KR100748252B1 - Composition for injection containing florfenicol and tylosin - Google Patents

Abstract

Provided is a composition for injection containing florfenicol and tylosin which has improved stability by reducing viscosity and is able to inhibit solubility lowering of florfenicol and content lowering of tylosin during storage while high concentration of florfenicol is contained by using safe solvent. The composition for injection contains 15-30 wt.% of florfenicol, 2-8 wt.% of tylosin or veterinarily acceptable salts thereof, 30-70 wt.% of dimethylsulfoxide, 2-20 wt.% of propylene glycol and 5-30 wt.% of water, further contains 0.5-5 wt.% of benzyl alcohol or 0.01-0.5 wt.% of dexamethasone or veterinarily acceptable salts thereof, wherein the composition has viscosity of 1-10 cp.

Description

Composition for injection containing florfenicol and tylosin}

The present invention relates to a pharmaceutical composition containing florfenicol and tylosin as active ingredients, and more particularly to a low viscosity injectable composition containing a large amount of florfenicol and having excellent storage stability.

2,2-dichloro - N- [(1 S, 2 R) -1- ( fluoromethyl) -2-hydroxy-2- [4- (methylsulfonyl) phenyl] ethyl] acetamide the flow pe Nicole Is a bactericidal and antimicrobial agent developed for animals and is known to be useful for veterinary purposes. Such fluorphenic acid has low solubility in water, making it difficult to prepare an injectable composition, and low solubility among many pharmaceutically acceptable organic solvents such as 1,2-propanediol, glycerin, benzyl alcohol and the like.

It is sometimes desirable to administer a composition containing a high concentration of florfenicol when treating a large animal such as cattle, pigs, etc. using such florfenicol. For this purpose, Korean Patent Registration No. 104,340 (pharmaceutical composition of florfenicol, Schering Corporation) is 10 to 50% by weight of florfenicol, 10 to 65% by weight of pyrrolidone, 5 to 15% by weight of ethanol or propylene glycol and Fluphenicol-containing pharmaceutical compositions comprising 5 to 40% by weight polyethylene glycol (PEG) are disclosed, but their viscosity is high to about 40 cP, making it difficult for users to inject animals into farms. In the case of injections injected into animals, the viscosity is preferably 20 cP or less, and more preferably 10 cP or less.

In addition, in some cases, an emulsion-containing injectable composition of florfenicol using a hydrophilic solvent, an oil and a surfactant is disclosed, but it has a disadvantage of poor stability in long-term storage, especially in the case of a composition containing a high dose of florfenicol Stability needs to be improved, for example, precipitation is formed due to a decrease in the solubility of Nicole.

Meanwhile, Korean Patent Registration No. 548,948 (pharmaceutical composition of florfenicol, Handong Co., Ltd.) is 5 to 40% by weight of florfenicol, 10 to 50% by weight of dimethylformamide, 20 to 60% by weight of propylene glycol and polysorb Although it is disclosed a florfenicol-containing injection composed of 2 to 10% by weight of bait 80, in some cases, the viscosity is still high, it is not preferable for injection, there is a disadvantage that the toxicity of dimethylformamide is severe.

Tyrosin is a macrolide antibiotic that is known to be effective against various bacteria such as Streptococcus and Staphylococcus aureus. It is used to treat or prevent various diseases of various animals such as swine pigs and dog colitis. come. Such tyrosine has a disadvantage in that the water solubility is large and easy to prepare as an injection, whereas in the case of tyrosine injection, the content of tyrosine is low during storage and thus the storage stability is very bad.

Therefore, the technical problem to be achieved by the present invention is to use a relatively safe raw material, while containing a high volume of florfenicol, while having a low viscosity, the solubility of florfenicol and the content of tyrosine do not fall during storage, and thus the fluorphenicol has excellent stability. It is to provide a tyrosine-containing injectable composition.

