JP6753661B2 - Antidiarrheal composition - Google Patents

Description

The present invention relates to an antidiarrheal composition. More specifically, the present invention relates to an antidiarrheal composition having an improved antidiarrheal effect of trimebutine and / or a salt thereof.

Diarrhea is a symptom in which the amount of water in the stool increases and the stool becomes watery due to increased intestinal motility. Indigestion due to cold or poor physical condition, overeating or drinking too much, mentally. It is caused by various causes such as stress and intestinal infections. Although diarrhea is not a life-threatening disease, it may reduce the quality of life (QOL) and interfere with daily life, so early improvement of its symptoms is required.

On the other hand, trimebutine and / or a salt thereof has both an inhibitory effect on the intestinal tract in a hyperkinetic state and an enhancing effect on the intestinal tract in a hypokinetic state, and the intestinal tract in an abnormal state. It is used to improve diarrhea because it suppresses exercise and restores normal conditions. In addition, various techniques for formulating trimebutine and / or a salt thereof have been conventionally studied. For example, Patent Document 1 reports that the bitterness derived from trimebutine maleate can be masked by granulating trimebutine maleate together with a water-insoluble polymer. Further, Patent Document 2 discloses that the unpleasant taste of trimebutine can be improved by using trimebutine and tea powder in combination.

Further, although trimebutine and / or a salt thereof has a certain antidiarrheal effect, further improvement of the antidiarrheal effect is required for diarrhea symptoms and the like, which are required to have a strong effect. Conventionally, as in Patent Document 1, a formulation technique for facilitating the administration of trimebutine and / or a salt thereof has been studied, but a formulation technique for improving the antidiarrheal effect of trimebutine and / or a salt thereof has been studied. At present, it cannot be said that sufficient consideration has been given.

Japanese Unexamined Patent Publication No. 8-40885 Japanese Unexamined Patent Publication No. 2004-91420

An object of the present invention is to provide a formulation technique for improving the antidiarrheal action of trimebutine and / or a salt thereof.

The present inventor has conducted diligent studies to solve the above problems, and found that, despite the fact that diarrhea is known as a side effect of antidiarrheal agents, when used in combination with trimebutine and / or a salt thereof, trimebutine and / Alternatively, it has been found that the antidiarrheal effect of the salt can be improved. The present invention has been completed by further studies based on such findings.

That is, the present invention provides an antidiarrheal composition according to the following aspects.
Item 1. An antidiarrheal composition comprising (A) trimebutine and / or a salt thereof, and (B) a pain reliever.
Item 2. Item 2. The antidiarrheal composition according to Item 1, which contains 1 to 1500 parts by weight of the (B) painkiller per 100 parts by weight of (A) trimebutine and / or a salt thereof.
Item 3. Item 2. The antidiarrheal composition according to Item 1 or 2, which is administered by oral administration.
Item 4. Item 2. The antidiarrheal composition according to any one of Items 1 to 3, which is a solid preparation.

According to the antidiarrheal composition of the present invention, the antidiarrheal action of trimebutine and / or a salt thereof is dramatically improved, and diarrhea can be effectively treated.

It is a figure which shows the result of having measured the number of feces when trimebtin maleate and a pain-relieving agent were used in combination in a stress-induced diarrhea model rat.

1. 1. Antidiarrheal composition The antidiarrheal composition of the present invention is characterized by containing (A) trimebutine and / or a salt thereof, and (B) a pain reliever. Hereinafter, the antidiarrheal composition of the present invention will be described in detail.

(A) Trimebutine and / or a salt thereof The antidiarrheal composition of the present invention contains trimebutine and / or a salt thereof. Trimebutine and / or a salt thereof is an intestinal motility-controlled opioid receptor agonist that has both an inhibitory effect on the intestinal tract in a hypermotor state and an enhancing effect on the intestinal tract in a hypokinetic state.

The salt of trimebutine is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include maleate.

In the antidiarrheal composition of the present invention, either trimebutine or a salt thereof may be used alone, or these may be used in combination. From the viewpoint of reducing side effects while improving the antidiarrheal effect more effectively, trimebutine maleate is preferable.

In the antidiarrheal composition of the present invention, the content of trimebutine and / or a salt thereof may be appropriately set according to the dosage form and the like of the antidiarrheal composition so that the dose described later can be appropriately set. 1 to 90% by weight, preferably 3 to 80% by weight, still more preferably 5 to 60% by weight.

(B) Antidiarrheal agent The antidiarrheal composition of the present invention contains the antidiarrheal agent together with the trimebutine and / or a salt thereof. As described above, by using the pain-relieving agent in combination with the trimebutine and / or its salt, it becomes possible to improve the antidiarrheal action of trimebutine and / or its salt.

