KR960015952B1 - Antidiarrheial therapeutic agents for animal and the pharmaceutical compositions comprising them - Google Patents

Abstract

The anti-diarrheal therapeutic agent for animal comprises loperamide, an antibiotic of a sustaining tetracycline group and a sulfa drug. The antibiotic of a sustaining tetracycline group is particularly minocycline, and the sulfa drug is a complex of sulfamethoxazole & trimethoprim. The anti-diarrheal therapeutic agent contains 1-2 wt% loperamide, 50-100 wt% minocycline, 200-400 wt% sulfametoxazole and 40-80 wt% trimethoprim.

Description

[Name of invention]

Hari therapeutic composition of animals and preparation containing the same

Detailed description of the invention

The present invention relates to a hari-therapeutic composition and an agent containing the same, and in particular, a composition for use in hari-treatment of an animal comprising an antibacterial agent, an antibiotic and a sulfa agent, and a digestive enzyme agent as an essential component, and an animal formulated with the same. It is about medicines.

In recent years, as the consumption of meat and dairy products has increased due to the increase of national income and the improvement of living standards, the livestock industry in Korea is also becoming a trend of multi-duty breeding, and various animal diseases are becoming a problem. In particular, hari (下痢) varies depending on animal species, region, and breeding conditions, but is an important disease that affects the livestock industry with a high incidence rate in any animal.

The incidence of hari in pigs is 41.6% of all diseases, and in particular, the percentage of hari in pigs has been reported to be 88.6%. The incidence of gastrointestinal disease in cows was 37.7%, and the highest percentage of hari was 68.5%, especially in calf less than 1 year of age. It is said that it is similar to Korean beef.

Hari of the animal is caused by various factors acting alone or in combination. In the case of livestock, the factors are becoming more and more complicated as they are full-fledged in the form of multi-dwelling. In particular, as can be seen in the above report, the hari will not develop fully in the function of the digestive system and immune system will occur a lot in young livestock with weak adaptability. Hari in young livestock not only causes sluggish development and growth disorders, but also causes rapid economic loss due to atrophy or death accompanied by dehydration if rapid treatment is not performed. Therefore, early treatment of hari occurs is essential for minimizing livestock losses and subsequent economic losses. In particular, if treatment is delayed for more than three days, there is a concern that the development and growth retardation cause the problem to become more serious due to the spread of disease infection, not to mention the increase in the administration cost and labor cost, in addition to the loss of actual economic value.

The biggest problem in treating the hari of livestock is that the causes are diverse, and especially in hari, which occurs naturally in the field, it is virtually impossible to distinguish the causative organism. The causative agents known to date include bacteria such as Escherichia coli (E. coli), Salmonella, Clostridium perfringens type C for piglets, Rotavirus, Coronavirus, etc. In the case of calves, there are Escherichia coli, Salmonella, Clostridium perfringens type B and type C, Proteus, Pseudomonas bacteria, Candida fungi and rotaviruses, coronaviruses. In addition to these infectious hari, non-infectious hari occurs due to overeating, low quality substitute oil, and intestinal disaccharide deficiency. That is, in livestock, such infectious and non-infectious agents act alone or in combination to cause hari, thus making hari treatment more difficult.

As such, it is dangerous to administer a single item of drug when effectively treating the hari of livestock caused by various causes in a short time, and a combination treatment should be used in consideration of various causes.

Conventionally, when a harib occurs in an animal, especially a livestock, it has been administered alone or in combination with an intestinal fungicide, sulfa agent, digestive agent and the like. However, these conventionally used alone or combination prescriptions for veterinary treatment for veterinary animals often lose treatment value and cause economic loss because the duration of treatment is prolonged if their effects are not limited. Therefore, there is a demand for the development of a complex medicine that can effectively treat hari caused by various causes in a short time.

In view of the various problems as described above, the present inventors have been widely applied to the hydration caused by various causes in livestock, and in order to develop a hari treatment agent that works quickly and effectively, various antibacterial agents are mixed in various ratios for each agent. The synergistic effect was investigated by studying the mechanism of hyperactivity and the physiological reactions of animals. In other words, as a preliminary study, antimicrobial drugs were selected for primary infectious hari treatment by separating and cultivating the causative organism of hari from naturally occurring livestock and selecting antibiotics such as antibiotics or other sulfa agents with antibacterial activity against as many causative organisms as possible. At the same time, by selecting a symptomatic treatment for Hari caused by other factors, and prepared in various compositions and mixing ratios, the comparative test was repeated to complete the Hari therapeutic composition of the present invention.