In order to achieve the above technical problem, the present invention provides an injectable composition comprising a fluorphenicol, tyrosine or a veterinary acceptable salt thereof, dimethyl sulfoxide, propylene glycol and water, preferably, 15-30% by weight of florfenicol, 2-8% by weight of tyrosine or a veterinary acceptable salt thereof, 30-70% by weight of dimethylsulfoxide, 2-20% by weight of propylene glycol and 5-30% by weight of water It provides an injectable composition comprising a%.

More preferably, the present invention provides an injectable composition, characterized in that the composition further comprises 0.5 to 5% by weight of benzyl alcohol relative to the total weight of the composition.

The present invention also provides an injectable composition, wherein said composition further comprises dexamethasone or a veterinary acceptable salt thereof, preferably wherein said dexamethasone or veterinary acceptable salt thereof is relative to the total weight of the composition. It provides an injectable composition, characterized in that it comprises 0.01 to 0.5% by weight.

More preferably, the present invention provides an injectable composition, characterized in that the viscosity of the composition is 1 to 10 cP.

Hereinafter, the injectable composition containing florfenicol and tyrosine of the present invention; Or injectable compositions containing florfenicol, tyrosine and dexamethasone.

The present invention provides an injectable composition comprising florfenicol, tyrosine and a veterinary acceptable salt thereof, dimethylsulfoxide, propylene glycol and water, and more preferably, florfenicol relative to the total weight of the composition 15 to 30 wt%, 2 to 8 wt% of tyrosine or a veterinary acceptable salt thereof, 30 to 70 wt% of dimethylsulfoxide, 2 to 20 wt% of propylene glycol and 5 to 30 wt% of water. It provides a composition for injection.

The injectable composition of the present invention preferably contains 15 to 30% by weight of florfenicol, one of the active ingredients, relative to the total weight of the composition. If it is less than 15% by weight, there is a problem of injecting too much volume in order to obtain a sufficient effect when injected into the target animal, and if it exceeds 30% by weight, it is difficult to make an injection drug having excellent stability due to the relatively low content of other components. .

Injectable compositions of the present invention preferably contain 2 to 8% by weight of tyrosine, one of the active ingredients, or a pharmaceutically acceptable salt thereof, relative to the total weight of the composition. Tyrosine or its veterinary acceptable salt is hydrophilic and easy to dissolve in water, whereas fluorphenicol is difficult to dissolve in solvents such as water and alcohol due to its low hydrophilicity. Therefore, if the content is out of the above range, the content of other components is relatively increased or decreased, and thus, it is difficult to prepare an injection in which both fluorphenicol and tyrosine are dissolved, and the viscosity may increase.

Injectable compositions of the present invention may further comprise an anti-inflammatory dexamethasone or veterinary acceptable salt thereof, preferably 0.01 to 0.5% by weight of dexamethasone or a veterinary acceptable salt thereof relative to the total weight. . Since the content of dexamethasone included in the injectable composition according to the present invention is relatively small compared to the content of the other ingredients, it is considered that the effect on the solubility and stability of florfenicol and tyrosine is small.

The veterinary acceptable salts referred to in the present invention are acetate salts, benzenesulfonate salts, benzoate salts, bicarbonate salts, bitartrate salts, camsylate salts, carbonate salts, chloride salts, bromide salts, Iodide salt, citrate salt, dihydrochloride salt, edetate salt, edisylate salt, estrate salt, ecylate salt, fumarate salt, glutceptate salt, gluconate salt, glutamate salt, lactate Salts, maleate salts, maleate salts, mandelate salts, mesylate salts, methylsulfate salts, nitrate salts, phosphate / diphosphate salts, salicylate salts, stearate salts, succinate salts, sulfate salts, tartrates Salts, etc. include, but are not limited to, veterinary acceptable salts within the scope of not impairing the object of the present invention It can be used either.

