WO2023032049A1 - Oral administration drug for aquatic animals - Google Patents

Abstract

The oral administration drug for aquatic animals of the present invention, which is in a powder form without granulation, contains 0.1 wt% or more of a medicinal ingredient based on the total weight of the drug, 15-96.9 wt% of a carbon powder based on the total weight of the drug, and 3-15 wt% of moisture based on the total weight of the drug. This oral administration drug for aquatic animals suppresses a decrease in the potency of the medicinal ingredient during storage, is less likely to scatter during handling, and has excellent adhesion to feeds. The powdery oral administration drug for aquatic animals without granulation can be used in aquaculture of aquatic animals.

Description

Orally administered drug for aquatic animals

The present disclosure relates to an orally administered drug for aquatic animals that contains a medicinal ingredient, carbon powder and water and is not granulated. Further, the present disclosure relates to a method for producing the orally administered aquatic pharmaceutical and a method of administering the orally administered aquatic pharmaceutical to an aquatic animal to prevent and/or treat diseases of the aquatic animal.

In the aquaculture of aquatic animals, pathogenic bacteria and parasites can invade from the outside to the cage in which aquatic animals are cultivated, so prevention and treatment of aquatic animal diseases caused by these must always be considered. . In order to treat a disease, generally, a disease-appropriate drug is attached to or mixed with feed for aquatic animals, and this feed for aquatic animals is administered to aquatic animals. In recent years, in the aquaculture of red sea bream and yellowtail, conventional mixed feed, that is, moist pellet (MP) feed is artificial solid feed for reasons such as improving the meat quality of farmed fish and making farming work easier. There is a transition to extruder pellet (EP) feed. When administering a drug to fish using MP feed, the drug could be reliably administered to the fish because the drug could be kneaded into the feed.

On the other hand, in the case of EP feed, since the drug cannot be mixed into the EP feed, a water-soluble spreading agent such as guar gum is used to attach the drug to the surface of the EP feed, which is then administered to fish. . However, since the EP feed contains a large amount of lipid, the water-soluble spreading agent is not effective for the EP feed. Easily released from feed. In the case of the EP feed, 50% or more of the adhered drug may be washed away into the seawater and not taken into the body of the fish. The outflow of drugs into environmental water not only causes economic losses, but also poses the risk of emergence of drug-resistant bacteria. In addition, when a conventional water-soluble spreading agent is used, a mixture of the water-soluble spreading agent and the agent adheres to the equipment used to attach the agent to the EP feed, and the agent remains on the equipment. I was afraid. If a device with residual chemicals is used to feed fish just before shipment, there is a possibility that the residual chemicals will be detected in the fish at the time of shipment and shipment will be suspended.

In order to solve the above-mentioned problems, Patent Document 1 (Japanese Patent Application Laid-Open No. 2006-340622) reports a technique of using carbon powder as a spreading agent for binding EP feeds and drugs. In the case of using carbon powder as a spreading agent, the technique used differs depending on the user, and even if the same amount of the same agent is mixed, there may be a large difference in the therapeutic effect.

A technique has been reported in which carbon powder is used as an excipient for drugs, instead of using carbon powder as a spreading agent (Patent Document 2: Japanese Patent Application Laid-Open No. 2007-523108). In addition, as a drug containing a medicinal ingredient and carbon powder, a solid orally administered drug for fish formed by a method including a step of granulating a mixture containing a medicinal ingredient and carbon powder has been reported (Patent Document 3: Japanese Patent Laid-Open No. 2017-8012). As a result of examination by the present inventors, some drugs using carbon powder as excipients show a marked decrease in potency of medicinal ingredients during long-term storage due to the inherent water absorption of the carbon powder. rice field. When the carbon powder is used as a spreading agent in aquaculture, the carbon powder is mixed with the medicinal ingredient and immediately administered to the aquatic animals, and is not stored for a long period of time. Therefore, since the water absorbency of carbon powder does not deny the use of carbon powder as a spreading agent, it was unexpected that the potency of the medicinal ingredient decreased when carbon powder was used as an excipient. .

In order to avoid the above-mentioned problems caused by using carbon powder as an excipient, it was considered to reduce the amount of water contained in carbon powder. However, since carbon powder has a low specific gravity, it has been found that if the amount of water contained in carbon powder is reduced, the carbon powder tends to scatter under the influence of wind during aquaculture work. As described above, when carbon powder is used as an excipient for pharmaceuticals, it has become clear that it is necessary to strike a balance between suppressing a decrease in potency and ease of handling, such as suppressing scattering at aquaculture sites. rice field.

Japanese Patent Application Laid-Open No. 2006-340622 JP-A-2007-523108 Japanese Patent Application Laid-Open No. 2017-8012

An object of the present invention is to provide an orally administered drug for aquatic animals that can suppress the decrease in the potency of the medicinal ingredient during storage, is less likely to scatter during handling, and has excellent adhesion to feed.

One embodiment of the present invention comprises 0.1% or more of active ingredient by weight based on the total weight of the drug, 15-96.9% by weight of carbon powder based on the total weight of the drug, and the total weight of the drug. To provide a non-granulated powdery orally administered drug for aquatic animals containing 3 to 15% by weight of water based on .
An embodiment of the present invention comprises preparing a carbon powder containing water in an amount of 3-15% by weight based on the total weight of the drug, and mixing the carbon powder containing water with the active ingredient, A method is provided for producing the above-described orally administered aquatic animal medicament.
One embodiment of the present invention provides a method of preventing and/or treating a disease in an aquatic animal by administering to the aquatic animal the above-described orally administered aquatic animal medicament.

