JPH02193926A - Gastrointestinal drug - Google Patents

Abstract

PURPOSE:To provide a gastrointestinal drug useful for treating and preventing various gastrointestinal diseases caused by excessively drinking alcoholic drinks by compounding cysteine with a stomach galenical and/or a specific antacid. CONSTITUTION:Cysteine is compounded with an antacid and a stomach galenical in a weight ratio of 1:0.01:0.02-1:400:200, respectively, and further, if necessary, with a membrane mucosa-repairing agent, a perfume, etc., and subsequently prepared into tablets, granules, capsules, liquids, dry syrups, etc., to provide the objective drug. The antacid is selected from sodium bicarbonate, synthetic hydrotalcite, magnesium silicate aluminate and magnesium metasilicate aluminate. The stomach galenical is an extract of Glycyrrhiza glabra L., Gentiana lutea L., Panax ginseng C.A. Meyer, ginger, dried orange peel, Magnoliae cortex, Pachyma hoelen Rumph, Coptis japonica Makino, etc.

Description

Detailed Description of the Invention: Recapture 1 (7) JLr The present invention relates to a cysteine-containing gastrointestinal drug that exhibits excellent effects on the treatment and prevention of various gastrointestinal diseases caused by excessive drinking of alcoholic beverages.

Traditionally, the following medicines have been confirmed to be effective in treating and preventing symptoms of hangover and hangover caused by drinking too much alcoholic beverages.

l) Chinese herbal formulas such as Orengedokuto and Anchusan; 2) Compositions consisting of multiple plant components and/or extracts such as Oriental laurel, clove, and cinnamon bark; 3) Antacids and/or
or a composition consisting of a mucosal repair agent and/or an antipyretic analgesic; 4) a composition containing cysteine and vitamins; however, both have weak efficacy in acting on the detoxification and metabolism of alcohol, and symptoms of gastrointestinal diseases caused by drinking too much alcohol. There was a problem that improvements had not been made sufficiently.

The present invention aims to provide a cysteine-containing gastrointestinal drug that is not only safe but also highly effective against various symptoms of gastrointestinal diseases caused by excessive drinking of alcohol by promoting the detoxification and metabolism of alcohol. The purpose is to provide.

The gastrointestinal medicine of the present invention comprises cysteine and an antacid selected from sodium bicarbonate, synthetic aluminum silicate, synthetic hydrotalcite, aluminum hydroxide, magnesium aluminate silicate, and magnesium aluminate metasilicate. Alternatively, it is characterized by containing a stomachic herbal medicine, or both the above-mentioned antacid and stomachic herbal medicine.

For gastrointestinal diseases, by combining cysteine, which has a different mechanism of action, with the above-mentioned specific antacids, or herbal medicines for stomach health such as licorice, beetroot, ginseng, and gentian, the alcohol detoxification metabolism of cysteine and the effects of antacids can be improved. The gastric acid neutralizing effect, mucosal coating effect, gastric mucosal cell activation effect of stomachic herbal medicines, and stomachic effect act synergistically, making it more effective against various subjective symptoms such as hangovers and hangovers caused by drinking too much alcoholic beverages. Excellent and has a wide range of effects.

The present invention will be explained in more detail below.

As cysteine, the optical isomer L form is preferably used, but racemic forms, hydrochlorides, etc. may also be used.

In the present invention, one or more of sodium hydrogen carbonate, synthetic hydrotalcite, aluminum hydroxide, magnesium aluminate silicate, and magnesium aluminate metasilicate are used as the antacid.

In addition to these specific antacids, magnesium oxide,
Magnesium carbonate, magnesium silicate, aluminum glycinate, borey, funnel extract, aminoacetic acid, calcium hydrogen phosphate, magnesium hydroxide, aluminum hydroxide gel, dried aluminum hydroxide gel, aluminum hydroxide/sodium hydrogen carbonate coprecipitation product .

Aluminum hydroxide/magnesium carbonate mixed dry gel,
Other antacids such as aluminum hydroxide/magnesium carbonate/calcium carbonate coprecipitated products, synthetic aluminum silicate, etc. can also be used in combination.

In the present invention, the term "herbal medicine" is a concept that includes crude drug extracts such as extracts. Herbal medicines for stomach health include fenugreek, scutellariae, kobokou, chimpi, oren, trumpet, shukusha, kankyou, ginger, japonica, licorice, japonica, japonica, ginseng, bukuriyo, hops, swamp, clove, gentian, or these. Crude drugs with relatively low aldehyde content, such as extracts, are preferred. Among these, daylily, gentian, carrot, ginger, chimpi, kobo, birch, and kankyo.

Preferred are Physcomitrella sinensis, Oren or extracts thereof.

