JP6490742B2 - Composition for internal use - Google Patents

Description

  The present invention relates to an internal composition, particularly an internal composition effective for diarrhea and the like.

  Usually, most of the amount of water loaded in the digestive tract is reabsorbed and only a small amount is excreted in the feces. Diarrhea is a condition in which this amount of water has increased. Diarrhea is ultimately caused by an increase in intestinal motility. The detailed mechanism of diarrhea is considered to be roughly divided into the following three types depending on the cause of its occurrence. (1) Due to increased osmotic pressure in the intestinal lumen, diarrhea occurs due to an increase in the amount of water in the intestinal lumen. Such diarrhea is also called “osmotic diarrhea”. (2) Due to the secretion of electrolyte from the intestinal wall into the lumen, diarrhea occurs due to the accompanying movement of water. Such diarrhea is also called “secretory diarrhea”. (3) Diarrhea occurs due to increased intestinal motility itself. Such diarrhea is also called “hyperkinetic diarrhea”. Diarrhea is observed in various diseases, and each of the above mechanisms is considered to work alone or in combination.

  Conventionally, various intestinal motility improvers have been used to improve diarrhea. Intestinal motility improvers improve diarrhea by normalizing or suppressing intestinal motility. Intestinal motility-improving drugs are classified into (1) intestinal motility improving drugs having opioid receptor activation action, (2) intestinal motility improving drugs having parasympathetic blocking action, and (3) sympathetic nerve stimulating action. And (4) an intestinal motility improving agent having an astringent action. For example, as an intestinal motility improving agent (opioid receptor agonist) having an opioid receptor activating effect, trimebutine maleate (trimebutine maleate) having an effect of regulating intestinal motility is known (non-patent document). Reference 1).

Akio Miyoshi, 12 others, “Clinical evaluation of trimebutine for gastrointestinal indefinite complaints by multi-center double blind method”, Internal Medicine Hoho, Internal Medicine Hoho Press, June 1980, 27 (6), pp. 169-186

  The present inventor has found that these intestinal motility improving drugs do not have a sufficiently long drug effect time, so that diarrhea may recur immediately even when administered. That is, the present inventors have a problem that a conventional internal use composition containing an intestinal motility improving agent needs to be continuously ingested in a short time in order to realize the effect. I found.

  The present invention has been made in view of the above-mentioned problems of the prior art, and its main purpose is to provide a composition for internal use in which the sustained efficacy of the intestinal motility improving drug is improved.

  The inventor has conducted extensive research to achieve the above-mentioned purpose, and by taking an aluminum-containing compound in addition to the intestinal motility improving drug, the internal use in which the sustained efficacy of the intestinal motility improving drug has been improved. It has been found that a composition can be prepared.

The present invention has been completed based on these findings, and provides the following embodiments.
Item 1. A composition for internal use containing an intestinal motility improving agent and an aluminum-containing compound.
Item 2. Item 2. The composition for internal use according to Item 1, wherein the intestinal motility improving agent is an opioid receptor agonist.
Item 3. Item 2. The composition for internal use according to Item 1, wherein the intestinal motility improving agent has intestinal motility rhythmic action.
Item 4. Item 2. The composition for internal use according to Item 1, wherein the intestinal motility improving agent is trimebutine maleate.
Item 5. Item 5. The internal use composition according to any one of Items 1 to 4, wherein the aluminum-containing compound is a gastrointestinal drug.
Item 6. Item 6. The composition for internal use according to Item 5, wherein the gastrointestinal drug that is an aluminum-containing compound is at least one gastrointestinal drug selected from the group consisting of aluminum silicate, aluminum hydroxide, kaolin, and aluminum hydroxynaphthoate.
Item 7. Item 6. The composition for internal use according to Item 5, wherein the gastrointestinal drug which is an aluminum-containing compound is aluminum silicate.
Item 8. Item 8. The composition for internal use according to any one of Items 1 to 7, which is used for alleviating diarrhea.

  By using the composition for internal use of the present invention, the duration of the intestinal motility improving effect by the intestinal motility improving drug can be extended.

It is drawing which shows the observation result of the feces external appearance shape among the results of Experimental example 1. FIG. It is drawing which shows the measurement result of carmine excretion time among the results of Experimental example 1. FIG. It is drawing which shows the measurement result of the measurement result of feces wet weight among the results of Experimental example 1. FIG. It is drawing which shows the measurement result of the number of feces among the results of Experimental example 1. FIG.

