JP2006052170A - Oral antimicrobial agent for animal - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To surely enhance effectiveness of medicinal effects of an ST mixture [a pharmaceutical preparation comprising SMX (sulfamethoxazole) and TMP (trimethoprim)] by supplying the ST mixture to an animal. <P>SOLUTION: The oral antimicrobial agent for the animal comprises rice bran, the SMX and TMP and an elution inhibitor. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to an oral antibacterial agent for animals that can significantly increase the efficacy of its efficacy when an ST combination of sulfamethoxazole and trimethoprim is provided to an animal.

  A preparation containing sulfamethoxazole (SMX) and trimethoprim (TMP) (hereinafter referred to as ST combination) is known as an oral preparation for bacterial diarrhea caused by swine E. coli, and various ST combinations are commercially available. Has been. A commercial product of a general ST combination is an ST additive that is adjusted so that sulfamethoxazole and trimethoprim have a specified mixing ratio (usually sulfamethoxazole: trimethoprim = 5: 1). A predetermined amount is blended with rice bran as a product. The blending ratio of the ST mixture contained in the commercial product is specified in the commercial product, and the user orally administers it to the animal by mixing the predetermined amount described in the above-mentioned commercial product with the food. A commercial product based on the above-mentioned ST mixture is expected to be effective for animals other than pigs, such as chickens.

  On the other hand, it is considered that the above-mentioned ST mixture is dissolved in drinking water and used as a solution. For example, when this solution is given to chickens, the main components sulfamethoxazole and trimethoprim do not meet the taste of chickens. Because of this, the amount of water consumed by chickens decreases. Decreasing the amount of drinking water is a major problem because it leads to a decrease in drug efficacy and a decrease in the rate of weight gain.

For this reason, Patent Document 1 discloses an antibacterial oral preparation for poultry containing glutamic acid or a salt thereof in the ST mixture to prevent a decrease in the amount of drinking water, and glycols and dioctyl are included in the ST mixture. Patent Document 2 discloses an antibacterial solution for animals which contains a sulfosuccinate and is stable and has improved water solubility.
Japanese Patent Application Laid-Open No. 06-263637 Japanese Patent Laid-Open No. 06-263642

  Patent Documents 1 and 2 described above all relate to a liquid agent obtained by dissolving an ST mixture in water, and by increasing the amount of drinking water by providing the liquid agent, the amount of ST mixture supplied to animals is increased. The purpose is to increase the efficacy of the ST mixture on animals.

  On the other hand, from the dairy farmer who uses the ST mixture, when the commercial product (powder) of the ST mixture is donated to animals, there is a difference in the amount (intake) of the ST mixture depending on the commercial product. It has been pointed out that even if the same amount of ST mixture is given to animals, it has been pointed out that the efficacy of the drugs varies depending on the type of commercially available product. Although it is effective to increase the dose of the ST mixture, it has been found that simply increasing the dose of the ST mixture to the animal may not necessarily increase the effectiveness of the drug effect on the animal.

  An object of the present invention is to provide an oral antibacterial agent for animals in which the effectiveness of the drug effect by the ST mixture is surely enhanced by donating the ST mixture to animals.

  The invention according to claim 1 relates to an oral antibacterial agent for animals comprising rice bran, sulfamethoxazole and trimethoprim, and an elution inhibitor.

  The invention according to claim 2 is characterized in that the rice bran contains 4 to 16% by weight of a combination of sulfamethoxazole and trimethoprim and 0.1 to 1% by weight of an elution inhibitor. 1. The oral antibacterial agent for animals according to 1.

  The invention according to claim 3 relates to the oral antibacterial agent for animals according to claim 1 or 2, wherein the rice bran is a fine rice bran having a path of 250 μm or less.

  The invention according to claim 4 relates to the oral antibacterial agent for animals according to any one of claims 1 to 3, wherein the elution inhibitor is agar.

  The invention according to claim 5 relates to the oral antibacterial agent for animals according to any one of claims 1 to 3, wherein the elution inhibitor is carboxymethylcellulose.

  The invention according to claim 6 relates to the oral antibacterial agent for animals according to any one of claims 1 to 3, wherein the elution inhibitor is xanthan gum.