Although the amount of each of the above ingredients is not particularly limited,
The daily dose of the gastrointestinal drug of the present invention is 25 mg to 2500 mg, particularly 50 mg to 250 mg of cysteine and its salts.
It is preferable to set it to 0 mg. Similarly, the amount of the antacid is not particularly limited and is appropriately selected depending on the type, etc., but is preferably 0.1 to 10 g, more preferably 0.1 to 10 g.
It is 5-5g. Similarly, there is no limit to the amount of herbal medicine for stomach health, and it is selected appropriately depending on the type, etc., but preferably 0.005 to 5 g, more preferably 0.1 to 2.5 g.
It is.

The most important factor in improving the pharmacological effect of combining cysteine with antacids and/or herbal medicines is the mixing ratio of these drugs. The blending ratio is preferably 1:0.01 (antacid): by weight based on cysteine.
0.02 (healthy herbal medicine) to 1:400:200, particularly preferably 1:2:0.4 to 1:10
It was 0:40.

Note that the gastrointestinal drug of the present invention may contain other mucosal repair agents, fragrances, etc. in addition to the above-mentioned components, if necessary, as shown in the formulation examples described below.

Further, the dosage for humans (adults) is usually 50 to 240 mg of cysteine hydrochloride for 7 days, and the daily dosage of antacids and stomachic herbal medicines is preferably the same as in normal clinical use.

The dosage form of the gastrointestinal drug of the present invention is not particularly limited, and it can be formulated into various dosage forms such as tablets, granules, capsules, liquids, and dry syrups.

When manufacturing tablets, in addition to the above ingredients, ingredients normally used when manufacturing tablets, such as lactose, mannitol, sugars with zero sucrose, celluloses such as microcrystalline cellulose, calcium sulfate, calcium phosphate, and precipitate. Excipients such as inorganic salts such as calcium carbonate, starches such as corn starch and potato starch, and disintegrants such as various types of starch microcrystalline cellulose, carboxymethyl cellulose, calcium salts of carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose. Cellulose derivative.

Explotab (trade name), starch derivatives, etc. can be used, and magnesium stearate, calcium stearate, stearic acid, talc, hydrogenated vegetable oil, etc. can be used as lubricants. In addition, if a binder is required.

Polyvinylpyrrolidone, hydroxypropylcellulose, methylcellulose, starch paste, etc. are used as binders, and if necessary, sweeteners such as sucrose, glucose, sodium saccharin, acidifying agents such as citric acid, tartaric acid, malic acid, fragrances, etc. Additionally, a flavoring agent may be added.

Tableting methods include direct tableting, in which the main ingredients and the above additives are simply mixed and tableted, and dry granulation by compression molding, or kneading and granulation by adding a mixed solvent of water. Alternatively, an indirect tableting method may be used, in which compressed tablets are produced after drying into wet granules, or a combination of these methods may be used.

Furthermore, in order to mask the taste of each tablet, each tablet can be coated with a film or coated with sugar.

To produce granules, dry granules or wet granules can be produced by the granulation method described in the above-mentioned method for producing tablets.

When making capsules, the herbal drug ingredients alone may be filled into the capsules, or an appropriate amount of excipients and lubricants may be added and the capsules filled, but after being made into granules in the same way as the tablets above. , it can also be filled into capsules.

When preparing a liquid formulation, the ingredients of the present invention are dissolved in an aqueous solution containing sweeteners, thickeners, surfactants, antifoaming agents, preservatives, fragrances, etc.
It can be manufactured by dispersing it. In addition, granules containing the above ingredients, such as dry syrup, are manufactured in advance.
It can be dissolved or dispersed in water when taken.

Here, specific examples of the above additives include sweeteners such as sucrose, D-mannitol, glucose, fructose, etc.
M, synthetic sweeteners such as sodium saccharin and aspartame, and thickeners include cellulose derivatives such as methylcellulose, sodium carboxymethylcellulose, and hydroxypropylcellulose, synthetic polymer compounds such as polyvinylpyrrolidone, sodium polyacrylate, and polyvinyl alcohol; Sodium alginate, gelatin, xanthan gum, guar gum, gum tragacanth,
Examples include natural polymeric substances such as gum arabic, surfactants include orally available surfactants such as polysorbate 80 and HCO-60, antifoaming agents include silicones, and preservatives include Sodium benzoate, propyl hydroxybenzoate, etc. are used. Furthermore, there is no problem in applying appropriate sterilization operations such as steam sterilization and intermittent sterilization to the prepared liquid preparation.

According to the gastrointestinal drug of the present invention, by using cysteine in combination with stomachic herbal medicines and/or specific antacids, better efficacy against gastrointestinal diseases caused by alcoholic beverages can be obtained. It is suitable as a highly useful medicine for gastrointestinal diseases.

