HK1139064B

HK1139064B - Therapeutic agent for meniere's disease

Info

Publication number: HK1139064B
Application number: HK10105173.6A
Authority: HK
Inventors: 竹田节子
Original assignee: 竹田节子
Filing date: 2007-01-10
Publication date: 2013-08-02

Description

Therapeutic agent for meniere's disease

Technical Field

The present invention relates to a therapeutic agent for Meniere's disease, and particularly to a therapeutic agent for Meniere's disease, which contains a sugar or a sugar alcohol as an active ingredient and has no purgative effect as a side effect.

Background

Although the cause of meniere's disease is still unknown, it is known that the morbid state is labyrinthine hydrops, based on histological examination results of a caesarean section of a meniere patient. It is considered that this labyrinthine hydrops is caused by retention of labyrinthine fluid due to excessive production of labyrinthine fluid, malabsorption, and abnormal water metabolism in the inner ear, and causes characteristic symptoms of meniere's disease such as tinnitus, hearing loss, vertigo, and feeling of ear plug. Thus, it can be appreciated that the reduction of this labyrinthine hydrops is associated with treatment of meniere's disease.

Most sugars and sugar alcohols exhibit an osmotic effect after administration and have therefore been used as osmotic diuretics, osmotic laxatives. Examples of the agent having a dehydrating action by utilizing an osmotic pressure effect include sorbitol, mannitol and the like having a purgative action, mannitol, glycerin and the like having a diuretic action. In the treatment of meniere's disease, the morbid state of which is labyrinthine hydrops, it is also considered that hydrops can be reduced by this dehydration action. That is, since these agents produce an osmotic pressure gradient of the perilymph fluid after oral administration, it is considered that the volume of the labyrinthine space is reduced, and the labyrinthine space collapse effect or the labyrinthine water reducing effect is produced.

Actually, a part of sugar or sugar alcohol as an osmotic diuretic is used for diagnosis of meniere's disease (cherimoya lang, otorhinolaryngology, P174, L34-P175, L2, non-patent document 1), and in this examination, a hearing improving effect is observed by an osmotic diuretic as an examination drug (bifidobacterium minutum, Client 21, P368, right L23-24, non-patent document 2), and therefore, a therapeutic effect is expected, and various attempts are being made.

But contrary to expectation, these attempts all end up in failure, the reason for which has not yet been elucidated. As shown in P201 of angelberg c.et al and table 1, only glycerol was observed in more than half of cases in which improvement in hearing was observed (non-patent document 3), and when 2.8g/kg of glycerol was orally administered to guinea pigs, collapse was observed in normal ears 2 hours after administration, but rather mild hydrocele formation was observed at 6 hours (non-patent document 4). Namely, a histological rebound phenomenon was observed. In the glycerol test for diagnosing meniere's disease, after improvement of hearing was temporarily observed about 2 hours after administration, hearing deteriorated after 6 hours, and a so-called "rebound phenomenon" was generated (non-patent document 5), which was confirmed histologically. Because of this rebound phenomenon, glycerol has not been used as a therapeutic agent in japan.

In the nineties of the twentieth century, the presence of water channels was gradually confirmed in each organ. Studies have been conducted on the elucidation of the mechanism of production and absorption of inner ear fluid in the inner ear having a tissue structure relatively similar to that of the kidney, and the presence of aquaporin (aquaporin) has also been confirmed in the inner ear (non-patent document 6). In recent years, as one of the mechanisms that act on the water metabolism of the inner ear, the arginine vasopressin-aquaporin 2(arginine vasopressin-aquaporin 2) system has been attracting attention (non-patent document 7).

However, after systemic administration of OPC31260, which is a vasopressin type II receptor antagonist, no effect of reducing labyrinthia hydrops was observed to a desired extent, and instead, labyrinthia hydrops was formed in normal ears (non-patent document 8). This is because arginine vasopressin (hereinafter referred to as AVP), which is an antidiuretic hormone (hereinafter referred to as ADH), is increased in the plasma due to the strong diuretic action.

Clinically, it has been reported that AVP increases in patients with meniere' disease in the acute phase (non-patent document 9). This result is in good agreement with the fact that meniere's disease is thought to be susceptible to epidemics of stress. Furthermore, AVP1 mu/kg/min was continuously administered subcutaneously to guinea pigs with normal Prille reflex (Preyer's reflex) using a micropump, resulting in formation of significant endolymphatic hydrops (non-patent document 10). As shown in table 1 below, plasma AVP increased in proportion to the amount of AVP administered, and the area of the labyrinth cavity increased histologically (formation of labyrinthine hydrops). When AVP1mu/kg was continuously administered, serum AVP increased several times as high as that of normal human plasma AVP (approximately the same value as that of serum AVP in the acute stage of meniere's disease), and this was extremely dangerous (non-patent document 10). In the treatment of meniere's disease, special attention must be paid so that AVP does not rise due to stress, dehydration, or the like.

[ Table 1]

(inventor et al, Heart Res.2000. non-patent paper 10)

Administration speed of AVP: mU/kg/min

Units of plasma AVP: pg/ml

The upper limit of the plasma AVP concentration in normal humans is 3.5 pg/ml.

It is presumed that, in the case where sugar or sugar alcohol is originally used as an osmotic pressure-purging agent, a large amount of oral administration at one time produces an osmotic pressure gradient in the digestive organs, resulting in gastrointestinal symptoms such as diarrhea. There are many cases in which severe diarrhea, in which general gastrointestinal drugs do not show effects, is produced. Dehydration symptoms continue to develop during severe diarrhea, and the anti-diuretic AVP has also been reported to increase 10 to 15 times (non-patent document 11). As described above, since AVP rises to form labyrinthine hydrops, if diarrhea with fructose or sugar alcohol is unsuccessful, the labyrinthine hydrops-reducing effect is considered to be offset by dehydration continued with diarrhea. Therefore, when sugar or sugar alcohol is used for the treatment of meniere's disease, care must be taken so that digestive organ symptoms such as diarrhea do not appear.

Patent document 1 describes a therapeutic agent for meniere's disease, which contains erythritol as a four-carbon sugar alone as an active ingredient. Erythritol is excellent in flavor, but it has been reported that a sports drink containing erythritol added as a low-calorie sweetener when ingested in large amounts in a short time exhibits temporary severe diarrhea, and therefore, it is considered that a therapeutic effect on meniere's disease cannot be expected without achieving antidiarrheal effect.

Currently, isosorbide (1, 2: 3, 6-dianhydro-D-sorbitol), which is a sugar alcohol clinically used as a therapeutic agent for meniere's disease, is weak in clinical purgation, but has a peculiar bitter taste, and since this bitter taste remains in the oral cavity for a long time, and the dose is 30ml or more at a time, and it is necessary to take 3 times a day, and the dose is large, there are many cases where the administration is interrupted for patients who feel difficult. Further, since the dosage form is liquid, it is inconvenient in view of hygienic problems because a bottle containing 500ml must be carried.

Further, glycerin as a three-carbon sugar exhibits an effect within about 2 hours after oral administration, whereas isosorbide as a six-carbon sugar requires about 6 hours to exhibit an effect (non-patent document 12).

Patent document 1: japanese patent laid-open No. 11-180863

Non-patent document 1: ertiyilang, otorhinolaryngology

Non-patent document 2: vaccinium uliginosum, Client 21,

Non-patent document 3: angelberg, c.et al.: hyperatmospheric solutions and respiration in Meniere's disease. am. J. Otol. 3: 200-2(1982)

Non-patent document 4: takeda, t.et al.: the bound phenomenon of glycerol-induced changes in The endo-lytic space, acta Otolaryngol.119: 341-4(1999)

Non-patent document 5: matsubara, h.et al: rebound phenomenon in glycocoltest. acta otolaryngol. suppl.419: 115-22(1984)

Non-patent document 6: sawada, s.et al.: aquaporin-1(AQP1) is expressed in the strain vascularis of rat cochlea.heel.Res.181: 15-9(2003)

Non-patent document 7: sawada, s.et al.: aquaporrin-2 regulation bvsopression in the rat inner ear.Neuroreport.13: 1127-9(2002)

Non-patent document 8: takeda, t.: the effects of V2 antagonist (OPC-31260) on endolymphatic hydrops. heel. Res.183: 9-18(2003)

Non-patent document 9: takeda, t.et al.: antioxidant ketones (ADH) and dendrolymphatic hydroxides. 219-22(1995)

Non-patent document 10: takeda, t.et al.: endo-hydrophilic hydrops induced branched administration of vasopressin. heel.res.140: 1-6(2000)

Non-patent document 11: safgate a.et al: renin-aldosterone system and obtaining meal vasopressin in diarhoeic valves. Br. vet. J.147: 533-7(1991)

Non-patent document 12: kakigi, a.et al.: time core of dehydrated effects of exogenous activities induced end enzymic hydrops in guineaps, ORL J.Otorhinolaryngol.Relat.Spec.66: 291-296(2004)

Disclosure of Invention

Technical problem to be solved by the invention

As described above, conventional therapeutic agents for meniere's disease containing a sugar or a sugar alcohol as an active ingredient require a long time to exhibit a reducing effect and cause a rebound phenomenon. In addition, in the treatment, a large amount (20 to 30g at a time) is orally administered, 3 times a day, and about two weeks, so that the degree is poor, a special purgative effect is observed, and diarrhea is also temporarily stopped. Therefore, dehydration is likely to continue, and as a result, the increase in plasma AVP inevitably occurs, and in order to obtain a reliable therapeutic effect, it is necessary to add a drug having an antidiarrheal effect to suppress the increase in plasma AVP. However, although the diarrhea symptoms caused by sugar or sugar alcohol are not the original state of administration of laxatives such as constipation, there is a situation in which a large amount of sugar or sugar alcohol must be continuously taken, and therefore, the diarrhea symptoms occur in a special situation in which the sugar serving as a laxative is continuously administered, and diarrhea must be prevented, and therefore, it is difficult to expect improvement by antidiarrheal drugs and intestinal tract control drugs which are generally used.

As side effects associated with large amounts of administration, digestive organ symptoms such as abdominal distension and borborygmus (ゴロゴロ sensation) are known in addition to diarrhea. Although not limited by the mechanism of action, the administered carbohydrate is directly transported from the small intestine to the large intestine undigested, and is fermented by the action of the large intestine microorganisms to produce short-chain fatty acids such as butyric acid and propionic acid, which stimulate the intestinal mucosa to promote peristalsis. This is caused by an increase in the production of intestinal gas such as carbon dioxide, hydrogen, and methane, which are produced simultaneously, and by the sugar itself, and therefore, as described above, it cannot be solved by a normal intestine-regulating agent.

