JPS6335610B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the following formula The present invention relates to a preparation for preventing and treating fish diseases, which contains a water-soluble salt of 5-nitro-(2'-p-carboxystyryl)furan as an active ingredient. The sodium salt of a compound of the formula also called niflustyrenic acid is a fish drug that is well absorbed by the fish body and exhibits effects against bacterial diseases in cultured fish both in baths and when administered orally. Generally, when a drug is used for medicinal bathing, it is required to have high solubility in water. Sodium niflustyrate has a low solubility in water.
It is 3.860 μg/ml (10°C), which fully satisfies this condition. On the other hand, in the case of so-called oral administration, in which drugs are added to the feed of farmed fish, the method of administering them to farmed fish is by adding them to minced raw feed, or adding them to mash or pellets. . At this time, due to the high solubility of sodium niflustyrate in water, a considerable amount is dissipated into the water, and it is often observed that the amount actually taken orally and absorbed into the body is significantly lower than the administered dose. Ta. The present inventors conducted various studies to solve this problem, and found that by coating the water-soluble salt of niflustyrenic acid with a specific coating agent, it was possible to prevent the active ingredient from dissipating into the water, and furthermore, to prevent the active ingredient from dissipating into the water. We have found that it is possible to improve the absorption of The present invention is based on this knowledge, and uses a water-soluble salt of 5-nitro-(2'-p-carboxystyryl)furan as an active ingredient coated with higher fatty acids and/or glycerin fatty acid esters that are solid at room temperature. It is a preparation for the prevention and treatment of bacterial diseases. As water-soluble salts of niflustyrenic acid, for example, alkali metal salts, ammonium salts, quaternary ammonium salts, etc. are used, and potassium salts and especially sodium salts are preferable for reasons of administration. The higher fatty acid or glycerin fatty acid ester used as a coating agent in the present invention is solid at room temperature and generally has a melting point of about 40°C or higher.
This type of higher fatty acids generally contains 12 or more fatty acids,
Preferably those having 12 to 22 carbon atoms are used. As glycerin fatty acid ester,
For example, hydrogenated animal and vegetable oils, such as rapeseed oil (melting point
60-63℃), hydrogenated castor oil (melting point 80-85℃), hydrogenated whale oil (melting point 50-52℃), hydrogenated beef tallow oil (melting point 54℃)
~60℃), mono- or di-fatty acid glycerides,
Examples include beef tallow, pork fat, and whale oil. These coating agents can also be used as a mixture of two or more. Also, part of the coating can be replaced by a surface active agent such as lecithin, sorbitan fatty acid ester, sucrose fatty acid ester, propylene glycol fatty acid ester, and/or an emulsifier such as beeswax. The amount of surfactant and emulsifier is generally preferred to be 0.1 to 20% of the coating. Furthermore, the formulations according to the invention can also contain active substances other than niflustyrenate. The coating preparation of the present invention can be prepared by, for example, melting the coating agent and, if desired, an emulsifier and/or a surfactant, dispersing the niflustyrenate in the melt, and then applying this dispersion to, for example, a pressure nozzle or a normal pressure nozzle. It can be produced by spray cooling using a rotating disk or the like. Further, when the niflustyrene salt dispersion in the melt is solidified while being stirred until it returns to room temperature, a granular coating preparation can be obtained. The amount of coating agent used is generally 0.1 to 5 times, preferably 0.1 to 4 times, the amount of niflustyrenate. What is important in the present invention is that the water-soluble salt of niflustyrenic acid is substantially coated with the above-mentioned higher fatty acid and/or glycerol fatty acid ester, rather than the coating method used to produce the preparation. . This is because the desired effects of the present invention can