JP2011032288A - Remedy for meniere's disease - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide remedies for Meniere's disease safely, surely and quickly expressing the drug effect and suitable for long-term administration, to solve problems that the existing remedies for Meniere's disease containing a sugar or a sugar alcohol as active ingredients suffer from problems such as requiring a large dose, reduction of the amount of administration is difficult, requiring a long time before the expression of the drug effect, being unsuitable for long-term administration and so on, by clarifying the reasons for these problems and reducing amount of administration. <P>SOLUTION: The effects of sugars or sugar alcohols serving as the principal agent on internal ears have been monitored in both of the operated side and the normal side. As a result, it has been confirmed that a rise in the osmotic pressure of plasma and an increase in plasma AVP can be prevented and the effect of reducing endolymphatic hydrops can be safely expressed without fail by reducing the dose of the principal agent. Eliminating additives not directly related to the treatment as much as possible, prevents a rise in the osmotic pressure of plasma and an increase in plasma AVP caused by the additives, the sure expression of the effect of the principal agent can be successfully established even by using the principal agent only in a small amount. The side effect expression of the principal agent has been prevented by reducing the amount of the principal agent. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

The present invention is a Meniere's disease therapeutic drug containing a monosaccharide or a sugar alcohol thereof, and exhibits a reliable endolymphedema reduction effect by reducing the amount of the main monosaccharide or the sugar alcohol. In addition, the present invention relates to a therapeutic agent for Meniere's disease that suppresses systemic and local side effects due to large-scale administration of a main drug.

Although the etiology of Meniere's disease is still unknown, it is widely known that the pathological condition is endolymphatic edema from the results of histological examination of autopsy cases of Meniere's disease patients (Non-patent Document 1). This endolymphatic edema is formed by the accumulation of endolymph fluid due to abnormalities in water metabolism in the inner ear, such as excessive production of endolymph fluid and absorption disorders, and characteristic symptoms of Meniere's disease such as tinnitus, hearing loss, dizziness, and ear closure Is expressed. Therefore, it is considered that reducing the endolymphedema is the goal of Meniere's disease treatment (Non-patent Document 2).

Historically, sugars such as urea and osmotic diuretics such as glycerol and mannitol have been used as therapeutic agents for Meniere's disease to reduce endolymphatic edema. Many of sugars and sugar alcohols have been used as osmotic diuretics and osmotic pressure reducing agents because they exhibit an osmotic effect after administration. Examples of drugs having a dehydrating action due to an osmotic pressure effect include sorbitol and mannitol having a laxative action, mannitol and glyceol as osmotic diuretics. In the treatment of Meniere's disease whose pathological condition is endolymphatic edema, it was considered that this dehydration can reduce edema. That is, since these drugs produce an osmotic pressure gradient in the internal and external lymph after oral administration, the volume of the internal lymph space is reduced, and it is thought that the internal lymph space collapse effect or the internal lymphedema reduction effect occurs. is there.

However, even though many trials and errors have been made to use sugar alcohols for the treatment so far, no results have been obtained for clinical application (Non-Patent Documents 3, 4, 5). ).

Since the 1990s, the presence of water channels has been confirmed in each organ one after another. In the inner ear having a tissue structure relatively similar to that of the kidney, research on elucidation of the mechanism of inner ear fluid production and absorption has progressed, and the presence of aquaporin (water channel protein) has also been confirmed in the inner ear (Non-patent Document 6). ). In recent years, an arginine vasopressin-aquaporin 2 system has attracted attention as one of the water metabolisms of the inner ear (Non-patent Document 7). However, when OPC31260, a vasopressin type 2 receptor antagonist, was systemically administered, the effect of reducing endolymphedema as expected was not observed, and conversely, endolymphedema was formed in the normal ear. It was found that this was due to dehydration due to strong diuretic action (Non-patent Document 8).

Clinically, in patients with Meniere's disease, an increase in the antidiuretic hormone (ADH) arginine vasopressin (hereinafter AVP) has been reported in the acute phase (Non-patent Document 9). AVP is one of the stress hormones, and this result agrees well with the epidemiological fact that Meniere's disease is likely to develop during stress. Further, when AVP 1 mu / kg / min was continuously administered to the guinea pig under normal Pryel reflex with a minipump, clear endolymphatic edema was formed (Non-patent Document 10). As shown in Table 1, plasma AVP increased in proportion to the intradermal dose of AVP, and histologically the area of the endolymphatic space increased (formation of endolymphatic hydrops). In the case of continuous administration of AVP 1 mu / kg, serum AVP increased to several times that of normal human plasma AVP (approximately the same value as serum AVP in the acute phase of Meniere's disease), and became extremely dangerous (Non-Patent Document 10).

Considering the fact that by increasing plasma AVP as described above, endolymphatic edema also occurred in the normal inner ear, in patients with Meniere's disease with some predisposition such as impaired absorption of endolymph fluid, Special attention must be paid so that AVP does not increase due to dehydration or the like.

As can be inferred from the fact that sugar or sugar alcohol was originally used as an osmotic pressure reducing agent, sugar or sugar alcohol produces an osmotic gradient in the digestive tract when orally administered in large quantities at once, causing gastrointestinal tracts such as diarrhea. Severe diarrhea occurs that is symptomatic and in which common gastrointestinal drugs are ineffective. In this case, it has been reported that dehydration continues, and the antidiuretic hormone AVP increases 10 to 15 times (Non-patent Document 11). As described above, since an increase in AVP forms endolymphatic edema, it is considered that the effect of reducing endolymphatic edema is offset by dehydration secondary to diarrhea unless the sugar or sugar alcohol is successfully stopped. Therefore, when sugar or sugar alcohol is used for the treatment of Meniere's disease, extreme caution is required so as not to cause digestive symptoms such as diarrhea.

Patent Document 1 describes a Meniere's disease therapeutic agent containing erythritol, which is a monosaccharide alcohol, as an active ingredient. Since the inventors have reported that transient severe diarrhea has occurred due to ingestion of a large amount of sports drink with erythritol added, it is impossible to expect a therapeutic effect without stopping antistasis. Thought.

As a result of research, it has been found that, when not only erythritol but also many sugars or sugar alcohols are administered in a large amount in a simple manner, the effect of reducing endolymphedema due to its armpit action is not exhibited (Patent Documents 2, 3, 4) . By adding polysaccharides to sugar or sugar alcohol, it was possible to achieve the prevention of sugar or sugar alcohol, thereby preventing the rapid increase in plasma AVP and succeeding in reducing the load of endolymphatic hydrops It was confirmed. When a polysaccharide was added to a monosaccharide or its alcohols, the action was manifested 3 hours after administration, and a therapeutic drug for Meniere's disease was rapidly developed (Patent Documents 2, 3, and 4).

Furthermore, sugars or sugar alcohols also act as osmotic diuretics and promote dehydration, resulting in an increase in AVP. The kidney has a structure very similar to that of the inner ear, and there are almost common aquaporins among 10 or more types of aquaporins, which are responsible for water metabolism (Non-patent Document 12). Therefore, if the sugar or sugar alcohol is allowed to act only on the inner ear, it cannot be considered other than local administration such as injecting the drug directly into the inner ear by surgery or continuous infusion. Although systemic administration by internal use is preferred for patients, at present, there is no way to accurately block only the diuretic effect, so complete antistasis is important.

Each sugar or sugar alcohol has a known maximum no-effect level (ED _{50 for} diarrhea), is in the range of 0.2 to 0.5 g / kg, and diarrhea occurs unless this is exceeded. It is said that it is difficult. Conventional Meniere's disease medications are taken in large doses (21-30 g at a time) three times a day, which means that you are taking a dose that exceeds the maximum no-effect amount every time for treatment. means. It is desired to reduce the dose and develop a certain therapeutic effect.

However, not only in the case of Meniere's disease treatment, but also in the case of using sugar or sugar alcohol as a medicine, a large dose is required. Sugar or sugar alcohol moves into the blood, reaches the site of action, develops an osmotic effect, and is excreted in the urine as it is without being affected by drug metabolizing enzymes. In order to develop the osmotic effect necessary for treatment, it has been necessary to take a large amount of sugar or sugar alcohol. With large doses, side effects are also a concern, but monosaccharides or their alcohols differ in their digestion and absorption due to their molecular size, chemical and biological properties. It is not uniform.

For example, glycerol, which is a sugar alcohol having 3 carbon atoms, reaches the site of action quickly, and an endolymphatic unloading action occurs about 2 hours after administration, but a rebound phenomenon (endolymphedema formation) occurs after about 6 hours. ) Occurs and a therapeutic effect cannot be expected (Non-patent Document 4). This phenomenon was confirmed histologically in animal experiments (Non-patent Document 5). It is also known that liver damage occurs as a systemic side effect.

About 90% of erythritol, a sugar alcohol having 4 carbon atoms, is absorbed in the small intestine and excreted in the urine without being metabolized. The remaining 10% moves to the large intestine, but it is reported that the microorganisms of the large intestine cannot be fermented and are excreted as they are (Non-patent Document 14). Not being metabolized not only by the human body but also by intestinal microorganisms is preferable in terms of “non-calorie” (maximum calorie 0.2 Kcal / g), but when taken in large quantities, undegraded sugar is 10% of the total amount However, it will cause severe diarrhea. However, if the suspension was successful by adding polysaccharides, a load-reducing effect was produced in 2 to 3 hours after administration (Patent Document 2). The site of action appears to be the second fastest after glycerol. Furthermore, other gastrointestinal symptoms such as bloating did not occur, and there was no rebound phenomenon. (Patent Document 2).

Many sugars or sugar alcohols have excellent sweetness, and if used as an alternative sweetener for sucrose, there is almost no generation of organic acids by bacteria and enzymes in the oral cavity, so there is no cause of dental caries and anti-corrosion The effect (and caries prevention effect) can be expected. Among these, xylitol having 5 carbon atoms has excellent sweetness and has been reported to directly prevent touching, but liver damage has been reported in animals such as dogs (Non-patent Document 15).

Currently, the sugar alcohol currently clinically applied in Japan as a treatment for Meniere's disease is isosorbide (1,2: 3,6-dianhydro-D-sorbitol), which is a sugar alcohol having 6 carbon atoms. Therefore, there is a site with a short molecular diameter, which is considered to easily penetrate the biological membrane. Compared to mannitol, sorbitol, etc. having the same carbon number of 6, it is considered preferable for the expression of the unloading action (Non-patent Document 13).

Isosorbitol has a comparatively weak armpit action and no serious side effects have been reported, but it has a unique bitterness. The isosorbitol preparation (manufactured by Kowa Pharmaceutical Co., Ltd .: generic name isosorbide) is an aqueous solution having an isosorbitol content of 70%. One dose is 30 ml or more, and it is necessary to take three times a day. Since the dose is large, many patients find it difficult to take and there are cases where the dose is interrupted. Sweet ingredients and flavors have been added to relieve bitterness, but the taste has not always been improved.