Further, since a large amount of the drug is administered, ease of administration and portability are required.

Accordingly, an object of the present invention is to provide a therapeutic agent for meniere's disease, which contains a sugar or a sugar alcohol as an active ingredient and does not show digestive organ symptoms such as a purgative effect or the like, or which alleviates the symptoms, and further to provide a therapeutic agent for meniere's disease which can be easily taken and carried, and particularly to provide a therapeutic agent for meniere's disease which can rapidly exhibit its effect.

Means for solving the problems

The present inventors have conducted extensive studies to solve the above problems, and as a result, have found that digestive organ symptoms such as purgative action can be eliminated by blending a certain amount of polysaccharides in monosaccharides, oligosaccharides, or sugar alcohols thereof. It has also been found that by making a gel, powder or granular formulation, both the volume and weight can be significantly reduced to, for example, about one-half. The present invention has been completed based on these findings.

Specifically disclosed is a therapeutic agent for Meniere's disease, which contains (a) at least one member selected from the group consisting of monosaccharides, oligosaccharides and sugar alcohols thereof and (b) at least one member selected from the group consisting of polysaccharides, and which is contained in an amount of about 2-50 parts by weight per 100 parts by weight of the component (a).

In another aspect, the present invention provides a therapeutic agent for meniere's disease in the form of a gel preparation comprising (a) at least one member selected from monosaccharides, oligosaccharides and sugar alcohols thereof, and (b) at least one member selected from polysaccharides, wherein the amount of the component (b) is about 2 to 50 parts by weight based on 100 parts by weight of the component (a).

In another aspect, the present invention provides a method for producing a gel preparation, including the steps of: and a step of adding water to 100 parts by weight of at least one member selected from the group consisting of monosaccharides, oligosaccharides and sugar alcohols thereof and 2 to 50 parts by weight of at least one member selected from the group consisting of polysaccharides, wherein the amount of water used is about 10 to 55 parts by weight based on 100 parts by weight of the total amount of the components (a) and (b).

In another aspect, the present invention provides a method for producing a drug for treating meniere's disease, which comprises using (a) at least one selected from monosaccharides, oligosaccharides and sugar alcohols thereof, and (b) at least one selected from polysaccharides in a specific ratio, that is, in a ratio of about 2 to 50 parts by weight of the component (b) to 100 parts by weight of the component (a).

In another aspect, the present invention provides a method for treating meniere's disease, which comprises administering a therapeutically effective amount of the therapeutic agent to a patient suffering from meniere's disease.

Effects of the invention

The therapeutic agent for meniere's disease of the present invention can reduce or eliminate the side effects mainly manifested by digestive organ symptoms such as diarrhea caused by sugars and/or sugar alcohols by blending polysaccharides in a predetermined range of amounts in monosaccharides, oligosaccharides and/or sugar alcohols thereof (hereinafter referred to as "sugars and/or sugar alcohols"), and can effectively and reliably achieve the therapeutic goal of meniere's disease, i.e., the reduction of labyrinthine water. Further, the rebound phenomenon can be reduced or prevented, and further, the time until the effect is exhibited can be shortened as compared with the case where only sugar or/and sugar alcohols are administered.

In another aspect, the complex can be easily stored, carried and taken by compressing the volume by making into a gel, and further, it is more convenient to store, carry and take by drying the gel, pulverizing, granulating, and making into any preparation such as powder, granule, and the like. A dry preparation such as powder or granule can be directly made into gel (jelly) for easy administration by adding a small amount of water.

Drawings

FIG. 1: with respect to the change with time in the decrease caused by the administration of erythritol, a scatter plot and a regression line are used to show that in example 2: graph of operative side membrane stretch (IR-L) versus area increase (IR-S) for group 1.

FIG. 2: regarding the difference in the amount of the polysaccharide (pectin) added, the difference in the amount of the polysaccharide (pectin) used in the observation of example 2 was represented by a scatter plot and a regression line: group 2, 2-1: a graph showing the relationship between the membrane extension rate (IR-L) and the area increase rate (IR-S), which shows how different the reduction effect on the surgical side is due to the difference in the amount of pectin added.

FIG. 3: the change with time after addition of polysaccharides (0.5 g/kg of pectin) is shown in the scattergram and the regression line in example 2: 2-2 of group 2: in group 8 (after 3 hours with pectin added at 0.5g/kg), the time-dependent change in the reduction effect was observed on the operative side.

FIG. 4: the results are shown in the graph showing the change in the film and the change in the area of the group to which xylitol alone was administered and the group to which xanthan gum was added as a polysaccharide.

FIG. 5: the figure shows the change in membrane and area of the group to which isosorbide alone was administered and the group to which sodium alginate was added as a polysaccharide.

FIG. 6: the results are shown for the membrane change and the area change of the group to which isosorbide alone was administered and the group to which agar was added as a polysaccharide.

FIG. 7: the figure shows the change in the membrane and the change in the area of the group to which glycerin was administered alone and the group to which sodium carboxymethylcellulose was added as a polysaccharide.

FIG. 8: the results are graphs showing the changes in the membrane and the area of the groups to which xylose was administered alone and the groups to which xanthan gum was added as a polysaccharide.

FIG. 9: the graph is used for observing the difference of the lightening effect of the present development product and the conventional product on the operation side, and shows the relationship between the stretching rate and the area change rate of the film.

FIG. 10: the graph shows the relationship between the change in the operation-side membrane and the change in the area between the group containing erythritol and polyvinylpyrrolidone (a thickener) and the group containing erythritol alone.

FIG. 11: is a reference example: graph comparing the membrane change and area change of the group given pectin only with the control group (distilled water).

Detailed Description

The therapeutic agent for meniere disease of the invention has the following characteristics: contains (a) at least one member selected from the group consisting of monosaccharides, oligosaccharides and sugar alcohols thereof, and (b) at least one member selected from the group consisting of polysaccharides as essential components at a given ratio.

In the present specification, the terms "monosaccharide", "oligosaccharide", "polysaccharide" and "sugar alcohol" have meanings commonly understood in the art [ for example, refer to Kirk-Othmer: encyclopedia of Chemical Technology, 4th Ed. Vol.4, page912 (1992); the publication of "chemical dictionary" contract plate, 4 volumes 807, 5 volumes 662 pages, 762 pages, 6 volumes 306 pages, 308 pages, 369 pages (1984) ]. For example, "monosaccharide", "oligosaccharide", and "polysaccharide" are understood to mean a hydrocarbon that is a molecule that is not further decomposed by hydrolysis, a hydrocarbon that yields a certain small number (e.g., 2 to 10) of monosaccharide molecules by hydrolysis, and a hydrocarbon that yields a variable number (e.g., at least 35) of monosaccharide molecules by hydrolysis, respectively. The oligosaccharide is preferably a disaccharide. "sugar alcohols" are understood to mean polyols which are equivalent to reducing the aldehyde and ketone groups of sugars to form primary and secondary alcohol groups, respectively.

In the present invention, among the monosaccharides, oligosaccharides and sugar alcohols thereof used as component (a), preferred examples include glycerol, erythritol, xylitol, xylose, sorbitol, isosorbide, maltitol, lactitol, mannitol, and the like, and particularly preferred examples include erythritol, xylitol, and isosorbide. Further, among the polysaccharides used as component (b), preferred are, for example, pectin, xanthan gum, guar gum, gum arabic, locust bean gum, tara gum, sodium alginate, sodium carboxymethylcellulose, hydroxypropyl cellulose, agar, carrageenan, etc., and pectin, xanthan gum, sodium alginate and sodium carboxymethylcellulose are particularly preferred. One or more kinds may be used in any case.

The ratio (weight ratio) of the polysaccharide as the component (b) to the monosaccharide, oligosaccharide or/and sugar alcohol thereof as the component (a) is about 100: 2 to 2: 50, preferably about 100: 5 to 50, and particularly preferably about 100: 10 to 40. When the amount is outside this range, it is difficult to sufficiently achieve the purgative effect of the polysaccharide.

When pure water is added in an amount of about 10 to 55 wt%, preferably about 15 to 50 wt%, based on the total amount of the mixture of the component (a) and the component (b), and the mixture is mixed at room temperature or under heating as necessary, the mixture is gelled to form a gel. The amount of pure water is not preferable because the viscosity becomes too high when the amount is less than about 10% by weight, and becomes too thin when the amount exceeds about 55% by weight, and a good gel cannot be obtained.

Drying the gel, and pulverizing to obtain powder. The mixture is granulated and dried by a method such as extrusion granulation, and then granulated to obtain granules.

Drying, pulverizing and granulating may be carried out by any conventional method.

When formulated, a pharmaceutically acceptable carrier, excipient, diluent, binder, preservative, stabilizer, flavor, coloring agent, etc. may be added in addition to the active ingredient as required.

In addition, as long as the object of the present invention is not impaired, one or more kinds of other medicinal components other than sugar or sugar alcohol, for example, a drug having an antacid action and/or an intestinal function such as dried aluminum hydroxide gel, natural aluminum silicate or precipitated calcium carbonate, a drug having an inner ear circulation improving action such as a sympathetic β agonist, a vasodilator or a cerebral circulation improving agent, a drug for reducing labyrinthic hydrops such as a diuretic, a drug for tranquilizing or antiemetic such as a sedative or an autonomic nerve regulator, and the like may be appropriately blended.

The therapeutically effective amount of the sugar or sugar alcohol may vary depending on various factors such as the disease state of the patient to be treated, the age, sex and general health of the subject, for example, about 0.5 to 3.0g/kg, preferably 0.8 to 1.5g/kg per day for an adult, and it is administered in 1 or more divided doses, for example, in 3 divided doses.

The therapeutic agent for meniere's disease of the present invention may be a gel obtained by mixing a sugar or a sugar alcohol with a polysaccharide, or a powder or granules obtained by formulating a gel by a predetermined method.

The powder or granule obtained from the gel has a significantly reduced volume, for example, about 50%, preferably about 60% or more, as compared with the sugar or sugar alcohol-based raw powder, and is therefore advantageous in storage and carrying, and the burden on patients to take the powder or granule is reduced.

In addition, when water is added to the powder or granule in an amount of about 10 to 55 wt%, the powder or granule can be re-gelatinized to form a gel, and thus the administration of the powder or granule is facilitated.