  The composition for internal use of the present invention contains an intestinal motility improving agent and an aluminum-containing compound as essential components. Moreover, you may contain the other component further.

  Hereinafter, each of these components will be described.

1. Intestinal motility-improving drug Intestinal motility-improving drug is not particularly limited, but specifically, it can be classified as follows depending on the mechanism of action.
(1) Intestinal motility improving agent having opioid receptor activating action (2) Intestinal motility improving drug having astringent action (3) Intestinal motility improving drug having sympathetic nerve stimulating action (4) Intestinal motility having parasympathetic nerve blocking action Hereinafter, these various intestinal motility improving agents will be described.

1.1 Intestinal motility improving drug having opioid receptor activating action An intestinal motility improving drug having opioid receptor activating action exhibits an action to improve intestinal motility by specifically binding to an opioid receptor. It is an intestinal motility improving drug. A drug having an opioid receptor activation action is also referred to as an opioid receptor agonist.

  An opioid receptor is a receptor that specifically binds to an opioid drug and exhibits an action. It is classified as a 7-transmembrane receptor (GPCR). There are three subtypes: μ (also called MOP), κ (also called KOP) and δ (also called DOP).

The intestinal motility improving agent having an opioid receptor activating action is preferably one having an MOP (μ) receptor activating action.

  The intestinal motility improving agent having an opioid receptor activating action can be further divided into those having an intestinal motility inhibitory action and those having an intestinal motility rhythmic action, both of which can be used in the present invention.

  The intestinal motility improving agent having an opioid receptor activating action is not particularly limited as long as the effects of the present invention can be obtained, and examples of the intestinal motility inhibiting action include loperamide hydrochloride. Examples of those having an intestinal motility rhythm include trimebutine maleate.

1.2 Intestinal motility improving drug having a convergent action An intestinal motility improving drug having a convergent action has an action of suppressing intestinal motility by converging the intestinal tract. The intestinal motility improving agent having an astringent action is not particularly limited as long as the effect of the present invention can be obtained. Specific examples include bismuth hyponitrite, bismuth subgallate, and albumin tannate.

1.3 Intestinal motility improving drug having sympathetic nerve stimulating action An intestinal motility improving drug having sympathetic nerve stimulating action has an action of suppressing intestinal motility by stimulating the sympathetic nerve. The intestinal motility improving agent having a sympathetic nerve stimulating action is not particularly limited as long as the effects of the present invention can be obtained, and specific examples include berberine chloride hydrate.

1.4 Intestinal motility improving drug having a parasympathetic nerve blocking action An intestinal motility improving drug having a parasympathetic nerve blocking action has an action of suppressing an increase in intestinal movement by blocking the parasympathetic nerve. The intestinal motility improving agent having a parasympathetic nerve blocking action is not particularly limited as long as the effects of the present invention can be obtained, and specific examples include funnel extract, butyl scopolamine bromide, and belladonna total alkaloids.

1.5 More Detailed Description of Intestinal Motility Improvement Agent The composition for internal use of the present invention may contain these intestinal motility improvement agents alone, and the mechanism of action is the same or different from each other. Regardless of whether or not, two or more kinds may be arbitrarily combined and contained.

  The composition for internal use of the present invention preferably has an opioid receptor activating action in that it is relatively small in dosage and relatively painless when taken as an intestinal motility improving agent. It contains an intestinal motility improving drug (that is, an opioid receptor agonist), an intestinal motility improving drug having a sympathetic nerve stimulating action, or an intestinal motility improving drug having a parasympathetic nerve blocking action.

  Moreover, the composition for internal use of this invention contains the intestinal motility improving agent which has an opioid receptor activation effect | action more preferably at the point that there are few side effects as an intestinal motility improving agent.

  The composition for internal use of the present invention contains, more preferably, an intestinal motility improving agent having an opioid receptor activating action, which has an intestinal motility rhythmic action in that the risk of constipation is low.

The composition for internal use of the present invention most preferably contains trimebutine maleate (trimebutine maleate) as an intestinal motility improving agent.

  Although it does not specifically limit, As said intestinal motility improving agent, the commercially available thing can be used, respectively.

