JPH0782141A - Injection for animal - Google Patents

Abstract

PURPOSE:To obtain an injection for animals hardly recognizing leavings of an antimicrobial agent into tissue of livestock or poultry and injury of an injected part when administered to the livestock or the poultry and causing no deposition of insoluble foreign matters during storage. CONSTITUTION:This injection for animals is obtained by blending difloxacin [chemical name: 6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4- oxo-3-quinoline carboxylic acid] which is an excellent medicinal compound having strong antibacterial activity against gram-positive and gram-negative bacteria having broad spectra and mycoplasma or its pharmacologically permissible salt with a base, preferably an alkali metal hydroxide and propylene glycol. The base is preferably used in a blend amount capable of keeping pH of the solution to 10-12 and the propylene glycol is preferably used in a blend amount of 4-8 pts.wt. based on 1 pts.wt. of the antibacterial agent. An aromatic alcohol, especially benzyl alcohol is preferably blended as a solubilizer in order to provide high concentration of the antibacterial agent.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to an injection for animals.

[0002]

Difloxacin [Chemical name: 6-fluoro-1- (4-fluorophenyl) -1,4-dihydro-]
7- (4-methyl-1-piperazinyl) -4-oxo-
3-quinolinecarboxylic acid] is an excellent pharmaceutical compound having a strong antibacterial activity against a wide spectrum of Gram positive and negative bacteria and mycoplasma.

On the other hand, in the fields of livestock and dairy farming, pneumonia and diarrhea are inevitable infectious diseases as livestock diseases. As a composition for treating these, animals in which a new quinolone antibacterial agent is dissolved with a base are dissolved. Antibacterial agents for use are known (JP-A-62-22716), and commercially available products are also known.

[0004]

However, difloxacin has a low solubility, and when a solution having a high pH by adding a base such as sodium hydroxide as described above is administered to an animal, tissue damage at the injection site is caused. There is a problem in that such damages or drug-remaining sites must be removed in order to commercialize the product because it is generated or the drug remains in the tissue.

[0005]

Means for Solving the Problems The present inventors have found that if a solution of difloxacin in which a base is added and dissolved therein is mixed with propylene glycol, when administered to livestock and poultry, the injection site is damaged and difloxacin is diminished. Remains in the tissue of
The present invention has been completed by discovering that it is improved to a degree that is hardly recognized, and the present invention based on such knowledge is that difloxacin or a pharmacologically acceptable salt thereof, a base and propylene glycol are blended. It is an animal injection.

In the injectable composition of the present invention, difloxacin may be a free form or a pharmaceutically acceptable salt. The pharmaceutically acceptable salt is preferably an inorganic or organic acid addition salt or an alkali metal salt or an alkaline earth metal salt, specifically, for example, hydrochloride, hydrobromide, sulfate, acetate. , Tartrate, benzoate, methanesulfonate, lactate, fumarate, succinate, citrate, sodium salt, potassium salt, calcium salt, magnesium salt and the like.

In the present invention, the base for dissolving difloxacin is preferably an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide.

Propylene glycol can be preferably used as long as it is used in the field of formulation technology.

In the present invention, the concentration of difloxacin in the injectable solution is not particularly limited, but a sufficient amount of difloxacin to exert a drug effect can be administered by one to several injections depending on the animal to be administered. It just needs to be a concentration,
For example, if the subject of administration is so-called pet animals such as dogs and cats, the dose is about 1-10 W / V%, preferably about 2-8.
The concentration is about W / V%, and in the case of livestock such as cattle, horses, pigs and sheep, it is about 2 to a saturated concentration, preferably about 2.5 to 30 W / V%, particularly preferably about 3 to.
It is about 15 W / V%.

The base is not particularly limited as long as it is sufficient to dissolve difloxacin. For example, the solution pH is about 1
An amount of about 0 to 12 is suitable. The blending amount of propylene glycol may be determined by the ratio to difloxacin, and in this case, about 1 part by weight or more, for example, about 3 to 10 parts by weight, preferably about 4 parts by weight, relative to 1 part by weight of the antibacterial agent.
The amount of propylene glycol in the injection is about 10 to 60 W / V%, preferably about 15 to 50 W / V when the amount of the propylene glycol is determined to be 8 parts by weight.
It is preferable to mix them so as to be about 10%.

Furthermore, in the case of increasing the concentration of difloxacin in the injectable composition of the present invention, good results can be obtained by adding an aromatic alcohol as a solubilizing agent. Examples of the aromatic alcohol include benzyl alcohol, phenylethyl alcohol, methylphenylcarbinol, cinnamyl alcohol, and the like. Among them, benzyl alcohol is preferable. For example, if benzyl alcohol is added at about 20 W / V%, the concentration of difloxacin is increased. An injectable solution of about 10 W / V% can be obtained. The blending amount of the aromatic alcohol may be appropriately determined in consideration of the blending amounts of the above-mentioned base and propylene glycol, but if benzyl alcohol is taken as an example,
It is preferable to mix it in an injection to be about 0.5 to 30 W / V%.

In the injection of the present invention, an antioxidant,
Various additives such as a thickener, a preservative and a soothing agent can be added.

The injection of the present invention is prepared by adding difloxacin to distilled water for injection and then adding a base with stirring to dissolve it, and then adding propylene glycol, or adding difloxacin to a water-propylene glycol mixture.
It can be prepared by adding a base with stirring and dissolving it to prepare a solution in which the three components are uniformly dissolved, filtering, and then filling a vial or ampoule and performing sterilization. Further, various additives to be added as needed can be appropriately added at any stage according to a conventional method of formulation technology.