The gel obtained according to the present invention has a volume reduced to about one third of that of a saturated aqueous solution of a sugar or a sugar alcohol raw powder, and therefore is extremely advantageous in administration as compared with a conventional liquid preparation.

The present invention will be described in detail below with reference to examples and comparative examples, but the present invention is not limited to these examples. In making the experimental plan, efforts are made to avoid laparotomy (slaughter) of a large number of animals, taking into account the fact that it can be judged sufficiently by observation, visual inspection and palpation of the experimental animals and the excreted feces, and taking into account a social situation called animal protection. In order to avoid the influence of repeated administration, animals to which sugar or sugar alcohol is administered are not used only once.

The abbreviations in the tables of the following examples and comparative examples have the following meanings:

ery: erythritol and its preparation method

IB: isosorbide

P: pectin

XG: xanthan gum

Al: sodium alginate glycerin

Gly: glycerol

CMC: sodium carboxymethylcellulose

PVP: polyvinylpyrrolidone

GG: guar gum

AG: arabic gum

The criteria for determining the state of feces (i.e., hardness, shape, and stool interval in the intestine) are shown in table 2.

[ Table 2]

The hardness and shape of feces of the group given distilled water were evaluated as "normal feces", and the evaluation was classified as 3; the evaluation of "soft stool" which is normal in shape but relatively easily deformed when pressed with a finger was divided into 2; the evaluation that the shape has been deformed is "soft stool", and the evaluation is divided into 1; the non-shaped article was evaluated as "muddy feces", and the evaluation was 0. According to the shape of the feed, the watery feces and the muddy feces are equivalent to the watery feces and the muddy feces of people.

Further, as a result of detailed examination by laparotomy, when feces of 2 to 3cm are formed in the rectal region, feces excreted to the outside of the body have hardness of a degree of soft feces, and thus it is judged that diarrhea is successful. The muddy state contains a large amount of water, and therefore, the abdominal pressure increases, causing an abdominal distension. In addition, the following examples are also given for animals with feces formed in the intestine: when the intestinal tract is opened, the generation of gas can be confirmed by puncturing or the like at a portion where the interval is greatly opened. Many examples of gas generation are assumed, and it is considered that the abdominal distension is synergistically worsened, and it is estimated that the symptoms are unpleasant. Therefore, not only the hardness of feces but also the size and surface smoothness of feces, the amount of feces, and the like are carefully evaluated.

Example 1

Diarrhea caused by sugar or sugar alcohols and a solving method thereof were investigated. Among sugars and sugar alcohols, erythritol which is a four-carbon sugar, xylitol which is a five-carbon sugar, xylose, isosorbide which is a six-carbon sugar, and the like are added with polysaccharides and the like, and orally administered to guinea pigs, and feces are observed up to 6 hours after the administration.

Subjects and methods) guinea pigs weighing 280-320 g and exhibiting normal stools were divided into 4 groups, and groups 1-a were orally administered with xylitol only [ comparative example 1], xylitol and xanthan gum or pectin, groups 1-b were orally administered with xylose only [ comparative example 2], xylose and xanthan gum or pectin, and groups 1-c were orally administered with erythritol only [ comparative example 3], erythritol and pectin, erythritol and xanthan gum, erythritol and pectin, and natural aluminum silicate gel or calcium carbonate. Groups 1-d were given orally isosorbide alone [ comparative example 4], isosorbide and xanthan gum or pectin.

The amounts of sugar or sugar alcohols and polysaccharides to be administered are shown in tables 3, 4 and 5. The administration agent was dissolved in distilled water, and the amount of the aqueous solution administered at one time was 8ml/kg in any case.

The feces were observed 6 hours after administration, and the hardness and shape of the feces at the time when the symptoms became more severe were determined as symptoms caused by sugar or sugar alcohol, and the results are shown in tables 3, 4, and 5.

[ Table 3]

[ Table 4]

A1: natural aluminium silicate 0.17g/kg

A2: natural aluminium silicate 0.35g/kg

A3: natural aluminium silicate 0.7g/kg

C1: calcium carbonate 50mg/kg

C2: calcium carbonate 100mg/kg

[ Table 5]

[ Table 6]

The results of example 1 are as follows.

1-a) case of administration of xylitol

Before administration, the guinea pigs 45 showing normal stools were divided into 9 groups of 5 animals each, and an aqueous solution of xylitol or the like was orally administered as shown in table 3.

First) influence of the amount of xylitol alone [ comparative example 1]

Although xylitol 1.4g/kg did not cause diarrhea, 2.1g/kg was administered to 1 animal having soft stool to the extent that the feces easily deformed when pressed with fingers after 3 hours. No abnormality was observed within 1 hour after 2.8g/kg administration, but all animals showed a difference in degree after 2 hours of administration, and a significant diarrhea symptom was observed. After 3 to 4 hours of administration, the symptoms became severe, and more than half of the animals became muddy stools, but approximately recovered to normal stools after 6 hours.

B) adding xanthan gum into xylitol

When 0.12g/kg, 0.2g/kg and 0.3g/kg of xanthan gum were added to 2.8g/kg of xylitol, respectively, and the mixture was orally administered, abnormal stools were hardly observed up to 2 hours, but symptoms appeared after 3 to 4 hours. The evaluation of feces at this time is shown in table 3. As the amount of xanthan gum increased, the number of guinea pigs whose stools showed normal stools increased, and no soft stools were observed in the group of 0.3g/kg during the observation period.

C) adding pectin into xylitol

0.25g/kg and 0.35g/kg of pectin were added to 2.8g/kg of xylitol, respectively, and the mixture was orally administered, and feces in the group of 0.2g/kg showed a tendency to soften from the 2 nd hour and peaked at 3 to 4th hours. No loose stools were observed in the group of 0.3 g/kg.

1-b) administration of xylose

Guinea pigs 16 showing normal stools were divided into 3 groups as shown in table 3 only. In 5 guinea pigs administered with 2.8g/kg xylose alone, 4 animals exhibited muddy stools or soft stools, and in the group to which 0.2g/kg xanthan gum or 0.3g/kg pectin was added to xylose, normal stools were observed except for 1 animal with slight softness, and no soft stools were observed, and the hardness of the stools was significantly different from that of comparative example 2 (P < 0.01, mann-whitney test). During the duration of diarrhea, mild or moderate abdominal distension was felt in the abdomen and slight movements of gas were felt.

1-c) case of administration of erythritol

Before administration, 75 guinea pigs showing normal stools were divided into 15 groups of 5 animals each, and the erythritol solution and supplement were orally administered as shown in table 4.

A) case where erythritol alone was administered at 2.8g/kg [ comparative example 2]

After 3 hours all animals had muddy stools, and after 6 hours 3 had continued muddy stools.

B) adding pectin into erythritol

0.1g/kg, 0.3g/kg, 0.5g/kg, 1.0g/kg, and 1.5g/kg of pectin were added to 2.8g/kg of erythritol, respectively, and the mixture was orally administered. More than half of the stools were normal when 0.5g was added, and stools were judged to be slightly harder than normal when 1.5g/kg was added.

C) adding pectin, natural aluminum silicate and calcium carbonate into erythritol

As shown in Table 4, when 0.5g/kg of pectin and 0.17g/kg of natural aluminum silicate (Adsorbin) were added to 2.8g/kg of erythritol, and when 0.5g/kg of pectin, 0.17g/kg of natural aluminum silicate and 50mg/kg of calcium carbonate were added to 2.8g/kg of erythritol, almost all animals were normal stools.

The results were not significantly different from the case of erythritol alone, and no preferable synergistic effect due to addition of the conventional intestine-regulating agent was observed (mann-whitney test).

D) adding xanthan gum to erythritol

Addition of 0.05g/kg of xanthan gum to 2.8g/kg of erythritol did not produce any antidiarrheal effect, but no soft feces were observed when 0.1g/kg of erythritol was added, and 4 of 5 were normal feces in the group of 0.15g/kg (P < 0.01, Mann-Whitney test).

Penta) natural aluminium silicate and calcium carbonate are added into erythritol

As shown in Table 4, when 0.17g/kg, 2-fold amount of 0.35g/kg, 4-fold amount of 0.7g/kg and/or 2-fold amount of 100mg/kg of calcium carbonate, which is a conventional natural aluminum silicate (Adsorbin), was added to 2.8g/kg of erythritol, no antidiarrheal effect was observed (Mann-Whitney test).

1-d) case of administration of isosorbide

Before administration, guinea pigs 61 showing normal stools were divided into 12 groups as shown in table 5, and an aqueous solution of isosorbide alone or an aqueous solution obtained by adding xylitol or the like thereto was orally administered.

First) influence of the amount of isosorbide alone [ comparative example 4]

Only 1 of the groups with 1.4g/kg isosorbide gave a slightly softer stool. 2.1g/kg of the animals with soft stools were administered to the group to such an extent that stools were easily deformed when pressed with fingers after 3 hours, and 2 animals with slightly soft stools. Although no abnormality was observed within 1 hour after 2.8g/kg administration, most of the animals began to develop diarrhea symptoms 2 hours after administration, and the symptoms became severe 3 to 4 hours after administration, but almost returned to normal stool 6 hours later.

B) adding xanthan gum to isosorbide

When 0.05g/kg (1.8 wt%) and 0.15g/kg (5.4 wt%) of xanthan gum were added to 2.8g/kg of isosorbide and the mixture was orally administered, abnormal stool was hardly observed up to 2 hours, but diarrhea symptom was observed after 3 to 4 hours. The evaluation of feces at this time is shown in table 5. As the amount of xanthan gum increased, the number of guinea pigs whose stools showed normal defecation increased, and no soft stools were observed in the group of 0.15g/kg during the observation period.

C) adding pectin to isosorbide

When 0.15g/kg and 0.3g/kg of pectin were added to 2.8g/kg of isosorbide and the mixture was orally administered, almost no diarrhea symptom was observed. No soft stools were observed in the 0.15g/kg group, and all animals were normal stools in the 0.3g/kg group through observation.

1-e) case of administration of maltitol

Guinea pigs 38 showing normal stools were divided into 9 groups as shown in table 6, and an aqueous solution of maltitol alone or xanthan gum or guar gum added thereto was orally administered.

A) case of administering maltitol alone

All animals in the group administered disaccharide maltitol 2.8g/kg became muddy feces.

The course of diarrhea is delayed in symptoms compared to the administration of monosaccharides or their alcohols (peak diarrhea at 3 hours after administration), with stool softening starting at 3 hours and stool softening in all animals within 4 hours, of which 5 became muddy stools. All 6 had become muddy stools at 5 hours, which lasted for 12 hours. The tendency to recover was seen little by little from the 18 th hour, and recovered to normal stool in the latter half of 24 hours.