In one embodiment of the present invention, the orally-administered drug for aquatic animals is capable of suppressing a decrease in efficacy of medicinal ingredients during storage, is less likely to scatter during handling such as attachment to feed, and adheres to feed. There is an advantageous effect that it is excellent in

Fig. 10 is a graph showing the relationship between the ratio of the medicinal ingredient washed out into water from the drug spread on the EP feed and the content of carbon powder in the drug. 1 is a graph showing changes over time in potency of erythromycin remaining in drugs when drugs containing 11-15% by weight of water are stored. 1 is a graph showing changes over time in the potency of erythromycin remaining in drugs when drugs containing 20-25% by weight of water are stored.

One embodiment of the present invention comprises 0.1% or more of active ingredient by weight based on the total weight of the drug, 15-96.9% by weight of carbon powder based on the total weight of the drug, and the total weight of the drug. It contains 3 to 15% by weight of water based on , and is a non-granulated powdery drug for oral administration for aquatic animals.

In the present invention, the medicinal ingredient is not particularly limited as long as it has some useful effect on aquatic animals. In one embodiment of the present invention, the medicinal ingredient is a medicinal ingredient that prevents and/or treats diseases of aquatic animals, and a medicinal ingredient that maintains the health and/or improves meat quality of aquatic animals. Possible. In one embodiment of the present invention, medicinal ingredients can be, for example, antibiotics, synthetic antibacterial agents, antiparasitic agents, vitamins, minerals, amino acids, color enhancing agents (eg, carotenoids), and the like. In one embodiment of the present invention, the medicinal ingredients include macrolides, tetracyclines, fluoroquinolones, thiamphenicols, benzimidazoles, sulfa drugs, ursodeoxycholic acid, amino acids, water-soluble vitamins (e.g. , vitamins B1, B2, niacin, pantothenic acid, B6, biotin, B12, folic acid, and ascorbic acid), fat-soluble vitamins (such as vitamins A, D, and E), minerals, carotenoids (such as astaxanthin , canthaxanthin, carotenes, and lutein). In one embodiment of the present invention, active ingredients include, for example, praziquantel (PZQ), salicylanilide drugs, ivermectin, erythromycin (EM), oxytetracycline (OTC), florfenicol, thiamphenicol, and oxolinic acid. , sulfamonomethoxine sodium (Dimeton (registered trademark) soda), sulfizol sodium (Islan (registered trademark) soda), ST formulation (a combination of sulfamethoxazole and trimethoprim), febantel, albendazole, acetic acid Tocopherols, ascorbic acid, glutathione, astaxanthin, and the like can be mentioned. In one embodiment of the invention, the active pharmaceutical ingredient can be oxytetracycline. The active ingredient may be in the form of not only the compound itself, but also its hydrates and salts. For example, oxytetracycline may be in the form of its hydrochloride salt. In addition, the medicinal ingredient contained in the drug for oral administration for aquatic animals of the present invention may be of not only one kind but also a plurality of kinds. famethoxazole and trimethoprim)).

In one embodiment of the present invention, the amount of the active ingredient contained in the orally administered drug for aquatic animals is 0.1% by weight or more, preferably 0.1 to 77% by weight, based on the total weight of the drug. and more preferably 1 to 70% by weight.

In the present invention, the carbon powder may be derived from any substance. For example, the carbon powder can be prepared by pulverizing any charcoal such as Bincho charcoal, black charcoal, coconut husk charcoal, coffee charcoal, bamboo charcoal, and activated charcoal. In one embodiment of the present invention, the carbon powder may include bamboo charcoal powder, charcoal powder, coconut husk charcoal powder, coffee charcoal powder, activated carbon powder, and the like. In one embodiment of the present invention, preferably the carbon powder is selected from the group consisting of bamboo charcoal powder, charcoal powder and coconut husk charcoal powder, more preferably the carbon powder is bamboo charcoal powder or coconut husk charcoal powder, still more Preferably, the carbon powder is bamboo charcoal powder.

The size of the carbon powder is not particularly limited as long as it does not contradict the purpose of the present invention, but the particle size of the carbon powder is preferably a size that passes through 50 mesh. As used herein, with respect to particle size, the "size that passes through the X mesh" is also referred to as the "X mesh pass", and the "size range that passes through the X mesh but does not pass through the Y mesh" is referred to as "X Also referred to as "mesh pass Y mesh on". 

In one embodiment of the present invention, the amount of carbon powder contained in the orally administered drug for aquatic animals is preferably 15-96.9% by weight based on the total weight of the drug, and more preferably, 30 to 90% by weight.

In one embodiment of the present invention, from the viewpoint of suppressing a decrease in the potency of the medicinal ingredient during storage and preventing solidification of the powdered drug, the amount of water in the orally administered drug for aquatic animals is Based on the total weight, it is preferably 15 wt% or less, more preferably 12 wt% or less. In one embodiment of the present invention, from the viewpoint of suppressing scattering of carbon powder during aquaculture work and improving workability, the water content in the orally administered drug for aquatic animals is , preferably 3% by weight or more, more preferably 4% by weight or more. In one embodiment of the present invention, the water content in the orally administered drug for aquatic animals is preferably 3-15 wt%, more preferably 4-12 wt%, based on the total weight of the drug. is.