  The content ratio of the intestinal motility improving agent in the composition for internal use of the present invention is not particularly limited as long as the effect of the present invention can be obtained, but it is blended as an active ingredient in the composition for internal use depending on its specific use. As a blending ratio in the case of, it can be suitably selected from the range normally selected. Depending on the type of the intestinal motility improving agent, for example, it can be contained in the composition for internal use in a proportion of usually 0.0005% to 60% by weight, preferably 0.0005% to 30% by weight. . Moreover, although it depends on the type of the intestinal motility improving agent, the daily intake of the composition for internal use can usually contain 0.5 mg to 600 mg, preferably 1 mg to 300 mg.

2. Aluminum-containing compound In the present invention, the aluminum-containing compound is a general term for compounds having aluminum as a constituent element. The aluminum-containing compound is preferably a gastrointestinal drug.

  The effect of the present invention is not particularly limited as long as the effects of the present invention can be obtained. Specific examples of the gastrointestinal drug that is an aluminum-containing compound include aluminum silicate, aluminum hydroxide, kaolin, and hydroxynaphthoic acid aluminum.

  Among these, as aluminum silicate, more specifically, any of synthetic aluminum silicate, natural aluminum silicate, and a mixture thereof can be used. Although it does not specifically limit, As a synthetic aluminum silicate, what is commercially available as an antacid can be used. Although it does not specifically limit as a synthetic aluminum silicate, For example, the aluminum cloth etc. by Mylan Pharmaceutical Co., Ltd. can be used. Moreover, although it does not specifically limit, what can be obtained commercially as an anti-diarrhea thing can be used as natural aluminum silicate. Although it does not specifically limit as natural aluminum silicate, For example, Daiso Sankyo Co., Ltd. adsorbine etc. can be used.

  As aluminum hydroxide, more specifically, aluminum hydroxide gel and dry aluminum hydroxide gel can be used. Although it does not specifically limit, What can be obtained commercially as an antacid can be used as aluminum hydroxide gel and dry aluminum hydroxide gel. Although it does not specifically limit as a dry aluminum hydroxide gel, For example, the "pure raw" aluminum gel by a pure biochemical industry company etc. can be used.

  Although it does not specifically limit as kaolin, The commercially available thing can be used for diarrhea prevention. Although not particularly limited, for example, kaolin bulk powder “Maruishi” manufactured by Maruishi Pharmaceutical Co., Ltd. can be used.

  Although it does not specifically limit as aluminum hydroxy naphthoate, The commercially available thing for diarrhea prevention can be used.

  The composition for internal use of this invention may contain these aluminum containing compounds each independently, and may contain it combining 2 or more types arbitrarily.

  As the aluminum-containing compound, aluminum silicate is particularly preferable. As aluminum silicate, synthetic aluminum silicate is particularly preferable.

  The content ratio of the aluminum-containing compound in the composition for internal use of the present invention is not particularly limited as long as the effect of the present invention can be obtained, but is usually selected as the composition ratio when blended as an active ingredient in the composition for internal use. It can be suitably selected from the range. The aluminum-containing compound can be contained in the composition for internal use in a proportion of usually 10% by weight to 95% by weight, preferably 58% by weight to 92% by weight, depending on the type. Moreover, although it is based on the kind, the aluminum containing compound can be normally contained in 150 mg-3000 mg, preferably 1000 mg-2000 mg in the daily intake of the composition for internal use.

  The compounding ratio of the aluminum-containing compound in the composition for internal use of the present invention is preferably such that the weight ratio to the intestinal motility improving agent is aluminum-containing compound: intestinal motility improving agent = 1: 0.0003- 4, more preferably aluminum-containing compound: intestinal motility improver = 1: 0.0005-0.3.

  The composition for internal use of the present invention exhibits an excellent effect that the medicinal effect of such an intestinal motility improving agent is sustained by using an intestinal motility improving agent as an active ingredient and adding an aluminum-containing compound.

3. The composition for internal use of the present invention The composition for internal use of the present invention may be composed of only the intestinal motility improving agent and the aluminum-containing compound, and may be a pharmaceutically acceptable carrier or additive. These components may be included. The kind and amount of such a carrier or additive can be appropriately selected and adjusted according to the dosage form or intended use of the composition for internal use of the present invention, as long as the effects of the present invention are not impaired.

  The composition for internal use of the present invention exhibits an excellent effect that the intestinal motility improving agent is maintained as an active ingredient as described above, and the efficacy of the intestinal motility improving agent is sustained by adding an aluminum-containing compound. .