One of the more serious problems with isosorbitol preparations is that it takes about 6 hours after oral administration until onset of action. This phenomenon was confirmed by animal experiments (Non-patent Document 13). Glycerol, which is a trisaccharide, takes about 2 hours to achieve its effect (Non-patent Document 5), and erythritol, which is a monosaccharide, is effective in 3 hours if it is successfully stopped (Patent Document 2). It takes a long time until the action is manifested. The reason for this cannot be explained by the molecular diameter or the armpit action.

Since the unloading action is due to the osmotic action, the strength of the action is proportional to the number of moles of the drug to be administered, but it is necessary to reach the action site for the onset of action. The molecular diameter and molecular structure of the sugar alcohol must be taken into consideration. In addition, the risk of side effects increases with large doses of sugar or sugar alcohol, so the properties must be examined in detail when selecting. In addition, the additives must be noted.

In addition, a more fundamental problem is that long-term continuous use is dangerous because the plasma AVP continues to rise if it is taken for a long time (Non-patent Document 16).

Therefore, we investigated why the conventional isosorbitol preparation takes a long time until onset of action and if plasma AVP is elevated even if it is taken for a long time, the problem is improved. Thus, an attempt was made to develop a drug that produces an effect more quickly and has no rebound phenomenon.
JP-A-11-180863 Japanese Patent No. 3947796 Japanese Patent Application No. 2007-127390 (Japanese Patent No. 4081131) Switching Ichiro, Otolaryngology Atsushi Komatsuzaki, Client 21, Angelborg C. et al: Hyperosmotic Solutions and hearing in Meniere's disease. Am J Otol. 3: 200-2 (1982) Matsubara H et al: Rebound phenomenon in glycerol test. Acta Otolaryngol Suppl. 419: 115-22 (1984) Takeda T et al: The rebound phenomenon of glycerol-induced changes in the endolymphatic space. Acta Otolaryngol 119: 341-4 (1999) Sawada S et al: Aquaporin-1 (AQP1) is expressed in the stria vascularis of rat cochlea. Hearing Res. 181: 15-9 (2003) Sawada S et al: Aquaporin-2 regulation by vasopressin in the rat inner ear.Neuroreport 13: 1127-9 (2002) Takeda T: The effects of V2 antagonist (OPC-31260) on endolymphatic hydrops. Hear Res. 183: 9-18, (2003) Takeda T et el: Antidiuretic hormone (ADH) and endolymphatic hydrops. Acta Otolaryngol Suppl 519: 219-22, (1995) Takeda T et al: Endolymphatic hydrops induced by chronic administration of vasopressin.Hear Res. 140: 1-6, (2000) Safwate A et al: Renin-aldosterone system and arginine vasopressin in diarrhoeic calves. Br Vet J 147: 533-7, (1991) Kwon TH, Nielsen S. et al .: Physiology and pathophysiology of renal aquaporins.Semin Nephrol 21: 231-8, (2001) Kakigi A et al: Time course of dehydratic effects of isosorbide on experimentally induced endolymphatic hydrops in guinea pigs. ORL J Otorhinolaryngol Relat Spec 66: 291-296 (2004) Arrigoni E, Human gut microbiota does not ferment erythritol. Br J Nutr 2005 Nov; 94 (5): 643-6. Dunayer EK, Gwaltney-Brant SM.Acute hepatic failure and coagulopathy associated with xylitol ingestion in eight dogs.J Am Vet Med Assoc.229 (7): 1113-7. (2006). Kakigi A et al: Antidiuretic hormone and osmolality in isosorbide therapy and glycerol test. ORL J Otorhinolaryngol Relat Spec. 68: 279-82. (2006) Robertson GL et al: The osmoregulation of vasopressin. Kidney International 10: 25-37. (1976) Wise B L. et al: The effects of isosorbide on serum and cerebrospinal fluid osmolality and on the spinal fluid pressure in man. J Neuro-surg. 28: 124-8 (1968).

Conventional Meniere's disease therapeutic agents containing saccharides or sugar alcohols as active ingredients are those that require a long time to develop a reduction effect and rebound phenomena. Therefore, the first problem to be solved by the present invention is to find out the reason why a conventional therapeutic agent requires a long time until the onset of action and to improve it.

Conventional Meniere's disease drugs are taken in large amounts (21-30 g at a time) three times a day, so that they are not only difficult to take, but also the maximum ineffective amount of sugar or sugar alcohol (ED _{50 for} diarrhea) ) Is administered for treatment each time. Furthermore, since it is orally administered for about 2 weeks, there is a risk of side effects inherent to sugar or sugar alcohol. If a large dose is continued for a long time, the plasma osmotic pressure and the high value of plasma AVP continue, and the treatment goes against the treatment.

The inventor of the present application has succeeded in expressing the edema-reducing action of sugar or sugar alcohol by adding polysaccharide (Patent Document 2). It was also found that there was a difference in degree depending on the sugar alcohol. Patients are likely to have a predisposition to onset, such as impaired absorption of endolymph fluid, and it is considered undesirable that the volume of the endolymphatic cavity on the healthy side changes greatly due to the strong action of sugar alcohols. Therefore, the second problem to be solved by the present invention is to reduce the dose as much as possible in consideration of the properties of each sugar or sugar alcohol, so that it is safe, but surely and quickly. The purpose is to develop a treatment for Meniere's disease that has an effect and is suitable for long-term administration.

As a result of intensive studies to solve the above-mentioned problems, the present inventor found out that conventional Meniere's disease therapeutic agents easily incorporated additives such as solubilizing agents and sweeteners ([Example 1-1). ]). It has been discovered that a conventional drug containing an additive produces a degrading effect on the edema side, but produces endolymphatic edema while being mild on the normal side ([Example 1-4]).

Next, when isosorbitol alone was administered, edema formation on the normal side was mild, and no collapse effect (effect leading to a therapeutic effect) was observed ([Example 1-2]). The inventor considered that there is a possibility that the dose of isosorbitol may be small, and when it was administered in a large amount 3 to 6 times, edema of the same level as the conventional isosorbitol formulation was formed, and the large dose was counterproductive. It was found ([Example 1-3]).

The present inventor considered this reason as follows. That is, when the drug moves into the blood, the plasma osmotic pressure rises and the plasma AVP rises in conjunction (Non-patent Documents 17 and 18). It is preferable to reduce as much as possible the sugar or sugar alcohol that has osmotic action and causes diarrhea and diuresis. Furthermore, as with the main drug, the additive also increases plasma AVP when it enters the blood. Therefore, it has been found that additives that are not effective in treating Meniere's disease should be kept to a minimum while simultaneously reducing the active ingredient as much as possible.

That is, the present invention is as follows.
(1) A therapeutic agent for Meniere's disease, characterized by being used so that 0.1 to 0.75 g / kg body weight of erythritol or isosorbitol sugar alcohol is orally administered per day for an adult.

In the present invention, examples of the sugar or alcohol (hereinafter also referred to as “sugar alcohols”) include monosaccharides such as glycerol, erythritol, xylitol, xylose, sorbitol, isosorbitol, mannitol, or sugar alcohols thereof.

The dose of the drug must be adjusted appropriately according to individual differences, the severity of the medical condition, etc. Even if the dose is reduced, it is frequently observed that the same or equivalent effect can be obtained. It is to encounter. However, the meaning of reducing the dose in the present invention is different from the so-called “doctor's scoop”. The essence of the present invention is that the therapeutic effect is not sufficiently exhibited if the amount of the administered drug is as it is, and the therapeutic effect is surely enhanced only after the dose is reduced. This is because we have developed a therapeutic drug that can solve various problems caused by.

First, by reducing the dose, we succeeded in preventing the expression of osmotic pressure peculiar to sugar alcohols. Administration of large amounts of sugar alcohols exceeding the maximum no-acting dose has been shown to result in dehydration due to diarrhea, raising plasma AVP and countering the therapeutic effect of Meniere's disease. Although it has succeeded in achieving antiprurisy by adding polysaccharides (Patent Document 2), there is no doubt that a drastic reduction in dosage is most effective.

Furthermore, when the sugar alcohols and additives are transferred into the blood, the plasma osmotic pressure increases, and the plasma AVP increases in proportion to this. By reducing the total dose, the plasma osmotic pressure, the plasma AVP are increased. The prevention of the increase in the blood pressure was realized, which improved the therapeutic effect in the inner ear. In addition, because the effect on the healthy (normal) side is small, we have succeeded in developing a locally safe treatment. Not only local but also reduction of dosage is more preferable to prevent systemic side effects of sugar alcohol itself, and succeeded in developing a safe therapeutic agent systemically.

Moreover, reduction of dosage has been an essential proposition for many years, and the present invention has solved it. It has been said that large doses of drugs are required to produce an osmotic effect in the inner ear. Therefore, sugar alcohols have been listed as candidates because they are less toxic even if administered in a large amount and are not digested and decomposed in the digestive tract, and the dosage is 21-30 g, as shown in [0025]. The bulk is 50-70 ml in the form of a powder, and it is almost the same even in liquid, and reduction of oral dose has been a long-standing problem. The present inventor succeeded in reducing the bulk by adding polysaccharide (Patent Document 2), but was able to reduce the bulk most effectively by greatly reducing the dose.

The essence of the present invention is not the development of a drug that exhibits a therapeutic effect even if the dose is reduced, but it has been discovered that reducing the dose is essential for the sure therapeutic effect. The development of therapeutic drugs.

The dose of sugar alcohols depends on the disease state, but is 0.15 to 0.75 g / kg or less per day for an adult, preferably 0.15 to 0.6 g / kg, more preferably 0.15 to 0.5 g. / Kg, more preferably 0.15 to 0.4 g / kg, 0.15 to 0.35 g / kg, which are administered 1 to several times, for example, in 3 divided doses. Or, a preparation containing 3 to 15 g per dosage unit, preferably 3 to 12 g, more preferably 3 to 10 g, more preferably 3 to 8 g, 3 to 7 g. And

Hereinafter, the present invention will be described in detail with reference to Examples and Reference Examples, but the present invention is not limited thereto. Considering the social circumstances where animal welfare is screamed, we devised to avoid fixing (and killing) a large number of animals. In addition, the animals to which sugar alcohols or sugar alcohols were mixed with polysaccharides were used only once.

Criteria for determining the state of stool (ie, hardness, shape, and interval between stool in the intestines) are as shown in Table 2.

  The hardness and properties of the stool of the group administered with distilled water for 3 days or more are “normal stool”: as evaluation point 3, as shown in 1) of Table 2, “slightly soft stool”: evaluation point 2, “soft stool”: evaluation Point 1, “mud stool”: score 0. In the case of guinea pigs, there is no watery stool due to the shape of the feed. Mud stool corresponds to watery stool in humans, and guinea pig soft stool corresponds to that including mud stool and soft stool in humans.