Next, experimental examples will be shown to specifically explain the effects of the present invention.

Experimental Example 1: (Protective effect against acute gastric mucosal damage caused by hydrochloric acid and ethanol) Seven-week-old Donryu male rats were used, and after an overnight fast, the drugs listed in Table 1 were orally administered.

30 minutes later, 120 cod hydrochloric acid 4, which is a substance that damages the gastric mucosa,
A 0% ethanol solution was administered orally at a dose of 5 ml/kg. After leaving it for 1 hour, the stomach was removed and the length of the band-shaped bleeding damage that had occurred in the axillary mucosa was measured. The results are shown in Table 1.

Each drug was used after being suspended in a 0.5% sodium salt solution of carboxymethyl cellulose (CMC-Na). In addition, only a 0.5% CMC-Na solution was administered to the control group.

As L-cysteine, hydrochloride was used.

As shown in Table 1, L-cysteine prevents mucosal damage caused by hydrochloric acid and ethanol, which are mucosal necrotic substances, in a dose-dependent manner, and the inhibition rate was 50 mg/Kg and 100 mg/Kg.
Kg dose were 21.1 and 27.8%, respectively. Furthermore, among the antacids, magnesium aluminate metasilicate, synthetic hydrotalcite, and sodium bicarbonate, which have foreign acid neutralizing and/or mucosal coating effects, alone showed a strong mucosal damage prevention effect. Gentiana and ginseng, which are stomach-promoting herbal medicines, had no significant effects when used alone. Furthermore, it has been found that the combined use of L-cysteine and an antacid produces a synergistic effect.

That is, in the past, addition and synergy were merely conceptual;
Although it was said that quantitative handling was difficult, Gaddum
("Pharmacology,"0xfordU
university Press London, 19
53. ) has shown an empirical investigation method, and many researchers have used this to investigate interactions in two-drug combinations and provide theoretical support for empirical judgments.

According to this, when drugs A and B are used together, the corresponding doses that show the same effect of both drugs are [A] and [B], respectively.
given that.

If combined efficacy ([A/2+[B]/2) > independent efficacy [A or [B], then it is a synergistic effect, and if the left and right sides of the above formula are equal, it is concluded that it is an additive effect. ing. Therefore, using the same theory, we investigated the combined effects of L-cysteine and antacids as shown in Table 1, and found that, for example, 1/2 amount of synthetic hydrotalcite was added to 200 mg/kg of L-cysteine. When used in combination, the inhibition rate was 57.3%, which exceeded the inhibition rate when each was used alone, confirming a synergistic effect. This effect is thought to be due to the synergistic effect of L-cysteine on protecting gastric mucosal cells and the acid-neutralizing effect of antacids. The preventive and therapeutic effects were confirmed.

On the other hand, when L-cysteine was used in combination with gentian herbal medicine at 200 mg/kg of L-cysteine, no significant changes were observed compared to the L-cysteine alone administration group. In addition to gentian and carrots, the same was true for herbal medicines containing comparatively few aldehydes, such as licorice, yakujutsu, clove, and bukuriyo.

(Leaving space below) Experimental example 2: (Blood acetaldehyde lowering effect in ethanol-loaded animals) SD male rats, 7 weeks old, were orally administered the drugs shown in Table 2 after an overnight fast, and the drugs shown in Table 2 were orally administered for 1 hour. Thereafter, 5 ml/kg of a 20% ethanol aqueous solution was orally administered. After leaving for 1 hour, the abdomen was opened under ether anesthesia, 1n+1 acquired venous blood was collected, protein was removed with 5+wl of 0.6N perchloric acid aqueous solution, and after centrifugation, 0.5ml of the supernatant was used as a sample, and the blood was transferred to the head according to the usual method. It was determined by space-gas chromatography, and the results are shown in Table 2.

Note that each drug was used after being suspended in a 0.5% CMC-Na aqueous solution. In addition, 0.5% CM C-N was added to the control group.
Only the aqueous solution was administered. Note that hydrochloride of L-cysteine was used.

As shown in Table 2, L-cysteine dose-dependently suppressed the increase in blood acetaldehyde concentration after ethanol administration. That is.

In the control group, blood acetaldehyde concentration increased to 25.1 μM/l due to ethanol metabolism, whereas
In the L-cysteine group, at a dose of 200 mg/kg, 2
At 2.5,400 mg/kg, inhibition was 20.4 μM/l, which was 10.2% and 18.7% compared to the control group, respectively.

On the other hand, no change was observed in the blood acetaldehyde concentration compared to the control group in synthetic hydrotalcite, which was used as an antacid alone, and in gentian and licorice, which were treated with herbal medicine alone.