A pain reliever is a drug that reduces the sensitivity of the sensory area of the cerebral cortex and suppresses pain by blocking the conduction of pain sensation at at least one of the pain conduction pathways that transmit pain. The type of painkiller used in the present invention is not particularly limited, but for example, acetaminophen, ibuprofen, loxoprofen, aspirin, aspirin aluminum, diclofenac, etenzamid, sazapyrin, salicylamide, lactylphenetidine, salicylic acid, aminopyrin. , Antipyrine, isopropylantipyrine, lactylphenedin, tolfenamic acid, mephenamic acid, oxyphenbutazone, clofezone, sulpyrine, phenylbutazone, metamizole, clofezone, naproxen, ketoprofen, indomethacin, sulpyrine, acemetamol, tolmethin and the like. In addition, these compounds may be used in the form of salts where they can take the form of salts. Such salts are not particularly limited as long as they are pharmaceutically acceptable, but in the case of, for example, loxoprofen, diclofenac, salicylic acid, tolmethin, etc., alkali metal salts such as sodium salt, potassium salt, etc. Preferred are sodium salts. In addition, these compounds may be in the form of anhydrides or hydrates.

These pain relievers may be used alone or in combination of two or more.

Among these pain relievers, acetaminophen, loxoprofen, ibuprofen, and salts thereof, more preferably acetamino, are preferable from the viewpoint of further effectively improving the antidiarrheal action of trimebutin and / or a salt thereof. Examples include fen, loxoprofen sodium hydrate, and ibuprofen.

In the antidiarrheal composition of the present invention, the ratio of trimebutine and / or a salt thereof to a pain reliever is usually 1 to 1500 parts by weight of the pain reliever per 100 parts by weight of the total amount of trimebutine and / or a salt thereof. It should be set to. From the viewpoint of more effectively improving the antidiarrheal action of trimebutine and / or its salt, the pain-relieving agent is preferably 10 to 1000 parts by weight, more preferably 10 to 1000 parts by weight, per 100 parts by weight of the total amount of trimebutine and / or its salt. 10 to 800 parts by weight, particularly preferably 30 to 500 parts by weight.

Regarding the content of trimebutine and / or its salt in the antidiarrheal composition of the present invention, the ratio of the above-mentioned trimebutine and / or its salt and the pain-relieving agent depends on the type and type of the pain-relieving agent used. It may be appropriately set so that the above can be satisfied, but it is usually 1 to 90% by weight, preferably 3 to 80% by weight, and more preferably 5 to 60% by weight.

Other Ingredients The antidiarrheal composition of the present invention may contain, if necessary, other pharmacological components in addition to the trimebutine and / or a salt thereof and a pain reliever. The type of such pharmacological component is not particularly limited, but for example, an intestinal motility improving agent other than trimebutin and / or a salt thereof, an antacid, a stomachic agent, a digestive agent, an intestinal regulator, an antispasmodic agent, a mucosal repair agent, and an anti-inflammatory agent. , Convergent, antitussive, antitussive, expectorant, anti-inflammatory enzyme, sedative hypnotic, antihistamine, caffeine, cardiotonic diuretic, antibacterial, vasodilator, vasodilator, local anesthetic, crude drug, crude drug extract powder , Vitamin, caffeine, menthol, etc. These pharmacological components may be used alone or in combination of two or more. The content of these pharmacological components may be appropriately set according to the type of the pharmacological component used, the dosage form of the antidiarrheal composition, and the like.

The antidiarrheal composition of the present invention may contain a pharmaceutically acceptable base, additive, or the like, if necessary, in order to prepare the desired dosage form. Such bases and additives include, for example, excipients, binders, disintegrants, lubricants, isotonic agents, plasticizers, dispersants, emulsifiers, solubilizers, wetting agents, stabilizers. Agents, suspending agents, adhesives, coating agents, brighteners, water, fats and oils, waxes, hydrocarbons, fatty acids, higher alcohols, esters, water-soluble polymers, surfactants, metal soaps , Lower alcohols, polyhydric alcohols, pH adjusters, buffers, antioxidants, UV inhibitors, preservatives, flavoring agents, fragrances, powders, thickeners, pigments, chelating agents, etc. These bases and additives may be used alone or in combination of two or more. The content of these bases and additives may be appropriately set according to the type of additive component to be used, the dosage form of the antidiarrheal composition, and the like.

Dosage Form / Dosage Form / Use Examples of the administration form of the antidiarrheal composition of the present invention include oral administration (oral administration) or enteral administration, and oral administration is preferable.