In one embodiment of the present invention, the orally administered drug for aquatic animals is in the form of a non-granulated powder. The term “non-granulated powder” refers to the method disclosed in Patent Document 3 (Japanese Patent Application Laid-Open No. 2017-8012), which includes the step of “granulating a mixture containing a medicinal ingredient and carbon powder. This clarifies the difference from the solid form of oral administration drug for fish. That is, in the drug of the invention disclosed in Patent Document 3, a mixture of a medicinal ingredient and carbon powder is granulated and integrated by applying pressure or using a binder such as starch or flour. It has a shape of molded body (for example, granule, tablet, pellet, etc.). On the other hand, the drug of the present invention is "ungranulated powder" and is different from the drug disclosed in Patent Document 3.

In one embodiment of the present invention, where agglomerates that are easily broken by hand are partially present in the powdery mixture, such agglomerates are granulated into a unitary solid form. Not applicable to the body.

In the present invention, "aquatic animals" are animals that live in water, and include, but are not limited to, fish and decapods such as shrimp and crab. Preferably, the aquatic animal is fish.

The orally administered drug for aquatic animals of the present invention may further contain any other materials other than carbon powder and water, such as excipients, as long as it does not contradict the purpose of the present invention. Excipients include, but are not limited to, glucose, lactose, calcium carbonate, talc, bentonite, rice bran, and the like.

In one embodiment of the present invention, the orally administered drug for aquatic animals of the present invention can be produced by mixing the active ingredients, carbon powder, and water as raw materials. If the carbon powder and/or medicinal ingredients used as raw materials contain a sufficient amount of water to be contained in the drug, the drug of the present invention can be produced by mixing these raw materials without adding additional water. can be manufactured by (In this specification, the carbon powder used as a raw material can also be referred to as a carbon powder material. In this specification, the medicinal ingredient used as a raw material can also be referred to as a medicinal ingredient material.) This mixing method is , but not particularly limited as long as it does not contradict the object of the present invention. In this embodiment, the order of mixing the medicinal ingredient, carbon powder, and water is not particularly limited, but after preparing the carbon powder containing water in an amount of 3 to 15% by weight based on the total weight of the drug, It is preferable to mix the water-containing carbon powder and the medicinal ingredient.

In one embodiment of the present invention, the medicinal ingredient used as a raw material for producing the drug for oral administration for aquatic animals of the present invention may be in the form of a powder or a solution in a solvent such as an aqueous solution. state. When the medicinal ingredient used as a raw material is a medicinal ingredient powder, the size of the medicinal ingredient powder is not particularly limited, and is preferably a size that can pass through 50 mesh.

In one embodiment of the present invention, the orally administered drug for aquatic animals is obtained by mixing carbon powder containing water in an amount of 3 to 15% by weight based on the total weight of the drug, and active ingredient powder. can be manufactured. In another embodiment of the present invention, an orally administered drug for aquatic animals can be produced by mixing carbon powder, which may contain water, active ingredient powder, and additional water. One embodiment of the present invention comprises 0.1% or more by weight of active ingredient powder based on the total weight of the drug, 15-96.9% by weight of carbon powder based on the total weight of the drug, and the total weight of the drug. It is a non-granulated, powdery orally administered drug for aquatic animals containing 3 to 15% by weight of water.

In one embodiment of the present invention, the orally administered drug for aquatic animals of the present invention may be enclosed in a sealed container. By enclosing the drug in a sealed container, it is possible to suppress the reduction and increase of water contained in the drug, and to maintain the drug in an appropriate state. The hermetic container is not particularly limited as long as it can suppress fluctuations in water content in the sealed medicine. Examples of sealed containers include, but are not limited to, aluminum foil bags, polypropylene bags, and the like. Also, the sealed container may be a container formed of two or more layers.

In one embodiment of the present invention, the orally administered drug for aquatic animals can be used together with feed for aquatic animals, preferably feed for fish farming. The form of the feed for aquatic animals that can be used together with the orally administered drug for aquatic animals is not particularly limited, but the feed for aquatic animals is preferably in a solid form, for example, in the form of pellets, and more preferably extruder pellets (EP). It is fodder. In one embodiment of the present invention, the powdered orally administered aquatic medicament may be present on the surface of the aquatic feed. In one embodiment of the present invention, the orally administered pharmaceutical agent for aquatic animals of the present invention can be used in a state of adhering to the surface of feed for aquatic animals. In one embodiment of the present invention, the orally administered drug for aquatic animals of the present invention is a drug that is adhered onto the surface of extruder pellets and orally administered to aquatic animals.

The raw material for extruder pellet feed for aquatic animals may be a general raw material for manufacturing extruder pellet feed for aquatic animals, and is not particularly limited. In addition, the manufacturing method may also be a general method. For example, extruder pellet feed for aquatic animals is formed by extruding and granulating the raw material mixture with an extruder to form granules, and if necessary, can be produced by drying

Further, the extruder pellet feed for aquatic animals preferably contains 10 to 50% by weight of fishmeal, 5 to 30% by weight of soybean meal, 1 to 5% by weight of starch, 3 to 30% by weight of fish oil, and 1 to 2% by weight of vitamins. , and 5 to 30% by weight of water (100% by weight in total) as raw materials, but are not limited thereto.