  The invention according to claim 7 relates to the animal oral antibacterial agent according to any one of claims 1 to 3, wherein the elution inhibitor is sodium alginate.

  The invention according to claim 8 relates to the oral antibacterial agent for animals according to any one of claims 1 to 3, wherein the elution inhibitor is mannan oligosaccharide.

  Since the oral antibacterial agent for animals of the present invention contains fine rice bran, sulfamethoxazole and trimethoprim, and an elution inhibitor, the combination of the fine rice bran and the elution inhibitor keeps the dissolution of the ST mixture low. The effectiveness of the ST mixture provided to the animal is reliably increased by increasing the amount of the animal remaining in the intestinal lining of the animal, and the palatability is impaired by the combination of the fine rice bran and the dissolution inhibitor. Therefore, it is possible to maintain a high dose of the ST mixture to the animal, and thus to further increase the effectiveness of the medicinal effect of the ST mixture supply.

  Embodiments of the present invention will be described below with reference to the accompanying drawings.

  The present inventors conducted various investigations, studies, and tests in order to ascertain the necessary conditions for maintaining high efficacy of the ST combination provided to animals.

  The present inventors first selected six main commercial products A to F of the commercially available ST mixture, and conducted an interview survey on the effectiveness of the drug efficacy when each of the commercial products A to F was given to animals. Carried out.

The results show that as shown in [Table 1], commercial product A shows the highest efficacy, followed by B, E, D, and F in decreasing order, and C has the lowest effectiveness. found.
[Table 1]
Commercial products Effectiveness ranking A 1
B 2
C 6
D 4
E 3
F 5

  In order to find out the cause of the variation in the efficacy of the above-mentioned commercial products A to F, the powder properties (slack apparent specific gravity, compressibility, dispersity) of the commercial products A to F were investigated. There was no significant relationship between physical properties and the ranking of effectiveness.

  Then, the elution test for investigating the elution property of the main ingredient of commercial item AF was implemented. At this time, the elution test of sulfamethoxazole (SMX) and the elution test of trimethoprim (TMP) in commercial products A to F were performed separately. Furthermore, the dissolution test of SMX and the dissolution test of TMP are conducted for 3 types of pH 1.2 test solution, pH 4.0 test solution and pH 6.8 test solution according to the pharmacopeia dissolution test method 2 (paddle method). did.

  The results for the SMX dissolution test for the pH 1.2 test solution are shown in FIG. 1 (A), the results for the pH 4.0 test solution are shown in FIG. 1 (B), and the results for the pH 6.8 test solution are shown. Is shown in FIG. The results for the pH 1.2 test solution in the TMP dissolution test are shown in FIG. 2 (A), the results for the pH 4.0 test solution are shown in FIG. 2 (B), and the results for the pH 6.8 test solution are shown. The results are shown in FIG.

  As shown in FIG. 2, from the results of the dissolution test of TMP with a small ST mixture content, no significant difference in dissolution rate was observed between each of the commercial products A to F.

  On the other hand, as shown in FIG. 1, in the results of the dissolution test of SMX with a large content ratio of the ST mixture, a significant difference in dissolution rate was observed between each of the commercial products A to F. In particular, in the pH 4.0 test solution, a significant difference in elution rate was observed between the commercial products A to F. Usually, the pH value of animal gastric juice such as pigs and chickens is about 3 to 4, and the pH value is considered to be about 4 depending on the diet. Therefore, commercially available products A to F cause a large difference in the dissolution rate in animal gastric juice. You can see that

  1, the commercial product A having the highest medicinal efficacy in the interview survey is the least soluble, followed by the commercial product B, the commercial product E, the commercial product D, and the commercial product F in that order. It was found that the commercial product C having the lowest medicinal efficacy was most soluble.

  From this, the effectiveness of the drug effect by the provision of the ST mixture is greatly related to the dissolution rate of the main agent, and those having low dissolution properties (not easily soluble) have high efficacy and high dissolution properties (easily soluble). ) Was found to be less effective.