Comparing detailed observation inside the digestive tract by laparotomy and observation of feces excreted outside the body, it was found that gastrointestinal symptoms such as diarrhea cannot be determined only by observation of stool firmness. Therefore, in addition to stool firmness, the amount, shape, size, surface smoothness, etc. are evaluated, and by abdominal inspection and finger palpation, abdominal fullness and gas generation, gas movement, and lower abdomen We examined in detail and evaluated whether it would be easy to defecate by applying pressure.

The therapeutic agent currently used clinically in Japan is isosorbitol (manufactured by Kowa Pharmaceutical Co., Ltd .: generic name isosorbide), and according to the labeling, the isosorbitol content is an aqueous solution of 70%. This single dose is 30 ml and the content of isosorbitol is 21 g. In order to dissolve isosorbitol stably in this solution, a solubilizing agent and a stabilizer are added, and a sweetener, a flavor and the like are added to adjust the taste to be easily taken.

The effects of isosorbide preparation (hereinafter also referred to as IB conventional product, <IB>) and IB plain aqueous solution on endolymph volume were examined and compared.

[1-1: IB Conventional Formulation Additives]
In order to dissolve 21 g of isosorbitol in distilled water and dissolve it stably, a necessary amount of xanthan gum was added to make 30 ml. The weight of this aqueous solution was compared with the weight of <IB>.
Formula 1
Isosorbitol 21g
Xanthan gum 0.15g
Distilled water
30ml

The weight of the aqueous solution of Formulation 1 was 34.74 g, while the weight of <IB> 30 ml was 36.67 g. The weight of the additive was found to be 2.08 g (about 9.9 wt%). Sugar alcohols are absorbed from the digestive tract and move into the blood. As a result, plasma osmotic pressure increases, and plasma AVP increases almost in proportion to the increase (Non-patent Document 17). Additives also exert plasma osmotic pressure increasing effects, so it is desirable to minimize the amount, but <IB> was selected after careful examination of the additives, and the amount of addition required It is doubtful whether it is the minimum.

The problems of <IB> were examined in detail, and the influence of the additive on the endolymphedema reduction effect, which was the original purpose, was also investigated. After administration of sugar alcohols such as isosorbitol, gastrointestinal symptoms are examined during perfusion fixation, and the state of the large intestine, colon, and rectum is closely examined. Two points were specifically observed: the formed length, the interval between stools, and the arrangement state.

After fixation by perfusion, the temporal bone was removed, decalcified with trichloroacetic acid, dehydrated with an alcohol series, and double-embedded with paraffin and celloidin. Cochlear shaft slices obtained by slicing were stained with hematoxylin and eosin, observed with a light microscope mainly on the normal side (right side), and observed and measured changes in the length of the Lysnel membrane and the area of the endolymphatic cavity. went. For each rotation, the extension of the Risnel membrane and the volume change of the endolymphatic space were measured, and the results were integrated by the following formula to determine the membrane stretch rate and the endolymphatic sac area increase rate for each cochlea. On the left side of the normal side, the endolymphatic collapse effect was evaluated from the volume change of the endolymphatic space. Details of the tissue preparation method, measurement method, and evaluation method are the same as in Non-Patent Document 4 (Takeda T et al: Acta Otolaryngol 119: 341-4 (1999)).

[1-2: When only isosorbitol (IB) is administered]
50 guinea pigs were divided into 6 groups, and each group was administered drugs as shown below. The dose of IB was 2.8 g / kg (Non-patent Document 13), which is an effective amount for reducing the load on experimental endolymphatic hydrops. This is thought to correspond to 21-30 g / dose administered to Meniere's disease patients. The aqueous solution was adjusted so that the single dose was 8 ml / kg.
Group Administered drug Perfusion (after administration)
Group 1: Control group Distilled water 3 hours later Group 2: IB2H group IB 2.8 g / kg 2 hours later Group 3: IB3H group 3 hours later Group 4: IB4H group 4 hours later Group 5: IB6H Group 6 hours later Group 6: IB12H group 12 hours later

A) Examination of gastrointestinal symptoms Table 3 shows the results.

The firmness of the stool was evaluated by observing the stool discharged at the time of perfusion and the stool of the rectum. All control groups were normal stool. In the IB2H group, normal stool was formed in the vicinity of the rectum, but gradually shifted to soft stool (stiffness of the stool, the sequence was P <0.01, P <0.001, Mann-Whitney U test, respectively) . The size was irregular and the intervals were inconsistent, and unpleasant gastrointestinal symptoms were estimated. Diarrhea became severe after 3, 4 and 6 hours (P <0.01, P <0.001, P <0.01, Mann-Whitney U test, respectively), and the stool sequence became irregular ( All are P <0.001, Mann-Whitney U test). Gas generation was observed at the site where the stool interval was widened by puncture into the intestinal tract. In the IB12H group, almost normal stool was formed in all animals.

From the above, it was found that diarrhea and gastrointestinal symptoms due to IB administration became serious in 2 to 4 hours and continued after 6 hours, but returned to normal after 12 hours.

B) Effects on endolymphatic volume (relationship between membrane extension and area increase on the normal side)
Table 4 shows the average ± standard deviation of the membrane extension rate (IR-L) and the area increase rate (IR-S) on the normal side of each group, and they were compared.

Two hours after administration, endolymphatic edema was formed, and the rate of increase exceeded about 12% was 7 out of 8 (P <0.001, t-test). However, after 3 hours, there were 3 animals comparable to the control group, 3 animals with 5-8% collapse (decrease in volume), 2 animals with a volume increase rate of about 14%, There were large variations in the volume of the endolymphatic space. As a result, there was no significant difference from the control group, but the volume was significantly reduced compared to the second group (P <0.01, t-test, respectively), and the effect of reducing the load by IB was manifested. I can say that. After 4 hours, the mean endolymphatic volume increased again, but there was no significant difference compared to the control group. A similar situation continued until 12 hours later. On the other hand, the Risnel membrane significantly extended at 2 hours and 4 hours (P <0.05).

When IB plain is taken at 2 g / kg (50% aqueous solution), serum osmotic pressure starts to increase immediately after the oral administration, then increases by 17 to 30 mOsm / liter after 40 to 90 minutes, reaches a peak, and takes about 6 to 7 hours. (Non-patent Document 18). Similarly, Becker (Becker B: Isosorbide: An oral hyperosmotic agent. Arch. Ophthalmol. 78: 147-50.) Reports an increase of 19-30 mOsm / liter 1 to 2 hours after oral administration. Considering Non-Patent Document 17 and Table 1 (Non-Patent Document 10), the increase is sufficient to form obvious edema. On the other hand, the increase in cerebral spinal fluid (hereinafter referred to as CSF) osmotic pressure is the result of observation in only 3 cases, but it starts to increase after 1-2 hours and remains high after 4 hours (Non-patent Document 18).

As shown in Table 4, the formation of endolymphatic edema 2 hours after oral administration is considered to be due to an increase in plasma AVP in synchronization with plasma osmotic pressure. In addition, the inner ear structure has a barrier similar to the blood-brain barrier, but considering that the osmotic pressure of CFS starts to increase after 2 hours after administration, and the size of the molecule, the inner ear is not later than 3 hours. It can be said that the lymphoid collapse effect appears.

[1-3: When a large amount of isosorbitol (IB) is administered]
Since glycerol decreases (collapses) the volume of the normal endolymphatic space after 2 hours (Non-patent Document 5), there is a possibility that the dose reduction of isosorbitol is not sufficient, so that the sufficient load-reducing effect is not exhibited. I thought it was. Therefore, the amount of IB was increased to 8.5 g / kg (dose in Non-Patent Document 5) equivalent to glycerol used for glycerol test, and further doubled to 17 g / kg, and digestive symptoms and normal side were increased. The volume change of the endolymphatic space was observed. The results are shown in Tables 5 and 6.

IB *: 8.5 g / kg isosorbitol
IB **: 17.0 g / kg isosorbitol

Increasing the amount of IB resulted in severe diarrhea in soft stools and mud stools in about half of the animals, and irregular stool intervals (P <0.001, Mann-Whitney U test) ). Symptoms became severe in proportion to the dose of IB. Gas accumulation was also observed in the intestine. Endolymphedema became prominent compared to the distilled water administration group and the IB normal dose administration group (Group 3) (P <0.001, t-test). It was speculated that this was the result of an increase in plasma osmotic pressure, and it was obvious that a dose reduction was necessary to ensure safety.

[1-4: When conventional isosorbitol is administered]
40 guinea pigs having normal stool were divided into 4 groups, and <IB> was administered to groups 10 to 13 so that the IB was 2.8 g / kg. At time 6 and 6 (<IB> 6 hours after the maximum reduction effect (Non-Patent Document 13), perfusion was fixed at 12 hours, and tissues were collected to observe the endolymph reduction effect. Gastrointestinal symptoms continued until the time of perfusion, stool firmness was the same as at the time of perfusion, and each group was prepared so that a single dose was 8 ml / kg.

Group Administered drug Perfusion (after administration)
Group 10: <IB> Group 3H Containing 2.8 g / kg of isosorbitol 3 hours later Group 11: <IB> Group 4H After 4 hours Group 12: <IB> Group 6H Group 6 hours after Group 13: <IB> 12H group 12 hours later

A) Examination of gastrointestinal symptoms Table 7 shows the observation results of the hardness and shape of the stool.

In the <IB> administration group, stool began to soften after 2 hours, diarrhea symptoms were worst 3 to 4 hours later (Groups 10 and 11), and somewhat improved after 6 hours (Group 12). In both groups, diarrhea symptoms were significantly worse than the control group administered with distilled water (P <0.01, Mann-Whitney U test), and compared to the IB plain group (Groups 2 to 5). No significant difference was observed (Mann-Whitney U test. In group 12 (<IB> 6H group), the length of stool formed was 60.2 ± 15.8 cm, but 9 out of 10 animals. The stool interval is scattered or mud, and there are some places where the interval of about 20 to 40 cm is open, and gas is generated in the intestinal tract, so it is estimated that considerable gastrointestinal symptoms appeared. Compared with the control group, a significant difference was observed in the 10th to 12th groups (P <0.001, Mann-Whitney U test), showing that gastrointestinal symptoms such as diarrhea had appeared. The fact is that digestive organs such as diarrhea, bloating, and groovy feeling that patients sometimes complain of after <IB> administration After 12 hours, the stool firmness returned to normal, but only 2 out of 10 animals returned to a constant interval, which was significantly different from the first group. (P <0.001, Mann-Whitney U test) However, recovery was observed compared with 3 hours after the most severe symptoms (P <0.01, Mann-Whitney U test).

