JP6556526B2 - Preventive or therapeutic agent for bovine digestive diseases in mosapride citrate - Google Patents

Description

  The present invention relates to a preventive or therapeutic agent for bovine digestive system diseases. More specifically, 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-formonyl] methyl] benzamide (hereinafter sometimes referred to as “mosapride”) or its The present invention relates to a preventive or therapeutic agent for digestive tract diseases of cattle due to a gastrointestinal motility function promoting action comprising a physiologically acceptable salt as an active ingredient.

For humans, mosapride citrate is a selective serotonin 5-HT ₄ receptor agonist and is known as a gastrointestinal motility function promoter that does not show a dopamine D ₂ receptor blocking action (Patent Document 1).
A preparation containing mosapride citrate as an active ingredient has already been put into practical use for the purpose of improving gastrointestinal symptoms associated with chronic gastritis and assisting in pretreatment of barium enema X-ray imaging with an oral intestinal irrigant. Is marketed under the trade name "".

  In the veterinary field, mosapride citrate has already been marketed as a drug for improving upper gastrointestinal motility in dogs, and an application for marketing approval has been filed for the improvement and reduction of gastrointestinal motility in equine constipation. .

  On the other hand, the application of mosapride citrate to the improvement of gastrointestinal motility in cattle has not been reported so far and has been considered difficult because of the special and complicated structure of the stomach in cattle.

Unlike the stomachs of humans and other mammals, the bovine stomach has four stomachs from the first stomach to the fourth stomach instead of one stomach. Among them, mammals such as humans and dogs have so-called “stomach”. It is known that the only organ that has the function of secreting gastric acid and degrading protein called “the stomach 4”, and the first to third stomachs do not have such a function. Among the four stomachs, the rumen is responsible for the unique digestive mechanism of cattle. The rumen is very large, has a volume of ~ 200 liters for beef cattle, ~ 300 liters for dairy cows, and has a size exceeding 180 liters for drums, and foods such as cellulose contained in grass that cannot be digested by normal mammals. The fiber has the function of facilitating fermentation and digestion absorption with the help of a huge number of microorganisms present in the rumen, and absorbing digested nutrients.
And cows also have a unique digestion mechanism called so-called “rumination” that sends the gastric contents once chewed and swallowed back into the oral cavity, and chews and swallows again. Because of these complicated mechanisms of the digestive tract, Drugs intended to improve gastrointestinal motility function applied to normal mammals have been considered ineffective or limited effects.

Of the diseases affecting domestic cattle, the incidence of gastrointestinal diseases thought to be caused by gastrointestinal tract is considered to be about 10% of the total, but metoclopramide has been mainly used for the treatment. Metoclopramide has a pharmacological action of both dopamine D ₂ receptor antagonism and serotonin 5-HT ₄ receptor stimulation, and has been approved for use in animals, such as rumen stagnation, bloating and simple dyspepsia. Widely used as a medicine.

  However, although metoclopramide is often used in clinical settings for digestive diseases of cattle, there are many doubts about the effect and many opinions are not necessarily clear. In addition, it has been reported that metoclopramide has almost no action to promote gastrointestinal motility in cattle (see Non-Patent Document 1). An effective and practical new therapeutic agent was eagerly desired in the veterinary field of animal husbandry.

U.S. Pat. No. 4,870,074

Constable PD, Nouri M, Sen I, Baird AN, Wittek T. Evidence-based use of prokinetic drugs for abomasal disorders in cattle.Vet Clin North Am Food Anim Pract. 2012 Mar; 28 (1): 51-70.

  An object of the present invention is to provide an effective and practical preventive and therapeutic agent for bovine digestive tract diseases.

While the present inventors have intensively studied as a new bovine digestive tract disease treatment to replace metoclopramide, it has not been reported to be applied to cattle due to the complicated structure of the bovine stomach. The mesoclopramide is a selective serotonin 5-HT ₄ receptor agonist that has a different mechanism of action and does not show a dopamine D ₂ receptor blocking action, and focused on mosapride citrate, which has a gastrointestinal motor function promoting action. Regarding serotonin 5-HT ₄ receptor operation, which is the main action of mosapride citrate, the non-patent document 1 shows that the effect of promoting the digestive motility in the serotonin 5-HT ₄ receptor operation mechanism on the ruminant bovine is very In spite of such findings, mosapride citrate was actually applied to cattle with digestive illnesses, but never before for various digestive illnesses in cattle. It has been found that a remarkable effect is exhibited, and also has a strong contracting action on the rumen, and the present invention has been completed.

  That is, the present invention relates to the following.

<1> A therapeutic and / or preventive agent for bovine gastrointestinal diseases, comprising mosapride or a physiologically acceptable salt.

<2> Bovine gastrointestinal disorders are rumen stasis, bloating, rumen acidosis, acute ruminal dilatation, stagnation of the stomach, ruminal displacement / torsion, liponecrosis, and / or gastritis / enteritis The therapeutic and / or prophylactic agent of <1>, which is anorexia due to, and the like.