  Therefore, in order to investigate the conditions for suppressing the elution of the ST mixture, a test was conducted to examine the elution of SMX with respect to the pH 4.0 test solution in various materials mixed with the ST mixture.

  First, about rice bran generally used as a bulking agent, the same blending ratio (sulfamethoxazole: trimethoprim = 5: 1) with respect to each of crude rice bran (500 μm pass) and fine rice bran (250 μm pass). ) Prepared by adding 8% by weight of the base powder of the ST mixture was subjected to the dissolution test of SMX.

  Furthermore, an elution inhibitor that has no effect on the ST mixture, is easily available, and has an effect of suppressing elution of the ST mixture was selected. As the dissolution inhibitor, agar, carboxymethyl cellulose (CMC), xanthan gum, sodium alginate, and mannan oligosaccharide, which are thickening polysaccharides, were selected, and each of the dissolution inhibitors was reduced to 0.5% for fine rice bran (250 μm pass). 5% by weight, and further, 8% by weight of ST mixture powder adjusted to the same blending ratio as the above-mentioned commercial product to fine rice bran added with dissolution inhibitor. It used for the dissolution test of SMX.

  In addition, as a comparative example, the commercial product A having the highest medicinal efficacy and the commercial product C having the lowest medicinal efficacy (commercial products A and C are all mixed with rice bran 5: 1) The same composition as that of the above-mentioned commercial product was obtained by using a pulverized product obtained by further pulverizing the SMX base powder with respect to the crude rice bran (500 μm pass). A mixture obtained by adding 8% by weight of the pulverized ST mixture adjusted to a ratio was subjected to an SMX dissolution test.

  Commercially available SMX performs particle size distribution measurement using iso-octane containing 0.1% Sorbitan Trioleate as a solvent using a laser diffraction particle size distribution analyzer (manufactured by Seishin Enterprise, LMS-24). It was. In addition, the particle size measurement of the raw material powder was carried out three times, and the average value is shown in FIG. 4, and the pulverized product obtained by further pulverizing the SMX raw material powder was also subjected to particle size measurement three times, and the average value is shown in FIG. It was shown to. The commercially available SMX base powder had a coarse particle size including 60% particle size of 65 μm or more, 80% particle size of 40 μm or more, and 90% particle size of 25 μm or more. Further, the pulverized product obtained by further pulverizing the SMX raw powder had a fine particle size including 60% of a particle size of 15 μm or less and 90% of a particle size of 40 μm or less.

  The above-described SMX dissolution test was performed on each test material, and the results are shown in FIG.

  As shown in FIG. 3, each of the commercial product A and the thin rice bran added with 0.5% each of agar, carboxymethylcellulose (CMC), xanthan gum, sodium alginate and mannan oligosaccharide as an elution inhibitor is about 60. A low elution rate of around 00% was obtained, but a mixture of ground rice bran (500 μm pass) with ground ST mixture, a commercial product C, and a mixture of ST rice mixed with crude rice bran (500 μm pass) Showed a high dissolution rate of about 80.00% or more, and a mixture of ST mixture with fine rice bran (250 μm pass) showed an intermediate dissolution rate of about 70.00%.

  From FIG. 3, it was found that fine rice bran is suitable as a bulking agent used when donating the ST mixture to animals, and that crude rice bran is inappropriate.

  Further, when the pulverized ST mixture and the unmixed raw powder ST mixture mixed with crude rice bran were compared, the pulverized ST mixture showed a higher elution rate. That is, the coarse particle size containing 60% of the particle size of 65 μm or more, which is not the SMX base powder, compared to the fine particle size SMX containing 60% of the particle size of 15 μm or less, which is a pulverized product of the SMX base powder. It was found that the use of SMX had a lower elution rate, and the ST mixture had a larger particle size.

  Furthermore, the addition of agar, carboxymethylcellulose (CMC), xanthan gum, sodium alginate, and mannan oligosaccharides to elaborate fine rice bran (250 μm pass) has the lowest elution rate and the highest efficacy. In addition, the elution rate was equal to or lower than that of the commercial product A. In particular, the elution rate of the commercial product A significantly increased with the passage of time, but those with the addition of the elution inhibitor were able to maintain a low elution rate over time. One of the elution inhibitors may be selected and added to the fine rice bran (250 μm pass), or a plurality of dissolution inhibitors may be added simultaneously to the fine rice bran (250 μm pass). In addition, the elution inhibitor is not limited to the above.