B) Volume change of endolymphatic space
Relationship between the rate of membrane extension and the rate of area increase on the normal side The extension of the Risnel membrane and the volume change of the endolymphatic space were measured for each rotation, and the results are shown in Table 8.

Group 10 (<IB> 3 hours later) was not significantly different from the control group, but endolymphatic edema was formed after 4 hours and 6 hours. Group 10 had a significantly increased volume of endolymphatic space (P <0.05) compared to Group 3 that received IB alone. At 4 hours (Group 11), the tendency of increase in endolymphatic volume was further clarified, and there was a significant difference compared with the control group (P <0.05 compared with the control group), and endolymphatic edema was observed. . The Ricenell membrane was significantly extended at 3 and 4 hours (P <0.05).

In [1-2] of [Example 1], IB showed a slight tendency to decrease the volume of the endolymphatic space because of its small armpit action. However, when [1-3] increased IB 3 times or 6 times, the armpit action increased and the endolymphatic volume increased. It is thought that plasma osmotic pressure and plasma AVP were increased by large-scale administration of IB. In addition, when 2.8 g / kg was administered as a simple IB, the volume of the endolymphatic space tended to decrease after 3 hours, but the same amount was administered in the conventional <IB> containing additives. Even after 3 hours, the volume tended to increase ([Example 1-4]).

These facts are the reason why <IB> does not show a collapse effect 3 hours after administration even though diarrhea is mild, and 6 hours until the treatment effect (endolymphedema unloading effect) appears. Patent Document 13) This is considered to be the reason. That is, since the plasma osmotic pressure is further increased by the excessive additive as compared with the case of sugar alcohol alone, the increase in plasma AVP is also large (Non-patent Documents 17 and 18). As a result, the endolymph inherent in sugar alcohols It is considered that the endolymphatic edema was formed by offsetting the effect after 2 to 3 hours when the effect of reducing the cavity volume was most remarkable. Although the additive causes an increase in osmotic pressure, it is considered that the molecule was large and did not express the endolymphatic collapse effect. The volume decreased after 6 hours, probably because the plasma osmotic pressure was restored at 6 hours (Non-patent Document 18). It is thought that the effect of reducing the load is first manifested by the osmotic action of the molecules remaining in the perilymph space after the plasma osmotic pressure and plasma AVP are restored to the normal range.

This has been attributed to unnecessary or unnecessary additives, which have been found to go against treatment. This fact is further verified in [Example 3-2-a]. Although IB has a small armpit action, it exhibits a certain amount of load reduction even if it is simple, but it cannot be said that it has an excellent load reduction action, although the formulated <IB> has a weak IB itself. It turned out that it can never be said that it has succeeded in expressing the unloading effect which it has. Additives should be reduced to the minimum necessary.

When IB was administered in a large amount, the increase in plasma osmotic pressure and plasma AVP became larger, and thus clear endolymphatic edema was formed ([Example 1-3]). For this reason, the dose of sugar alcohols, the main drug, must be reduced as much as possible.

The inventor has found that sugar alcohols other than IB have an excellent load-reducing action if they can be stopped (Patent Document 2). Since these have excellent sweetness, they are easy to take, and do not require additives to adjust the taste. Devised.

In [Example 2] to [Example 8], sugar alcohols are variously changed, and the effect on the volume (normal side) of the endolymphatic space is observed.

Endolymphatic sac closure was performed only on the left side of the guinea pig to create an “experimental endolymphatic hydrops model animal”. The endolymphatic sac was closed by burning the extraosseous portion of the endolymphatic sac with a bipolar electrocoagulator. Ablation of the endolymphatic sac that plays an important role in the absorption of endolymph results in impaired absorption of the endolymph and experimental endolymphatic hydrops. This edema is progressively formed, and its size becomes almost constant after about 2 weeks to 1 month and lasts for several months. The details of the surgical method are the same as in the previous report (Non-Patent Document 8). Endolymphatic volume was measured on both the right side of the normal side and the left side of the surgical side.

In addition, the left side of the first, third, fifth, tenth and twelfth groups of [Example 1] was subjected to endolymphatic sac closure, and the endolymphedema reduction effect was observed and measured.

Endolymphedema reduction effect: The results of the relationship between the rate of membrane extension and the area increase rate on the operation side ([Example 1-2-C], [Example 1-4-C]) are shown in Tables 9 and 9 10 shows.

In the case of IB simple administration ([Example 1-2-C])

In the case of administration of IB conventional preparation ([Example 1-4-4-C])

Although it could be estimated from the normal side, both IB plain and <IB> showed no significant reduction effect after 3 hours, and a reduction effect after 6 hours.

Pectin (Pec) 0.3g / kg was added to IB 2.8g / kg, and it was orally administered to observe digestive tract symptoms. After a predetermined time, perfusion was fixed, and the effect of reducing endolymphedema was observed. (IB + P * group). Furthermore, the dose was observed at half of both IB and Pec (IB + P ** group). The results are shown in Tables 11, 12, and 13 below, and the measurement results on the operation side are shown in FIGS.

Group Administered drug Perfusion (after administration)
Group 14: IB + P * 3H group containing 2.8 g / kg of isosorbitol 15 hours after group 15: IB + P * 6H group 6 hours later Group 16: IB + P ** 3H group 3 hours later 17th group: IB + P * * 6 hours after 6 hours

A) Table 11 shows the results of examination on gastrointestinal symptoms.

By adding Pec, an antipruritic effect was observed after 3 hours and 6 hours regardless of the dose (P <0.05, P <0.01). Fecal arrangement also improved after 6 hours (both P <0.05, P <0.01).

B) Effects on endolymphatic volume (relationship between membrane extension and area increase on the normal side)
Table 12 shows the average ± standard deviation of the membrane extension rate (IR-L) and the area increase rate (IR-S) on the normal side of each group, and comparatively examined.

  On the normal side, mild collapse was observed in all groups, but collapse was not observed in 16 groups with the dose reduced by half. In addition, there were no cases in which clear edema was observed in all groups, and it was confirmed that the edema was safe as compared with IB conventional products.

C) Endolymphedema reduction effect: Table 13, FIG. 1, FIG. 2, and FIG. 3 show the related results of the membrane extension rate and the area increase rate on the operation side.

The degree of formation of experimental edema by occlusion varies widely, from several percent to several hundreds of percent. By comparing the average ± standard deviation of the membrane extension rate and the area increase rate, the IB unloading effect and its change over time It is difficult to consider such things. 1, 2, and 3, the horizontal axis represents the membrane extension rate, and the vertical axis represents the area increase rate, and shows a scatter diagram and regression line of two variables on the operation side for each animal group. When endolymphatic edema occurs, the volume of the endolymphatic space increases and the Lysnel membrane extends. From FIG. 1, it is estimated that there is a statistical first-order correlation between the two in the control group operation side administered with distilled water. When edema is reduced by drug administration, the area of the endolymphatic space is reduced despite the extension of the membrane, and the regression line moves downward. FIG. 1 is for comparing changes over time of IB + Pec (Groups 14 and 15). FIGS. 2 and 3 show a group administered with a normal dose of IB + P and a group administered with IB + Pec in half after 3 hours ( 14th and 16th group), and 6 hours later (15th and 17th group), the change over time in the reduction effect was observed and compared.

On the surgical side of the group to which Pec was added, the effect of reducing the load was observed at 3 hours after administration, and continued even after 6 hours. The significant difference is as shown in Table 13. Even when the dose was halved, a sufficient reduction effect was recognized. Moreover, compared with the corresponding IB simple group, the load reducing action was significantly superior. There is almost no difference in effect even if the dose of IB is reduced, but this is a result of reducing the dose and reducing diuretic and diuretic effects and preventing the increase in plasma osmotic pressure. Conceivable.

D) Subjects and methods for studying the effects on the general condition 16 guinea pigs weighing 280-320 mg and normal stool are divided into 4 groups, and the first group (5 animals) contains only physiological saline. The second group received IB half dose, the third group administered IB 2.8 g / kg + Pec 0.3 g / kg, and the fourth group administered IB + P ** (IB 1.4 g / kg + Pec 0.15 g / kg). Three hours after administration, decapitation and blood collection were performed using guillotine, and plasma AVP and plasma osmotic pressure were measured by the method described in Non-Patent Document 8 in the specification. Table 14 shows the drugs administered and the test results. For reference, plasma AVP and plasma osmotic pressure of the group administered with Ery simple of Example 3 are shown. A single dose of the aqueous solution was adjusted to 8 ml / kg.

The dose, diarrhea, and plasma AVP value were examined. In the group administered with 2.8 g / kg of IB simple substance, the plasma osmotic pressure increased by 30-40 mOsm and the plasma AVP increased by 10-12 pg / ml (both P <0.05, t-test). In the group to which Pec was added (group 14), diarrhea was not observed, plasma osmotic pressure increased by 15 to 40 mOsm, plasma AVP increased by 1.5 to 4 pg / ml, and plasma AVP increased only slightly (IB alone). Significant difference from taste group is P <0.05, t-test). When both IB and Pec were halved, the fecal properties became more favorable and the plasma osmotic pressure increased by 12 to 15 mOsm, but no increase in plasma AVP was observed (no significant difference from the distilled water administration group. Significant difference from group is P <0.05, t-test).

The measurement result of the plasma osmotic pressure is in agreement with the above non-patent document 18. As described in [0059], Non-Patent Document 18 reports that when 2g / kg (50% aqueous solution) of IB plain is taken, it increases by 17 to 30 mOsm / liter after 40 to 90 minutes after taking it. Similarly, Becker reports an increase of 19 to 30 mOsm / liter 1 to 2 hours after oral administration. Considering Non-Patent Document 17 and Table 1 (Non-Patent Document 10), the increase is sufficient to form obvious edema. It is thought that edema formation can also be prevented by stopping the tumor and halving the dose.

In the Ery simple group of Example 3, all animals became muddy stool, and plasma osmotic pressure and plasma AVP were extremely high (Table 19 described later). As shown in Table 14, the plasma osmotic pressure and plasma AVP were significantly lower as described above in the 14th and 15th groups in which Pec was added to IB, and in the 16th and 17th groups in which half doses were administered. . It can be concluded that the normal side does not cause so much edema or collapse, is safe, and is consistent with exerting a reduction effect on the surgical side, and is a preferable therapeutic agent.

Erythritol, a monosaccharide alcohol, was selected as the sugar alcohol, and the effects on the volume of the endolymphatic space and the risk on the general condition were observed and evaluated together with digestive symptoms.