It is an object of the present invention to provide a hari-therapeutic composition and a pharmaceutical preparation comprising the same, which can effectively treat hari arising in animals, particularly livestock, in a short time.

Hari therapeutic composition of the present invention for achieving the above object is characterized in that the essential components of loperamide, long-acting tetracycline antibiotics and sulfa agent.

In the hari-therapeutic composition, the persistent tetracycline-based antibiotics include doxycycline or minocycline, but minocycline is preferred, and sulfamethol is preferably a combination of sulfamethoxazole-trimethoprim, sulfonamide. Furazolidone and the like may be used as an antimicrobial agent other than antibiotics, which is used for treating intestinal infections as well as a family of sulfa agents. In addition, it is preferable that the composition of the present invention further comprises a digestive enzyme, in particular, a starch degrading enzyme such as a diastatase is preferably included.

Each of the components of the composition of the present invention are all registered in the Korean Pharmacopoeia, and the effectiveness and safety are established. Hereinafter, each component will be described in detail.

Loperamide is an anti-diarrheal agent that acts on the intestinal muscles and lowers the motility of the gastrointestinal tract. Suppress the long axis. Fecal hardening action is strong, long working time, less retrograde or other side effects on the central nervous and cardiovascular system. Commercially available as loperamide hydrochloride (loperamide HCl), in humans, the usual dose is 4 to 8 mg per day, not to exceed 16 mg per day, usually 4 mg once per adult, followed by 2 mg once daily.

Doxycycline and minocycline as long-acting tetracycline antibiotics of the present invention are administered at lower doses than other tetracyclines because both have long half-lives (17-20 hours) and are well absorbed. Blood levels by oral administration are equivalent to those by parenteral administration, but absorption by oral administration is not inhibited by food. Minocycline has different antibacterial spectra against gram-positive bacteria such as pneumococci, streptococci, staphylococcus and Haemophilus influenzae, gram-negative bacteria such as Escherichia coli, Shigella, Salmonella, Proteus, Pseudomonas, and Leptospira, Rickettsia, and large viruses. Like tetracycline antibiotics, but its action is strong and durable. The action is bacteriostatic, but it is bactericidal at concentrations of four times the minimum developmental arrest concentration. It is well absorbed by oral administration and maintains high blood concentration for a long time, and shifts to about 4.2 times the concentration of blood in tissues, especially bile, and urinary excretion is late and mainly excreted in feces. The mean blood concentration at 200 mg orally in adults is 1.96 μg / ml (maximum) after 4 hours, 0.52 μg / ml after 12 hours, urinary excretion is 1.77% up to 6 hours, 4.02% up to 12 hours, 5.71 up to 24 hours %to be. When administered orally, intraperitoneally, and intravenously to rats, rabbits, and dogs, it is recognized that the liver and kidney are about 10 times the blood, about 5 times the lungs, about 2 times the spleen, and about 30 times the bile. Acute toxicity is LD50 of 154-158 mg / kg intravenously in mice, 1510-2200 mg / kg subcutaneously, and 3600-4250 mg / kg orally. In the subacute toxicity test, dogs were injected intravenously with 5 mg / kg daily for 1 month, and with chronic toxicity test, 10-20 mg / kg daily for 6 months intraperitoneally or orally. There was no death, and even the fetality test was not recognized in the fetal test using mice and rabbits. As an oral preparation, infections caused by Staphylococcus, Streptococcus, Pneumococcus, Cyclopsium, Escherichia coli, Citrubacter, Klebsiella, and Enterbacter are the main indications and are marketed as Minocycline HCl. Silver minocycline is the first 100-200mg, then orally administered 100mg every 12 hours, children are given oral doses 2-4mg / kg 1-2 times daily. For intravenous injection, dissolve 100 mg in 5 ml of injectable distilled water, add 500 ml of auxiliary solution, and instill dropwise at a rate not exceeding 20 ml per minute.The first 100-200 mg, then 100 mg every 12-24 hours, orally If possible, change to oral administration. In the case of livestock, 1.5-3.0 mg / kg for large animals and 2.0-4.0 mg / kg for small and medium animals are injected orally or intravenously.