Over time, starting at more than 5 hours, the animals were seen to present a painful model with a flatus when pressure was applied to the abdomen. The abdominal distension may also be confirmed by external examination of the abdomen.

B) addition of Xanthan Gum to maltitol

0.07g/kg, 0.14g/kg, 0.28g/kg, 0.56g/kg, and 1.12g/kg of xanthan gum were added to 2.8g/kg of maltitol, respectively, and administered orally.

In the group to which xanthan gum was administered at 0.07g/kg, the antidiarrheal effect of polysaccharides was hardly observed. In the group administered with 0.14g/kg, the feces softened from hour 3, the symptoms worsened, and 2 had muddy stools at hour 5, and the remaining 2 had soft stools. This state persists after 12 hours, with some recovery seen after 18 hours and all animals recover to normal stool after 24 hours. No diarrhea-preventing effect of xanthan gum was seen (no significant difference, mann-whitney test).

In the group to which 0.28g/kg of xanthan gum was administered, as in the group to which 0.14g/kg was administered, softening of feces was seen from the 3 rd hour, and no normal stool was shown after 6 hours. Among them, 1 stool was soft, half of normal stools were shown after 12 hours, and all animals recovered to normal after 24 hours. The effect of xanthan gum on preventing diarrhea is insufficient.

The abdominal distension was seen in both groups by examination of the abdomen, gas production was confirmed in palpation, and the animals were seen to present a painful pattern.

In both groups administered with 0.56g/kg (20 wt%) and 1.12g/kg (40 wt%) of xanthan gum, the animals became slightly soft stools after 6 hours, and then the same state continued until 18 hours, but the stool hardness of all animals returned to normal after 24 hours. The effect of preventing diarrhea by xanthan gum was confirmed (P < 0.05, Mann-Whitney test in both groups), and the amount of feces was sharply decreased from the 5 th hour to a usual one-third or less in 9 to 15 hours.

C) addition of Guar Gum (GG) to maltitol

0.28g/kg, 0.56g/kg and 1.12g/kg of GG was added to 2.8g/kg of maltitol and administered orally.

In the group to which GG was administered at 0.28g/kg (10 wt%), softening of feces was observed from the 2 nd hour, and sludge-like feces were observed after 4 hours, except for 1 soft feces. All animals became muddy stools at 5 hours, which continued until 12 hours. There were 4 soft stools at 18 hours, but returned to normal at 24 hours. Diarrhea prevention effect was poor compared to XG. Abdominal distension was confirmed by visual examination of the abdomen, and generation and movement of gas were confirmed by palpation.

In the group to which GG was administered at 0.56g/kg (20 wt%), softening of feces was observed from the 3 rd hour, and after 5 to 6 hours, 1 feces was found to be normal, 1 feces was found to be slightly soft, and 1 feces was found to be soft, and diarrhea reached the peak. The size and shape of the feces are small and irregular except 1 normal stool, and the amount is reduced to about one half. Abdominal distension was confirmed by visual examination of the abdomen, and generation and movement of gas were confirmed by palpation. The diarrhea prevention effect was poor compared with the case where the same amount of XG was added, but the amount of feces was increased to about half of that of XG, which is common, and abdominal distension was slight.

In the group to which GG was administered at 1.12g/kg (40 wt%), feces decreased from hour 3, and the shape was also small and irregular. After 5 hours the feces were slightly softened. Half of the animals became slightly soft stools and then continued to be in the same state until 18 hours, but the stool consistency returned to normal after 24 hours for all animals. The effect of XG on diarrhea prevention was confirmed (P < 0.05, Mann-Whitney test in both groups). Digestive organ symptoms became heavier in proportion to the increase in the amount of GG added. The generation of gas was confirmed by palpation, and when the gas was heard and touched by a finger to move in the intestine, the animal was vigorously buzzed and a painful pattern was displayed when a strong pressure was applied to the abdomen. The diarrhea-preventing effect was inferior to that obtained by adding an equal amount of XG, but the amount of feces was about half of that in the case of XG and was larger than that in XG. Abdominal distension was of the same extent but palpation pain was reduced.

Maltitol of the disaccharides is largely different from the monosaccharides by: diarrhea is delayed from monosaccharides, and after about 4 to 5 hours, the peak lasts about 12 hours, during which abnormal fermentation in the intestine is severe. Addition of relatively large amounts of xanthan gum or guar gum can achieve diarrhea resistance, but is different from monosaccharides in terms of abnormal fermentation in the intestine, etc. Changes in stool consistency over time (average of 4 individuals) are shown in Table 7.

[ Table 7]

In addition, the purgative effect of other sugars or sugar alcohols in combination with polysaccharides has also been studied.

[ mannitol and sodium carboxymethylcellulose ]

Guinea pigs 8 showing normal stools were divided into 2 groups, drug administration was performed as shown below, and stools were observed 6 hours thereafter. The results are shown in Table 8.

[ Table 8]

Mannitol-induced diarrhea was significantly reduced by the addition of about 7.1 wt% CMC (P < 0.05, Mann-Whitney test in both groups). Abdominal distension was not confirmed by both visual examination and palpation, and reduction in digestive organ symptoms was presumed.

[ sorbitol and hydroxypropyl cellulose ]

Guinea pigs 8 showing normal stools were divided into 2 groups, drug administration was performed as shown below, and stools were observed 6 hours after the drug administration, and the results are shown in table 9.

[ Table 9]

CMC (sodium carboxymethylcellulose) 0.05g/kg was added and the HPC was suspended.

The sorbitol-induced diarrhea was significantly reduced by the addition of about 5.4 wt.% hydroxypropyl cellulose (suspended with about 0.18 wt.% carboxymethyl cellulose) (P < 0.05, Mann-Whitney test). Abdominal distension was not confirmed by both visual examination and palpation, and reduction in digestive organ symptoms was presumed.

[ sorbitol and guar Gum (Sigma Co.) ]

The guinea pigs 10 showing normal stools were divided into 2 groups, drug administration was performed as shown below, and stools were observed 6 hours after the drug administration, and the results are shown in table 10.

[ Table 10]

10% by weight of guar gum was added, 2 normal stools and 2 slightly soft stools, and sorbitol-induced diarrhea was almost successfully antidiarrheal (P < 0.05, Mann-Whitney test). However, 3 to 4 hours after administration, the amount of feces was reduced to about one third, and a slight abdominal distension was confirmed by visual examination and palpation, and when the abdomen was pressed with fingers, gas was generated and moved by touch. When the lower abdomen is pressed, small stools, which are irregular in shape and whose amount is normally one-half or less, are excreted little by little.

[ erythritol and Arabic gum (Sigma Co.) ]

The guinea pigs 10 showing normal stools were divided into 2 groups, drug administration was performed as shown below, and stools were observed 6 hours after the drug administration, and the results are shown in table 11 and compared with the E3H group.

[ Table 11]

Even if 20 wt% of acacia gum was added, the diarrhea with sorbitol could not be stopped (no significant difference). After 40 wt% of the drug was added, diarrhea was reduced (P < 0.01, Mann-Whitney test), but more reliable diarrhea was desired. In both groups, the amount of feces was reduced to about one third at 3 to 4 hours, and the abdominal distension feeling in the abdomen was confirmed by visual examination and palpation, and when the abdomen was pressed with a finger, the patient was assumed to be in an uncomfortable state by touching the gas and moving, and excreted only a small amount of muddy feces.

[ erythritol and guar gum (Sigma Co.) ]

The guinea pigs 15 showing normal stools were divided into only 2 groups, drug administration was performed as shown below, and stools were observed 6 hours after the drug administration, and the results are shown in table 12 and compared with the E3H group.

[ Table 12]

Guar gum is added in 20 wt%, 2 are normal stools and 2 are slightly soft stools, and basically and successfully stop diarrhea (P < 0.01, Mann-Whitney test). However, the amount of feces was reduced to about one third in 3 to 4 hours after administration, abdominal distension was confirmed by visual examination and palpation, and when the abdomen was pressed with a finger, gas was generated and moved. When the lower abdomen is pressed, small stools that are irregular in shape and less than half of the normal amount are excreted little by little, and it is estimated that the lower abdomen is in an uncomfortable state.

From the above results, it was confirmed that oral administration of sugar or sugar alcohols resulted in diarrhea symptoms, which reached the peak top 3 to 4 hours after administration, but showed a tendency to recover at 6 hours, and that the antidiarrheal effect was improved in proportion to the amount of the added polysaccharides, while the antidiarrheal effect was reduced by the addition of sugar or sugar alcohols. Although the effect tends to be more ensured by the addition of the antacid and intestinal function-controlling drugs, no significant synergistic effect and no adverse inhibitory effect are observed. This is also observed in other polysaccharides such as sodium alginate.

Example 2

In order to evaluate the effect of reducing labyrinthine hydrops of sugars and sugar alcohols, 3 series of tests were performed as described below. First, a "model animal for experimental labyrinthine hydrops" was prepared by performing a labyrinthine cystectomy on only the left side of guinea pigs. Occlusion of the labyrinth capsule is performed by sintering the extraosseous part of the labyrinth capsule with a bipolar electrocoagulator (bipolarelectrocoagulator). The labyrinth capsule which plays an important role in absorbing the labyrinth fluid is burnt to cause the absorption obstacle of the labyrinth fluid, and experimental labyrinth hydrops is formed. This water is progressively formed, with a size that is approximately constant after about 2 weeks or 1 month, for several months. The details of the surgical method are the same as those reported (non-patent document 8).

After one month, the test pieces were divided into three groups, i.e., 60 in the 2-1 (1 st to 6 th) groups, 40 in the 2-2 (7 th to 10 th) groups, and 66 in the 2-3 (11 th to 20 th) groups. Group 2-1 was administered with only sugar or sugar alcohol [ comparative example 5], and group 2-2 was orally administered with a drug prepared by adding polysaccharide to sugar or sugar alcohol. The composition of group 2-3 modified with sugar or sugar alcohol and polysaccharides is administered orally. After a set time has elapsed, the animals are fixed by perfusion, and histological changes of the cochlea on the operation side (left side), particularly the effect of alleviating the labyrinthine hydrops, are mainly observed and studied by using gastrointestinal symptoms as the main factors.

