JP2016074659A - Antidiarrheal composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a pharmaceutical preparation technique to improve the antidiarrheic action of trimebutine and/or a salt thereof.SOLUTION: A pain-killer agent is known to cause diarrhea as a side effect, but its use in combination with trimebutine and/or a salt thereof makes it possible to improve the antidiarrheic action of trimebutine and/or a salt thereof.SELECTED DRAWING: None

Description

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

  Diarrhea is a symptom of increased water content in feces due to increased intestinal motility and watery stool, dyspepsia due to colds and poor physical condition, overeating and drinking, mental It can be caused by various causes such as stress and intestinal infections. Although diarrhea is not a life-threatening disease, it lowers the quality of life (QOL) and may interfere with daily life. Therefore, early improvement of symptoms is required.

  On the other hand, trimebutine and / or a salt thereof has both an inhibitory action on the intestinal tract in the enhanced movement state and an enhancement action on the intestinal tract in the reduced movement state. It is used to improve diarrhea because it has the effect of suppressing exercise and returning to normal. Various preparation techniques for trimebutine and / or a salt thereof have been conventionally studied. For example, Patent Document 1 reports that the bitter taste derived from trimebutine maleate can be masked by granulating trimebutine maleate together with a water-insoluble polymer. 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 have a certain antipruritic action, further improvement of the antidiarrheal action is required for diarrheal symptoms and the like that require a strong effect. Conventionally, as in Patent Document 1, although formulation technology for facilitating taking of trimebutine and / or its salt has been studied, formulation technology for improving antipruritic action by trimebutine and / or its salt At present, it cannot be said that sufficient consideration has been made.

JP-A-8-40885 JP 2004-91420 A

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

  As a result of intensive studies to solve the above problems, the present inventor has found that trimebutine and / or its salt can be used in combination with trimebutine and / or a salt thereof even though diarrhea is known as a side effect. Or it discovered that the antipruritic action of the salt could be improved. The present invention has been completed by further studies based on such knowledge.

That is, this invention provides the antidiarrheal composition of the aspect hung up below.
Item 1. An antidiarrheal composition comprising (A) trimebutine and / or a salt thereof, and (B) an analgesic.
Item 2. Item 2. The antidiarrheal composition according to Item 1, comprising 1-1500 parts by weight of the (B) painkiller per 100 parts by weight of (A) trimebutine and / or a salt thereof.
Item 3. Item 3. The antidiarrheal composition according to Item 1 or 2, which is administered by oral administration.
Item 4. Item 4. 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 antipruritic action of trimebutine and / or its salt is dramatically improved, and diarrhea can be effectively treated.

It is a figure which shows the result of having measured the number of feces at the time of using a combination of a trimebutine maleate and a painkiller in the stress induction diarrhea model rat.

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

(A) Trimebutine and / or 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-type opioid receptor agonist that has both an inhibitory action on the intestinal tract in an enhanced movement state and an enhancement action on the intestinal tract in a reduced movement 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 a combination thereof may be used. Trimebutine maleate is preferably used from the viewpoint of reducing side effects while further improving the antipruritic action.

  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 of the antidiarrheal composition, etc., so that the dose described later can be satisfied. 1 to 90% by weight, preferably 3 to 80% by weight, and more preferably 5 to 60% by weight.

(B) Painkiller The antidiarrheal composition of the present invention contains a painkiller along with the trimebutine and / or salt thereof. Thus, it becomes possible to improve the antipruritic action of trimebutine and / or its salt by using in combination with the above-mentioned trimebutine and / or its salt together with the painkiller.