be achieved with any coated preparation produced by any method. The coating preparation of the present invention is used for the prevention and treatment of bacterial diseases in fish in the cultivation of various freshwater and saltwater fish such as carp, rainbow trout, yellowtail, eel, salmon, sweetfish, and sea bream. In use, the preparation can be administered by spraying it on water, but it is usually particularly advantageous to administer it by adding it to feed. Examples of the feed include minced live feed, mash, pellets, and commercially available feed for farmed fish. The coated formulation of the present invention very effectively prevents niflustyrenate from dissipating into water when administered to fish. Furthermore, after oral uptake, the coating is gradually digested and then absorbed, resulting in higher plasma concentrations than when niflustyrenate itself is administered, and these high concentrations remain for a long time. Lasts for hours. This fact was confirmed by the fact that when the same amount of niflustyrenate was administered orally by force in the form of pure powder and coated formulation, the coated formulation reached a higher plasma concentration. Yes (see Experimental Example 2, Table 3). As described above, according to the present invention, it is possible to obtain not only the effect of simply preventing the dispersion of drugs into water, but also the effect of improving absorption, which was completely unexpected. The excellent effects of the present invention can be obtained even when the amount of coating material is 0.1 times that of niflustyrenate, which is extremely small (see each experimental example). It is presumed that it is sufficient that the surface is partially or intermittently coated. Formulation example 1 Hardened beef tallow oil (melting point 60℃) 5.63Kg, beeswax 0.83
After heating and melting 0.21Kg of soybean lecithin and 0.21Kg of soybean lecithin, the temperature was kept at 80℃, and sodium niflustyrate was melted.
Add 3.33Kg and disperse with a homogenizer for 10 minutes. When this mixture is supplied to a rotating disk with a rotation speed of 6000 rpm and sprayed into a room controlled at 20 to 30 degrees Celsius,
A powder formulation of sodium niflustyrate is obtained whose surface is coated with hydrogenated oil. Formulation example 2 After heating and melting 0.48 kg of stearic acid (melting point 67-70°C) and 0.02 kg of sorbitan tristearate (Span 65), keeping the temperature at 80°C, add 0.5 kg of sodium nifurstyrate and disperse for 5 minutes with a homogenizer. let Thereafter, this mixture is treated in the same manner as in Example 1 to obtain a powder preparation of sodium niflustyrate whose surface is coated with stearic acid. Formulation Example 3 After heating and melting 0.8 kg of hydrogenated rapeseed oil (melting point 63°C), maintain the temperature at 80°C, add 0.2 kg of sodium nifurstyrate, and disperse for 10 minutes using a homogenizer. Thereafter, this mixture is treated in the same manner as in Example 1 to obtain a coated powder preparation of sodium niflustyrate. Formulation example 4 Put 0.18 kg of hardened beef tallow oil (melting point 60°C) and 0.02 kg of soybean lecithin into a kneader with a jacket, heat and melt, then maintain the temperature at 85°C, gradually add 1.8 kg of sodium nifurstyrate, and mix the molten hardening. Mix thoroughly so that the oil and sodium niflustyrate are evenly mixed. Next, stop heating and continue mixing. As the temperature drops, the hydrogenated oil will solidify.
Grinding yields a granular formulation of sodium niflustyrate, which is optionally sieved through a suitable sieve. The coated formulation used in the following experimental example was produced in the same manner as Formulation Example 3 by coating sodium niflustyrate with a predetermined coating agent. Experimental example 1 In a beaker filled with water (20℃) from 1, pure sodium niflustyrate powder or this
Add the preparation coated with 0.1 to 6 times the amount of hydrogenated beef tallow oil,
After stirring with a stirrer, the concentration of sodium nifurstyrate in water was determined after 60 minutes, and the dissolution rate was calculated.
The results are shown in Table 1, and it is recognized that elution can be significantly prevented even when a small amount of coating agent is used.

