

Compositions for injection were prepared in the compositions shown in Table 1-2 below. Specifically, glycerol foam, 1-methylpyrrolidone, dimethylacetamide, and propylene carbonate were mixed in a beaker, and then flouropenicol was added to dissolve completely. To this, terephthalic acid dexamethasone acetate and butylhydroxytoluene and butylhydroxyanisole are added sequentially to complete dissolution. The mixture was filtered through a pre-sterilized sterile filter paper to obtain a composition of each of the Examples.

In the case of the comparative example, the main solvent is added to the beaker, and florfenicol, terephthalic acid, and dexamethasone acetate are added and dissolved completely. 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 Florphenicol 300 300 300 New tartaric acid as a tile 84.4 84.4 84.4 Dexamethasone acetate 0.75 0.75 0.75 Glycerol foam 100 120 150 Butylhydroxytoluene 0.2 0.2 0.2 Butylhydroxyanisole One 5 5 1-Methylpyrrolidone 50 70 60 Dimethylacetamide 100 100 150 Propylene carbonate 450 410 340

Ingredients (unit mg / ml) Comparative Example 1 Comparative Example 2 Comparative Example 3 Florphenicol 300 300 300 New tartaric acid as a tile 84.4 84.4 84.4 Dexamethasone acetate 0.75 0.75 0.75 Glycerol foam 70 - 70 Dimethylsulfoxide - 330 - Butylhydroxytoluene 0.2 - 0.2 Butylhydroxyanisole 5 - 5 1-Methylpyrrolidone 660 - 100 Polyethylene glycol 400 - 500 2-pyrrolidone - - 560

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 Comparative Example 1 Comparative Example 2 Comparative Example 3 Viscosity 8.0 cP 8.1 cP 8.9 cP 8.2 cP 20.0 cP 17.2 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: Syringe barrel ( barrel ) Safety Sho sign

2 ml of the compositions of the above Examples and Comparative Examples were taken and filled into a polystyrene syringe having a length of 199 mm and a length of 3.3 cm and having a length of 179 mm to prepare a syringe sample. After injecting with 2 mL of the model-HSW ECO-Matic 2 mL LL with bottle attachment at HENKE SASS WOLF (Germany) at room temperature, after 4 hours of filling, the syringe barrel ) Was measured, and it is shown in Table 4 below.

Example Syringe barrel Comparative Example Syringe barrel One Good One Cloudy 2 Good 2 Cloudy 3 Good 3 Cloudy

As shown in Table 4, when the composition of the present invention was compared with the composition of the comparative example, the syringe barrel was not changed into a puffy shape when injected by a continuous syringe, and thus it was easy to inject. As a result, it is possible to inject the composition smoothly without stiffness at the time of injecting the composition, and it is economically advantageous when injecting a large number of animals by increasing the lifetime of the expensive continuous syringe.

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 acetate were determined by high performance liquid chromatography (HPLC). The HPLC was performed using a YL9101 vacuum degasser, a YL9110 quaternary pump, a YL9131 column compartment, a YL9120 uv / vis detector, a YL9150 Autosampler System (Youngin Instruments), a column: Cosmosil 5C18-AR- ), Mobile phase: Florfenicol (Acetonitrile: Water: Acetic acid = 1000: 2000: 3), Tylosin (0.85 m / l sodium perchlorate: Acetonitrile = 600: 400, pH 2.5 adjusted with diluted hydrochloric acid), Dexamethason acetate Phosphate Buffer = 52: 48), wavelength: Florenicol (224 nm), Tylosin (280 nm), Dexamethason acetate (254 nm) Flow rate: 1.0 ml / The changes in the content of lepenicol, tylosin, and dexamethasone acetate are shown in Tables 5 and 6.

Storage period
(40 DEG C) Example 1 Example 2 Example 3 Florphenicol God with tiles Dexamethasone acetate Florphenicol God with tiles Dexamethasone acetate Florphenicol God with tiles Dexamethasone acetate Early 100.1 106.9 100.8 101.2 107.3 102.0 100.5 107.2 102.2 3 months 100.0 104.0 100.5 101.0 104.6 101.3 100.3 105.0 101.7 6 months 99.9 103.5 99.9 100.6 102.9 100.8 100.1 102.8 101.1

Storage period
(40 DEG C) Comparative Example 1 Comparative Example 2 Comparative Example 3 Florphenicol God with tiles Dexamethasone acetate Florphenicol God with tiles Dexamethasone acetate Florphenicol God with tiles Dexamethasone acetate Early 101.3 106.9 102.0 101.0 106.1 102.5 101.9 105.9 101.5 3 months 100.9 103.8 101.5 100.4 96.5 101.0 100.7 97.1 100.3 6 months 100.3 101.9 99.9 100.0 79.9 100.2 100.2 75.8 100.0

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 compositions of Comparative Examples 2 and 3.