The sulfa agent as the composition component of the present invention is sulfamethoxazole and co-trimoxazole which is a combination of tremethoprim. Sulfamethoxazole is not well absorbed and fast excretion, so the systemic action is not enough blood concentration and maintains a high concentration in the urinary tract is mainly used for urinary tract infections. The initial dose of 2.0g for sulfa susceptible bacteria (E. coli, gonococcus, Staphylococcus aureus, Streptococcus, etc.), then orally administered 1.0g every 12 hours. When rapid effects are required, 1.0-2.0 g is slowly injected intravenously. It is thought to be effective for pyelonephritis caused by single, scarlet fever, and susceptible Escherichia coli, tonsillitis caused by susceptible hemolytic streptococci, and sore throat. In combination with trimethoprim, which acts on the biosynthetic pathway of folic acid and inhibits nucleic acid synthesis, it acts as a cooperative formulation. Trimethoprim-sulfmethoxazole complex preparations have a synergistic effect against bacteria, and are effective for various gram-positive and gram-negative bacteria and are mainly used for acute and chronic urinary tract infections. It is also effective for the treatment of typhoid and paratyphoid, and is effective against bacterial infections of the upper respiratory tract, gonorrhea and certain kinds of malaria.

On the other hand, as a digestive enzyme preferably included in the composition of the present invention, diazatase (Diastase) or biodiastase (Biodiastase) is an enzyme agent excellent in starch digestibility mainly made of malt. Among the malt diastases are α- and β-amylases, and the two enzymes work together on starch. The β-limit dextrin, a product by β-amylase, is also degraded by α-amylase, which in turn is degraded by β-amylase, so that the final product is mainly maltose and else glucose or lower dextrin.

That is, the present invention uses a tetracycline-based antibiotic that is effective against a wide range of causative organisms in the hari of the animal and a sulfa agent having bacteriostatic action in the same manner to expand the antimicrobial range and to minimize dehydration and nutrient loss. The loperamide with the anti-diabetic effect was used together. In particular, both minocycline and sulfamemethazole-trimethoprim have a long duration of action, such as loperamide, so it is effective to use 1-2 times a day, so it is convenient to use. Here, it is preferable to further include a starch degrading enzyme, diastase, and the like, so that the treatment of Hari's symptoms as well as the rapid recovery therefrom can be helped.

The composition of the present invention may be administered in a mixture of livestock feed or may be formulated into various formulations by mixing with a pharmaceutically acceptable excipient or adjuvant for precise control of the dosage. Such formulations include, for example, powders, granules, tablets, capsules, liquids such as trenches, oral preparations such as emulsions and suspensions, and injections as parenteral preparations.

Hari therapeutic composition of the present invention can be adjusted in various ratios according to the type and age of the animal, preferably 1 to 2 parts by weight of loperamide, 50 to 100 parts by weight of minocycline, 200 to 400 parts by weight of sulfamemethazole And trimethoprim in a ratio of 40 to 80 parts by weight, and it is preferable that 30 to 60 parts by weight of diastase is further added thereto.

In addition, the formulation including the hari-therapeutic composition of the present invention may also be formulated into a dosage form containing a convenient dosage for administration, including various ratios of the composition as described above. That is, the loperamide is 1 to 4 mg, the minocycline is 50 to 200 mg, the sulfamethoxazole is 200 to 800 mg, the trimethoprim is 40 to 160 mg, and the diastaze is 30 to 120 mg per 15 kg body weight of the animal. It may be administered 1-2 times a day, and when formulated into a formulation containing the above dose, it is convenient to administer.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are only examples of the present invention, and the present invention is not limited thereto.

Formulation Example

First, as loperamide, loperamide hydrochloride in an amount equivalent to 2 g and lactose 18 g. Mix (A), 100 g of minocycline, minocycline hydrochloride, 400 g of sulfamethoxazole, 80 g of trimethoprim, and 66 g of biodiastatase, 1659.5 g of lactose and 50 g of ac-di-sol (2%) The mixture is mixed (B), and 125 g of polyvinylpyrrolidone (K-30) is dissolved separately in a 5% solution of isopropyl alcohol (C).

The A, B, C are combined to pass through a 20 mesh sieve and then dried at 40 ° C. for 60 minutes. The dried granules are again sieved through a 20 mesh sieve, to which 24 g of adisol (1%), 5 g of magnesium stearate and 2 g of talc are added, mixed for 1 minute, and then compressed into tablets to obtain 1000 tablets. The ratio of each component in about 1 tablet is as follows:

Loperamide 2mg

Minocycline 100mg

Sulfamethoxazole 400mg

Trimethoprim 80mg

Biodiastat 66mg

Hari therapy tablets prepared as described above can be administered orally based on 1 tablet per 15 kg body weight for large animals such as cows, water based on 1 tablet per 15 kg body weight for small and medium animals such as pigs It may be suspended orally in a glucose or electrolyte solution and orally administered by a pump injector.