The dosage form of the antidiarrheal composition of the present invention is not particularly limited as long as it can be applied to the above-mentioned administration form, and may be solid, semi-solid, or liquid. Specifically, as the dosage form of the antistatic composition of the present invention, solid preparations such as tablets, pills, capsules (soft capsules, hard capsules), powders, granules (including dry syrup); jelly. Semi-solid preparations such as preparations; liquid preparations such as liquid preparations, suspension preparations and syrup preparations can be mentioned. Among these dosage forms, a solid preparation is preferable from the viewpoint of stability and portability of the contained components.

In order to prepare the antidiarrheal composition of the present invention in the above-mentioned dosage form, a drug using trimebutine and / or a salt thereof, a pain-relieving agent, and a pharmacological component, a base, and an additive added as needed are used. It may be formulated according to the usual formulation method adopted in the field.

The antidiarrheal composition of the present invention is used for the purpose of alleviating or curing diarrhea symptoms. The dose of the antidiarrheal composition of the present invention is appropriately set according to the type of trimebutine and / or a salt thereof or an antidiarrheal agent used, the type of antidiarrheal composition, the age of the patient, the degree of diarrhea, etc. However, for example, the daily dose may be 10 to 1000 mg, preferably 100 to 600 mg in terms of weight of the trimebutine and / or a salt thereof.

2. 2. Pharmaceutical Composition As described above, although diarrhea is known as a side effect of a pain reliever, its antidiarrheal effect can be improved when used in combination with trimebutine and / or a salt thereof. In addition, painkillers have anti-inflammatory and anti-fever effects as well as analgesic effects, and gastrointestinal discomfort due to indigestion and overeating and overdrinking; gastrointestinal pain due to mental stress; gastrointestinal pain due to intestinal infections, etc. It can also relieve cold symptoms such as pain; muscle inflammation; migraine; and abdominal pain, nausea, loss of appetite, sore throat, chills, fever, headache, joint pain, muscle pain and the like. Therefore, the combined use of trimebutine and / or a salt thereof and an antidiarrheal agent is a pharmaceutical composition aimed at alleviating various symptoms associated with dyspepsia, stress gastritis, intestinal infection, myalgia, migraine, neuropathy, and cold. The object can be provided with an additional effect of excellent antidiarrheal action.

Therefore, as another aspect of the present invention, there is provided a pharmaceutical composition characterized by containing (A) trimebutine and / or a salt thereof, and (B) a pain reliever. Hereinafter, the pharmaceutical composition of the present invention will be described in detail.

(A) Trimebutine and / or a salt thereof The pharmaceutical composition of the present invention contains trimebutine and / or a salt thereof. Trimebutine and / or a salt thereof is an intestinal motility-controlled opioid receptor agonist that has both an inhibitory effect on the intestinal tract in a hypermotor state and an enhancing effect on the intestinal tract in a hypokinetic state.

The salt of trimebutine is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include maleate.

In the antidiarrheal composition of the present invention, either trimebutine or a salt thereof may be used alone, or these may be used in combination. From the viewpoint of reducing side effects while improving the antidiarrheal effect more effectively, trimebutine maleate is preferable.

In the pharmaceutical composition of the present invention, the content of trimebutine and / or a salt thereof may be appropriately set according to the dosage form and the like of the pharmaceutical composition so that the dose described later can be appropriately set, but usually 1 to 1 90% by weight, preferably 3 to 80% by weight, more preferably 5 to 60% by weight.

(B) Pain Relief Agent The pharmaceutical composition of the present invention contains a pain reliever as well as the trimebutine and / or a salt thereof. In this way, the combined use of a pain reliever with trimebutine and / or a salt thereof not only improves the stagnation effect of trimebutine and / or a salt thereof, but also improves the efficacy of the pain reliever (dyspepsia and overeating). Gastrointestinal discomfort due to overdrinking, gastrointestinal pain due to mental stress, gastrointestinal pain due to intestinal infection, muscle inflammation, migraine, relief of cold symptoms, etc.) can be provided. ..
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A pain reliever is a drug that reduces the sensitivity of the sensory area of the cerebral cortex and suppresses pain by blocking the conduction of pain sensation at at least one of the pain conduction pathways that transmit pain. The type of painkiller used in the present invention is not particularly limited, but for example, acetaminophen, ibuprofen, loxoprofen, aspirin, aspirin aluminum, diclofenac, etenzamid, sazapyrin, salicylamide, lactylphenetidine, salicylic acid, aminopyrin. , Antipyrine, isopropylantipyrine, lactylphenedin, tolfenamic acid, mefenamic acid, oxyphenbutazone, clofezone, sulpyrine, phenylbutazone, metamizole, clofezone, naproxen, ketoprofen, indomethacin, sulpyrine, acemethasin, tolmethin, etc. Drugs can be mentioned. In addition, these compounds may be used in the form of salts where they can take the form of salts. Such salts are not particularly limited as long as they are pharmaceutically acceptable, but in the case of, for example, loxoprofen, diclofenac, salicylic acid, tolmethin, etc., alkali metal salts such as sodium salt, potassium salt, etc. Preferred are sodium salts. In addition, these compounds may be in the form of anhydrides or hydrates.