Injectable compositions of the present invention contain dimethylsulfoxide and preferably contain 30 to 70% by weight relative to the total weight of the composition. If it is less than 30% by weight, the solubility of the active ingredient florfenicol is poor, making it difficult to obtain a high content of florfenicol injectable compositions, it is also difficult to secure stability, and when it exceeds 70% by weight, the relatively active ingredient is florfenicol. Or the content of tyrosine is reduced, there is a disadvantage that the solubility of tyrosine may be lowered because the content of other solvents such as water is lowered.

For example, 18% to 20% by weight of flofenicol, 5.4% by weight of tyrosine tartrate, 0.05% by weight of dexamethasone acetate, 27.54% by weight of dimethylsulfoxide, 27.54% by weight of propylene glycol, 1.84% by weight of benzyl alcohol and 19.28% by weight of water For the compositions used, the solubility is relatively poor and recrystallization may occur at 5 ° C refrigeration.

Dimethyl sulfoxide of the present invention is LD ₅₀ of 14.5g / kg (rat, oral) N-methylpyrrolidone (LD ₅₀ mainly used to dissolve the fluorphenicol in conventional commercial formulations 3.91 g / kg, rat, oral), dimethylformamide (LD ₅₀ 2.8g / kg, rat, oral) and the like has an advantage that the safety is excellent compared to the solvent, and also good diffusion and permeability into the cell tissue is considered to be useful as a component of the injectable composition of the present invention.

Injectable compositions of the invention contain propylene glycol and preferably contain 2 to 20% by weight relative to the total weight of the composition. If it is less than 2% by weight, the viscosity of the injectable composition of the present invention may be increased, and if it is more than 20% by weight, the dosage of other solvents may be reduced relatively, solubility of florfenicol and tyrosine may be decreased, and the viscosity of the injection may be increased. have.

Injectable compositions of the present invention contain water, preferably distilled water for injection, and more preferably contain 5 to 30% by weight of distilled water for injection, relative to the total weight of the composition. If it is less than 5% by weight, solubility of tyrosine may be lowered and the viscosity of the composition may be increased. If it is more than 30% by weight, there may be a problem in solubility of florfenicol. Water contained in the composition of the present invention may serve to relieve tissue irritation during injection.

Florfenicol-containing injectable compositions of the present invention may also further comprise 0.5 to 5% by weight of benzyl alcohol relative to the total weight of the composition. Such benzyl alcohol may serve to relieve pain and improve preservation during injection.

Hereinafter, the present invention will be described in more detail with reference to examples. However, the scope of the present invention is not limited by the following examples, and the following examples are given by way of example to describe the present invention more specifically to those skilled in the art. Will be.

<Production of Examples 1-3>

To prepare the Examples 1 to 3 in the composition and content of Table 1. Specifically, dimethyl sulfoxide, benzyl alcohol and water were mixed, followed by addition of florfenicol to completely dissolve it. After dissolving tyrosine tartrate and dexamethasone acetate therein, propylene glycol was added, stirred until an even solution, and filtered through pre-sterilized sterile paper to prepare the injectable compositions of Examples 1 to 3.

Example 1 Example 2 Example 3 mg / ml content% mg / ml content% mg / ml content% Florfenicol 200 18.36 200 17.69 200 17.71 Tyrosine tartrate 58.8 5.4 58.8 5.2 58.8 5.21 Dexamethasone acetate 0.5 0.05 0.5 0.04 0.5 0.04 Propylene glycol 100 9.18 50 4.42 50 4.43 Dimethyl sulfoxide 560 51.41 651 57.6 700 61.99 Benzyl alcohol 20 1.84 20 1.77 20 1.77 water 150 13.77 150 13.27 100 8.86

<Production of Comparative Example 1>

Each component was weighed and mixed so as to have the following composition and content, and then filtered by sterile filter paper to prepare an injectable composition.