  [Example 3] is divided into three groups. Example 3-1, 50 animals, Example 3-2-a, 20 animals, Example 3-2-b, 50 animals were divided into 3 groups. In Example 3-1, only Ery was administered and administered. Later, changes in stool and gastrointestinal symptoms and the volume of the inner ear and endolymphatic space were examined and compared with the results on the surgical side of Patent Document 2. In Example 3-2-a, a drug obtained by adding pectin (Pec) as a polysaccharide to Ery was orally administered, and the same observation was performed to examine the amount of the endolymphatic cavity collapse effect. It has been found that there is a common correlation between the plasma AVP and the collapse effect in common with the results of Patent Document 2. In Example 3-2-b, it is not preferable that the effect changes with time and further collapse occurs. Therefore, both Ery and Pec are reduced in dosage to one-half to one-fourth, and the effect is observed. And found that collapse is reduced. It was confirmed that a reliable endolymphedema reduction effect was also exhibited on the operation side.

[3-1: When erythritol (Ery) is administered alone]
Sixty guinea pigs were divided into 6 groups of 10 animals in each group, and drugs were administered to each group as shown below. The Ery aqueous solution was adjusted so that the single dose was 8 ml / kg.
Group Administered drug Perfusion (after administration)
Group 1: Control group Distilled water 8 ml / kg 3 hours later Group 18: E1H group Ery 2.8 g / kg 1 hour later Group 19: E2H group 2 hours later Group 20: E3H group 3 hours later 21 Group: E6H group 6 hours later Group 22: E12H group 12 hours later

A) Study on gastrointestinal symptoms Table 15 shows the results.

A) Determination of stool firmness The stool firmness was evaluated by observing the stool discharged at the time of perfusion and the stool of the rectum. All control groups were normal stool. In the E1H and E2H groups, normal stool was formed near the rectum, but gradually shifted to soft stool. The E3H and E6H groups were all muddy stool. In 1 of 5 animals in the E6H group, a slight slight stool was observed in mud stool, but no shape was formed. In the E12H group, stools with almost normal hardness were formed in all animals.

B) The length of the formed stool, the interval between the stool and the arrangement state control group was 55.0 ± 8.8 cm, the size of the stool was constant, and the interval was also constant, but in the E1H group Some of the stools were indeterminate, with irregular sizes and irregular intervals, suggesting the appearance of unpleasant gastrointestinal symptoms. The length of feces formed was 22.8 ± 6.9 cm. In the E2H to E6H groups, there were some parts close to soft stool, but the intestine was almost filled with mud stool, and the formation of stool was 0 cm. In the E12H group 12 hours after administration, stool having an almost uniform shape was formed at 66.0 ± 12.1 cm. The stool interval is usually about 0.7 to 1 cm in the control group and is almost constant. In some animals in the E12H group, there are 8 to 10 cm. Generation of gas was observed by puncture into the intestinal tract.

From the above, it was found that diarrhea caused by Ery administration became serious in 2 to 3 hours and continued after 6 hours, but returned to normal after 12 hours.

B) Effects on endolymphatic volume (relationship between membrane extension and area increase on the normal side)
As shown in Patent Document 2, on the operation side, Ery showed no reduction effect at all. Table 16 shows the average ± standard deviation of the stretch rate (IR-L) and the area increase rate (IR-S) of the normal side membrane, and they were compared and examined. Decalcification, dehydration, embedding, staining, observation with an optical microscope and measurement after perfusion fixation were performed in the same manner as in Example 1.

At 1 hour after Ery administration, the Ricenell membrane stretched, and at 2 hours, obvious endolymphedema was formed and continued until 6 hours, which was significantly different from the control group ( P <0.01, P <0.05, P <0.01, t-test respectively). Some animals had edema after 12 hours, but some returned to normal, and no significant difference was observed.

The reduction effect expected by administration of sugar alcohols was not observed on the operation side when administered as a simple substance (Patent Document 2), and it was found that endolymphedema was formed on the normal side. The reason for this is considered to be an increase in plasma AVP due to dehydration associated with the armpit effect (Non-Patent Document 11) and an increase in plasma AVP accompanying an increase in plasma osmotic pressure (Non-Patent Documents 17 and 18).

[3-2: When pectin (P) is added to erythritol (Ery) and administered]
Twenty guinea pigs were divided into two groups of 10 in each group, each group was administered a drug as shown below, and perfusion was fixed after a certain period of time.

[3-2-a: Observe the difference in effect depending on the amount of pectin (P) added]
Group Administered drug Perfusion (after administration)
Group 23: E + P0.1g group Ery2.8g / kg + P0.1g / kg 3 hours later Group 24: E + P3H group Ery2.8g / kg + P0.5g / kg 3 hours later After perfusion fixation, colon and colon The condition of the rectum, especially the state of stool formation, was observed.

A) Examination of gastrointestinal symptoms The firmness and interval of stool and the length of stool formation were observed in the above two groups. The results are shown in Table 17.

In the E3H group of Example 3-1 (Pec was not added and only Ery was administered, 3 hours later), all 10 animals were muddy feces, but the 23rd group (E + P 0.1 g group: Pec 0.1 g / kg added) ), 10 out of 10 animals were muddy stool and 3 animals were loose stool, and a stool shape of about 2-3 cm from the anus was observed. The remaining two were slightly soft stools and 23 cm and 42 cm stools were formed, but the intervals were indefinite, and there were some places where the intervals were more than 10 cm. The average of 10 animals was 7.3 ± 13.3 cm. In group 24 (E + P3H group: Pec 0.5 g / kg added), 3 animals were mud stool, of the other 7 animals, soft stool, 1 soft stool each, 3 animals were normal firmness, and a stiffening effect was observed (P <0.01, Mann-Whitney U test). However, the interval between these seven stools was indefinite. The average length (10 animals) of stool formed was 19.2 ± 21.7.

B) Effects on endolymphatic volume (relationship between membrane extension and area increase on the normal side)
It was confirmed that the reduction effect of Ery was expressed by adding 0.5 g / kg of Pec to the operation side (Patent Document 2). Therefore, on the normal side, in order to investigate the difference in the volume of the endolymphatic space due to the difference in the amount of Pec added, the average and standard deviation of the membrane extension rate and area change rate of each group were compared. The results are shown in Table 18.

Group 23 (Pec 0.1 g / kg added, about 3.6 wt% added) formed endolymphatic edema (significant difference compared to control group, P <0.05), but Pec In the 24th group to which 0.5 g / kg was added, the volume of the endolymphatic cavity decreased (collapsed) (P <0.05 compared to the control group. P <0.01 compared to the Ery plain 20th group). , T-test).

When the amount of polysaccharide pectin added was 0.1 g / kg, sufficient stasis could not be achieved, and the effect of reducing endolymphedema did not appear (Patent Document 2). Endolymphatic edema was formed on the normal side (P <0.01, t-test). When Pec was added at 0.5 g / kg, the volume of endolymphatic space in 3 out of 8 ears increased by about 10% and edema was formed, but in other cases, 5 ears were reduced by 5-10%. There were also two ears with 15% reduction, and the variation was large, but there was a tendency to collapse (P <0.01, t-test), and it seemed desirable to reduce the dose. Therefore, when the dose was halved, a sufficient effect was obtained ([3-3-3-b]).

C) Subjects and methods for studying the effects on the general condition 20 guinea pigs weighing 280-320 mg and normal stool are divided into 4 groups, the first group is physiological saline only, the second group Was administered Ery alone, the third group was administered Ery + Pec 0.1 g / kg, and the fourth group was administered Ery + Pec 0.5 g / kg. Three hours after administration, decapitation and blood collection were performed using guillotine, and blood AVP was measured by the method described in Non-Patent Document 8 in the specification. Table 19 shows the drugs administered and the test results. The dose of Ery was 2.8 g / kg in all cases, and the single dose of the aqueous solution was adjusted to 8 ml / kg.

A) Examination of diarrhea and plasma AVP level Severe diarrhea symptoms occurred (Table 17), and the plasma AVP level was high when the polysaccharide was mixed with sugar alcohol at about 3.6% by weight (Pec 0.1 g / kg). On the other hand, when 17.9% by weight (Pec 0.5 g / kg) was added, 3 out of 5 animals had normal stool, and plasma AVP also decreased (Table 19). As shown in Non-Patent Document 10 and Table 1, the value of plasma AVP is proportional to the rate of increase in endolymph volume. Table 19 (Plasma AVP value) and the histological examination results shown in Table 19 above, that is, the fact that the Ery simple group had a high plasma AVP value and formed endolymphatic hydrops, was found in Non-Patent Document 10. , Consistent with Table 1.

At Pec of 0.5 g / kg, plasma AVP is relatively low, and the osmotic effect of sugar alcohol is expressed, and it is considered that the collapse phenomenon was observed. When the amount of polysaccharide added was small, diarrhea occurred and dehydration continued, but a sufficient volume addition of the endolymphatic space was confirmed.

Plasma osmotic pressure increases in proportion to the number of moles of drug administered unless there are special factors. In the Ery simple group, the osmotic pressure increased by 58 mOsm / liter, and in the group to which 0.1 g / kg of Pec was added, it increased by 45 mOsm / liter, but in the group to which 0.5 g / kg was added, the increase was only 37 mOsm / liter. The increase in osmotic pressure when Pec is insufficient is due to dehydration due to severe diarrhea. However, it was also found that plasma osmotic pressure was greatly increased by the administration of Ery and Pec in amounts necessary for treatment. Therefore, reduction of the dose of drugs including additives is an important issue for the expression of therapeutic effects.

[3-2-b: Add 0.5 g / kg of pectin (P), observe the change over time after administration, and further reduce the dose to 1/2 and 1/4 for both Ery and Pec. Observe] From the results of Group 3-2-a, by adding 0.5 g / kg of Pec, it is possible to expect a safe and reliable effect of reducing endolymphedema without fear of dehydration. As it was found (Patent Document 2), 50 guinea pigs were divided into 5 groups of 10 in each group, drug administration was performed as shown below, gastrointestinal symptoms were observed, and perfusion was fixed after a certain period of time. . In the 27th to 29th groups, the mixed suspension of Ery and Pec was diluted 2 to 4 times, and the dose of Ery and Pec was reduced to 1/2 or 1/4. The left side of the 25th and 26th groups is undergoing endolymphatic sac closure. The single dose of the drug is 8 ml / kg for all groups.

Group Administered drug Perfusion (after administration)
Group 25: E + P6H group Ery2.8g / kg + P0.5g / kg 6 hours later Group 26: E + P12H group Ery2.8g / kg + P0.5g / kg 12 hours later Group 27: E + P / 2 · 3H group Ery1.4g / kg + P0.25g / kg 3 hours later 28th group: E + P / 2 · 6H group Ery1.4g / kg + P0.25g / kg 6 hours later 29th group: E + P / 4 · 3H group Ery0. 7g / kg + P0.125g / kg 3 hours later

A) Study on gastrointestinal symptoms Table 20 shows the results.