  An analgesic is a drug that reduces pain sensitivity by reducing the sensitivity of the sensory area of the cerebral cortex by blocking the conduction of pain at least in one pain conduction pathway that transmits pain. The type of painkiller used in the present invention is not particularly limited. For example, acetaminophen, ibuprofen, loxoprofen, aspirin, aspirin aluminum, diclofenac, ethenamide, sazapyrine, salicylamide, lactylphenetidine, salicylic acid, aminopyrine , Antipyrine, isopropylantipyrine, lactylphenezin, tolfenamic acid, mefenamic acid, oxyphenbutazone, clofesone, sulpyrine, phenylbutazone, metamizole, clofesone, naproxen, ketoprofen, indomethacin, sulpyrine, acemetacin, tolmethine and the like. In addition, these compounds may be used in the form of a salt if they can take the form of a salt. Such a salt is not particularly limited as long as it is pharmaceutically acceptable. For example, in the case of loxoprofen, diclofenac, salicylic acid, tolmetin, and the like, an alkali metal salt such as a sodium salt or a potassium salt, A sodium salt is preferable. In addition, these compounds may be in the form of anhydrides or hydrates.

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

  Among these analgesics, acetaminophen, loxoprofen, ibuprofen, and salts thereof, more preferably acetamino, from the viewpoint of further effectively improving the antipruritic action of trimebutine and / or a salt thereof. Fen, loxoprofen sodium hydrate, and ibuprofen.

  In the antidiarrheal composition of the present invention, the ratio of trimebutine and / or its salt to the painkiller is usually 1 to 1500 parts by weight of the painkiller per 100 parts by weight of the total amount of trimebutine and / or its salt. Should be set. From the viewpoint of further effectively improving the antipruritic action of trimebutine and / or its salt, the painkiller is preferably 10 to 1000 parts by weight, more preferably 100 parts by weight of the total amount of trimebutine and / or its salt. 10-800 weight part, Especially preferably, 30-500 weight part is mentioned.

  In the antidiarrheal composition of the present invention, the content of trimebutine and / or a salt thereof depends on the type, dosage form, etc. of the painkiller used, and the ratio of the above-mentioned trimebbutin and / or salt thereof to the painkiller May be appropriately set so as to satisfy the above, but usually 1 to 90% by weight, preferably 3 to 80% by weight, and more preferably 5 to 60% by weight.

Other components The antidiarrheal composition of the present invention may contain other pharmacological components, if necessary, in addition to the trimebutine and / or its salt and the painkiller. The type of such pharmacological component is not particularly limited. For example, an intestinal motility improving agent other than trimebutine and / or a salt thereof, an antacid, a stomachic agent, a digestive agent, an intestinal adjuster, an antispasmodic agent, a mucosal repair agent, an anti-inflammatory agent , Astringent, antiemetic, antitussive, expectorant, antiphlogistic enzyme, sedative hypnotic, antihistamine, caffeine, cardiotonic, antibacterial, vasoconstrictor, vasodilator, local anesthetic, herbal medicine, herbal extract powder , Vitamins, caffeine, menthol and the like. These pharmacological components may be used alone or in combination of two or more. Moreover, what is necessary is just to set suitably about content of these pharmacological components according to the kind of pharmacological component to be used, the dosage form of an antipruritic composition, etc.

  The antidiarrheal composition of the present invention may contain a pharmaceutically acceptable base or additive as necessary in order to prepare a desired dosage form. Examples of such bases and additives include excipients, binders, disintegrants, lubricants, isotonic agents, plasticizers, dispersants, emulsifiers, solubilizers, wetting agents, and stabilization. Agent, suspending agent, adhesive, coating agent, brightening agent, water, fats and oils, waxes, hydrocarbons, fatty acids, higher alcohols, esters, water-soluble polymer, surfactant, metal soap , Lower alcohols, polyhydric alcohols, pH adjusters, buffers, antioxidants, UV inhibitors, preservatives, corrigents, fragrances, powders, thickeners, dyes, chelating agents, and the like. These bases and additives may be used individually by 1 type, and may be used in combination of 2 or more type. Moreover, what is necessary is just to set suitably about content of these bases and additives according to the kind of additive component to be used, the dosage form of an antipruritic composition, etc.

Administration Form / Dosage Form / Use Examples of the administration form of the antidiarrheal composition of the present invention include oral administration (internal use) and enteral administration, preferably oral administration.