Subjects to which the orally administered drug for aquatic animals of the present invention is administered are not particularly limited as long as they are aquatic animals such as fish and decapods, but are preferably perciformes, such as yellowtail, red sea bream, horse mackerel, greater amberjack, Sea bass, striped trevally, amberjack, tuna, bluefin tuna, yellowfin tuna, mackerel, Japanese cedar, longtooth grouper, grouper, ara, grunt, tilapia, etc. Salmoniform fish such as Atlantic salmon (Atlantic salmon), salmon trout, Chinook salmon (King salmon), Coho salmon, rainbow trout, yamame trout, amago, char, cherry salmon, satsuki trout, sweetfish, flatfish, such as flounder, spotted flounder, marbled flounder, matsukawa, puffer fish, such as tiger puffer, filefish, and black tang, cyprinid fish, Examples include carp, forsythia, grass carp, catfish, catfish, eels, such as eel, more preferably yellowtail, amberjack, amberjack, red sea bream, tuna, bluefin tuna, Atlantic salmon (Atlantic salmon ), silver salmon, rainbow trout, cherry salmon, satsuki trout, flounder, tiger puffer fish, tilapia, carp, forsythia, grass carp, catfish, eel, and more preferably yellowtail, amberjack, amberjack, tuna, Atlantic salmon (Atlantic salmon). , tilapia, carp, forsythia, grass carp, catfish, eel.

One embodiment of the present invention is a method of preventing and/or treating a disease in an aquatic animal by administering the orally administered drug for aquatic animal of the present invention to the aquatic animal. The mode of administering the orally administered drug for aquatic animals of the present invention to an aquatic animal may be a mode in which the drug is directly administered to the aquatic animal, or an aquatic animal feed with the drug adhered to the surface, preferably feed for aquatic animals. Alternatively, the extruder pellet feed may be administered to an aquatic animal. A disease targeted for prevention and treatment is a disease targeted for prevention and/or treatment by an active ingredient contained in a drug, and is not particularly limited. Moreover, the aspect which simultaneously prevents and treats several types of diseases is also included in the scope of the present invention. The dose and administration period of the drug to aquatic animals vary depending on the type of medicinal ingredient, the size of the target aquatic animal, the water temperature, etc., and are not particularly limited.
EXAMPLES The present invention will be described in detail below with reference to examples, but the present invention is not limited to the scope of the examples.

Test Example 1: Spreading property of the agent of the present invention to extruder pellet (EP) feed In Test Example 1, a conventional spreading agent other than carbon powder was used to spread the medicinal ingredient to the EP feed. The spreadability of the drug of the present invention was examined in comparison with the case.
The preparation method of the EP feed on which the drug was spread was as follows.
Example 1: The carbon powder material used to make the drug of Example 1 contains 5.6 wt% moisture based on the weight of the carbon powder material and is bamboo charcoal with a size of 100 mesh pass. It was powder. In addition, the active ingredient material used to manufacture the drug of Example 1 was praziquantel (PZQ) powder (praziquantel bulk powder, 100 mesh pass). A powder drug was prepared by mixing 0.18 g of carbon powder material and 0.02 g of active ingredient powder material. The amounts of bamboo charcoal powder, PZQ, and water in the prepared drug were 74.4 wt%, 20 wt%, and 5.6 wt%, respectively, based on the total weight of the drug. This drug (0.2 g) was added to 20 g of EP feed (size: 13 mm, fat content: 22%), stirred for 1 minute and allowed to stand for 15 minutes to obtain an EP feed spread with the drug of the present invention. rice field.
Comparative Example 2: To 20 g of EP feed (size 13 mm, fat content 22%), a powder drug (0.2 g) containing PZQ powder and glucose (PZQ: glucose = 2:8 weight ratio) was added, and water was added to 0.2 g. After adding 2 mL, 0.2 g of guar gum was added and allowed to stand for 15 minutes to allow the active ingredient (PZQ) to spread on the EP feed.

Elution test method Put 500 mL of artificial seawater in a beaker equipped with a stirring bar, rotate the stirring bar at 150 rpm, and put the EP feed spread with the drug of Example 1 or Comparative Example 2 into the artificial seawater. After 5 seconds and 30 seconds, a portion of artificial seawater and EP diet were collected respectively. HPLC samples were prepared from the collected artificial seawater and EP feed according to the HPLC sample preparation method described below. Each sample was analyzed by HPLC under the following HPLC conditions to determine the amount of PZQ in artificial seawater and the amount of PZQ remaining in the EP feed. The washout rate was determined according to the following formula:
Washout rate = (total weight of PZQ in artificial seawater)/(total weight of PZQ in artificial seawater + total weight of PZQ remaining in EP feed).

Method of preparing samples for HPLC About 1 g of recovered EP feed or artificial seawater was precisely weighed into a 100 mL volumetric flask. Add about 50 mL of ethanol to the volumetric flask, apply ultrasonic waves for 20 minutes to dissolve PZQ, then add ethanol to the contents of the volumetric flask to adjust the contents of the volumetric flask to 100 mL, to obtain a PZQ-containing sample solution. got The PZQ-containing sample solution was diluted with ethanol so that the concentration of PZQ was approximately 100 μg/mL. The diluted PZQ-containing sample solution was filtered through a 0.45 μm membrane filter to obtain a sample for HPLC.
The HPLC analysis conditions were as follows.
Column: C18, Wako Handy ODS 150 mm
Mobile phase: acetonitrile: water = 60:40
Column temperature: room temperature
Flow rate: 1.0ml/min
Injection volume: 10 μL
Detection: UV (210 nm)
Analysis time: 8 minutes Quantification: Absolute calibration curve method (PZQ standard: Wako Pure Chemical)
Measurement range: 0.01-10 μg/mL.