Experimental Example  4: Properties of the injectable composition ( Precipitation - Visual observation)

The thus prepared compositions of Examples 1-3 and Comparative Examples 1-3 were placed in a 20 ml vial and stored at room temperature for 6 months to observe precipitation (visual observation) and the like.

Storage period
(Room temperature) Example 1
(Presence or absence of precipitation) Example 2
(Presence or absence of precipitation) Example 3
(Presence or absence of precipitation) Comparative Example 1
(Presence or absence of precipitation) Comparative Example 2
(Presence or absence of precipitation) Comparative Example 3
(Presence or absence of 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 Precipitation 3 months Visual observation Light yellow liquid Visual observation Light yellow liquid Visual observation Light yellow liquid Visual observation Light yellow liquid Visual observation Slight deposition Visual observation stop 6 months Visual observation Light yellow liquid Visual observation Light yellow liquid Visual observation Light yellow liquid Visual observation Light yellow liquid Visual observation stop Visual observation stop

As shown in Table 7, precipitation (visual observation) and the like were not observed in all of Examples 1, 2, and 3 of the present invention.

Comparative Example 2-3 was precipitated after all the preparation and the experiment was stopped.

Experimental Example  5: injectable composition pain test

The compositions of Examples 1-3 and Comparative Examples 1-3 prepared above were injected into a swine of a pig farm with a continuous syringe to measure the degree of response to swine pain. At the time of the experiment, 20 pigs were randomly assigned to each sample in order to increase the confidence of each sample, and the response of the pigs was shown in the range of 0 to 5 when the sample was injected. Are shown in Table 8.

Example Degree of pain Comparative Example Degree of pain One 0.6 One 0.9 2 0.5 2 4.4 3 0.4 3 4.5

* Reaction Level: 5 (very loud and restless), 4 (louder and restless), 3 (louder and restless), 2 (louder and slightly backward), 1 Standing in place without kinking)

Through these experiments, it was confirmed that unlike the composition of the comparative example, the composition of the example showed little pain in the animal at the time of injection, and no stress reaction or shock reaction such as a loud sound of the pig or a restlessness was hardly observed.

Claims (7)

A pharmaceutical composition comprising 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 as a pharmaceutically active ingredient, 1 to 30 wt% of butylhydroxytoluene, 0.01 to 0.1 wt% of butylhydroxytoluene, 0.1 to 2 wt% of butylhydroxyanisole, 1 to 20 wt% of 1-methylpyrrolidone, 1 to 30 wt% of dimethylacetamide, 25 to 60% by weight as an excipient. The pharmaceutical composition according to claim 1, which comprises at least one selected from the group consisting of florfenicol 300 mg / ml, tylosin tartaric acid 84.4 mg / ml, dexamethasone acetate 0.75 mg / ml, glycerol foaming 100-150 mg / ml, butylhydroxytoluene 0.2 mg / Animal composite antibiotic composition containing anisole 1 to 5 mg / ml, 1-methylpyrrolidone 50 to 70 mg / ml, dimethylacetamide 100 to 150 mg / ml and propylene carbonate 340 to 450 mg / ml. 1 to 30% by weight of glycerol foam, 1 to 20% by weight of 1-methylpyrrolidone, 1 to 30% by weight of dimethylacetamide and 25 to 60% by weight of propylene carbonate, Wherein the tile comprises 2 to 10% by weight of ginseng or a veterinarily acceptable salt thereof, 0.01 to 0.5% by weight of dexamethasone or veterinarily acceptable salt thereof, 0.01 to 0.1% by weight of butylhydroxytoluene and 0.1 to 2% by weight of butylhydroxytoluene, By weight based on the total weight of the antibiotic composition. 4. The method according to claim 3, further comprising mixing 100 to 150 mg / ml of glycerol foam, 50 to 70 mg / ml of 1-methylpyrrolidone, 100 to 150 mg / ml of dimethylacetamide and 340 to 450 mg / The resulting solution was added with 300 mg / ml of florfenicol, 84.4 mg / ml of neat tartaric acid, 0.75 mg / ml of dexamethasone acetate, 0.2 mg / ml of butylhydroxytoluene and 1 to 5 mg / ml of butylhydroxyanisole ≪ / RTI > [Claim 2] The composition according to claim 1, wherein the composition comprises glycerol foams, 1-methylpyrrolidone, dimethylacetamide or a mixture thereof as a solvent. The composition according to claim 1, wherein the composition comprises propylene carbonate as a solubilizing agent. The antibiotic composition for an animal according to claim 1, wherein the composition for animal antibiotics is formulated as an injectable, liquid or injectable preparation for animals.

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