  The dosage form of the antidiarrheal composition of the present invention is not particularly limited as long as it can be applied to the administration form, and may be any of solid, semi-solid, or liquid. Specifically, solid dosage forms such as tablets, pills, capsules (soft capsules, hard capsules), powders, granules (including dry syrup), etc. as dosage forms of the antipruritic composition of the present invention; And semi-solid preparations such as liquids; liquid preparations such as liquids, suspensions, and syrups. Among these dosage forms, a solid preparation is preferable from the viewpoints of stability of components and portability.

  In order to prepare the antipruritic composition of the present invention into the above dosage form, trimebutine and / or a salt thereof, an analgesic agent, and a pharmacological component, a base, and an additive that are added as necessary are used. What is necessary is just to formulate according to the normal formulation method employ | adopted by the field | area.

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

2. Pharmaceutical Composition As described above, although antidiarrheal agents are known to have diarrhea as a side effect, when used in combination with trimebutine and / or a salt thereof, the antipruritic action can be improved. In addition, painkillers have anti-inflammatory and antipyretic effects as well as analgesic effects, gastrointestinal discomfort due to indigestion and overdose, gastrointestinal pain due to mental stress; gastrointestinal pain due to intestinal infections, etc. Pain; muscle inflammation; migraine; and abdominal pain, nausea, loss of appetite, sore throat, chills, fever, headache, joint pain, muscle pain, and other cold symptoms. Therefore, the combination of trimebutine and / or its salt and painkiller is a pharmaceutical composition for the purpose of alleviation of various symptoms associated with dyspepsia, stress gastritis, intestinal infections, muscle pain, migraine, neurosis, colds, etc. The object can be provided with an additional effect of excellent anti-pasting action.

  Therefore, as another embodiment of the present invention, there is provided a pharmaceutical composition comprising (A) trimebutine and / or a salt thereof, and (B) an analgesic. Hereinafter, the pharmaceutical composition of the present invention will be described in detail.

(A) Trimebutine and / or 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-type opioid receptor agonist that has both an inhibitory action on the intestinal tract in an enhanced movement state and an enhancement action on the intestinal tract in a reduced movement 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 a combination thereof may be used. Trimebutine maleate is preferably used from the viewpoint of reducing side effects while further improving the antipruritic action.

  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 of the pharmaceutical composition and the like so as to satisfy the dosage described below. 90% by weight, preferably 3 to 80% by weight, more preferably 5 to 60% by weight.

(B) Painkiller The pharmaceutical composition of the present invention contains a painkiller along with the trimebutine and / or salt thereof. Thus, by using a combination of painkillers with trimebutine and / or its salt, not only improves the antipruritic action of trimebutine and / or its salt, but also the effects of painkillers (indigestion and overeating) Gastrointestinal discomfort due to excessive drinking, gastrointestinal pain due to mental stress, gastrointestinal pain due to intestinal infection, etc., muscle inflammation, migraine, and relief of various cold symptoms, etc.) .
Do

  An analgesic is a drug that reduces pain sensitivity by reducing the sensitivity of the sensory area of the cerebral cortex by blocking the conduction of pain at least in one pain conduction pathway that transmits pain. The type of painkiller used in the present invention is not particularly limited. , Antipyrine, isopropylantipyrine, lactylphenezin, tolfenamic acid, mefenamic acid, oxyphenbutazone, clofesone, sulpyrine, phenylbutazone, metamizole, clofesone, naproxen, ketoprofen, indomethacin, sulpyrine, acemetacin, tolmethine, etc. Medicines. In addition, these compounds may be used in the form of a salt if they can take the form of a salt. Such a salt is not particularly limited as long as it is pharmaceutically acceptable. For example, in the case of loxoprofen, diclofenac, salicylic acid, tolmetin, and the like, an alkali metal salt such as a sodium salt or a potassium salt, A sodium salt is preferable. In addition, these compounds may be in the form of anhydrides or hydrates.