  As described above, the combination of fine rice bran and an elution inhibitor can suppress the elution of the ST mixture to a low level. Furthermore, the dissolution rate of the ST mixture is kept low in the same pH 4.0 test solution as the animal gastric fluid of pigs and chickens, so that the amount of the ST mixture stays on the intestinal lining of the animal increases. Thus, it is considered that the efficacy of the ST mixture is significantly enhanced.

  In addition, rice bran is generally used as a feed for livestock animals such as cattle, pigs and chickens, and has good palatability. Therefore, by mixing the above ST mixture with rice bran, Since the supply rate can be increased, the effectiveness of the medicinal effect by the ST mixture can be greatly increased as a result in combination with keeping the dissolution property low as described above.

  Next, the effect confirmation test for confirming the effectiveness of the medicinal effect of the product of the present invention when the coccidium attack was carried out on the chicken was carried out.

As a test chicken, a primary chick (male) of a chunky species (special broiler species) is used, and a broiler test standard feed (for the previous period, manufactured by Clea Japan Co., Ltd.) is used as the feed. On the 9th day, the animals were challenged with a coccidium-attacking strain (Eimerianateella) at an attack amount of 10 × 10 ⁴ cells / feather, then were reared with the above-mentioned feed until the age of 16 days and sampled at the age of 16 days. As test chickens, 10 birds were used for each of the following reagent agents.
As an effect confirmation test, the following measurement items were measured.

1. Rearing results (weight gain and feed intake)
Weight (when 16 days old)
Weight gain (9-16 days old)
Cumulative feed intake (9-16 days of age)
Feed demand rate

2. Clinical results (lesion)
Caecal lesion score incidence lesion improvement rate

3. ACI (Anticoccidia 1 Index)
ACI = (relative weight gain + survival rate)-(lesion value + oocyst value)

  As the reagent agent, the product 1 of the present invention according to Example 1, the commercial products A and C as comparative examples, and a high-elution formulation containing the raw powder of the ST mixture in crude rice bran (500 μm pass) Measurements were made on a non-infected control and an infected control as control examples.

  The results of the SMX dissolution test with respect to the pH 4.0 test solution in each of the present invention product 1, the commercial product A, the commercial product C, and the high-elution prescription reagent were as shown in FIG. Each reagent included 10 g of sulfamethoxazole and 2 g of trimethoprim in 150 g, and the reagent was added at a rate of 5 kg per 1 t of feed.

  The body weight as the breeding result is shown in FIG. 6, the weight gain is shown in FIG. 7, the cumulative feed intake is shown in FIG. 8, and the feed request rate is shown in FIG.

  Furthermore, the cecal lesion score as clinical results is shown in FIG. 10, the lesion improvement rate is shown in FIG. 11, and the onset rate is shown in FIG.

  The cumulative feed intake (9 to 16 days of age) in FIG. 8, which is a breeding result, is not significantly different from each of the above-mentioned reagent reagents, but the non-infected control in particular has a lower intake compared to the others, and the present invention Product 1 has a significantly higher intake than others. In addition, the feed demand rate shown in FIG. 9 is almost the same for the product 1 of the present invention, the commercial product A and the commercial product C, and the non-infection control, whereas the infection control and the high-elution formulation are high.

  On the other hand, in the body weight (16 days old) shown in FIG. 6 and the body weight gain (9 to 16 days old) shown in FIG. 7, the non-infected control, the infected control, and the high-elution formulation are low, respectively. The product A and the commercial product C are high. In particular, the product 1 of the present invention is significantly higher than the commercial product A and the commercial product C. This represents that the medicinal effect of the product 1 of the present invention was enhanced and the breeding of chickens was enhanced.

  Next, in the incidence of clinical results in FIG. 12, the infection control is 100%, the high-elution prescription is 60%, the commercial product A is 30%, and the commercial product C is 40%. In contrast, the product 1 of the present invention has a very low incidence of 10%.