<3> The therapeutic and / or prophylactic agent of <1> or <2>, wherein the mosapride or physiologically acceptable salt is mosapride citrate.

<4> The therapeutic and / or prophylactic agent according to any one of <1> to <3>, which is an oral preparation.

<5> The therapeutic and / or prophylactic agent according to any one of <1> to <3>, which is an injection.

<6> The therapeutic and / or prophylactic agent according to <4>, which is administered at 0.01 to 100 mg / kg per day.

<7> The therapeutic and / or prophylactic agent according to <5>, which is administered at 0.01 to 100 mg / kg per day.

<8> A method for treating and / or preventing bovine gastrointestinal diseases, comprising administering a therapeutically effective amount of mosapride or a physiologically acceptable salt to a bovine.

<9> Bovine gastrointestinal disorders are rumen stasis, bloating, rumen acidosis, acute ruminal dilatation, stagnation of the stomach, ruminal displacement / torsion, steatosis, and / or gastritis / enteritis <8> A method for the treatment and / or prevention of anorexia due to, and the like.

<10> A composition comprising mosapride or a physiologically acceptable salt for use in the treatment and / or prevention of digestive tract diseases in cattle.

<11> Use of mosapride or a physiologically acceptable salt for producing a therapeutic and / or preventive agent for bovine digestive diseases.

According to the present invention, mosapride citrate is very useful for the prevention and treatment of digestive diseases in cattle.
In addition, since the therapeutic effect can be expected even in cases where metoclopramide is not effective, it is economical because it can be treated even in cases that have been treated by surgery or cases that have been discarded without expectation of recovery. Loss can be greatly reduced.
Furthermore, in the present invention, since the effect can be obtained even by oral administration despite the complicated stomach structure of bovine, aseptic treatment in the manufacture of parenteral agents and aseptic handling at the time of administration are possible. It can be unnecessary.

  Hereinafter, the present invention will be described in detail with reference to the meanings of terms and the like described in the present specification and the embodiments of the present invention.

  The physiologically acceptable salt of mosapride is preferably an acid addition salt. For example, organic acid addition salts include formate, acetate, lactate, adipate, citrate, tartrate, fumarate, methanesulfonate, maleate, etc. Examples of the salt include hydrochloride, sulfate, nitrate, phosphate and the like. Of these, citrate is particularly preferable. Furthermore, mosapride or a physiologically acceptable salt thereof may be a solvate, a hydrate and a non-hydrate. Citrate hydrate is preferred, and citrate dihydrate is particularly preferred.

  As used herein, “bovine gastrointestinal disease” refers to ruminal stagnation, bloating, rumen acidosis, acute ruminal dilatation, stagnation of the stomach, displacement and torsion of the stomach, and fatty necrosis And anorexia due to gastritis and enteritis.

  The dose (therapeutically effective amount) of mosapride or pharmaceutically acceptable salt used in the present invention is not particularly limited as long as the therapeutic effect is obtained, but 0.01 mg per day for oral administration. It is used at -100 mg / kg, preferably 0.05-50 mg / kg, more preferably 0.05-25 mg / kg. Moreover, if it is an injection, it is used at 0.01-100 mg / kg per day, Preferably it is 0.01-50 mg / kg, More preferably, it is used at 0.01-25 mg / kg. Moreover, it may be administered 1 to 4 times a day, preferably 1 to 3 times.

The dosage form of the present invention may be either an oral preparation or an injection. Examples of oral dosage forms include tablets, capsules, powders, granules, solutions, suspensions, and syrups. As an oral preparation, it may be forcibly fed to cattle or taken with food. Injectables can be administered intravenously, subcutaneously, or intramuscularly.
The composition of the present invention is prepared in a general pharmaceutical preparation form containing an effective amount of the compound of the present invention or a salt thereof together with a pharmaceutically acceptable carrier.

Oral preparations are formulated with pharmaceutically acceptable excipients and additives. Examples of pharmaceutically acceptable excipients and additives include carriers, binders, fragrances, buffers, thickeners, colorants, stabilizers, emulsifiers, dispersants, suspending agents, preservatives, and the like. It is done. Specifically, the compound of the present invention is mixed with lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, metasilicic acid, magnesium aluminate and the like, and the mixture is shaped according to a conventional method. it can. The mixture further includes suitable additives such as lubricants such as magnesium stearate; disintegrants such as calcium calcium glycolate; stabilizers such as lactose; solubilizing aids such as glutamic acid and aspartic acid. An agent or the like can be blended. Sweetening agents, flavoring agents, fragrances, preservatives and the like can also be added and blended.
Capsules can be formulated by placing a compound according to the invention in a pharmaceutically acceptable carrier. The compounds according to the invention can be mixed with pharmaceutically acceptable excipients or placed in capsules without excipients.
Solutions, suspensions and the like suitable for oral administration can be produced by adding the compound of the present invention to water and adding a colorant, a fragrance, a stabilizer, a sweetener, a solubilizer, a thickener and the like as necessary. it can. Solutions, suspensions and the like suitable for oral administration can also be produced by adding the compound of the present invention together with a dispersant to water to make it viscous. Examples of the thickener include pharmaceutically acceptable natural or synthetic gum, resin, methylcellulose, sodium carboxymethylcellulose, or a known suspending agent.
Powders are formulated with a pharmaceutically acceptable powder base. Examples of the base include talc, lactose, starch and the like.