In group 24 of 3-2-a (3 hours later), 3 stool stools were collected, and in group 25 perfused 6 hours after administration, 1 was muddy stool, 2 were soft stool and mild diarrhea symptoms. Turned. In the 20th group (3 hours later) of Ery only in Example 3-1, all 10 animals were muddy stool, and in the 21st group (6 hours later), 7 animals were muddy stool. The effect is prominent (stool stiffness, spacing, P <0.01, P <0.01, Mann-Whitney U test). The group 25 after 6 hours was not significantly different from the group 24 after 3 hours (Mann-Whitney U test), but the formed stool length was 30.8 ± 23.6 cm (10 animals) A clear recovery was observed. In group 26 (12 hours later) all animals were normal stool. It should be noted that the stool interval is constant in 9 out of 10 animals, and gastrointestinal symptoms were significantly improved compared to the Ery-only group 22 (E12H group: 12 hours later) (P < 0.001, Mann-Whitney U test).

When the amount of Ery and Pec was halved or quartered, it was assumed that Ery's swallowing action became even lighter, the stool arrangement in the gastrointestinal tract was regular, and the subjective symptoms were mild. Compared with the Ery-only group (20 group, 21 group), all showed significant improvement (P <0.001, Mann-Whitney U test). Compared with the 24 and 25 groups that received normal doses of Ery and Pec, there was no clear significant difference between the 27 and 28 groups, which were reduced by half, and the 29 group, which was reduced to a quarter. It was recognized between the 24 groups (length of stool, firmness, interval, P <0.001, P <0.05, P <0.01, Mann-Whitney U test).

By adding Pec, as shown in the results after 3 hours and 6 hours, no gas in the intestine was observed, gas generation was suppressed, and uncomfortable gastrointestinal symptoms could be suppressed as much as possible, and early It was also confirmed from the result after 12 hours (group 22) that it had returned to normal.

When Ery and Pec were reduced to one-half or one-fourth, diarrhea symptoms were further reduced compared to the usual dose. In particular, in the 27th group, the 28th group, and the 29th group, stool was formed, and the tendency of the stool arrangement to be regularized was observed. It was.

B) Volume change of endolymphatic space: relationship between membrane stretch rate and area increase rate on normal side Table 21 shows the average and standard deviation of the stretch rate and area increase rate of each group.

As shown in 3-2-a, the volume of the 24th group (after 3 hours) was significantly reduced compared with the control group (distilled water) and the E3H group (Ery only), that is, collapse occurred (P < 0.05, P <0.01, t-test). Furthermore, the 25th group (after 6 hours) is significantly collapsed compared to the control group and the E3H group (P <0.01, P <0.001, t-test, respectively). The 26th group (after 12 hours) was not significantly different from the control group and the E3H group. From the above, it was found that collapse occurred 3 hours after administration and continued even after 6 hours, but returned to normal after 12 hours.

Ery's armpit action peaked at 3 hours after administration and lightly after 6 hours. Therefore, dehydration due to diarrhea is considered to increase plasma AVP after 3 hours and decrease after 6 hours. In addition, plasma osmotic pressure must be taken into account. The plasma osmotic pressure starts to increase immediately after the oral administration, then reaches a peak after 40 to 90 minutes, and recovers in about 6 to 7 hours (Non-patent Document 18). Accordingly, plasma AVP also varies in synchronization.

On the other hand, the osmotic pressure of the inner ear necessary for expression of the action seems to start increasing after 1-2 hours and maintain a high value after 4 hours. In the meantime, plasma AVP rises, and it is considered that Ery's unloading action is offset in combination with the increase due to dehydration due to diarrhea (groups 19 to 22 and groups 20L and 21L described later).

When the amount of Ery and Pec is halved or ¼, endolymph collapse occurs as well. Significant differences were observed as compared with the groups administered with distilled water in groups 20 to 22 and the group administered with Ery alone (P <0.001, t-test). Although no significant difference was observed compared with the group administered with normal doses of Ery and Pec, the same collapse action was expressed despite the small dose of Ery. The reason is that it is preferable for the manifestation of the unloading action because Ery's effect on the armpit is hardly observed, and since the dose is small, the increase in plasma osmotic pressure is small.

C) Endolymphedema reduction effect: Table 22 and FIG. 4 show the related results of the membrane extension rate and the area increase rate on the operation side.

The 27L group (1/2 weight loss, 3 hours later) showed a significant reduction effect compared to the control group and Ery simple E3H group (P <0.001, ANCOVA). The 28th group (1/2, 6 hours later) was also significantly different from the control group and the E6H group (both P <0.001, ANCOVA), and a reduction effect was still observed. Furthermore, when compared with the 24L group and the 25L group to which Ery and Pec were administered in normal amounts, there was no significant difference between them (ANCOVA). From this, it was found that even if the dose was reduced to one half, a strong unloading effect equivalent to that of the normal dose was exhibited and continued for about 6 hours. In addition, since there is a significant difference (P <0.001, ANCOVA) between the 27th group and the 28th group, it can be seen that although the effect of reducing the load continues, it gradually decreases. This result was expected from the result on the normal side of 3-2-b.

Sodium alginate (Al) was added to IB and administered, and compared with <IB> of a conventional product in which various additives were blended.

30 normal stool guinea pigs were divided into 3 groups, and groups 30 and 31 were prepared by adding 0.11 g / kg alginate sodium and 0.09 g / kg inorganic salt (isosorbitol). 2.8 g / kg) and perfusion was fixed at 3 hours and 6 hours after administration (6 hours after administration that maximizes the effect of <IB> (Non-Patent Document 13)) IB + Al * group). In Group 32, 0.3 g / kg of Al was added, and after 3 hours, the perfusion was fixed (hereinafter also referred to as IB + Al ** group), and each tissue was collected to observe and evaluate changes in endolymph volume. . Gastrointestinal symptoms continued until perfusion. The firmness of the stool is that of the perfusion. All groups were prepared so that a single dose was 4 ml / kg. Procedures such as tissue creation and measurement were performed in the same manner as in Non-Patent Document 4.

Group Administered drug Perfusion (after administration)
Group 30: IB + Al * group IB 2.8 g / kg + Al + inorganic salt 3 hours later Group 31: IB + Al * group 6 hours later Group 32: IB + Al ** group IB 2.8 g / kg + Al 0.3 g / kg 3 hours later

A) Examination of gastrointestinal symptoms Table 23 shows the observation results of stool firmness and shape.

In the IB simple group and the <IB> administration group, about half of the animals became loose stools or mud stools, and gastrointestinal symptoms such as gas generation occurred. On the other hand, in the IB + Al * group, the hardness of the stool after 3 hours (Group 23) is slightly soft stool, the other 8 are normal stool, the stool interval is irregular, Since there were few compared with <IB>, it is estimated that the antipruritic effect was significantly superior (P <0.05) and the digestive symptom was light compared with <IB> (Group 10) (P < 0.01, Mann-Whitney U test). After 6 hours (Group 31), all animals were normal stool, the interval was constant at 6 animals, and digestive symptoms were significantly lighter than <IB> (Group 12). It was found (stool stiffness, interval, P <0.01, P <0.01, Mann-Whitney U test).

In the IB + Al ** group, the stool hardness after 3 hours (group 32) was slightly soft stool, only 1 out of 7 stools, the stool interval was irregular, and the stool was less in comparison with <IB> ( Stool firmness and interval, P <0.01, P <0.01, Mann-Whitney U test). Compared with the IB + Al * group (group 30), the amount of Al added was large, but no significant difference was observed (Mann-Whitney U test).

B) Volume change of endolymphatic space: relationship between the rate of membrane extension and area increase on the normal side The extension of the Risnel membrane and the volume change of the endolymphatic space were measured at each rotation, and the results are shown in Table 24.

Groups 10, 11 and 12 (respectively <IB> 3, 4 and 6 hours later) tend to increase in volume as compared to the control group, especially the 11th group (after 4 hours) is significant. There was a difference ([Example 1-4]). However, the 30th group and 31st group to which 0.11 g / kg of Al was added tended to decrease in volume. There was a significant difference from the control group (P <0.05, t-test) and mild but collapse was observed. Group 25, 3 hours after administration, was not significantly different from IB plain third group, but the volume was clearly reduced compared to <IB> group 10 (P <0). .01, t-test). Group 6 at 6 hours was significantly different from group 5 of IB plain and group 12 of <IB> (P <0.01, P <0.01, respectively, t-test). In group 32 to which Al was added at 0.3 g / kg, the volume was further reduced. There was a significant difference from the control group (P <0.05, t-test), and collapse was observed (P <0.01 compared to the control group, IB plain fifth group, <IB> All are P <0.001, t-test compared to 12 groups). However, there was no significant difference between the IB + Al * group (Group 31) (t-test).

From these facts, the collapse (load reduction) effect of the IB + Al * group appears surely 3 hours after administration (P <0.05, t-test), and the effect continues even after 6 hours. (P <0.05, t-test). Even when compared with <IB> of the conventional product, it was found that the effect at 3 hours after administration was significantly large (P <0.01, t-test), and the onset of action was rapid. The IB + Al ** group tended to have a stronger load reduction effect, but there was no significant difference compared to the IB + Al * group.

  Although there is no significant difference after 6 hours, the volume is reduced compared to the conventional product, and it is clear from the stool properties and gas generation status in the gastrointestinal tract that gastrointestinal symptoms were successfully improved, including sputum action. Therefore, it is expected that a sufficient effect can be expected without burdening the digestive tract with a smaller amount. In addition, the amount of the additive is about three-fourths of <IB>, which may be a factor that exerts a relatively good reduction effect. However, it was found that the effect of reducing the load of IB was small compared to Ery.

C) Endolymphedema reduction effect: Table 25 shows the relationship between the membrane extension rate and the area increase rate on the operation side.

The 30L group (3 hours later) showed a significant reduction effect compared to the control group and the 10L group 3 hours after administration of the IB conventional product (P <0.001, ANCOVA). The 31st group (after 6 hours) also showed a significant difference compared to the control group and <IB> 6H group (both P <0.01, ANCOVA), and the reduction effect was still recognized.

Glycerol was selected as the sugar alcohol and combined with sodium carboxymethylcellulose as the polysaccharide to observe the effect on endolymphatic volume. In Non-Patent Document 4, glycerol was administered at a dose of 12 ml / kg (Non-Patent Documents 1 and 2) when the glycerol test was performed, and changes over time were observed. The results are as shown in Table 26.

  When glycerol was administered, the molecular diameter was small, so it reached the perilymph space after 2 hours, and the perilymph pressure increased. Therefore, the endolymph space was significantly collapsed (reduced) by the osmotic effect (with the control group). P <0.001, Mann-Whitney U test). Since glycerol molecules then pass through the Ricenel membrane and enter the endolymphatic space, it is believed that the endolymph pressure rises and a rebound phenomenon occurs (Non-patent Document 5, paragraph [0015] above).