For gastrointestinal symptoms, the conditions of the large intestine, colon and rectum and the formation of feces when perfusion was fixed were observed specifically and judged by the criteria of table 2 for 1) the hardness and shape of feces and 2) the length of the feces having a shape and the interval and arrangement of feces. The length normally formed in the rectum and colon is measured from the anus and observed to see if the stool space is constant.

After perfusion fixation, the lateral skull was removed, decalcified with trichloroacetic acid, dehydrated with alcohols, and double embedded with paraffin-cotton gum. Hematoxylin and eosin staining is performed on the cochlear shaft section obtained by sectioning, observation of cochlear tissues is performed mainly with the surgical side (left side) as the center with an optical microscope, and changes in the length of the vestibular membrane and the area of the labyrinth are observed and measured.

The extension of the vestibular membrane and the volume change of the labyrinth chamber are measured for each rotation, and the results are integrated by the following calculation formula to obtain the extension rate of the membrane and the area increase rate of the labyrinth capsule for each cochlear tissue. On the operative side, i.e., the left side, the effect of reducing labyrinth dropsy was evaluated based on the volume change of the labyrinth cavity.

Details of the tissue preparation method, the measurement method, and the evaluation method are the same as those reported (non-patent document 8).

Vestibular membrane extension (IR-L) ═ 100 × Σ (Lx-L × x)/∑ L × x (x: 1 st, 2 nd, 3 rd, 4th rotation)

The rate of increase in cross-sectional area (IR-S) of the labyrinth cavity (scale media) is 100 × Σ (Sx-S × x)/∑ S × x (x: 1 st, 2 nd, 3 rd, 4th rotations)

(1) Group 2-1: case of administering erythritol alone (comparative example 4)

Guinea pigs 60 were divided into 6 groups of 10 animals each, and the drugs were administered to each group as follows. The amount of erythritol to be administered at a time was adjusted to 8 ml/kg.

[ Table 13]

Group of	Administration of pharmaceutical agents	Perfusion (after administration)
			Group 1: control group	Distilled water	After 3 hours
Group 2: group E1H	Ery 2.8g/kg	After 1 hour
			Group 3: group E2H	Ery 2.8g/kg	After 2 hours
Group 4: group E3H	Ery 2.8g/kg	After 3 hours
			Group 5: group E6H	Ery 2.8g/kg	After 6 hours
Group 6: E12HGroup of	Ery 2.8g/kg	After 12 hours

[0200] A) Study of gastrointestinal symptoms

The results are shown in Table 14.

[ Table 14]

Ery: erythritol 2.8g/kg

The hardness of the stool was determined at the time of perfusion.

A) determination of stool hardness

The control group was normal stool. Group E1H, E2H formed normal stool near the rectum, but gradually shifted to soft stools. E3H and E6H are all muddy feces. In 5 of group E6H, only 1 of the 5 had a slight decrease in the mud-like state, but the shape was not formed. Almost all animals in group E12H formed stools of normal firmness.

B) length formed by the shaped stools, and the stool interval and arrangement state

The control group is 55.0 + -8.8 cm, the size of the feces is fixed, and the interval is also fixed; some of the E1H groups had loose stools with irregular sizes and irregular intervals, and the stools were formed to have lengths of 22.8. + -. 6.9 cm. Group E3H-E6H had a part close to loose stool locally, and the intestine was almost filled with muddy stool, and the stool was formed to be 0 cm. In group E12H after 12 hours of administration, 66.0. + -. 12.1cm of stools exhibiting a substantially definite shape were formed. The interval between excrements was usually about 0.7 to 1cm in the control group, and was irregular in some animals of group E12H where the interval between excrements was 8 to 10cm, and the generation of gas was confirmed by puncture where the interval between excrements was not wide.

The diarrhea caused by erythritol administration became severe within 2 to 3 hours, and continued after 6 hours, but returned to normal approximately 12 hours later, as judged from the above.

B) Mitigation of lost circulation

Correlation of the stretching of the membrane on the operative side with an increase in the area

The mean. + -. standard deviation of the elongation (IR-L) and the area increase (IR-S) of the film on the operation side is shown in Table 15. The control group also measured the right side (control side) on which the occlusion surgery was not performed, and the extension rate of the vestibular membrane and the increase rate of the area of the labyrinth cavity, which were not subjected to the occlusion surgery, i.e., which were not treated, are shown in table 14.

[ Table 15]

No water was found on the control side of the control group. On the operation side, the degree of formation of experimental hydrops by occlusion surgery varies greatly from several% to a hundred and several tens%, and it is difficult to study the effect of erythritol, its change over time, and the like by comparing the average ± standard deviation of the elongation and area increase rate of the film.

FIG. 1 shows a scatter plot and a regression line of 2 variables on the operative side of each animal group, with the horizontal axis being the elongation of the membrane (IR-L) and the vertical axis being the area increase rate (IR-S), for the change with time in the alleviation obtained by the administration of erythritol. O: IR-S (distilled water) vs IR-L (distilled water), □: IR-S (1 hour) vs IR-L (1 hour), (white on the left and black on the right half): IR-S (2 hr) vs IR-L (2 hr), ●: IR-S (3 hr) vs IR-L (3 hr), ×: IR-S (6 hr) vs IR-L (6 hr), ■: IR-S (12 hours) vs IR-L (12 hours). Since there was little difference in the regression line between the groups, it was found that the effect of alleviation was not seen in the case of administration of erythritol alone. When the labyrinth hydrops is generated, the volume of the labyrinth cavity is increased, and the vestibular membrane is stretched. As is presumed from FIG. 1, a statistical correlation was found between the two on the operation side of the control group to which distilled water was administered. The regression line is 4.011+1.212 × IR-L (distilled water), R2 is 0.987; IR-S (1 hour) ═ 5.409+1.1 × IR-L (1 hour), R2 ═ 0.903; IR-S (2 hours) ═ 1.125+0.992 × IR-L (2 hours), R2 ═ 0.98; IR-S (3 hours) ═ 2.407+1.309 × IR-L (3 hours), R2 ═ 0.974; IR-S (6 hours) ═ 7.36+1.147 × IR-L (6 hours), R2 ═ 0.895; IR-S (12 hrs) ═ 8.089+1.152 × IR-L (12 hrs), R2 ═ 0.918. When the accumulated water is reduced by administering the drug, the area of the labyrinth cavity increases less although the membrane stretches, and the regression line moves downward.

In fig. 1, the regression line of the control group was compared with the regression lines of 5 groups in total, E1H group (1 hour later) to E12H group (12 hours later), and there was no significant difference between the groups (ANCOVA test). From this result, it was found that the effect of reducing the effect expected from the administration of sugar or sugar alcohols was not observed in the case of administering a single drug. The reason for this is considered to be that plasma AVP (plasma AVP: antidiuretic hormone) rises due to dehydration by the purgative effect (Safwate A et al: BrVet J147: 533-7 (1991)).

It is considered that a method for preventing the purgative effect of sugar or sugar alcohols must be considered in order to ensure the effect of reducing the labyrinthine hydrops of sugar or sugar alcohols.

(2) Groups 2-2: addition and administration of pectin to erythritol

After 1 month of the left-side labyrinth closure operation, the guinea pigs 40 were divided into 4 groups of 10 animals each, and each group was administered with the drugs as described below, and after a certain period of time, perfusion fixation was performed.

[ Table 16]

In addition, the dose of the drug administered at one time was 8ml/kg from group 7 to group 10.

When perfusion was fixed, the state of the large intestine, colon and rectum, particularly the state of formation of feces, was observed. Decalcification, dehydration, embedding, and staining after perfusion fixation were observed with an optical microscope, and measurement was performed in the same manner as in group 2-1.

A) Study of gastrointestinal symptoms

The hardness of feces, the judgment of the interval and the formed length of feces were observed in the above 2 groups.

[ 2-2-a: observation of the difference in Effect after 3 hours of administration due to the amount of addition of the causal gum

The results are shown in Table 17.

[ Table 17]

All 10 of the E3H groups (no pectin added but only erythritol added) in group 4 were muddy stools, but in the 7 th group (E + P0.1g group: 0.1g/kg pectin added), 5 of the 10 muddy stools were observed, 3 of the soft stools were observed, and a shape of stools of about 2 to 3cm from the anus was observed. The remaining 2 were slightly soft stools, forming stools of 23cm and 42cm, but were irregularly spaced and pulled apart by 10cm or more. The average of 10 was 7.3. + -. 13.3 cm.

The antidiarrheal effect was confirmed for group 8 (group E + P3H: pectin added at 0.5g/kg), 3 of these cases were muddy stools, and 1 and 3 of the other 7 cases were normal hardness for soft stools and slightly soft stools (P < 0.01, Mann-Whitney test). However, the stool interval of these 7 stools is not constant. The average length of the feces formed (10 feces) was 19.2. + -. 21.7 cm.

Reference) study of the Effect of the onset of diarrhea on the general State

Subjects and methods) with guinea pigs weighing 280-320 g, 12 animals showing normal feces were divided into 3 groups, and only physiological saline was administered to group 1, erythritol + pectin 0.1g/kg was administered to group 2, and erythritol + pectin 0.5g/kg was administered to group 3. After administration, blood was collected by cutting off the head with a knife within 3 hours, and AVP in blood was measured by the method described in non-patent document 8 in the specification.

The administration agents and the examination results are shown in Table 18. The erythritol administration amount was 2.8g/kg, and the one-time administration amount of the aqueous solution was adjusted to 8 ml/kg.

[ Table 18]

Ery: erythritol 2.8g/kg

^*: plasma AVP for soft stools was 3.2, 8.3, for muddy stools 25.5, 22.1, units: pg/ml.

^**: the AVP of plasma of soft stool is 10.9, and the AVP of plasma of normal stool is 3.1, 2.8, 4.0.

Plasma AVP is known to be proportional to the severity of diarrhea.

When about 3.6 wt% of polysaccharides (0.1 g/kg of pectin) was added to sugar or sugar alcohol, severe diarrhea symptoms appeared (Table 17), and plasma AV was high, while 3 of 4 stools were normal and plasma AVP was also decreased (Table 18) with respect to the amount added in the present invention.

As shown in table 1, plasma AVP values are proportional to the rate of increase in labyrinthine water. When the amount of compounded pectin was 0.1g/kg (about 3.6 wt%), the plasma AVP was high and no effect of alleviating edema was observed, and when the amount of compounded pectin was 0.5g/kg, the plasma AVP was low and a remarkable alleviating effect was observed. This result is consistent with non-patent document 10.