Ingredient weight / ml

Florfenicol 200 mg

Tyrosine Tartrate 58.8 mg

Dexamethasone acetate 0.5 mg

Dimethylformamide 350 mg

N-methyl-2-pyrrolidone 350 mg

130 mg distilled water for injection

<Production of Comparative Example 2>

Each component was weighed and mixed so as to have the following composition and content, and then filtered by sterile filter paper to prepare an injectable composition.

Ingredient weight / ml

Florfenicol 200 mg

Tyrosine Tartrate 58.8 mg

Dexamethasone acetate 0.5 mg

Dimethylformamide 700 mg

130 mg distilled water for injection

<Production of Comparative Example 3>

Each component was weighed and mixed so as to have the following composition and content, and then filtered by sterile filter paper to prepare an injectable composition.

Ingredient weight / ml

Florfenicol 200 mg

Tyrosine Tartrate 58.8 mg

Dexamethasone acetate 0.5 mg

N-methyl-2-pyrrolidone 700 mg

130 mg distilled water for injection

<Manufacture of Comparative Example 4>

Each component was weighed and mixed so as to have the following composition and content, and then filtered by sterile filter paper to prepare an injectable composition.

Ingredient weight / ml

Florfenicol 200 mg

Tyrosine Tartrate 58.8 mg

Dexamethasone acetate 0.5 mg

N-methyl-2-pyrrolidone 380 mg

Polyethylene glycol 320 mg

Benzyl alcohol 20 mg

110 mg distilled water for injection

<Manufacture of Comparative Example 5>

Each component was weighed and mixed so as to have the following composition and content, and then filtered by sterile filter paper to prepare an injectable composition.

Ingredient weight / ml

Florfenicol 200 mg

Tyrosine Tartrate 58.8 mg

Dexamethasone acetate 0.5 mg

N-methyl-2-pyrrolidone 380 mg

Dimethylformamide 430 mg

Benzyl alcohol 20 mg

Experimental Example 1 Viscosity Measurement

The viscosity of the said Example 1, Example 2, and the comparative example 4 was measured at 25 degreeC using the viscosity measuring device (AND SV-10, AND company, Japan). The results are shown in Table 2 below.

Example 1 Example 2 Comparative Example 4 Viscosity 9.7 cP 9.2 cP 35.5 cP

As shown in Table 2 above, the present invention can provide an injectable composition having a lower viscosity than the known fluorphenicol-containing injectable composition.

Experimental Example 2 Evaluation of Stability of Comparative Examples 1 to 5

The injectable compositions prepared in Comparative Examples 1 to 3 were stored at 40 ° C. and their contents were measured over time to evaluate the content stability. Tyrosine content evaluation was performed as follows, and the results are shown in Table 3 below.

HPLC was used to evaluate the content of tyrosine, and a symmetry C18 column was used to evaluate the flow rate of 0.5 ml / min at UV 280 nm. The mobile phase used a 0.85M NaClO ₄ : ACN (60:40) mixed solvent adjusted to pH 2.5 using 2N HCl.

Comparative Example 1 Comparative Example 2 Comparative Example 3 Early 100.0% 100.0% 100.0% 3 months 82.3% 87.3% 76.3% 6 months 75.8% 77.2% 66.5% 12 months 62.8% 64.8% 58.4%

As shown in Table 3, the tyrosine contained in the injection is very poor in storage stability due to a decrease in content over time.

In case of Comparative Example 4, the solubility in the manufacturing process was good, but when it was stored at 40 ° C., the appearance turned brown from about 15 days, and the stability was poor. In Comparative Example 5, the solubility in the manufacturing process was good, but room temperature and 40 ° C. When stored at about 18 days, the appearance turned brown and the stability was very poor.

<Experiment 3> Stability evaluation of Examples 1-3

The injectable compositions prepared in Examples 1 to 3 were stored at 5 ° C., room temperature and 40 ° C. to evaluate changes in properties and contents. The content of tyrosine was carried out in the same manner as in Experimental Example 2, Florfenicol content was carried out as follows, the results of Examples 1, 2 and 3 are shown in Tables 4, 5 and 6, respectively.