The following is to test the effect of the hari treatment agent of the present invention.

[Effective test 1-Control test with comparative pharmaceutical agent 1]

The hind-bearing piglets were divided into two groups: the administration group of the present invention (group A: 98 heads) and the control group administration group (group B: 66 heads). In group A, the tablets prepared in Formulation Example were suspended in water at a rate of 1 tablet per 15 kg of body weight, and administered once a day, and in group B, a conventional Hari therapeutic agent mixed with an intestinal disinfectant, sulfa agent, and digestive agent per day 1 Administration was twice. The following table shows the healing rate of each dosage group over the course of days of administration.

[Effective test 2-Control test with comparative pharmaceutical agent 2]

The calf that generated hari was divided into two groups: the administration group of the present invention (Group A: 59 heads) and the control group administration group (Group B: 40 heads). In group A, the tablets prepared in Formulation Example were administered orally once a day at a rate of 1 tablet per 15 kg of body weight, and in the group B, oral administration of a conventional Hari therapeutic agent mixed with an intestinal disinfectant, sulfa agent, and digestive agent once a day It was. The following table shows the healing rate of each dosage group over the course of days of administration.

[Effective test 3]

The hari is divided into two groups: young piglets weighing 6 kg or less and piglets weighing 6 kg or more, and the tablets prepared in the above examples are suspended in water at a ratio of 1 tablet per 15 kg of body weight three times a day and twice a day after the second day. By administering, the therapeutic effect of each dose was observed and the following results were obtained.

[Effect Test 4]

The calf was divided into two groups: a calf with a weight of 50 kg or less and a calf with a weight of 50 kg or more, and the tablets prepared in the above example were administered three times a day at a rate of 1 tablet per 15 kg of body weight and twice a day after 2 days. By observing the treatment effect by the number of times, the following results were obtained.

As a result of the above effects test, the hari treatment agent of the present invention showed a cure rate of 65.3% in piglets and 47.5% in calf after 1 day of administration, and showed a healing rate of 98% or more within 3 days of administration. On the other hand, in the case of the control drug, 77.3% of pigs healed and 77.5% of calves were healed within 3 days of administration, which showed low healing rate.

In addition, the Hari therapeutic agent of the present invention, when administered 2-3 times a day, showed a 94.7% heal rate in young piglets weighing 6 kg or less, and 86.7% in piglets weighing 6 kg or more. In young calf of less than 50kg, 90.0% in one day of administration and 47.3% of calf weighing more than 50kg were shown, and it was confirmed that the treatment effect is more excellent in young piglets and calves, which require prompt treatment.

As described above, loperamide, minocycline, and sulfa are essential components, and preferably, the composition for treating hari of the present invention further comprising a diastase, and a pharmaceutical preparation comprising the same according to various causes in livestock. It is very effective in minimizing economic losses such as mortality of livestock by showing rapid and effective effects in the treatment of hari, which occur, and especially in young livestock such as piglets and calves. It is a useful invention.

Claims (8)

A composition for the treatment of hari treatment of an animal, comprising loperamide, long-acting tetracycline antibiotics and sulfa as essential components. The method of claim 1, wherein the persistent tetracycline antibiotic is minocycline composition, characterized in that the minocycline. The method of claim 1, wherein the sulfa agent is a sulfamethoxazole-trimethoprim combination, the hari arapeutic composition of the animal, characterized in that. The method of claim 1, wherein the hari-therapeutic composition of the animal, characterized in that it further comprises a diasterase. The hari of animal according to claim 1, which is combined in a ratio of 1 to 2 parts by weight of loperamide, 50 to 100 parts by weight of minocycline, 200 to 400 parts by weight of sulfamethoxazole and 40 to 80 parts by weight of trimetapririm. Therapeutic composition. The method of claim 5, Hari therapeutic composition of the animal, characterized in that it further comprises 30 to 60 parts by weight of the diastatase. According to claim 6, Loperamide 1 part by weight, minocycline 50 parts by weight, sulfamethoxazole 200 parts by weight, trimethoprim 40 parts by weight and diastatase 30 parts by weight of the hari-therapeutic composition of the animal. A medicinal therapeutic agent for animals comprising the composition of any one of claims 1 to 7 and a pharmaceutically acceptable excipient.