These pain relievers may be used alone or in combination of two or more.

Among these pain relievers, the stagnation effect of trimebutin and / or its salt is further effectively improved, or the efficacy of the pain reliever (gastrointestinal discomfort due to indigestion or overdrinking, mental discomfort). From the viewpoint of effectively exerting gastrointestinal pain due to stress, gastrointestinal pain due to intestinal infection, muscle inflammation, migraine, and alleviation of cold symptoms, etc.), acetaminophen, loxoprofen, ibuprofen are preferable. , And salts thereof, more preferably acetaminophen, loxoprofen sodium hydrate, and ibuprofen.

In the pharmaceutical composition of the present invention, the ratio of trimebutine and / or a salt thereof to a pain reliever is usually 1 to 1500 parts by weight per 100 parts by weight of the total amount of trimebutine and / or a salt thereof. You can set it. Trimebutine and / or its salt from the viewpoint of further effectively improving the antidiarrheal action of trimebutine and / or its salt, or effectively exerting the effect of the pain-relieving agent (alleviation of various cold symptoms, etc.). The pain-relieving agent is preferably 10 to 1000 parts by weight, more preferably 10 to 800 parts by weight, and particularly preferably 30 to 500 parts by weight, based on 100 parts by weight of the total amount.

In the pharmaceutical composition of the present invention, regarding the content of the pain-relieving agent, the ratio of the above-mentioned trimebutine and / or its salt and the pain-relieving agent can be satisfied according to the type and dosage form of the pain-relieving agent used. Is appropriately set, but is usually 1 to 90% by weight, preferably 3 to 80% by weight, and more preferably 5 to 60% by weight.

Other Ingredients In addition to the above-mentioned trimebutine and / or a salt thereof, and a pain reliever, the pharmaceutical composition of the present invention may contain other pharmacological ingredients, if necessary. The type of such pharmacological component is not particularly limited, but for example, an intestinal motility improving agent other than trimebutin and / or a salt thereof, an antacid, a stomachic agent, a digestive agent, an intestinal regulator, an antispasmodic agent, a mucosal repair agent, and an anti-inflammatory agent. , Convergent, antiemetic, antitussive, expectorant, anti-inflammatory enzyme, sedative hypnotic, antihistamine, caffeine, cardiotonic diuretic, antibacterial, vasodilator, vasodilator, local anesthetic, crude drug, crude drug extract powder , Vitamin, caffeine, menthol, etc. These pharmacological components may be used alone or in combination of two or more. The content of these pharmacological components may be appropriately set according to the type of the pharmacological component used, the dosage form of the pharmaceutical composition, and the like.

The pharmaceutical composition of the present invention may contain a pharmaceutically acceptable base, additive, or the like, if necessary, in order to prepare a desired dosage form. Such bases and additives include, for example, excipients, binders, disintegrants, lubricants, isotonic agents, plasticizers, dispersants, emulsifiers, solubilizers, wetting agents, stabilizers. Agents, suspending agents, adhesives, coating agents, brighteners, water, fats and oils, waxes, hydrocarbons, fatty acids, higher alcohols, esters, water-soluble polymers, surfactants, metal soaps , Lower alcohols, polyhydric alcohols, pH adjusters, buffers, antioxidants, UV inhibitors, preservatives, flavoring agents, fragrances, powders, thickeners, pigments, chelating agents, etc. These bases and additives may be used alone or in combination of two or more. Further, the contents of these bases and additives may be appropriately set according to the type of additive component to be used, the dosage form of the pharmaceutical composition, and the like.

Dosage Form / Dosage Form / Use Examples of the administration form of the pharmaceutical composition of the present invention include oral administration (oral administration) or enteral administration, and oral administration is preferable.