In the case of the agent of the present invention using carbon powder (Example 1), the outflow rate of the medicinal ingredient into artificial seawater was 10.3% after 1 second, 12.9% after 5 seconds, and 12.9% after 30 seconds. Later it was 12.9%. On the other hand, when guar gum was used as the spreading agent (Comparative Example 2), the outflow rate of the medicinal ingredient into the artificial seawater was 17.0% after 1 second, 41.0% after 5 seconds, and 41.0% after 30 seconds. Later it was 61.8%. From this, it was clarified that the agent of the present invention containing carbon powder can significantly suppress the outflow of medicinal ingredients into seawater compared to the agent using a conventional spreading agent without using carbon powder. .

Test Example 2: Spreadability of the drug of the present invention to EP feed In Test Example 2, the difference in spreadability of the drug of the present invention to EP feed was examined when the type of carbon powder was changed. .
In Test Example 2, the following materials were used.
Praziquantel (PZQ) powder (praziquantel bulk powder, 100 mesh pass) was used as a medicinal ingredient material.
Bamboo charcoal powder (containing 5.6% by weight of water based on the weight of the carbon powder raw material) and coconut husk charcoal powder (containing 5.0% by weight of water based on the weight of the carbon powder raw material) were used as carbon powder materials. was used), and activated carbon powder (which contained 1.0 wt% moisture based on the weight of the carbon powder feedstock).
As the EP feed, yellowtail EP (13 mm, 22% fat) was used.

Preparation of Carbon Powder-Containing Drugs Carbon powder-containing drugs of Examples 3-5 were prepared as shown below.
Example 3: PZQ powder (0.13 g) was added to bamboo charcoal powder (0.4 g) and mixed to prepare a PZQ agent containing carbon powder. The formulation of Example 3 contained 4.5% water by weight based on the weight of the total formulation.
Example 4: PZQ powder (0.13 g) was added to coconut husk charcoal powder (0.4 g) and mixed to prepare a PZQ agent containing carbon powder. The formulation of Example 4 contained 4.0% water by weight based on the weight of the total formulation.
Example 5: PZQ powder (0.13 g) was added to activated carbon powder (0.4 g) and mixed to prepare a PZQ drug containing carbon powder. The formulation of Example 5 contained 0.8% water by weight based on the weight of the total formulation.

Spreadability test method 20 g of EP feed and the drug (0.53 g) of Example 3, Example 4 or Example 5 are stirred and mixed for 1 minute in a 500 ml beaker, and left for 15 minutes to spread to the EP feed. The drug was allowed to spread.
In a dissolution tester (NTR-6200A), while rotating the paddle at 150 rpm, the EP feed spread with the drug of Example 3, Example 4 or Example 5 was put into 500 ml of artificial seawater, and the contents The mass was stirred (150 rpm) for 1 minute. By this operation, the medicinal ingredient (PZQ) was washed away from the drug adhering to the EP feed into the artificial seawater, producing artificial seawater containing the medicinal ingredient. The EP feed and artificial seawater were each collected from the elution tester. Samples for HPLC were prepared from the recovered EP feed and artificial seawater. This sample was analyzed by HPLC to identify the amount of PZQ in the artificial seawater and the amount of PZQ remaining in the EP feed. The HPLC sample preparation method and HPLC measurement conditions were the same as in Test Example 1. Table 1 shows the results. The washout rate in Table 1 is the average of the values obtained in three tests.

Regardless of whether the carbon powder was bamboo charcoal powder, coconut husk charcoal powder, or activated charcoal powder, the drug containing carbon powder showed good spreadability to the EP feed.

Test Example 3: Spreadability of the drug of the present invention on EP feed In Test Example 3, the relationship between the content of carbon powder in the drug and the spreadability of the medicinal ingredient on EP feed was examined. was broken
In Test Example 3, the following materials were used.
Erythromycin (EM) powder (erythromycin bulk powder) was used as a medicinal ingredient.
Bamboo charcoal powder (150 mesh pass, moisture content 5.6% by weight) was used as the carbon powder material.
As EP diet, EP diet with 22% crude fat and 13 mm size was used.

In the amounts shown in Table 2 of the spreadability test method, the medicinal ingredient material (erythromycin (EM) powder) and the carbon powder material (bamboo charcoal powder containing 5.6% by weight of water) were mixed to obtain Examples 6 to 8 and Drugs of Comparative Examples 9-10 were prepared. The formulation of Example 6 contained 90% by weight carbon powder material (85.0% by weight bamboo charcoal powder and 5% by weight water). The formulation of Example 7 contained 22% by weight carbon powder material (20.8% by weight bamboo charcoal powder and 1.2% by weight water). The formulation of Example 8 contained 15% by weight carbon powder material (14.2% by weight bamboo charcoal powder and 0.8% by weight water). The formulation of Comparative Example 9 contained 10% by weight carbon powder material (9.4% by weight bamboo charcoal powder and 0.6% by weight water). The formulation of Comparative Example 10 did not contain a carbon powder material.