[Glycerol (Gly) and carboxymethylcellulose (CMC)]
The amount of Gly is the amount used for inspection. Therefore, Gly was reduced to about one third, and the change with time was observed. Twelve guinea pigs were divided into two groups, administered drugs as shown below, and fixed by perfusion after 3 hours. The results of the antipruritic effect are shown in Table 27, and the histological examination results are shown in Table 28.

An antipruritic effect was observed when CMC was added (10% by weight) (P <0.01, Mann-Whitney U test).

In the group to which CMC was administered as a polysaccharide, the collapse of the endolymphatic cavity was significantly observed as compared to the group of glycerol alone (P <0.001, t-test). In addition, on the operation side, a significant difference was observed in the group to which CMC was administered as compared to the Gly simple group (P <0.01, ANCOVA, Patent Document 3).

[Xylitol (XL) and xanthan gum (XG)]
Twelve guinea pigs were divided into two groups of 6 each, and drug administration was performed as shown below, and perfusion was fixed after 3 hours. The evaluation results of the antipruritic effect are shown in Table 29, and the histological examination results are shown in Table 30.

  An antipruritic effect was observed when XG was added (7.1% by weight) (P <0.05, Mann-Whitney U test).

In the group to which XG was added as a polysaccharide, a decrease in the volume of the endolymphatic cavity was observed compared to the XL simple group (P <0.01, t-test). In addition, on the operation side, a clear reduction effect of endolymphatic hydrops was recognized as compared with the XL simple group (P <0.01, ANCOVA, Patent Document 3).

[Xylose (XS) and xanthan gum (XG)]
Twelve guinea pigs were divided into two groups, administered drugs as shown below, and fixed by perfusion after 3 hours. Among these results, the results of antipruritic effect are shown in Table 31, and the histological examination results are shown in Table 32.

  An antipruritic effect was observed when XG was added (7.1% by weight) (P <0.01, Mann-Whitney U test). At 3 hours, it was difficult to defecate even with pressure applied to the lower abdomen by fingers. The arrangement of stool was not constant, but the generation of gas was not significant, with a gap of 2-3 cm.

In the group to which XG was added as a polysaccharide, marked collapse (reduced load) was observed as compared to the XS simple group (P <0.001, t-test). The fact that the 23rd group exhibited a significant reduction effect is thought to be due to the unique absorption process of XS from the digestive tract, but there is some objection to the absorption process and it is a subject for further study. In addition, on the operation side, a significant load reduction effect was recognized as compared with the XS simple group (P <0.001, Patent Document 3).

[Isosorbitol (IB) and agar]
Seven guinea pigs were administered drugs as shown below and fixed by perfusion after 3 hours. The results of the antipruritic effect are shown in Table 33, and the histological examination results are shown in Table 34.

By adding agar (10.7% by weight), an antipruritic effect was observed (P <0.05, Mann-Whitney U test)

  Compared with IB plain and <IB> by addition of agar, no significant difference was observed in volume reduction (collapse) of the endolymphatic space (Mann-Whitney U test). In addition, on the operation side, a clear effect of reducing endolymphatic hydrops was observed as compared with the IB simple group (P <0.01, ANCOVA, Patent Document 3). Furthermore, a clear effect of reducing endolymphatic hydrops was observed even when compared with the <IB> group (P <0.01, ANCOVA).

[Reference example: Antistatic action of polysaccharides]
Examples of the polysaccharide include xanthan gum, guar gum, gum arabic, locust bean gum, tara gum, pectin, sodium alginate, sodium carboxymethylcellulose, hydroxypropylcellulose, agar, carrageenan and the like. In addition, polysaccharides having a high molecular weight (such as xanthan gum) tended to show a strong antipruritic action in a small amount. Since the intake is small, intake is easy and there are few inconveniences.

Other groups represented by xanthan gum include guar gum, gum arabic, locust bean gum, tara gum, etc., but the higher the viscosity, the higher the antipruritic effect. However, the amount of stool is reduced to about one-third to one-third in 3 to 5 hours after ingestion, and the form tends to be irregular and the size tends to be small. It was speculated that there was a lingering feeling. Combining two or more species from this group dramatically increases the viscosity, thus improving the anti-principal action. It has been found that by utilizing this phenomenon and combining a plurality of types, it is possible to develop a sufficient antipruritic effect with a smaller blending amount, and at the same time, reduce the side effect of reducing defecation.

Pectin did not exhibit sufficient antipruritic action unless it was added in a relatively large amount, but it was excellent in intestinal regulation, and the amount of stool was similar to that of animals not administered anything. The properties were the same. When added in a large amount, the surface of the stool became smoother, stool was easy, and symptoms such as abdominal bloating were not observed. The group represented by pectin includes sodium alginate, agar, sodium carboxymethylcellulose, hydroxypropylcellulose, carrageenan, etc., and the higher the viscosity, the stronger the antipruritic action.

If necessary, one or more of these polysaccharides are added to achieve anti-tarching. However, when two or more are combined, they can be appropriately selected from the above two groups, combined, and added to At the same time, it was found that the intestinal regulating action can be achieved. In addition, various combinations such as combining multiple types from the same group are possible, and it is possible to improve the flow in some cases while reducing the amount added, so new excellent properties such as easy intake It has also been found that it is possible to aim at reducing or eliminating gastrointestinal symptoms while at the same time making use of it.

The blending amount of the polysaccharide is 1 to 30% by weight, 2 to 20% by weight and 3 to 20% by weight with respect to the sugar alcohols, and the upper limit is 15% by weight, 10% by weight and 5% by weight. It can also be made into -15 weight%, 2-10 weight%, etc. If the blending amount of the polysaccharide is out of the above range, the armpit effect may not be sufficiently achieved.

[Reference Example 1]
If diarrhea occurs, plasma AVP rises (Non-patent Document 11). If plasma AVP rises, endolymphedema is formed as described in Non-Patent Document 10, but 3-2- From the results of group a, as described in the previous paragraphs [0119] to [0122], it was confirmed that if the stasis was successful, the plasma AVP increased only slightly and the endolymph unloading effect was surely exhibited. It was. Based on these facts, it is clear that if the antipruritic effect can be achieved, the endolymphedema reduction effect will be manifested.

The combination of sugar alcohols and polysaccharides was further changed to investigate whether or not it could be successfully stopped. As sugar alcohols, erythritol, sorbitol, isosorbitol and mannitol were arbitrarily combined with sodium carboxymethylcellulose, carrageenan, guar gum and gum arabic as polysaccharides.

[1-1: Mannitol and sodium carboxymethyl cellulose (CMC)]
Eight guinea pigs having normal stool were divided into two groups, administered with drugs as shown below, and then stool was observed for 6 hours. The results are shown in Table 35.

Diarrhea due to mannitol was significantly lightened by the addition of about 7.1% by weight of CMC (P <0.05, Mann-Whitney U test). Abdominal fullness and gas generation were hardly observed.

[1-2: Sorbitol and guar gum (Sigma)]
Ten guinea pigs having normal stool were divided into two groups and administered with drugs as shown below. After that, stool was observed for 6 hours, and the results are shown in Table 36.

By adding 10% by weight of guar gum, 2 animals became normal stool, 2 animals became slightly stool and almost succeeded in stopping diarrhea caused by sorbitol (P <0.05, Mann-Whitney U test). However, at 3 to 4 hours after administration, the amount of stool is reduced to about one third, and a slight bloating is observed in the abdomen by visual inspection and palpation. Touched. When the lower abdomen was squeezed, the shape was irregular and small stools less than half the usual amount were excreted little by little.

[1-3: Erythritol and gum arabic (Sigma)]
Ten guinea pigs with normal stool were divided into two groups, administered drugs as shown below, and then stool was observed for 6 hours. The results are shown in Table 37 and compared with the E3H group.

Even when 20% by weight of gum arabic was added, diarrhea due to erythritol could not be stopped (no significant difference). When 40% by weight was added, the diarrhea was slightly reduced (P <0.01, Mann-Whitney U test), but more reliable stopping is desired. In both groups, the stool volume was reduced to about one third at 3 to 4 hours after administration, and abdominal bloating was observed by visual inspection and palpation. It was touched, but only a small amount of mud stool was excreted, and an unpleasant state was assumed.

[1-4: Erythritol and guar gum (Sigma)]
Fifteen guinea pigs having normal stool were divided into two groups, and drug administration was performed as shown below. Thereafter, stool was observed for 6 hours. The results are shown in Table 38 and compared with the E3H group.

Even when 5% by weight or 10% by weight of guar gum was added, erythritol-induced diarrhea could not be stopped. After addition of 20% by weight, 2 animals were normal stool, 2 animals were slightly soft stool and almost stopped successfully (P <0.001, Mann-Whitney U test). However, at 3 to 4 hours after administration, the amount of feces decreased to about one third, and abdominal bloating was observed by visual inspection and palpation. When the abdomen was compressed with fingers, gas generation and movement were touched. . When the lower abdomen was pressed, the shape was irregular, and small stools less than half the usual amount were excreted little by little.

[1-5: Isosorbitol (IB) and carrageenan]
Seven normal stool guinea pigs were administered IB aqueous solution (8 ml / kg) supplemented with 10.7% by weight of carrageenan, and then stool was observed for 6 hours. The results are shown in Table 39.

Diarrhea symptoms due to IB were improved by adding about 10.7% by weight of carrageenan. Isosorbitol is not as strong as other sugar alcohols even though it is simple, but it is considered effective that no mudous stool or loose stool was observed due to the addition of carrageenan. By visual inspection and palpation, no abdominal bloating was observed, and it was presumed that digestive symptoms were mild.

  Polysaccharides include those having excellent antipruritic effects as represented by i) xanthan gum (XG) and those having excellent intestinal action represented by b) pectin (Pec).

[I) Group represented by XG] Xanthan gum, guar gum, gum arabic, locust bean gum, tara gum, etc. belong to this group. As for the antipruritic action, xanthan gum was the strongest, the gum arabic was gentle, and generally the antistatic action became stronger as the viscosity of the suspension increased. On the other hand, the amount of feces tends to decrease 3 to 5 hours after ingestion.

[B) Group represented by pectin (Pec)] Examples include pectin, sodium alginate, agar, sodium carboxymethylcellulose, carrageenan, and hydroxypropylcellulose. In addition to Pec, this group of polysaccharides has an excellent intestinal regulating effect, but it requires a relatively large amount of antipruritic gland, and has the disadvantage of adding a large amount. However, even if a large amount is added, the surface of the stool is smooth, the amount of excretion is normal or more, there is no obstacle to the stool, the abdominal bloating and gurgling does not occur even by inspection and palpation, and the animal suffers There was no appearance. Agar with higher viscosity than Pec and sodium alginate were superior to Pec in antipruritic effect, and CMC exhibited almost the same antipruritic effect as Pec.