When the amount of the polysaccharide added is small, diarrhea may occur and dehydration may continue. The addition of a suspending agent or viscosity-increasing agent having a low viscosity to the extent that it is used causes an increase in plasma AVP, resulting in labyrinthine hydrops, which is a morbid state of meniere's disease (a dangerous state of the same value as AVP at onset).

[ 2-2-b: 0.5g/kg of pectin was added and the change with time after administration was observed ]

The results are shown in Table 19.

[ Table 19]

The hardness of the stool was determined at the time of perfusion.

In group 8 of 2-2-a (group E + P3H: perfusion was performed after 3 hours), 3 patients had a muddy state, and 4 patients had a normal state. In group 9 (group E + P6H) in which perfusion was performed 6 hours after administration, 1 was muddy stool, 2 was soft stool, 1 was slightly soft stool, and the remaining 6 were normal hardness. In group 5 (group E6H) to which erythritol alone was administered, 7 cases were muddy stool, and the antidiarrheal effect was confirmed (P < 0.01, Mann-Whitney test). The spacing was still irregular and the length of the formed faeces was 30.8. + -. 23.6cm (average of 10). Animals with purulent, soft stools near the rectum form generally normal stools near the colon, and diarrhea is considered transient.

In group 10 (group E + P12H: perfusion was performed after 12 hours), all animals were normal stools and the stool interval was constant. The stool was regularly arranged, and 9 of 10 were indeterminate for group 6 (group E12H) given erythritol alone, with a significant improvement seen (P < 0.001, mann-whitney test). It is assumed that the uncomfortable digestive organ symptoms such as abnormal intestinal fermentation have passed.

The length of the feces formed was 45.4. + -. 11.5 cm.

B) Mitigation of lost circulation

When the difference in the effect of reducing labyrinthine hydrops and the change in the effect of reducing labyrinthine hydrops with time due to the difference in the amount of pectin added were examined, the average and standard deviation of the extension rate and the area change rate of the membrane of each group were compared on the surgical side, and it was difficult to clearly determine the effect. Therefore, as with the observation in group 1, the study was conducted by comparing the slope of the straight line and the Y-slice of fig. 2 and 3.

[ 2-2-a: observation of the difference in Effect after 3 hours from the addition of the causal gum

The average and standard deviation of the stretching rate and the area increasing rate of the films of each group are shown in table 20, and a scatter plot and a regression line are shown in fig. 2.

[ Table 20]

Figure 2 as seen in group 1, the E3H group (erythritol alone) was not significantly different from the control group (distilled water). Group 7 (0.1 g/kg pectin added) was also not significantly different from the control group and group E3H, but group 8 (0.5 g/kg pectin) was significantly different (P < 0.001), and thus a significant alleviation effect was seen in group 8. O: IR-S (distilled water) vs IR-L (distilled water), ●: IR-S (E3 hr) vs IR-L (E3 hr), (white on the left and black on the right): IR-S (E + P0.1g) vs IR-L (E + P0.1g), ■: IR-S (E + P0.5g) vsIR-L (E + P0.5g). IR-S (distilled water) ═ 4.011+1.212 × IR-L (distilled water), R2 ═ 0.987; IR-S (erythritol 3 hr) ═ 2.407+1.309 × IR-L (erythritol 3 hr), R2 ═ 0.974; IR-S (erythritol + pectin 0.1g) 8.683+1.074 IR-L (erythritol + pectin 0.1g), R2 0.704; IR-S (erythritol + pectin 0.5g) — 15.925+0.79 × IR-L (erythritol + pectin 0.5g), R2 ═ 0.771.

No significant difference was seen between group 7 (0.1 g/kg pectin added, about 3.6 wt%) and the control group (distilled water), E3H group (erythritol alone administered) (ANCOVA test). On the other hand, the group 8 to which 0.5g/kg of pectin was added was significantly shifted downward compared to the control group and the group E3H (P < 0.01, P < 0.05, and ANCOVA test, respectively). From this, it was found that the effect of reducing the viscosity could not be obtained under the condition of the amount of addition (1% or less) of the suspending agent and the emulsifier which are generally used as the stabilizer, and that the addition of 0.5g/kg (17.9 wt%) of pectin finally exhibited a significant effect of reducing the viscosity.

Note that the stretch ratio and the area increase ratio of the film of group 7 in table 20 are both larger values than those of the other groups. This is due to the high degree of hydrocele formation by occlusion surgery due to individual differences in the animals. As shown in fig. 2, since there was no significant difference from the control group, it can be said that the administration of the drug did not worsen the hydrocele.

The mean and standard deviation of the stretching ratio and the area increasing ratio of each group are shown in table 21, and a scatter diagram and a regression line are shown in fig. 3.

[ Table 21]

In fig. 3, the difference between the group 9 (after 6 hours) and the control group was significant (P < 0.01), and thus the reduction effect was still observed, but the reduction effect was significantly reduced (P < 0.05) as compared with the group 8 (after 3 hours). In group 10 (after 12 hours), the reduction effect was further significantly reduced, and the difference from the control group (distilled water) was not significant. From these facts, it is considered that the lightening effect is reduced with the lapse of time, and the lightening effect disappears after 12 hours. O: IR-S (distilled water) vs IR-L (distilled water), ■: IR-S (E + P3 hr) vs IR-L (E + P3 hr), x: IR-S (E + P6 hr) vs IR-L (E + P6 hr), (white on the left and black on the right): IR-S (E + P12 hr) vs IR-L (E + P12 hr). IR-S (distilled water) ═ 4.011+1.212 × IR-L (distilled water), R2 ═ 0.987; IR-S (erythritol + pectin 3 hours) ═ -15.925+0.79 × IR-L (erythritol + pectin 3 hours), R2 ═ 0.771; IR-S (erythritol + pectin 6 hours) — 16.508+1.314 × IR-L (erythritol + pectin 6 hours), R2 ═ 0.784; IR-S (erythritol + pectin 12 hours) — 4.58+1.314 × IR-L (erythritol + pectin 12 hours), R2 ═ 0.913.

In fig. 3, as shown in 2-2-a, group 8 (after 3 hours) produced a significant reduction compared to the control group (distilled water), group E3H (erythritol alone). Furthermore, group 9 (after 6 hours) was also significantly reduced (P < 0.001) compared to the control group and group E3H. Group 9 was significantly shifted upward compared to group 8 (P < 0.05). Group 10 (12 hours later) was found to have a significant difference (P < 0.001 and P < 0.01, respectively) from groups E3H and E6H, but was not found to have a significant difference from groups E3H and the control group. From the above judgment, the effect of alleviation becomes maximum after 3 hours of administration, and the effect of alleviation is seen after 6 hours, but the effect is weakened compared with 3 hours, and the effect of alleviation disappears after 12 hours.

(3) Groups 2 to 3

The antidiarrheal effect was observed by changing the combination of sugar or sugar alcohols and polysaccharides, and evaluated based on the criteria of table 2. After one month of left-side closing operation of the labyrinth capsule, animals were orally administered, and then perfused for the 3 rd hour at which the largest cathartic action of sugar or sugar alcohols was achieved, and the lateral skull was taken out, and a specimen was prepared in the same manner as described above (non-patent document 8), and the inner ear was observed, and the effect of alleviating labyrinthic hydrops was measured and evaluated.

2-3-a) administration of Xanthan Gum to xylitol

The guinea pigs 12 were divided into 2 groups of 6 animals, and drug administration was performed as follows, and perfusion fixation was performed after 3 hours.

[ Table 22]

Group of	Administration of pharmaceutical agents	Perfusion (after administration)
			Group 11:	xylitol (2.8g/kg) alone	After 3 hours
Group 12:	xylitol (2.8g/kg) + xanthan gum (0.2g/kg)	After 3 hours

Among these results, the evaluation results of antidiarrheal effect are shown in table 23.

[ Table 23]

Antidiarrheal effect was confirmed by addition of xanthan gum (7.1 wt%) (P < 0.05, Mann-Whitney test).

The results of the histological study are shown in table 24 and fig. 4.

[ Table 24]

According to fig. 4, in the group to which xanthan gum was added as a polysaccharide, a significant labyrinthine water reducing effect was observed as compared with the group to which xylitol alone was administered (P < 0.01, ANCOVA test).

In fig. 4, o: IR-S (xylitol alone) vs IR-L (xylitol alone), ●: IR-S (xylitol + xanthan gum) vs IR-L (xylitol + xanthan gum). The regression lines are respectively the area of xylitol alone 2.371+1.208, R2 is 0.991; area of (xylitol + xanthan gum) -7.154+0.882 (xylitol + xanthan gum) and R2-0.82.

2-3-b) addition of sodium alginate to isosorbide

The guinea pigs 15 were divided into 2 groups, and drug administration was performed as follows, and perfusion fixation was performed after 3 hours.

[ Table 25]

Group of	Administration of pharmaceutical agents	Perfusion (after administration)
			Group 13 (8):	IB (2.8g/kg) alone	After 3 hours
Group 14 (7):	IB (2.8g/kg) + sodium alginate (0.2g/kg)	After 3 hours

Among these results, the results of antidiarrheal effect are shown in table 26.

[ Table 26]

Antidiarrheal effect was confirmed by the addition of sodium alginate (10.7 wt%) (P < 0.05, Mann-Whitney test).

The results of the histological study are shown in table 27 and fig. 5.

[ Table 27]

In group 2 to which sodium alginate was added as a polysaccharide, a significant labyrinthine hydrops-reducing effect (P < 0.01) was observed.

In fig. 5, o: IR-S (isosorbide alone) vs IR-L (isosorbide alone), ●: IR-S (isosorbide + sodium alginate) vs IR-L (isosorbide + sodium alginate). The regression lines are respectively the area of isosorbide alone 7.143+1.003 ═ film of isosorbide alone, R2 ═ 0.985; (isosorbide + sodium alginate) 2.691+0.704 (isosorbide + sodium alginate) and R2 0.977.

2-3-c) administration of isosorbide with addition of agar

[ Table 28]

Group of	Administration of pharmaceutical agents	Perfusion (after administration)
			Group 13 (8):	IB alone (2.8g/kg)	After 3 hours
Group 15 (7):	IB (2.8g/kg) + agar (0.3g/kg)	After 3 hours

Among these results, the results of antidiarrheal effect are shown in table 29.

[ Table 29]

The antidiarrheal effect was confirmed by the addition of agar (10.7 wt%) (P < 0.05, Mann-Whitney test).

The results of the histological study are shown in table 30 and fig. 6.

[ Table 30]

In group 2 containing agar as a polysaccharide, a significant effect of reducing labyrinthine hydrops was observed (P < 0.01).