The prepared drug (approximately 0.2 g) and the amount of EP feed shown in Table 2 (approximately 20 g) were stirred in a beaker for 1 minute and allowed to stand for 15 minutes to allow the drug to spread on the EP feed. rice field. 500 mL of water was placed in a beaker equipped with a stirrer (manufactured by AZ-ONE), and while the water was being stirred at a rotational output of the stirrer of 50%, the drug-spreading EP feed was put into the water. After 15 seconds, the EP feed was taken out and the water in the beaker was collected. Samples for HPLC for quantification of erythromycin were prepared from the collected water according to the following procedure. Two formulations were prepared for each of Examples 6-8 and Comparative Examples 9-10. Two spreading tests were performed for each example and comparative example using the two agents separately.

Method for preparing sample for HPLC A sample (that is, collected water) containing about 100 mg of EM (potency: weight as EM) was precisely weighed and placed in a 100 mL volumetric flask. 25 mL of methanol was added to the volumetric flask to dissolve the erythromycin contained in the sample. 0.1 mol/mL phosphate buffer of pH 8.0 was added to this solution to bring the contents of the volumetric flask to 100 mL. (The phosphate buffer solution is 250 mL of 0.2 mol/L potassium dihydrogen phosphate aqueous solution (this potassium dihydrogen phosphate aqueous solution is obtained by dissolving 27.218 g of potassium dihydrogen phosphate in water to make 1000 mL. ), 230.5 mL of 0.2 mol/L sodium hydroxide aqueous solution (this sodium hydroxide aqueous solution was prepared by adding freshly boiled and cooled water to 8.0 g of sodium hydroxide and dissolving it to make 1000 mL. ), and water to bring the total to 1000 mL). 2 filter paper. The filtered solution was diluted with 0.1 mol/mL phosphate buffer pH 8.0 to obtain 100 mL diluted solution so that the concentration of EM was about 1000 μg (potency)/mL. This diluted solution was filtered through a 0.45 μm membrane filter to obtain a sample for HPLC.

This HPLC sample is analyzed by HPLC and the amount of EM contained in the sample is measured to identify the amount of EM that has flowed out into the water when the drug-spreading EP feed is put into water, The EM washout rate was calculated according to the following formula:
Efficiency of medicinal ingredient = [total weight of EM in water/total weight of EM spread on EP feed (weight of EM shown in Table 2)].
Also, for each example or comparative example, the mean and standard deviation (SD) of two experiments were calculated.

The HPLC analysis conditions were as follows.
HPLC apparatus: Waters e2695,
Column: C18, Wako Handy ODS 150mm
Mobile phase: acetonitrile: water: 25% aqueous ammonia = 75:25:0.3
Column temperature: 40°C
Flow rate: 1.0 mL/min
Injection volume: 10 μL
Detection: UV (215 nm)
Quantification: Absolute calibration curve method (Erythromycin standard product: Wako Pure Chemical)
Measurement range: 100-10000 μg/mL.

The results are shown in Table 3 and Figure 1.

When the amount of bamboo charcoal powder was 85.0% by weight (Example 6), the outflow rate of the active ingredient was 2.35%. When the amount of bamboo charcoal powder was 20.8% by weight (Example 7), the outflow rate of the active ingredient was 7.89%. When the amount of bamboo charcoal powder was 14.2% by weight (Example 8), the outflow rate of the medicinal ingredient was 11.40%. When the amount of bamboo charcoal powder was 9.4% by weight (Comparative Example 9), the outflow rate of the medicinal ingredient was 55.37%. When the amount of bamboo charcoal powder was 0% by weight (Comparative Example 10), the outflow rate of the medicinal ingredient was 62.11%. In both cases, the outflow rate of medicinal ingredients into seawater was low, but the outflow rate exceeded 50% when the bamboo charcoal powder content became 10% or less, indicating that the bamboo charcoal powder is suitable for use as a medicine. It can be said that the content of is desirably 15% or more. From the above, it was confirmed that a drug suitable for oral administration to aquatic animals can be provided by adding 15% by weight or more of carbon powder to the drug, which can suppress the outflow of the medicinal ingredient into seawater.

Test Example 4: Scattering properties of the drug of the present invention In Test Example 4, the relationship between the water content in the drug and the scattering properties of the drug was examined when the content of carbon powder in the drug was relatively small. was done.
In Test Example 4, oxytetracycline (OTC) powder (oxytetracycline hydrochloride raw powder, 30 mesh pass) was used as the medicinal ingredient, and bamboo charcoal powder (100 mesh pass) was used as the carbon powder material. Medicinal ingredient material, carbon powder material and water were mixed so as to contain bamboo charcoal powder, oxytetracycline powder and water in the amounts shown in Table 4 to prepare the drugs of Comparative Examples 11 and 12 and Examples 13 and 14. bottom. In Test Example 4, the total amount of bamboo charcoal powder and water was set to 30% by weight based on the weight of the entire drug, and the amount of OTC was set to 70% by weight based on the weight of the entire drug. rice field.