  The composition for internal use of the present invention having such excellent effects can be widely used for alleviating gastrointestinal symptoms. Examples of such various symptoms include, but are not limited to, diarrhea, abdominal pain, and nausea. The composition for internal use of the present invention is particularly preferably used for alleviating diarrhea.

  In addition to the above components, the composition for internal use of the present invention can further contain other plant processed products, functional components, medicinal components and the like as long as the effects of the present invention are not hindered. In addition, these components may be used alone or in combination with the above components, or two or more types may be arbitrarily combined and used in combination with the above components.

  Although it does not specifically limit as a medicinal ingredient which can further be mix | blended with the composition for internal use of this invention, For example, a vitamin agent, a lactic acid bacteria formulation, etc. are mentioned.

  The composition for internal use of this invention can be prepared as a pharmaceutical or a quasi-drug.

  The composition for internal use of the present invention may be prepared by directly blending the above components as an oral composition, and if necessary, tablets, pills, capsules (soft capsules, hard capsules) , Various solid preparations such as powders (powder) and granules (including dry syrup), or liquid preparations such as liquids for internal use (including liquids, suspensions, and syrups) can do. From the stability and portability of each component, a solid preparation form (dosage form) is preferable.

  The formulation can be applied with a normal formulation method adopted in the field of medicine. For example, a tablet can be prepared by adding and blending each component according to the formulation, crushing, granulating, drying, sizing and mixing, and tableting the resulting preparation mixture.

  Furthermore, additives for formulation, for example, excipients, lubricants, binders, disintegrating agents, fluidizing agents, dispersing agents, wetting agents, preservatives, thickeners, pH adjustments as necessary An agent, a coloring agent, a flavoring agent, a surfactant, a solubilizing agent, and the like can be blended, and a coating tablet can also be formed using a coating agent. It can also be used as a paste glue.

  The estimated daily intake (daily intake) of the composition for internal use of the present invention can be appropriately set and adjusted according to the age, sex, weight, and symptoms of the subject. 60 kg), the daily intake of the intestinal motility improving drug is included in the range of 0.5 mg to 600 mg, preferably 1 mg to 600 mg, more preferably 1 mg to 400 mg, and even more preferably 1 mg to 300 mg. It is desirable. In addition, the composition for internal use of this invention can also be ingested in 1 to several times a day so that it may become said intake per day. The composition for internal use of the present invention is preferably taken in three divided doses per day. Although there is no restriction | limiting in particular also about dosing time, For example, it is an empty stomach, before a meal, between meals, or before bedtime.

  Hereinafter, the present invention will be specifically described by showing experimental examples, examples and comparative examples, and formulation examples. However, the present invention is not limited to these experimental examples.

1. Experimental Example 1 Verification of diarrhea alleviation effect 1.1 Preparation of test sample (Example 1 and Comparative Example 1)
A mixture of each component described in Table 1 (unit: mg) was dissolved in a medium to a predetermined concentration. Specifically, after weighing trimebutine maleate (manufactured by Wako Pure Chemical Industries, Ltd .; hereinafter simply referred to as “trimebutine”) and / or synthetic aluminum silicate (manufactured by Yoshida Pharmaceutical Co., Ltd.) Then, after grinding using an agate mortar, the suspension was suspended in a 0.5% CMC-Na solution (prepared using CMC-Na manufactured by Wako Pure Chemical Industries, Ltd.) to prepare a predetermined concentration.

  The following experiments were conducted using these as test samples (Example 1 and Comparative Example 1).

1.2 Evaluation of Improvement Effect on Rat Diarrhea Model Rats (SPF, strain Crl: CD (SD), obtained from Charles River Japan Co., Ltd. (Hino Breeding Center)) were used. This rat is an animal species that is generally used in pharmacological tests, and its strain maintenance is clear and has been used. The body weight range for one day after acquisition was 155 to 181 g. Obtained animals have a quarantine period of 5 days followed by a 2-day acclimatization period, during which 3 body weight measurements and daily general conditions are observed, and there is no abnormality in weight transition and general conditions Was used for the test.

  The effects of various preparations on diarrhea were examined using a rat picosulfate sodium-induced diarrhea model. Specifically, it was performed as follows.