The thus-obtained injectable composition of the present invention is a pet animal including birds such as dogs and cats domestically bred at home, livestock and poultry such as pigs, cows, horses, sheep and chickens,
Alternatively, it can be preferably used as an antibacterial agent for treating infectious diseases of various animals that can be raised according to the pet animals, livestock and poultry even if they are rarely raised.

[0015]

[Action]

Experimental Example 1 <Purpose> Tissue damage and persistence of the animal injection of the present invention were examined.

<Experimental Method> (1) Preparation Method of Antibacterial Agent for Injection 70 ml of distilled water for injection was placed in a beaker, each component shown in the table below and difloxacin 2.5 g were added, and sodium hydroxide was added with stirring. To dissolve the difloxacin. Then, distilled water for injection is added to make the total amount 100 ml, and after filtering with a membrane filter, it is filled in a vial bottle for 10 ml, stoppered, and sterilized by high pressure steam.

(2) Tissue damage test The injectable antibacterial agent obtained in (1) was applied to pigs (50 weeks old,
Male, weight 11 kg) in the buttocks muscle (about 1c from the muscle layer surface)
2 ml was injected into the (m deep part). On the 14th day after the administration, exsanguination was performed, the buttocks skin was peeled off, the injection site was incised, and the tissue damage at the injection site was visually observed.

(3) Tissue Persistence Test Approximately 5 to 10 g of muscle tissue around the injection site was sampled and homogenized into strips, and 1.0 g is weighed to obtain a sample. Add acetonitrile to the sample, homogenize and shake. Then, the mixture is centrifuged to separate the solvent layer. Acetonitrile is added to the precipitate and the mixture is shaken and then centrifuged to separate the solvent layer. The solvent layers are combined and concentrated to dryness, and the residue is 0.5M.
Add phosphate buffer and hexane, shake and centrifuge,
Separate the water layer. Extract the aqueous layer twice with dichloromethane,
The extract is concentrated to dryness. The obtained residue was dissolved in a mobile phase [McIlbein buffer (pH 4.4) + acetonitrile (8: 2)], and the residual amount was measured by HPLC.

(4) Results Table 1 shows the results of the above-mentioned in-tissue persistence test and storage stability test.

[0020]

[Table 1]

<Criterion for Tissue Damage> ++: Damage to muscular tissue (erythema or inflammation) of porcine injection site when a commercially available animal injection containing 2.5% enrofloxacin as an active ingredient was administered and Residual state +: Damage and residue are in a smaller range than "++" and mild, but obvious damage and residue can be confirmed.

+/-: Little damage and residue, and difficult to confirm.

-: No damage or residue can be confirmed.

Experimental Example 2 <Purpose> The formulation stability of the antibacterial agent for animals of the present invention during storage was examined.

<Experimental Method> (1) Preparation Method of Antibacterial Agent for Injection An injection was prepared in the same manner as in Experimental Example 1.

(2) Storage stability test The injectable antibacterial agent obtained in (1) was stored at 60 ° C and the appearance was examined after a certain period of time.

(3) Results The results of the storage stability test are shown in Table 2.

[0028]

[Table 2]

<Judgment> +: Precipitation of insoluble foreign matter is recognized. -: No change.

Example 1 2.5 g difloxacin and propylene glycol 2
0 g is added to 70 ml of distilled water for injection, and an aqueous sodium hydroxide solution is added with stirring to dissolve difloxacin. Then, distilled water for injection was added to make the total volume 100 ml, the mixture was filtered through a membrane filter, filled in a vial bottle for 10 ml, closed with a stopper, and sterilized under high pressure to obtain an injection for animals.

Example 2 5 g difloxacin and 50 g propylene glycol
Is added to 40 ml of distilled water for injection, and an aqueous sodium hydroxide solution is added with stirring to dissolve difloxacin.
Then, distilled water for injection was added to bring the total volume to 100 ml, filtered through a membrane filter, filled in a vial bottle for 10 ml, stoppered, and sterilized under high pressure to obtain an injectable solution for animals.

Example 3 10 g of difloxacin, 40 g of propylene glycol and 20 g of benzyl alcohol were added to 30 ml of distilled water for injection.
In addition, an aqueous sodium hydroxide solution is added with stirring to dissolve difloxacin. Then, distilled water for injection was added to make the total volume 100 ml, the mixture was filtered through a membrane filter, filled in a vial bottle for 10 ml, closed with a stopper, and sterilized under high pressure to obtain an injection for animals.

[0033]

INDUSTRIAL APPLICABILITY The injectable preparation of the present invention containing propylene glycol in a solution prepared by adding a base to difloxacin and adding it to livestock and poultry has no antibacterial agent remaining in tissues or damage to the injection site. However, it has a remarkable effect that it is hardly observed, and the formulation-preferred property that there is no precipitation of insoluble foreign matter during storage is obtained.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Motoaki Ohashi 2813-2 Angyo, Negishi, Kawaguchi City, Saitama Prefecture

Claims (2)

[Claims] 1. An injectable solution for animals, which comprises difloxacin or a pharmacologically acceptable salt thereof, a base and propylene glycol. 2. The injectable composition according to claim 1, which further contains benzyl alcohol as a solubilizing agent.