Chemical Scattering Test Method The chemical scattering test is a test that simulates chemical scattering when the chemical is spread on feed at aquaculture sites. The scattering property of the drug was evaluated by dropping the manufactured powdered drug from above and visually confirming the degree of scattering of the powdered drug when the falling powdered drug was subjected to a constant wind from an electric fan. The evaluation criteria are as follows: ○ (no problem with scattering), △ (a little problem with scattering, but usable level if endured), × (unsuitable for use at aquaculture sites due to excessive wind influence) ). The evaluations ◯ and Δ were regarded as acceptable, and the evaluation × was regarded as unacceptable. Results are shown in Table 4.

When the water content is 2% by weight or less based on the total weight of the drug (Comparative Examples 11 and 12), the drug is easily blown away by the wind when used at the aquaculture work site, and the worker ingests it, resulting in health hazards. It was confirmed that it is not suitable as a pharmaceutical for farmed fish. When the water content was 3% by weight based on the total weight of the drug (Example 13), there was a slight problem with scattering, but it was at a level that could be used if endured. It was confirmed that when the water content was 4% by weight based on the total weight of the drug (Example 14), there was no problem with scattering. From the above, it was clarified that the agent of the present invention can be used without problems at aquaculture sites if the water content is 3% by weight or more based on the total weight of the agent.

Test Example 5: Scattering properties of the drug of the present invention In Test Example 5, the relationship between the water content in the drug and the scattering properties of the drug was examined when the content of carbon powder in the drug was relatively high. was done.
In Test Example 5, oxytetracycline (OTC) powder (oxytetracycline hydrochloride raw powder, 30 mesh pass) was used as the medicinal ingredient, and bamboo charcoal powder (100 mesh pass) was used as the carbon powder material. The drug of Comparative Example 15 and Examples 16, 17, and 18 was prepared by mixing the active ingredient material, carbon powder material, and water to contain bamboo charcoal powder, oxytetracycline powder, and water in the amounts shown in Table 5. prepared. In Test Example 5, the total amount of bamboo charcoal powder and water was set to 99% by weight based on the weight of the entire drug, and the amount of OTC was set to 1% by weight based on the weight of the entire drug. rice field. The drug scattering test method was the same as in Test Example 4. Results are shown in Table 5.

When the water content is 1% by weight based on the total weight of the drug (Comparative Example 15), the drug is likely to be blown away by the wind when used in aquaculture work sites, and there is a risk of health hazards due to ingestion by workers. Therefore, it was confirmed that it is not suitable as a pharmaceutical for farmed fish. When the water content was 3% by weight based on the total weight of the drug (Example 16), there was a slight problem with scattering, but it was at a level that could be used if endured. It was confirmed that when the water content was 8% by weight (Example 17) and 10% by weight (Example 18) based on the total weight of the drug, there was no problem in scattering. From the above, it was clarified that the agent of the present invention can be used without problems at aquaculture sites if the water content is 3% by weight or more based on the total weight of the agent.

Test Example 6 Solidification of the Drug of the Present Invention In Test Example 6, the relationship between the amount of water in the drug and the solidification of the drug was investigated.
In Test Example 6, oxytetracycline (OTC) powder (oxytetracycline hydrochloride raw powder, 30 mesh pass) was used as the medicinal ingredient, and bamboo charcoal powder (100 mesh pass) was used as the carbon powder material. The medicinal ingredient material, carbon powder material and water were mixed so as to contain bamboo charcoal powder, oxytetracycline hydrochloride powder and water in the amounts shown in Table 6, and the compositions of Examples 19, 20 and 21 and Comparative Example 22 were prepared. A drug was prepared. In Test Example 6, the total amount of bamboo charcoal powder and water was set to 99% by weight based on the weight of the entire drug, and the amount of OTC was set to 1% by weight based on the weight of the entire drug. rice field.

Drug solidification test In the drug solidification test, each prepared powdered drug was sieved through a test sieve with an opening of 1 mm/18 mesh (manufactured by Tokyo Screen Co., Ltd.) and evaluated by whether or not lumps remained. The evaluation criteria were ∘ (entire amount passed), Δ (slight lump-like lumps remained, but immediately crushed when touched by hand), and × (large lumps remained, unsuitable as a formulation). When the evaluation result of solidification was ◯ or Δ, it was regarded as acceptable, and when it was ×, it was regarded as unacceptable. Table 6 shows the results.

When the water content was 16% by weight based on the total weight of the drug (Comparative Example 22), the degree of solidification of the drug was extremely high, and it was confirmed that the drug was in an unsuitable state as a formulation. When the water content was 15% by weight based on the total weight of the drug (Example 21), the drug solidified slightly, but was at a level usable as a formulation. It was confirmed that when the water content was 12% by weight (Example 20) and 10% by weight (Example 19) based on the total weight of the drug, the drug did not solidify at all and was in an appropriate state as a formulation. rice field. From the above, it was confirmed that the drug of the present invention does not cause solidification problems if the water content is 15% by weight or less based on the total weight of the drug.