Separate the required amount of Picosulfate Na (manufactured by Teijin Pharma Limited) and add water for injection.
It was prepared to 0.6 mg / mL and used as a laxative. Immediately after administration of the vehicle (Control) or the test sample (Example 1 and Comparative Example 1), 2.5 w / v% carmine suspension was orally administered to 8-week-old SD male rats at 0.4 mL / body. One hour later, laxative (picosulfate Na (3 mg / kg)) (dose volume: 5 mL / kg) was orally administered to induce diarrhea. The effect of improving diarrhea was examined using stool appearance and shape observation (score) up to 24 hours after laxative administration, carmine pigment excretion time (intestinal motility speed), fecal wet weight and fecal count as indices. The number of cases was performed in 10 cases in each group. From the sample administration to the observation 6 hours after the laxative administration, the animals were fasted and dehydrated.

  The oral administration was specifically performed as follows. In accordance with the usual method used in the test facility, oral administration was performed by using a disposable syringe (made by Terumo Corporation) made of polypropylene with a metal oral sonde for disposable rats (Fuchigami Instrument Co., Ltd.). At the time of administration, administration was performed with stirring using a magnetic stirrer. The number of administrations was 1, and the amount of administration liquid was calculated as 10 mL / kg from the body weight value on the day of administration.

  Specifically, the evaluation was performed as follows.

(1) Observation of appearance shape of stool Evaluation by stool shape scoring (below) was performed. In addition, when several stool was discharged | emitted in time, the stool with the highest score was set as the evaluation object.

Normal flights: score 0
Soft stool (tangible stool with high water content): Score 1
Diarrhea stool (intangible stool with water): Score 2
Watery stool (almost intangible, liquid stool): Score 3
(2) Carmine excretion time (hr)
The excretion of carmine pigment was confirmed.

(3) Fecal wet weight (g)
The stool wet weight for each collection time was measured.

(4) Fecal count (pieces)
The number of feces for each collection time was measured.

The results are shown below. Statistical processing was performed as follows. After laxative administration 0
The total score of each group, the carmine excretion time, the stool count, and the average and standard deviation of stool wet weight were calculated for each observation time of -6 and 6-12 h. The significant difference test performed the comparison test between 2 groups about the Control group and the test sample (Example 1 and Comparative Example 1) administration group. That is, in the score test, the Wilcoxon test was performed. In the test of carmine pigment excretion time, stool number and stool wet weight, the equidispersity test was conducted by F test, and in the case of equidispersion, Student's t test was conducted. On the other hand, when equal variance was not recognized, the Aspin Welch t-test was used. For the statistics, a commercially available statistical program (EXSUS version 7.6; CAC Excicare Corporation) was used. The significance level was 5%, and was divided into less than 5% (P <0.05) and less than 1% (P <0.01).

  The results for each evaluation item are shown below.

1.2.1 Observation results of the appearance of feces are shown in FIG.

  From the result of 6-12 hr, it was found that the effect of suppressing fecal property was prolonged in the combination of trimebutine and synthetic aluminum silicate.

1.2.2 Carmine excretion time (intestinal motility speed)
The results are shown in FIG.

  From the result of 6-12 hr, it was found that in the combination of trimebutine and synthetic aluminum silicate, the carmine excretion time was further prolonged and the intestinal motility rate was suppressed for a longer time.

1.2.3 Fecal wet weight results are shown in FIG.

  In the combination of trimebutine and synthetic aluminum silicate, it was found that the fecal wet weight tended to be normalized over a longer period of time than when trimebutine was used alone.

1.2.4 Fecal count results are shown in FIG.

  In the combination of trimebutine and synthetic aluminum silicate, it was found that the number of feces is not superior to that of Control, and thus there is no tendency for constipation.

1.3 Formulation Examples 1-102
Each ingredient was weighed according to the description in Tables 2 to 7 (unit: mg), and tablets (9 tablets (3 tablets once a day, 3 tablets once a day) according to the 16th revised Japanese Pharmacopoeia General Rules for Tablets) )) Was manufactured.

Claims (3)

Trimebutine maleate ,
An internal use composition comprising at least one gastrointestinal drug selected from the group consisting of aluminum silicate, aluminum hydroxide, kaolin, and aluminum hydroxynaphthoate. The composition for internal use according to claim 1, wherein the gastrointestinal drug is aluminum silicate. The composition for internal use of Claim 1 or 2 used for relief of diarrhea.

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