【table】

[Table] Experimental Example 2 14 carp weighing 850 to 1140 g were used as test fish. At a water temperature of 20°C, pure sodium niflustyrate powder or a preparation coated with 0.1 to 6 times the amount of stearic acid was added to the active substance 50% of each powder.
The drug was administered orally by force or by ad libitum feeding at a concentration of mg/Kg fish body weight, and the plasma concentration in the same individual was measured over time. The results are shown in Tables 2 and 3.
Shown in the table. The plasma concentration of sodium niflustyrate is
The blood collected from the Cupier's tube was centrifuged at 3000 rpm, and the concentration of sodium nifurstyrate in the supernatant was measured using the microbial assay method of Yone et al. using Bacillus natuto (Yasuo Yone, "Fish Disease Research", Vol. 7, 64). ~
66, 1972). In addition, in Experimental Examples 3 and 4 below, plasma concentrations were measured in the same manner.

【table】

[Table] From these experiments in carp, it was found that a preparation of sodium niflustyrate coated with 0.1 to 4 times the amount of stearic acid was absorbed into plasma for a long time at a significantly higher concentration than sodium niflustyrate itself. Is recognized. In addition, in a forced oral administration experiment, when comparing the absorption of the same amount of sodium niflustyrenate between pure powder and coated formulation, it was found that the coated formulation clearly maintained a higher plasma concentration for a longer period of time, indicating that the absorption was improved. Is recognized. In these experiments, preparations coated with higher fatty acids or glycerin fatty acid esters in an amount more than 6 times the amount of sodium niflustyrate were clearly poorly absorbed, so from then on, preparations coated with higher fatty acids or glycerin fatty acid esters in an amount of more than 6 times the amount of sodium niflustyrate were used. Experiments were conducted using formulations coated with the coating agent. Experimental Example 3 Thirty rainbow trout with an average weight of 40 g were used as test fish. At a water temperature of 12°C, pure sodium niflustyrenate powder or a preparation coated with 0.1 to 5 times the amount of hydrogenated beef tallow oil was administered to the fish at an amount of 50 mg of active substance/Kg of fish body weight, and then fed ad libitum. Blood was collected over time and the blood concentration was measured. The results are shown in Table 4.

[Table] From this experiment, it was confirmed that even in rainbow trout, a preparation of sodium niflustyrate coated with a coating agent of 0.1 to 5 times the amount maintains a higher concentration in the blood for a longer period of time than pure sodium niflustyrate powder. . Experimental Example 4 An experiment was conducted using yellowtail, which is a representative species of marine cultured fish. A yellowtail weighing 90 g was fed ad libitum with pure sodium niflustyrenate powder or a preparation coated with 0.1 to 5 times the amount of hydrogenated rapeseed oil at a water temperature of 25°C at a rate of 100 mg of active substance/kg of fish body weight. It was administered via feed, and blood was collected over time to measure the blood concentration. The results are shown in Table 5.

[Table] From these results, it is clear that the coated preparation of the present invention exhibits an excellent absorption improvement effect even in the marine fish yellowtail. In Experimental Examples 2 to 4 described above, it was confirmed that the absorption of water-soluble salts of niflustyrenic acid in healthy fish was significantly improved by the coated preparation of the present invention, and therefore, the administration of this preparation could protect fish from bacterial diseases. It can be prevented. Experimental Example 5 The effect of this coating preparation on tuberosity, which is a bacterial disease that occurs during the young yellowtail stage (the stage called mojiako), was tested. As the test fish, we used a porcupine fish with an average weight of 5.5 g. The number of fish in each test area was 2000, 3m x 3m x
They were kept in a small 3m cage. As for bait, sardines were fed twice a day in normal amounts. The water temperature during the experiment was 22-25°C. Four days after the start of the experiment, nodular disease developed, and at the same time this was confirmed by a bacterial test, drug administration was started and continued for 5 consecutive days.
The drug was mixed with the feed and administered at a dose of 50 mg/Kg. The effectiveness was evaluated based on the number of deaths up to 10 days after the start of drug administration. The results are shown in Table 6.

[Table] *Date of administration Due to individual differences in Mojiyako, the ease of infection, severity of disease, amount of food consumed, etc. will vary among each individual.
From these results, it is recognized that the coated preparation of the present invention enhances the effect of sodium niflustyrate itself and exhibits excellent preventive and therapeutic effects.

Claims (1)

[Claims] 1 5-nitro- coated with higher fatty acids and/or glycerin fatty acid esters that are solid at room temperature
A preparation for the prevention and treatment of bacterial diseases in fish, containing a water-soluble salt of (2'-p-carboxystyryl)furan as an active ingredient.