Test Example 7: Drug Stability Test In Test Example 7, a drug stability test was conducted in order to examine the effect of water content in the drug on changes in potency of the medicinal ingredient.
In Test Example 7, erythromycin (EM) powder (erythromycin bulk powder) was used as the active ingredient material. Moisture was added to bamboo charcoal powder (150 mesh pass) so that the water content in the finally prepared drug containing 20% by weight of erythromycin was 11% by weight, 13% by weight, or 15% by weight. was used as the carbon powder material. This carbon powder material was mixed with erythromycin powder to prepare the formulations of Examples 23-25. The formulation of Example 23 contained 20% by weight erythromycin, 11% by weight moisture, and 69% by weight bamboo charcoal powder. The formulation of Example 24 contained 20% by weight erythromycin, 13% by weight moisture, and 67% by weight bamboo charcoal powder. The formulation of Example 25 contained 20% by weight erythromycin, 15% by weight moisture, and 65% by weight bamboo charcoal powder. 100 g of each of the prepared drugs was packed in aluminum bags, and the drugs packed in aluminum bags were wrapped in polyethylene-coated kraft paper. Accelerated testing of the packaged drug was performed in a high humidity thermostat at a temperature of 40°C ± 2°C and a humidity of 75% ± 5%. The EM titer at the start of the accelerated test was measured using HPLC. This measured value is shown as "Initial" in FIG. 2 as an initial value. The HPLC sample preparation method and HPLC analysis method were the same as those described in Test Example 3. After 14 days, 28 days, 56 days and 112 days from the start of storage, the drug was taken out from the high-humidity thermostat and the EM titer remaining in the drug was measured. The evaluation of drug stability was based on the criteria that the potency of the medicinal ingredient remained 95% or more during storage. For each example, three formulations were prepared and subjected to stability testing. The mean and standard deviation of the EM titer remaining in the drug at each measurement time point obtained from the three drugs in each example (standard deviation is represented by error bars in the figure) are shown in FIG. .

From the results of Examples 23 to 25, it was confirmed that the lower the water content contained in the medicine, the less the potency change of the medicinal ingredient during storage. When the water content in the drug was 15% by weight, the EM titer remaining in the drug was 97.4% after 112 days. Therefore, if the water content is within 15% by weight based on the total weight of the drug, it is presumed that the change in potency of the medicinal ingredient in the drug is within the appropriate range as a drug.

Test Example 8: Drug Stability Test Example 8 was a drug stability test with a water content of 20% by weight or 25% by weight.
In Test Example 8, erythromycin (EM) powder (erythromycin bulk powder) was used as the active ingredient material. The formulations of Comparative Examples 26 and 27 were prepared by preparing a mixture of bamboo charcoal powder (150 mesh pass) and erythromycin powder, adding water to the mixture and mixing. The formulation of Comparative Example 26 contained 20% by weight erythromycin, 20% by weight moisture, and 60% by weight bamboo charcoal powder. The formulation of Comparative Example 27 contained 20% by weight erythromycin, 25% by weight moisture, and 55% by weight bamboo charcoal powder. 100 g of each of the prepared drugs was packed in aluminum bags, and the drugs packed in aluminum bags were wrapped in polyethylene-coated kraft paper. Accelerated testing of the packaged drug was performed in a high humidity thermostat at a temperature of 40°C ± 2°C and a humidity of 75% ± 5%. The EM titer at the start of the accelerated test was measured using HPLC. This measured value is indicated as "Initial" in FIG. 3 as an initial value. The HPLC sample preparation method and HPLC analysis method were the same as those described in Test Example 3. After 30 days, 60 days, 90 days and 184 days from the start of storage, the drug was removed from the high-humidity thermostat and the EM titer remaining in the drug was measured. Evaluation of drug stability was based on the criteria that the potency of the medicinal ingredient remained 95% or more during storage. For each example, one formulation was prepared and subjected to stability testing. In each example, the EM titer remaining in the drug at each time point is shown in FIG.

From the results of Comparative Examples 26 and 27, when the water content contained in the drug was 20% by weight or more, the EM titer remaining in the drug was less than 95% by weight after 90 days from the start of storage. Therefore, it was confirmed that when the water content is 20% by weight or more based on the total weight of the drug, it cannot be commercialized as a drug due to the lowered potency of the medicinal ingredient.

The orally-administered drug for aquatic animals of the present invention can be used for culturing aquatic animals.

Claims (8)

0.1% by weight or more of the active ingredient based on the total weight of the drug, 15-96.9% by weight of carbon powder based on the total weight of the drug, and 3-15% by weight based on the total weight of the drug. % moisture, non-granulated powdered orally administered drug for aquatic animals. Active ingredients include macrolides, tetracyclines, fluoroquinolones, thiamphenicol, benzimidazoles, sulfa drugs, ursodeoxycholic acid, amino acids, water-soluble vitamins, fat-soluble vitamins, minerals, and carotenoids. The orally administered drug for aquatic animals according to claim 1, which is selected from the group consisting of: The orally administered drug for aquatic animals according to claim 1, wherein the carbon powder is selected from the group consisting of bamboo charcoal powder, coconut husk charcoal powder and charcoal powder. The orally administered drug for aquatic animals according to claim 1, wherein the particle size of the carbon powder is a size that passes through 50 mesh. The orally administered drug for aquatic animals according to claim 1, for use with extruder pellet feed. The orally administered drug for aquatic animals according to claim 1, which is enclosed in a sealed container. The aquatic animal according to claim 1, comprising preparing a carbon powder containing water in an amount of 3 to 15% by weight based on the total weight of the drug, and mixing the carbon powder containing water with the medicinal ingredient. A method of manufacturing an orally administered medicament for use. A method for preventing and/or treating a disease in an aquatic animal by administering the orally administered drug for aquatic animal according to any one of claims 1 to 6 to the aquatic animal.

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