[B] Choose one from the group represented by XG and b) the group represented by Pec,
When combined)
By examining the characteristics of each polysaccharide and combining the two types of polysaccharides (a) and (b), which have different characteristics, one by one, gastrointestinal symptoms can be achieved while producing a more accurate antipruritic effect. It has been found that it is possible to excrete a normal amount of well-shaped stool without causing any problems. Furthermore, it has also been found that depending on the combination, such as XG + CMC and GG + CMC, the flow can be improved. This is suitable for administration to patients who have difficulty in swallowing, and can also be administered as an aqueous solution to microtubules without any trouble for administration to patients with tube feeding.

[A) When two or more types from a group represented by XG are combined
A) The viscosity of a group of polysaccharides represented by XG can be drastically increased when two or more kinds are combined. For example, in the case of the same 0.5% solution, the viscosity of XG1: Guar gum 3 is several times to several tens of times as much as the viscosity of the simple guar gum, which is almost the same as the 0.5% XG solution or It is known to become more viscous than that. The same phenomenon is known to dramatically increase the viscosity even with other polysaccharide combinations. Thereby, the dose can be reduced. When a plurality of types were actually combined, it was found that even with a small amount of addition, the antipruritic action was improved and the abdominal fullness and grooviness were also reduced.

[B) When two or more types are selected from the group represented by Pec]
The problem with adding Pec alone is that it must be added in large quantities to achieve anti-pruritus. The combination of two or more species from Pec's group has found that it exhibits antipruritic action with a relatively small addition amount while taking advantage of the respective characteristics. In addition, when Pec or sodium alginate is mixed with a sugar alcohol solution, it becomes a gel, and when the amount added is increased, the sense of unity may be lost and swallowing may be difficult. Found out to solve.

  In addition, combining 3 or more polysaccharides, (b) When selecting and combining 2 types from the group represented by XG and b) 1 type from the group represented by Pec], (b) Representative by XG 1) from the group to be selected and (b) two types selected from the group represented by Pec and combined], it is possible to make use of the advantages of each and make up for the shortcomings.

[Reference Example 2]
By adding two or more kinds of polysaccharides, it was examined whether or not a reliable antipruritic effect could be obtained in a smaller amount than the addition amount of one kind of polysaccharide.

[2-1: Erythritol and XG + pectin (Pec)]
Fifteen guinea pigs with normal stool are divided into three groups, XG with very high viscosity and Pec with high hydrophilicity are combined as shown in Table 40 and administered to Ery. The symptom was observed.

By combining XG 0.09g / kg + Pec 0.2g / kg (total polysaccharides 10.4% by weight), the amount of XG antipruritic action and Pec intestinal regulation is smaller than when Pec alone is added (17.8%). The effect could be expressed at the same time. When only XG is added, the antipruritic action is strong, but abdominal bloating is observed and fecal excretion decreases, but the animal suffers even when pressure is strongly applied to the lower abdomen by combining the two species However, it was confirmed that the objective was achieved by the appearance of smooth stool on the surface (P <0.001, Mann-Whitney U test).

[2-2: Erythritol and xanthan gum (XG) + Guar gum (GG) (when two types are selected from the XG group and combined)]
Divided 15 guinea pigs normal feces in the three groups were administered with relatively low viscosity GG viscosity is very high XG in XG group erythritol faded set as shown in Table 4 1, at 6 hours Until then, stool and digestive symptoms were observed.

A combination of XG 0.03 g / kg and GG 0.06 g / kg (3.2% by weight of the total amount of polysaccharides) did not show a sufficient anti-pruritic effect, and both increased to give XG 0.06 g / kg, GG 0. A significant antipruritic effect was recognized by combining 09 g / kg (5.4% by weight of the total polysaccharide) (P <0.001, Mann-Whitney U test). Feces were irregularly shaped and excretion decreased to about one-half, but no abdominal bloating was observed, and the animal did not suffer even if pressure was applied strongly to the lower abdomen.

[Erythritol and xanthan gum (XG) + pectin (Pec) + carboxymethylcellulose sodium (CMC)]
10 guinea pigs with normal stool are divided into 2 groups, and XG, Pec and CMC are added to Ery in combination as shown in Table 45. After observation of stool and digestive symptoms until 3 hours At 3 hours, the digestive organs were observed together with perfusion, fecal arrangement, etc., and the temporal bone was taken out and examined histologically.

The study results for A) gastrointestinal symptoms shown in Table 4 2.

XG: 0.06 g / kg, Pec: 0.15 g / kg, CMC: 0.2 g / kg
Stool firmness is determined during perfusion

XG 0.06 g / kg + Pec 0.15 g / kg + CMC 0.2 g / kg (polysaccharide total 1
(4.6% by weight), almost complete pinching was achieved (P <0.001, Mann-Whitney U test). When XG alone was added, the amount of stool decreased after administration, and gas generation was observed in the intestine. However, by adding two species from the pectin group, such problems did not occur and the patient stopped. succeeded in. In the observation in the gastrointestinal tract, as for the arrangement of stool, 2 out of 6 stools were formed at intervals of 4 to 7 cm, and a slight amount of gas was observed. It became regular and gastrointestinal symptoms were presumed to be mild (P <0.001, Mann-Whitney
U test). The length of the formed stool was also 57.0 ± 19.6 cm, and only 55 ml of distilled water was administered.
The value was close to 0 ± 8.8 cm.

B) Effects on endolymphatic volume (normal side) and endolymphatic edema reduction effect (surgical side)
Table 43 shows the average and standard deviation results of the extension rate and area increase rate of each group.

Compared with the E3H group (3 hours later) to which only erythritol was administered, the E + 3P group to which three kinds of polysaccharides were added was significantly collapsed (load reduction) (P <0.05). Moreover, although it moved slightly upward compared with the 24th group which added 0.5g (17.9 weight%) of only 1 type of Pec as a polysaccharide, there is no significant difference and it exhibits sufficient load-reducing effect. (Patent No. 4081131).

Pec is excellent in intestinal regulation, but it tends to be added in an amount that tends to increase the viscosity, and it is inevitable that the viscosity will increase. However, the addition of CMC improves the flow and improves the intake. It became a material with excellent mouth feel and touch. It can be taken without a sense of incongruity, and the range of applications for tube feeding and beverages is expanded.

Compared to the case where one kind of polysaccharide is added to a monosaccharide or its sugar alcohols in combination with a plurality of kinds of polysaccharides, the antistatic effect is dramatically improved and unpleasant gastrointestinal symptoms are reduced or prevented. I was able to measure. The goal of reducing additives could be achieved.

It is the figure which showed the time-dependent change of the endolymph edema reduction effect of isosorbitol (IB) with the scatter diagram and the regression line. At 3 hours after IB administration, the regression line moves downward compared to distilled water, but no significant difference is observed (ANCOVA). At 6 hours after administration, a significant load-reducing effect was observed (P <0.01, ANCOVA). ○: IR-S (distilled water) = 3.276 + 1.22 * IR-L (distilled water); R ^ 2 = .983, ■: IR-S (IB plain, 3 hr) = 6.542 + 1.011 * IR-B ( IB simple, 3hr); R ^ 2 = .987, □: IR-S (IB simple, 6hr) = 7.347 + .742 * IR-L (IB simple, 6hr); R ^ 2 = .901

Isosorbitol (IB) and pectin (Per) were added, and the normal dose and half dose were administered, and the reduction effect of endolymphatic hydrops at 3 hours was compared. A scatter diagram and a regression line are shown. In the administration of IB plain, no significant difference was observed compared with distilled water, but the effect of reducing the load in the group to which Per was added was significantly different from that in distilled water and IB simple group (P <0.01, ANCOVA). Even when the amount was reduced to half, the same level of reduction effect was recognized (P <0.01, ANCOVA). ○: IR-S (distilled water) = 3.276 + 1.22 * IR-L (distilled water); R ^ 2 = .983, ●: IR-S (IB plain, 3hr) = 6.542 + 1.011 * IR-B ( IB plain, 3hr); R ^ 2 = .987, ■: IR-S (IB + P, 3hr) = .303 + .701 * (IB + P, 3hr); R ^ 2 = .794, □: IR-S ( IB + P1 / 2/3) = 1.429 + .761 * IR-L (IB + P1 / 2/3); R ^ 2 = .858

Isosorbitol (IB) and pectin (Per) were added, and the normal dose and half dose were administered, and the reduction effect of endolymphatic hydrops at 6 hours was compared. A scatter diagram and a regression line are shown. The administration of IB alone showed a reduction effect compared to distilled water (P <0.01). In the group to which Per was added, significant differences were observed compared to the distilled water and IB simple groups (P <0.01, P <0.05, ANCOVA, respectively). Even when the amount was reduced to half, the same level of reduction effect was observed, indicating that the effect was sustained (both P <0.01 and ANCOVA). The weight reduction effect was not impaired by the weight reduction. ○: IR-S (distilled water) = 3.276 + 1.22 * IR-L (distilled water); R ^ 2 = .983, ●: IR-S (IB simple, 6hr) = 3.11 + .914 * IR-B (IB simple, 3 hr); R ^ 2 = .961, ■: IR-S (IB + P, 6 hr) = -2.141 + .862 * (IB + P, 6 hr); R ^ 2 = .874. □: IR-S (IB + P1 / 2/6) = -8.778 + .973 * IR-L (IB + P1 / 2/6); R ^ 2 = .945

It is the figure which decreased the dosage amount of erythritol (E) and pectin (P) to 1/2, and showed the time-dependent change of the endolymphatic edema reduction effect with a scatter diagram and a regression line. Since the regression line of the group reduced in half was not significantly different from the normal amount group, even if the dose is reduced, a sufficient load-reducing action can be expected. Even after 6 hours from the administration, a significant load-reducing effect was observed as compared with distilled water. : IR-S (distilled water) = 4.011 + 1.212 * IR-L (distilled water); R ^ 2 = .987, ●: IR-S (Ery simple) = 2.407 + 1.309 * IR-L (Ery simple) ); R ^ 2 = .974, ■: IR-S (E + P, 3hr) = -15.925 + .79 * IR-L (E + P, 3hr); R ^ 2 = .771, ×: IR- S (E + P6 hours) = -16.508 + 1.314 * IR-L (E + P6 hours); R ^ 2 = .784, □: IR-S (E + P1 / 2, 3hr) = -1.834 +. 559 * IR-L (E + P1 / 3 hr); R ^ 2 = .547.

Claims (1)

  A therapeutic agent for Meniere's disease, which is used so that 0.1 to 0.75 g / kg body weight of erythritol or isosorbitol sugar alcohol is orally administered per day for an adult.