  Injections include sterile aqueous or non-aqueous solutions, suspensions, emulsions and the like. An aqueous injection can be prepared according to a conventional method using, for example, distilled water for injection and physiological saline as diluents. Non-aqueous injections can be prepared according to conventional methods using, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil; alcohols such as ethanol; polysorbate 80 and the like as diluents or carriers. These injections may further contain additives such as preservatives, wetting agents, emulsifiers, dispersants, stabilizers (for example, lactose) and solubilizing agents (for example, glutamic acid and aspartic acid). . The prepared injection is sterilized according to a conventional method, for example, filtration through a bacteria-retaining filter, blending of a bactericidal agent, or irradiation with radiation such as gamma rays. In addition, the injection can be prepared in a form of a dissolution solution at the time of use, which is practically used by dissolving a sterile solid preparation in sterile water or a sterile solvent for injection after production.

  In order to show the advantageous effects of the present invention, examples will be shown below. However, these examples are illustrative, and the present invention is not limited to the following specific examples in any case. Those skilled in the art can implement the present invention by appropriately changing the conditions described in the following examples, and such changes are included in the scope of the claims of the present application.

Example 1. Cases where mosapride citrate was administered to cattle with liponecrosis. Three measles cattle with fat necrosis that did not improve after administration of metoclopramide were treated with 1 mg / kg of mosapride citrate. As a result of administration twice a day, defecation and appetite improvement were observed on the day after administration (Table 1).

Example 2 Cases where mosapride citrate was administered to bovines with left displacement of the left stomach As a result of administration of mosapride citrate at 1 mg / kg twice a day, the stool was excreted the day after administration, and the patient was completely cured without surgery (Table 2).

Example 3 Cases where mosapride citrate was administered to cattle with duodenal torsion and stagnation. After reduction, mosapride citrate was administered at a dose of 1 mg / kg twice a day. It recovered in one week later (Table 3, No. 1).
As a result of administration of mosapride citrate 1 mg / kg twice a day to stagnant cattle, defecation and appetite were improved the day after administration (Table 3, No. 2).

  For patients who have been treated with metoclopramide or pantethine, which is considered to have a gastrointestinal motility function promoting action in gastrointestinal diseases such as rumen stagnation and rumen displacement in cattle Since the therapeutic effect can be expected by using mosapride citrate in cattle, it can be expected to contribute greatly in the field of livestock production because it has a wide range of applications as a bovine gastrointestinal motility promoter.

Claims (11)

  A therapeutic and / or preventive agent for bovine digestive diseases, comprising mosapride or a physiologically acceptable salt.   Gastrointestinal disorders in cattle include rumen stasis, bloating, rumen acidosis, acute ruminal dilatation, third stomach stasis, fourth stomach displacement / torsion, fat necrosis, and / or appetite due to gastritis / enteritis, etc. The therapeutic and / or prophylactic agent according to claim 1, wherein the agent is poor.   The therapeutic and / or prophylactic agent according to claim 1 or 2, wherein the mosapride or physiologically acceptable salt is mosapride citrate.   The therapeutic and / or prophylactic agent according to any one of claims 1 to 3, which is an oral agent.   The therapeutic and / or prophylactic agent according to any one of claims 1 to 3, which is an injection.   The therapeutic and / or prophylactic agent according to claim 4, which is administered at a dose of 0.01 to 100 mg / kg per day.   The therapeutic and / or prophylactic agent according to claim 5, which is administered at a dose of 0.01 to 100 mg / kg per day.   A method for treating and / or preventing bovine gastrointestinal diseases, comprising administering to a bovine a therapeutically effective amount of mosapride or a physiologically acceptable salt.   Gastrointestinal disorders in cattle include rumen stasis, bloating, rumen acidosis, acute ruminal dilatation, third stomach stasis, fourth stomach displacement / torsion, fat necrosis, and / or appetite due to gastritis / enteritis, etc. The method of treatment and / or prevention according to claim 8, wherein the method is poor.   A composition comprising mosapride or a physiologically acceptable salt for use in the treatment and / or prevention of bovine gastrointestinal diseases.   Use of mosapride or a physiologically acceptable salt for the manufacture of a therapeutic and / or prophylactic agent for bovine gastrointestinal diseases.