In fig. 6, o: IR-S (isosorbide alone) vs IR-L (isosorbide alone), ●: IR-S (isosorbide + agar) vs IR-L (isosorbide + agar). The regression lines are respectively the area of isosorbide alone 6.542+1.011 isosorbide alone film, R2 is 0.987; (isosorbide + agar) area-0.574 +0.865 ═ isosorbide + agar) membrane, R2 ═ 0.984.

2-3-d) administration of glycerin with sodium carboxymethylcellulose

Guinea pigs 12 were divided into 2 groups, and drug administration was performed as follows, and perfusion fixation was performed after 3 hours.

[ Table 31]

Group of	Administration of pharmaceutical agents	Perfusion (after administration)
			Group 16 (6):	glycerol (2.8g/kg) alone	After 3 hours
Group 17 (6):	glycerol (2.8g/kg) + CMC (0.28g/kg)	After 3 hours

Among these results, the results of antidiarrheal effect are shown in table 32.

[ Table 32]

Antidiarrheal effect was confirmed by the addition of sodium carboxymethylcellulose (10 wt%) (P < 0.01, Mann-Whitney test).

The results of the histological study are shown in table 33 and fig. 7.

[ Table 33]

In the group containing sodium carboxymethylcellulose as a polysaccharide, a significant difference (P < 0.01) was observed compared with the group containing glycerin alone.

In fig. 7, o: IR-S (glycerol alone) vs IR-L (glycerol alone), ●: IR-S (Glycerol + sodium carboxymethylcellulose) vs IR-L (Glycerol + sodium carboxymethylcellulose). The regression lines are, respectively, the area of glycerol alone-2.455 +0.887 glycerol alone membrane, R2-0.982; (glycerol + sodium carboxymethylcellulose) 4.806+1.316 ═ area (glycerol + sodium carboxymethylcellulose) of the film, R2 ═ 0.995.

2-3-e) addition of Xanthan Gum to xylose

[ Table 34]

Group of	Administration of pharmaceutical agents	Perfusion (after administration)
			Group 18 (6):	xylose (2.8g/kg) alone	After 3 hours
Group 19 (6):	xylose (2.8g/kg) + Xanthan Gum (0.2g/kg)	After 3 hours

Among these results, the results of antidiarrheal effect are shown in table 35.

[ Table 35]

The antidiarrheal effect was confirmed by the addition of xanthan gum (7.1 wt%) (P < 0.01, Mann-Whitney test).

The results of the histological study are shown in table 36 and fig. 8.

[ Table 36]

In the group to which xanthan gum was added as a polysaccharide, a significant reduction effect (P < 0.001) was observed as compared with the group to which xylose was added alone.

In fig. 8, o: IR-S (xylose alone) vs IR-L (xylose alone), ●: IR-S (xylose + xanthan gum) vs IR-L (xylose + xanthan gum). The regression lines are respectively the area of xylose alone 1.197+1.364 x membrane of xylose alone, R2 is 0.933; area of (xylose + xanthan gum) -17.886+0.945 (xylose + xanthan gum) and R2-0.93.

In groups 2 to 3, the addition of a polysaccharide to a sugar or a sugar alcohol reduces the amount of labyrinthine water, thereby achieving the object of the present invention.

Example 3

Compared with the prior isosorbide (made by Xinghu Chuangyao corporation, common name: isosorbide, content of isosorbide is 70%) solution used in clinic in Japan

After one month, the labyrinth cystectomy was performed, and only guinea pigs 40 showing normal stools were divided into 4 groups as shown in table 36, each group consisting of 10 animals, and isosorbide preparations (hereinafter, referred to as "conventional isosorbide products") were administered to groups 20 and 21, and gel preparations (isosorbide 2.8g/kg) prepared by adding 0.11g/kg of sodium alginate and 0.09g/kg of inorganic salt to groups 22 and 23. The observation of digestive organ symptoms and labyrinthine alleviating effects was continued until 6 hours after the administration of the isosorbide-containing product, in which the alleviating effect was maximized (non-patent document 12), perfusion fixation was performed 3 hours and 6 hours after the administration, and tissues were collected and observed.

The amount administered at one time was adjusted to 4ml/kg for all groups. After the occlusion operation, the order and measurement of tissue preparation and the like are carried out by the same method as in a non-patent paper (Takeda T: Hear Res.183: 9-18, (2003)).

[ Table 37]

Group of	Administration of pharmaceutical agents	Perfusion (after administration)
			Group 13: IB alone	Isosorbide 2.8g/kg	After 3 hours
Group 20: IB original product group	Contains 2.8g/kg of isosorbide	After 3 hours
			Group 21: IB original product group	Contains 2.8g/kg of isosorbide	After 6 hours
Group 22: gel administration group	IB 2.8g/kg + Al + inorganic salt	After 3 hours
			Group 23: gel administration group	IB 2.8g/kg + Al + inorganic salt	After 6 hours

A) Study of gastrointestinal symptoms

The results of observing the hardness and shape of feces are shown in table 38.

[ Table 38]

Control group: example 2-1 group 1

IB: isosorbide 2.8g/kg

Al: sodium alginate 0.11g/kg

In the group to which the conventional isosorbide product was administered, feces began to soften after 2 hours, and diarrhea symptoms became the worst after 3 hours (group 20), with 2 normal feces among 10, 3 slightly soft feces, 4 soft feces, and 2 muddy feces. After 6 hours (group 21), 4 animals with normal stools, 3 animals with slightly soft stools, 2 animals with soft stools, and 1 animal with muddy stools were observed, and although the diarrhea symptoms were improved as compared with 3 hours after administration, no significant difference was observed between the group 20 and the group 21. The length of the formed stools was 60.2. + -. 15.8 hours after 6 hours, but 8 stools among 10 stools were scattered, and it was presumed that severe gastrointestinal symptoms occurred because gas was generated in the intestinal tract where the interval was pulled by about 20 to 40 cm. The results of observation of the stool hardness and the stool interval after 6 hours were significantly different from those of the control group (P < 0.01, P < 0.05, and Mann-Whitney test, respectively), indicating that the purgative effect was mild. This fact is consistent with the digestive organ symptoms such as diarrhea, abdominal distension, borborborygmus and the like which may be observed in patients after the conventional isosorbide products are administered.

On the other hand, the hardness of feces after 3 hours (group 22) in the group to which isosorbide + sodium alginate was administered was as follows, and the stool had only 2 slightly soft feces, the other 8 normal feces, irregular stool intervals, and less scattered than that of conventional isosorbide, so that the antidiarrheal effect was significantly superior (P < 0.05) to that of conventional isosorbide (group 20), and it was presumed that digestive organ symptoms were also reduced (P < 0.01, Mann-Whitney test). After 6 hours (group 23), all animals had stools of normal hardness with a constant interval of 6, and the digestive organ symptoms were significantly reduced as compared with the conventional isosorbide (group 21) (stools were hardened and spaced apart by P < 0.01, and Mann-Whitney test, respectively).

B) Mitigation of lost circulation

The extension of the membrane and the change in volume of the labyrinth chamber were measured for each rotation, and the results are shown in table 39 and fig. 9.

[ Table 39]

IB: isosorbide 2.8g/kg [ unit: cm ]

In fig. 9, o: IR-S vs IR-L of group 1 (distilled water), X: IR-S vs IR-L of group 2 (3 hours after the past isosorbide product) (□ having X therein): IR-S vs IR-L of group 3 (after 6 hours for isosorbide as a former product) (white circle on the left and black circle on the right): IR-S vs IR-L from group 4 (after 3 hours isosorbide + sodium alginate), A: IR-S vs IR-L from group 3 (after 6 hours isosorbide + sodium alginate), ●: IR-Svs IR-L isosorbide alone. The regression lines are, respectively, the area of distilled water is 2.537+1.23 × membrane of distilled water, and R2 is 0.984; (isosorbide + sodium alginate 3 hours) 2.387+0.633 ═ R2 0.651; (isosorbide + sodium alginate 6 hours) area 2.62+0.69 isosorbide + sodium alginate 6 hours), R2 0.881; (3 hours for the isosorbide precursor) 8.033+0.911 x (3 hours for the isosorbide precursor); a film having an area of-0.797 +0.855 (isosorbide precursor 6 hours) of R2 ═ 0.947, (isosorbide precursor 6 hours), and an area of R2 ═ 0.907; isosorbide alone area 6.542+1.011 isosorbide alone film, R2 0.987.

In FIG. 9, the regression lines of the 20 th group (after 3 hours from the conventional isosorbide product) and the 21 st group (after 6 hours from the conventional isosorbide product) were significantly different from the regression line of the control group (group 1) to which distilled water was added, by moving downward (P < 0.01, P < 0.001, and ANCOVA test, respectively).

The regression lines in group 22 (< isosorbide + sodium alginate > after 3 hours) and group 5 (< isosorbide + sodium alginate > after 6 hours) were further shifted downward, and the effects of alleviation were found to be greater than those in the control group, because they were significantly different (P < 0.001, and ANCOVA test, respectively). The effect of reducing the level of isosorbide + sodium alginate in the group < isosorbide + sodium alginate > at 3 hours after administration (group 22) was significantly different from that of the conventional isosorbide (group 20) (P < 0.01, ANCOVA test). On the other hand, in group 23 after 6 hours from the administration, there was no significant difference in comparison with the isosorbide product (group 21) (ANCOVA test).

From these facts, the effect of the group < isosorbide + sodium alginate > was confirmed to appear 3 hours after administration (P < 0.001), and the effect was sustained even after 6 hours (P < 0.001). The effect was more remarkable than that of the conventional products after 3 hours of administration (P < 0.01), and the effect was rapidly exhibited.

After 6 hours, there was no significant difference, and the regression line moved downward compared to the conventional one, and it was found that gastrointestinal symptoms including the purgative effect were successfully improved depending on the shape of feces and the state of gas generation in the digestive tract, and therefore, it was predicted that a sufficient therapeutic effect could be expected with a smaller amount without imposing a burden on the digestive organs.

Although it was judged that diarrhea caused by ingestion of sugar or sugar alcohols can be prevented by adding polysaccharides, in order to examine the effect, there is no feature in the combination of sugar or sugar alcohols and polysaccharides, polyvinylpyrrolidone used as an emulsifier, a suspending agent, a thickener, and the like as in the case of polysaccharides was used instead of polysaccharides [ comparative example 6], and a gum [ comparative example 7], and the diarrhea prevention effect was examined.