However, when L-cysteine was used in combination with antacids such as synthetic hydrotalcite, there was not much improvement in the suppressive effect; however, when L-cysteine was used in combination with antacids such as licorice, blood acetaldehyde levels were particularly noticeable. A concentration decreasing effect was observed.

Generally, when alcoholic beverages are ingested, ethyl alcohol is metabolized and acetaldehyde is produced in the body, which is known to be closely related to various unpleasant symptoms after ingesting alcohol, such as nausea, headaches, and nausea. It is also widely recognized that administration of disulfiram, which is used for treatment as an anti-alcoholic drug, increases blood acetaldehyde concentration after drinking alcohol, resulting in unpleasant symptoms such as nausea, headache, and nausea.

From these facts, the fact that L-cysteine suppressed the increase in blood acetaldehyde concentration after ethanol intake as shown in Table 2 suggests that L-cysteine may be effective in treating or preventing various unpleasant symptoms after drinking alcohol. Demonstrates clinical utility.

As described above, when cysteine is used in combination with the antacid of the present invention, it mainly exerts a protective effect against acute gastric mucosal damage, and has an excellent effect on the treatment and prevention of various gastrointestinal diseases caused by drinking too much alcoholic beverages. demonstrate.

Additionally, when cysteine and herbal medicines are used together, aldehyde metabolism is mainly improved.

Similarly, it is highly effective in treating and preventing various gastrointestinal diseases caused by drinking too much alcoholic beverages. Furthermore, when both the antacid of the present invention and the gastric herbal medicine are used together against cysteine, they act more synergistically.

Better effects can be obtained.

As described above, the present invention has demonstrated extremely high clinical utility in alleviating various unpleasant symptoms after drinking, as it can be used in combination with antacids and herbal medicines that have different mechanisms of action. It is something that exists.

(Left below) Experimental example 3: (Prophylactic effect of test drug on symptoms of hangover and hangover after drinking) Volunteers were randomly divided into groups of 10 people.
Participants were asked to drink alcoholic beverages (sake, beer, or whiskey) at their own discretion in larger amounts than normal over a two-hour period. The test drug was taken with a glass of water 15 minutes before the start of the experiment.

The experimental results are for each subjective symptom item shown in Table 4.
The number of people who complained of subjective symptoms immediately after drinking (2 hours) and the next day (15 hours) was also recorded (multiple answers allowed).

The formulation of the test drug used in the experiment is shown in Table 3 below.

(Left below) For each drug tested, subjective symptoms that appeared immediately after drinking alcohol and the next morning were confirmed through interviews. Table 4 shows the number of doses taken for each test drug.
The cumulative number of complaints of 0 people with subjective symptoms is shown.

Test drugs A, B, C, D, and E are single H of L-cysteine.
Compared to I, F, and G, there were fewer subjective symptoms, indicating that it is effective. That is, it is useful to use L-cysteine in combination with a specific antacid, such as synthetic hydrotalcite, which has a gastric acid neutralizing effect and/or a mucous membrane coating effect, or with a stomachic herbal medicine.

Specific examples of prescriptions are shown, and all numerical values in Prescription Examples 1 to 7 are daily clinical doses in mg.

Formulation example I L-cysteine 120 synthetic hydrotalcite 3000 gentian powder
500 stew powder
500 formulation example 2 L-cystine silicate magnesium aluminate lotus extract licorice powder clove oil formulation example 3 L-cystine metasilicate magnesium aluminate dimethyl borine siloxane gentiana powder quince silicate powder kankyo powder cypress powder total amount formulation example 4 L-cysteine carbonic acid Sodium hydrogen L-Glutamine Medicated carrot powder 1-Menthol Bean juice powder Licorice powder Prescription example 5 L-cystine polymigel Magnesium carbonate Licorice powder Medicinal carrot powder Gingerbread powder Gentian powder Prescription example 6 L-Cystine metasilicate Magnesium aluminate Acetamino Total amount of phene 2960 mg/day Prescription example 7 L-cystine rot extract Prescription example 8 L-cystine ginseng extract Aurean chinensis extract Prescription example 9 DL-cystine hydrochloride Licorice extract Aurentin xenthiana tin Kisoujira extract Total amount 0 mg 0 .3m! 0.1 0 mg 0.3+aQ O02 0.2 Amount 5mQ (Left below blank) Prescription example 10 L-cysteine sodium bicarbonate Licorice extract Citrus extract d-Lunitine chloride

Claims (1)

[Claims] 1. A gastrointestinal medicine characterized by containing cysteine and an antacid and/or a stomachic herbal medicine selected from sodium bicarbonate, synthetic hydrotalcite, magnesium aluminate silicate, and magnesium aluminate metasilicate.