HPLC was used to evaluate the content of florfenicol, and a symmetry C18 column was used to evaluate the flow rate of 0.5 ml / min at UV 230 nm. The mobile phase used a 0.85M NaClO ₄ : ACN (60:40) mixed solvent adjusted to pH 2.5 using 2N HCl.

Example 1 Storage condition Test Items first 3 months 6 months 12 months 5 ℃ Constellation Light yellow transparent liquid immutability immutability immutability content(%) Tyrosine 100.3 100.0 99.8 99.3 content(%) Florfenicol 100.7 100.6 100.5 100.1 Room temperature Constellation Light yellow transparent liquid immutability immutability immutability content(%) Tyrosine 100.3 99.7 98.5 97.2 content(%) Florfenicol 100.7 100.6 100.2 99.8 40 ℃ Constellation Light yellow transparent liquid immutability immutability immutability content(%) Tyrosine 100.3 99.2 97.6 95.8 content(%) Florfenicol 100.7 100.4 99.2 98.4

Example 2 Storage condition Test Items first 3 months 6 months 12 months 5 ℃ Constellation Light yellow transparent liquid immutability immutability immutability content(%) Tyrosine 100.5 100.2 99.8 99.0 content(%) Florfenicol 100.2 100.0 99.8 99.5 Room temperature Constellation Light yellow transparent liquid immutability immutability immutability content(%) Tyrosine 100.5 99.7 98.5 97.2 content(%) Florfenicol 100.2 100.0 99.7 99.2 40 ℃ Constellation Light yellow transparent liquid immutability immutability immutability content(%) Tyrosine 100.5 99.2 97.6 95.2 content(%) Florfenicol 100.2 100.0 98.9 98.0

Example 3 Storage condition Test Items first 3 months 6 months 12 months 5 ℃ Constellation Light yellow transparent liquid immutability immutability immutability content(%) Tyrosine 100.8 100.4 99.9 99.4 content(%) Florfenicol 100.7 100.5 100.3 100.0 Room temperature Constellation Light yellow transparent liquid immutability immutability immutability content(%) Tyrosine 100.8 99.7 98.9 97.5 content(%) Florfenicol 100.7 100.5 100.0 99.4 40 ℃ Constellation Light yellow transparent liquid immutability immutability immutability content(%) Tyrosine 100.8 99.5 98.4 95.6 content(%) Florfenicol 100.7 100.4 99.5 98.2

As shown in Table 4, 5 and 6, it can be seen that the composition for injection according to the present invention is very excellent in storage stability.

As described above, the present invention uses a relatively safe solvent such as dimethyl sulfoxide, water, and the like instead of organic solvents such as N-methylpyrrolidone and dimethylformamide, and contains a high dose of fenfranol, while having low viscosity, Stable florfenicol and tyrosine-containing injectable compositions can be provided that do not lower the solubility of lefenicol and the content of tyrosine.

Claims (6)

An injectable composition comprising florfenicol, tyrosine or a veterinary acceptable salt thereof, dimethylsulfoxide, propylene glycol and water. According to claim 1, wherein the composition is 15 to 30% by weight florfenicol, 2 to 8% by weight of tyrosine or a veterinary acceptable salt thereof, 30 to 70% by weight of dimethyl sulfoxide, 2 to propylene glycol relative to the total weight of the composition An injectable composition comprising 20% by weight and 5-30% by weight of water. The injectable composition of claim 2, wherein the composition further comprises 0.5 to 5 wt% of benzyl alcohol relative to the total weight of the composition. The injectable composition of claim 1, wherein the composition further comprises dexamethasone or a veterinary acceptable salt thereof. The injectable composition of claim 4, wherein the dexamethasone or a veterinary acceptable salt thereof is included in an amount of 0.01 to 0.5 wt% based on the total weight of the composition. The injectable composition according to any one of claims 1 to 5, wherein the composition has a viscosity of 1 to 10 cP.