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

  Among these painkillers, the antipruritic action of trimebutine and / or its salts is improved more effectively, or the effects of painkillers (gastrointestinal discomfort caused by indigestion and excessive eating, mental Gastrointestinal pain due to stress, gastrointestinal pain due to intestinal infection, etc., muscle inflammation, migraine, relief of various symptoms of cold, etc.), preferably acetaminophen, loxoprofen, ibuprofen And their salts, more preferably acetaminophen, loxoprofen sodium hydrate, and ibuprofen.

  In the pharmaceutical composition of the present invention, the ratio of trimebutine and / or its salt to the painkiller is usually 1 to 1500 parts by weight of the painkiller per 100 parts by weight of the total amount of trimebutine and / or its salt. You only have to set it. Trimebutine and / or a salt thereof from the viewpoint of more effectively improving the antipruritic action of trimebutine and / or a salt thereof, or effectively exerting the effects (relieving various symptoms of colds) by the painkiller. The amount of the pain-killer 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 per 100 parts by weight.

  In the pharmaceutical composition of the present invention, the content of the pain relieving agent can satisfy the above-mentioned ratio of trimebutine and / or a salt thereof and the pain relieving agent according to the type, dosage form, etc. of the pain relieving agent to be used. However, it is usually 1 to 90% by weight, preferably 3 to 80% by weight, and more preferably 5 to 60% by weight.

Other components The pharmaceutical composition of the present invention may contain other pharmacological components as necessary in addition to the trimebutine and / or salt thereof and the pain relieving agent. The type of such pharmacological component is not particularly limited. For example, an intestinal motility improving agent other than trimebutine and / or a salt thereof, an antacid, a stomachic agent, a digestive agent, an intestinal adjuster, an antispasmodic agent, a mucosal repair agent, an anti-inflammatory agent , Astringent, antiemetic, antitussive, expectorant, antiphlogistic enzyme, sedative hypnotic, antihistamine, caffeine, cardiotonic, antibacterial, vasoconstrictor, vasodilator, local anesthetic, herbal medicine, herbal extract powder , Vitamins, caffeine, menthol and the like. These pharmacological components may be used alone or in combination of two or more. Moreover, what is necessary is just to set suitably about content of these pharmacological components according to the kind of pharmacological component to be used, the dosage form of a pharmaceutical composition, etc.

  The pharmaceutical composition of the present invention may contain a pharmaceutically acceptable base or additive as necessary in order to prepare a desired dosage form. Examples of such bases and additives include excipients, binders, disintegrants, lubricants, isotonic agents, plasticizers, dispersants, emulsifiers, solubilizers, wetting agents, and stabilization. Agent, suspending agent, adhesive, coating agent, brightening agent, water, fats and oils, waxes, hydrocarbons, fatty acids, higher alcohols, esters, water-soluble polymer, surfactant, metal soap , Lower alcohols, polyhydric alcohols, pH adjusters, buffers, antioxidants, UV inhibitors, preservatives, corrigents, fragrances, powders, thickeners, dyes, chelating agents, and the like. These bases and additives may be used individually by 1 type, and may be used in combination of 2 or more type. Moreover, what is necessary is just to set suitably about content of these bases and additives according to the kind of additive component to be used, the dosage form of a pharmaceutical composition, etc.

Administration form / dosage form / use Examples of administration form of the pharmaceutical composition of the present invention include oral administration (internal use) and enteral administration, preferably oral administration.

  The dosage form of the pharmaceutical composition of the present invention is not particularly limited as long as it can be applied to the administration form, and may be any of solid, semi-solid, or liquid. Specifically, as a 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); And other semi-solid preparations; liquid preparations such as liquids, suspensions, and syrups. Among these dosage forms, a solid preparation is preferable from the viewpoints of stability of components and portability.