Comparative example 6

[ erythritol and polyvinylpyrrolidone ]

A guinea pig with a weight of 280-350 g and normal feces was subjected to labyrinth cystectomy only on the left side, and an experimental model animal of labyrinthine hydrops was prepared. The details of the operation are the same as in non-patent document 8.

One month later, 0.5g/kg (about 7.1 wt%) of polyvinylpyrrolidone was added to 2.8g/kg of erythritol and orally administered, and the shape of feces was observed after 6 hours, perfusion fixation was performed after 3 hours, and then tissue observation was performed in the same manner to determine the effect of reduction (table 40). The results are shown in FIG. 10, compared with group 4 of example 2 (erythritol 2.8g/kg alone, perfused 3 hours after administration).

FIG. 10 is a scatter diagram and a regression line showing 2 variables of the membrane stretch ratio on the horizontal axis and the area increase ratio on the vertical axis for each animal group on the operation side. In fig. 10, □: IR-S (erythritol alone for 3 hours) vs IR-L (erythritol alone for 3 hours), ●: IR-S (3 hours of tackifier addition) vs IR-L (3 hours of tackifier addition). Films with regression lines (erythritol alone for 3 hours) having an area of 2.407+1.309 × erythritol alone for 3 hours), R2 ═ 0.974; (3 hours of tackifier addition) area-7.511 +1.659 (3 hours of tackifier addition) of the film, R2-0.916.

No significant difference was observed from group 4, and it was judged that no mitigating effect was observed even when the thickener was added.

[ Table 40]

Erythritol: group 4 of example 2

At 2 hours after administration, 3 out of 5 had muddy stools, and 5 had all muddy stools after 3 hours. The degree of diarrhea was more severe than when erythritol was administered alone.

FIG. 10 is a scatter diagram and a regression line showing 2 variables of the membrane stretch ratio on the horizontal axis and the area increase ratio on the vertical axis for each animal group on the operation side. No significant difference was observed from group 4, and it was found that no reduction was observed even when a thickener was added alone.

Comparative example 7

[ erythritol, isosorbide and gum ]

Similarly, as shown in table 41, a gum as a thickening agent was added to erythritol or isosorbide as a sugar or sugar alcohol to 10 guinea pigs of 280 to 350g, and the mixture was orally administered, and the shape of feces was observed, and after 3 hours, the mixture was perfused and fixed, and the digestive tract was observed and evaluated.

[ Table 41]

Erythritol: group 4 of example 2

Isosorbide: examples 1-d, comparative example 4

In the group containing erythritol added with the jelly, some animals became soft stools at 2 hours after the administration, and all animals became muddy stools at 3 hours. This is the same severe diarrhea symptom as erythritol alone.

In the group containing isosorbide to which a gum was added, the feces became soft with time, and about half of the animals became muddy stools or soft stools at the 3 rd hour. This diarrhea was almost the same as that of isosorbide alone, and the diarrhea-preventing effect of the jelly was not observed at all in any combination of isosorbide and isosorbide alone.

It was judged that polysaccharides must be added to improve and prevent digestive organ symptoms caused by sugars or sugar alcohols.

[ reference example ]

Histologically, it was investigated whether polysaccharides themselves have an effect of alleviating labyrinthine hydrops. First, 5 guinea pigs were subjected to the left-hand cystotomy, and one month later, normal stools were confirmed and 0.5g/kg of pectin as a polysaccharide was orally administered, and perfusion fixation was performed after 3 hours. The procedure of occlusion surgery, tissue preparation, and the like, and observation and measurement of feces and tissue are performed in the same manner as described above.

Effect of pectin on digestive organs and Midao alleviating Effect

[ Table 42]

[ Table 43]

Elongation of film (%)	Area increase ratio (%)
		36.3±23.3	48.2±29.2

As a result, all 5 stools were normal with a constant interval. Further, the film stretching ratio and the increase rate of the area were plotted in the same manner as in example 2 on a scattergram and a regression line (fig. 11), and compared with the regression line of the control group, no significant difference was observed in the results that 2 lines were substantially overlapped. Thus, it was judged that the polysaccharide itself had no effect of reducing labyrinthine hydrops.

In fig. 11, o: IR-S (control) vs IR-L, ■: IR-S (pectin only) vs IR-L (pectin only). The regression lines are respectively IR-S (control group) ═ 4.011+1.212 × IR-L (control group) column 1, R2 ═ 0.987; IR-S (pectin only) ═ 3.018+1.244 IR-L (pectin only), R2 ═ 0.979.

Example 4

[ reduction in the volume of administered agent ]

When erythritol is administered to an adult (body weight 60kg), the amount is 10 to 80g, preferably 20 to 60g, at a time. When erythritol 21g was administered as a powder, the volume thereof was about 53 ml. Further, if the solution is administered as a saturated aqueous solution, 65ml of distilled water is required, and the volume thereof is 78ml and the weight thereof is 86 g. The gel of the present invention is significantly reduced in volume and weight as described below, as it is very inconvenient for patients with meniere's disease to carry it three times a day.

Formulation example 1

Erythritol 21g

Pectin 3.75g

Distilled water 11.25ml

The gel had a volume of 20.25ml and a weight of 36 g. When the gel is dried and pulverized, the volume of the gel is 33ml, but the gel is portable although the volume is increased. The particle size of the powder obtained by drying and pulverization is shown in table 44. In addition, when the composition is administered, 10ml of water is added again and mixed to obtain a gel with a volume of 23 ml.

Prescription example 2

Erythritol 21g

Xanthan gum 0.25g

Distilled water 3.75ml

The gel had a volume of 20.25ml and a weight of 26.1 g. When the gel was dried and pulverized, the volume thereof became 31.5 ml. The particle size of the dry powder is shown in table 44. Further, the gel obtained by mixing 3ml of water was added again, and the volume thereof was 24 ml.

[ Table 44]

Formulation examples 1 and 2 both changed the formulation to a gel type, whereby erythritol prepared in a saturated aqueous solution had a sharp decrease in volume to about one fourth and a sharp decrease in weight to one third, and both carrying and taking became easy.

While isosorbide preparations generally used in Japan have a volume of 30ml and a weight of 40.5g (the isosorbide content is 21g), the gel of the present invention can be made about two-thirds in volume and weight.

Further, although the unique bitterness and the difficulty of transporting and storing a 500ml (about 700g) bottled liquid are the most inconvenient for the patient in the use of the isosorbide preparation, the gel of the present invention is convenient because it can be carried in the form of powder or granules by the necessary number of administrations because it is dried and pulverized to prepare a powder and it is easy to granulate. In addition, the powder or granule can be rapidly converted into a gel by adding distilled water, and the gel can be prepared by adding water to a patient as required during administration, thereby facilitating administration.

Claims

1. A therapeutic agent for Meniere's disease, which comprises (a) at least one member selected from the group consisting of glycerol, erythritol, xylitol, xylose, sorbitol, isosorbide, maltitol and mannitol, and (b) at least one member selected from the group consisting of pectin, xanthan gum, guar gum, gum arabic, sodium alginate, sodium carboxymethylcellulose, hydroxypropylcellulose and agar, wherein the amount of component (b) is more than 10 parts by weight and not more than 40 parts by weight per 100 parts by weight of component (a).

2. The therapeutic agent for meniere's disease according to claim 1, wherein component (a) is erythritol, xylitol or isosorbide.

3. The therapeutic agent for meniere's disease according to claim 1, wherein the component (a) is isosorbide.

4. The therapeutic agent for meniere's disease according to claim 1, wherein component (b) is pectin and/or xanthan gum.

5. The therapeutic agent for Meniere's disease according to any one of claims 1 to 4, which is in the form of a gel preparation.

6. The therapeutic agent for Meniere's disease according to claim 5, wherein the amount of water is 10 to 55% by weight based on the total amount of the components (a) and (b).

7. The therapeutic agent for Meniere's disease according to any one of claims 1 to 4, which is in the form of a powder preparation.

8. The therapeutic agent for Meniere's disease according to any one of claims 1 to 4, which is in the form of a granular preparation.

9. A method for producing a gel-form treatment agent for Meniere's disease, comprising the steps of: and a step of adding water to 100 parts by weight of (a) at least one member selected from the group consisting of glycerol, erythritol, xylitol, xylose, sorbitol, isosorbide, maltitol, and mannitol, and (b) at least one member selected from the group consisting of pectin, xanthan gum, guar gum, gum arabic, sodium alginate, sodium carboxymethylcellulose, hydroxypropylcellulose, and agar in an amount of more than 10 parts by weight and not more than 40 parts by weight, and mixing the components, wherein the amount of water added is 10 to 55 parts by weight based on 100 parts by weight of the total amount of the components (a) and (b).

10. A method for producing a powdery Meniere disease treatment agent, comprising the steps of: adding water to 100 parts by weight of (a) at least one member selected from the group consisting of glycerol, erythritol, xylitol, xylose, sorbitol, isosorbide, maltitol, and mannitol, and (b) more than 10 parts by weight and not more than 40 parts by weight of at least one member selected from the group consisting of pectin, xanthan gum, guar gum, gum arabic, sodium alginate, sodium carboxymethylcellulose, hydroxypropylcellulose, and agar, wherein the amount of water added is 10 to 55 parts by weight relative to 100 parts by weight of the total amount of the components (a) and (b); and a step of drying and pulverizing the gel thus obtained.

11. A method for producing a particle-form meniere disease treatment agent, comprising the steps of: adding water to 100 parts by weight of (a) at least one member selected from the group consisting of glycerol, erythritol, xylitol, xylose, sorbitol, isosorbide, maltitol, and mannitol, and (b) more than 10 parts by weight and not more than 40 parts by weight of at least one member selected from the group consisting of pectin, xanthan gum, guar gum, gum arabic, sodium alginate, sodium carboxymethylcellulose, hydroxypropylcellulose, and agar, wherein the amount of water added is 10 to 55 parts by weight relative to 100 parts by weight of the total amount of the components (a) and (b); drying and pulverizing the gel thus obtained; and granulating the powder thus obtained.

12. The use of (a) at least one member selected from the group consisting of glycerol, erythritol, xylitol, xylose, sorbitol, isosorbide, maltitol, and mannitol, and (b) at least one member selected from the group consisting of pectin, xanthan gum, guar gum, gum arabic, sodium alginate, sodium carboxymethylcellulose, hydroxypropyl cellulose, and agar, for the production of a meniere's disease treatment agent, wherein the proportion of the component (b) is more than 10 parts by weight and not more than 40 parts by weight relative to 100 parts by weight of the component (a).