  In the cecal lesion score of FIG. 10, the non-infected control is 0 and the infected control is 2.6, which is a high value, 0.6 for the high-elution formulation, 0.3 for the commercial product A, and 0.3 for the commercial product C. In contrast to the cecal lesion score of 4, the product 1 of the present invention shows a very low cecal lesion score of 0.1.

  Furthermore, in the lesion improvement rate of FIG. 11, the non-infected control is 100%, the infected control is 0%, the high-elution formulation is 77%, the commercial product A is 88%, and the commercial product C is 85%. On the other hand, the product 1 of the present invention shows a significantly high lesion improvement rate of 96%.

The ACI of each reagent was as shown in [Table 2].
[Table 2]
Test category ACI
Non-infected control group 200
Infection control group 151
A 204
C 203
High dissolution formulation 196
Invention product 1 208

According to [Table 2], the product 1 of the present invention shows a higher value than any of the other reagent reagents.
In the above, the effectiveness against chicken coccidiosis and colibacillosis has been explained. However, the oral antibacterial agent for animals of the present invention is used for the prevention, treatment and other animals of bacterial diarrhea and hemophilus infections caused by swine E. coli. It can also be applied to the prevention and treatment of bacterial diseases.

  Examples of the present invention are shown below, but the present invention is not limited to these Examples.

  The present invention product 1 was obtained by adding 0.05 parts of agar powder and 1 part of ST mixture to a 250 μm thin rice bran. This product 1 of the present invention was added in an amount of 5 kg per ton of feed and fed to chickens with food.

The results of dissolution test of SMX are shown, (A) is a diagram showing the dissolution rate of commercially available products A to F with respect to pH 1.2 test solution, and (B) is the dissolution of commercially available products A to F with respect to pH 4.0 test solution. (C) is a diagram which shows the elution rate with respect to pH6.8 test solution of commercial item AF. The results of the TMP dissolution test are shown. (A) is a diagram showing the dissolution rate of commercially available products A to F with respect to the pH 1.2 test solution, and (B) is the dissolution rate of commercially available products A to F with respect to the pH 4.0 test solution. (C) is a diagram which shows the elution rate with respect to pH6.8 test solution of commercial item AF. It is a diagram which shows the dissolution test result of SMX with respect to pH4.0 test liquid with various materials. It is the particle size distribution figure which measured the particle size of the powder of SMX. FIG. 3 is a particle size distribution diagram in which the particle size of a pulverized product obtained by further pulverizing SMX powder is measured. It is the graph which showed and compared the body weight which is the breeding result by the reagent supply with respect to a test chicken. It is the graph which showed the amount of gain comparison. It is the graph which showed the cumulative feed intake compared. It is the graph which showed the feed request rate in comparison. It is the graph which showed and compared the cecal lesion score which is a clinical result by the reagent supply with respect to a test chicken. It is the graph which showed the lesion improvement rate in comparison. It is the graph which showed the incidence rate in comparison.

Claims (8)

  An oral antibacterial agent for animals, comprising rice bran, sulfamethoxazole and trimethoprim, and an elution inhibitor.   2. The oral antibacterial agent for animals according to claim 1, wherein the rice bran contains 4 to 16% by weight of a combination of sulfamethoxazole and trimethoprim and 0.1 to 1% by weight of an elution inhibitor. .   The animal antibacterial agent for animals according to claim 1 or 2, wherein the rice bran is a fine rice bran having a 250 µm pass or less.   The oral antibacterial agent for animals according to any one of claims 1 to 3, wherein the elution inhibitor is agar.   The animal antibacterial agent for animals according to any one of claims 1 to 3, wherein the elution inhibitor is carboxymethylcellulose.   The oral antibacterial agent for animals according to any one of claims 1 to 3, wherein the elution inhibitor is xanthan gum.   The animal oral antibacterial agent according to any one of claims 1 to 3, wherein the elution inhibitor is sodium alginate.   The oral antibacterial agent for animals according to any one of claims 1 to 3, wherein the elution inhibitor is mannan oligosaccharide.

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