  In order to prepare the pharmaceutical composition of the present invention in the above-mentioned dosage form, trimebutine and / or a salt thereof, an analgesic agent, and pharmacological ingredients, bases, and additives that are added as necessary are used in the pharmaceutical field. It may be formulated according to the usual formulation method adopted in the above.

  Since the pharmaceutical composition of the present invention contains the pain relieving agent, gastrointestinal discomfort due to indigestion or excessive eating and drinking; gastrointestinal pain due to mental stress; gastrointestinal pain due to intestinal infection; It can be used for alleviating muscle inflammation; migraine; and abdominal pain, nausea, loss of appetite, sore throat, chills, fever, headache, joint pain, muscle pain and other cold symptoms. In particular, in the pharmaceutical composition of the present invention, in view of the fact that the antipruritic action by trimebutine and / or its salt is improved and gastrointestinal discomfort can be effectively alleviated, stress accompanied by gastrointestinal symptoms (gastrointestinal discomfort) Use for the purpose of alleviation of symptoms and gastrointestinal symptoms due to intestinal infection and cold symptoms accompanied by gastrointestinal symptoms (gastrointestinal discomfort), especially stress symptoms accompanied by diarrhea and cold symptoms accompanied by diarrhea Is preferred.

  The dosage of the pharmaceutical composition of the present invention is appropriately set according to the type of trimebutine and / or its salt and painkiller used, the dosage form of the pharmaceutical composition, the patient's age, use, the degree of symptoms, etc. For example, the daily dose may be 10 to 1000 mg, preferably 100 to 600 mg in terms of the weight of trimebutine and / or a salt thereof.

  EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples.

Test example: Verification of antipruritic effect
1. Preparation of test solution Test solutions having the compositions shown in Table 1 were prepared. Specifically, a test solution was prepared by adding a predetermined amount of trimebutine maleate and a predetermined amount of an analgesic agent to an aqueous solution in which a predetermined amount of sodium carboxymethylcellulose was added and dissolved.

2. Method for evaluating antipruritic effect on stress-induced diarrhea model rats Rats (SPF, Slc: SD, obtained from Japan SLC Co., Ltd.) were used in this test. After obtaining at 6 weeks of age, a quarantine / acclimation period of 8 days was provided, and rats that were 7 weeks of age with no abnormalities in weight transition and general condition were used in the test. Each test solution shown in Table 1 is orally administered using a 1 ml disposable syringe (JMS Co., Ltd.) and a disposable oral sonde (Fuchigami Instrument Co., Ltd.) so that each rat has a 5 ml / kg body weight. After 60 minutes, the rats were anesthetized with isoflurane (trade name “Escaine Inhalation Anesthetic Solution”, manufactured by Mylan Pharmaceutical Co., Ltd.), and the upper body was fixed by wrapping the chest including the left and right upper limbs with adhesive tape (2 pieces of 5cm × 30cm). The load of restraint stress was given. Rats fixed with adhesive tape were immediately placed in observation cages one by one, and then the number of stools for 1 hour was measured. In this test, 10 rats were used for each group, and the average number of feces was calculated.

3. Test results The results obtained are shown in FIG. As a result, compared with the case where trimebutine maleate was administered alone (Comparative Example 1), when trimebutine maleate and the painkiller were used in combination (Examples 1 to 5), stress-induced diarrhea model rats The number of feces in the stool decreased, and it was revealed that the painkillers have the effect of improving the antipruritic action of trimebutine and / or its salts. It was also confirmed that the fecal properties were normalized when trimebutine maleate was used in combination with the painkiller (Examples 1 to 5).

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

Claims (4)

  An antidiarrheal composition comprising (A) trimebutine and / or a salt thereof, and (B) an analgesic.   The antidiarrheal composition according to claim 1, comprising 1-1500 parts by weight of the (B) painkiller per 100 parts by weight of (A) trimebbutin and / or a salt thereof.   The antidiarrheal composition according to claim 1 or 2, which is administered by oral administration.   The antidiarrheal composition according to any one of claims 1 to 3, which is a solid preparation.