The dosage form of the pharmaceutical composition of the present invention is not particularly limited as long as it can be applied to the above-mentioned administration form, and may be solid, semi-solid, or liquid. Specifically, as the dosage form of the pharmaceutical composition of the present invention, solid preparations such as tablets, pills, capsules (soft capsules, hard capsules), powders, granules (including dry syrup); jelly preparations. Semi-solid preparations such as; liquid preparations such as liquid preparations, suspensions, syrups and the like. Among these dosage forms, a solid preparation is preferable from the viewpoint of stability and portability of the contained components.

In order to prepare the pharmaceutical composition of the present invention into the above-mentioned dosage form, trimebutine and / or a salt thereof, a pain reliever, and a pharmacological component, a base, and an additive added as needed are used in the pharmaceutical field. It may be formulated according to the usual formulation method adopted in.

Since the pharmaceutical composition of the present invention contains the pain-relieving agent, gastrointestinal discomfort due to indigestion or overeating and drinking too much; gastrointestinal pain due to mental stress; gastrointestinal pain due to intestinal infection or the like; It can be used for the purpose of alleviating various cold symptoms such as muscle inflammation; migraine; and abdominal pain, nausea, loss of appetite, sore throat, cold, fever, headache, joint pain, muscle pain and the like. In particular, in view of the fact that the pharmaceutical composition of the present invention can improve the antidiarrheal effect of trimebutin and / or a salt thereof and effectively alleviate gastrointestinal discomfort, stress accompanied by gastrointestinal symptoms (gastrointestinal discomfort). It should be used for the purpose of alleviating symptoms, gastrointestinal symptoms due to intestinal infection, and cold symptoms with gastrointestinal symptoms (gastrointestinal discomfort), especially stress symptoms with diarrhea and cold symptoms with diarrhea. Is preferable.

The dose of the pharmaceutical composition of the present invention is appropriately set according to the type of trimebutine and / or a salt thereof or a pain reliever to be used, the dosage form of the pharmaceutical composition, the age of the patient, the intended use, the degree of symptoms, and the like. However, for example, the daily dose may be 10 to 1000 mg, preferably 100 to 600 mg in terms of weight of trimebutine and / or a salt thereof.

Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited thereto.

Test example: Verification of antidiarrheal effect
1. 1. Preparation of test solution A test solution having the composition shown in Table 1 was prepared. Specifically, a test solution was prepared by adding a predetermined amount of trimebutine maleate and a predetermined amount of a pain reliever to an aqueous solution prepared by adding a predetermined amount of sodium carboxymethyl cellulose.

2. 2. Evaluation method of antidiarrheal effect on stress-induced diarrhea model rats In this study, rats (SPF, Slc: SD, obtained from Nippon SLC Co., Ltd.) were used. After obtaining at 6 weeks of age, a quarantine / acclimatization period of 8 days was provided, and rats aged 7 weeks with no abnormalities in body weight transition and general condition were used in the test. Each test solution shown in Table 1 was orally administered using a 1 ml disposable syringe (JMS Co., Ltd.) and a disposable oral sonde (Fuchigami Instrument Co., Ltd.) so as to have a weight of 5 ml / kg-body weight for each rat. After 60 minutes, the rat was anesthetized with isoflurane (trade name "Eskine inhalation anesthetic", manufactured by Mylan Pharmaceutical Co., Ltd.), and the chest including the left and right upper limbs was wrapped with adhesive tape (using two 5 cm x 30 cm sheets) to fix the upper body. The load of restraint stress was given. The rats fixed with adhesive tape were immediately placed in the observation cage one by one, and the number of feces was measured for 1 hour thereafter. In this test, 10 rats in each group were used to calculate the average number of feces.

3. Test Results The results obtained are shown in FIG. As a result, stress-induced diarrhea model rats were treated with trimebutine maleate and a pain reliever (Examples 1 to 5) as compared with the case where trimebutine maleate was administered alone (Comparative Example 1). It was revealed that the pain-relieving agent has an action of improving the antidiarrheal action of trimebutine and / or a salt thereof. It was also confirmed that the properties of feces were normalized when trimebtin maleate and a pain reliever were used in combination (Examples 1 to 5).

Formulation Examples Tablets having the compositions shown in Tables 2 and 3 (333 mg per tablet) were prepared according to a conventional method.

Claims (3)

An antidiarrheal composition containing (A) trimebutine and / or a salt thereof, and (B) a pain reliever, wherein the component (B) is an antipyretic anti-inflammatory analgesic and is a solid preparation. The antidiarrheal composition according to claim 1, wherein (A) trimebutine and / or a salt thereof contains 1 to 1500 parts by weight of the (B) pain-relieving agent per 100 parts by weight. The antidiarrheal composition according to claim 1 or 2, which is administered by oral administration.