JPH07126170A - Glucide absorption inhibitor - Google Patents

Abstract

PURPOSE:To obtain a glucide absorption inhibitor for efficiently and stably inhibiting absorption of glucide without temperance in eating and specific therapy. CONSTITUTION:This glucide absorption inhibitor comprises a complex of a saccharide and an amino acid and is water-soluble.

Description

Detailed Description of the Invention

[0001]

The present invention relates to the prevention and treatment of obesity,
Alternatively, it relates to a sugar intestinal absorption inhibitor used as a therapeutic drug for diabetes.

[0002]

2. Description of the Related Art In recent years, eating habits have become rich, and due to obesity due to excessive intake of sugar, diabetes, arteriosclerosis,
Adult diseases such as heart disease and hypertension are increasing. Therefore, prevention of obesity has become very important for health.

Since obesity is basically a problem of calorie and metabolism, as a method for preventing obesity, reduction of calorie intake, control of calorie by exercise, and in some cases, temporary starvation therapy have been proposed. However, since appetite is a human instinct, it is not easy to reduce calorie intake by dieting, and calorie control by exercise and other therapies cannot be performed by anyone, and nutritional problems may occur depending on the therapy. is there.

As a simple method, a method of taking a substance which inhibits the action of a digestive enzyme of a carbohydrate (starch etc.) which occupies nearly 80% of the food at the time of meal is considered. As a digestive enzyme, α-amylase is present in saliva and pancreatic juice, and membrane digestive enzymes such as sucrase, maltase, isomaltase, and lactase are localized in the microintestinal mucosa of the small intestine. These digestive enzymes are involved in the digestion of carbohydrates, and in recent years several inhibitors of these digestive enzymes have been found.

Further, it has been clarified that absorption of carbohydrates in the intestinal tract is mainly performed by an active transport system localized in small intestinal mucosal cells. The mechanism is briefly summarized as follows. Na ⁺ and sugar bind to the carrier in the brush border membrane of absorbing epithelial cells, and the electrochemical gradient generated by the difference in Na ⁺ concentration passes through the membrane, Na ⁺ and sugar are taken in (Kozo Hayashi, Hisashi Kawasaki: Metabolism 19: 661, 1982, Hisashi Kawasaki: Pathophysiology 2:12, 1983). There is phlorizin as an inhibitor at this stage, and it is considered that the absorption amount of sugar can be reduced. However, these inhibitors are oligosaccharides and peptides obtained from microorganisms or plants, and have problems in terms of safety and efficacy, and most of them have not yet reached the stage of practical application. Not in. In addition, artificial sweeteners are also frequently used, but this only suppresses the amount of sugar added and does not affect the absorption of carbohydrates, which are decomposition products of carbohydrates, and cannot be expected to have a particularly great effect on obesity. .

In the case of progressing to diabetes, insulin administration controls the blood glucose level, or administration of drugs such as trazamide, glydimin sodium, tolbutamide and acetohexamide causes Langerhans islet β in the pancreas.
Therapies that stimulate cellular insulin secretion are used, while severe dietary restrictions are applied.

[0007] Insulin and insulin secretagogues have strong effects, but on the other hand, they have many side effects and are often reported to cause death or irreversible sequelae due to an extreme decrease in blood glucose level.

As a sugar absorption inhibitor, plants belonging to the genus Gymnema of the genus Potato have been studied in the past. Gymnema sylvestre has long been known as a folk medicine for diabetes in India. The warm water extract and alcohol extract of Gymnema sylvestre have the effect of suppressing the absorption of carbohydrates in the intestinal tract, and therefore have been proposed to be used as tea or added to foods (JP-A-63-105661). Japanese Patent Laid-Open No. Sho 61-5
No. 023).

Gymnema sylvestre contains Gymnema acid,
It is thought that this substance plays a central role in suppressing glucose absorption, but its mechanism of action is not clear (Shinichi Yoshioka: Yonago Medical Journal 37: 142, 1986).

However, gymnemic acid has been shown to bind to the taste receptor on the tongue and act as a sensory depressant of taste, and gymnema sylvestre is orally administered, and when administered orally. , Its effect is about 1
Lasts for hours. Therefore, after administration of Gymnema sylvestre, there is a problem that the food etc. becomes bland. Gymnemaic acid is extracted from Gymnema sylvestre, but it is relatively expensive and it is difficult to provide a stable supply because it is of natural origin.

[0011]

The object of the present invention was made in view of the above-mentioned problems in obesity prevention,
It is an object of the present invention to provide a novel carbohydrate absorption inhibitor that effectively inhibits carbohydrate absorption without depending on diet or special therapy and without causing disorders such as taste disorders.

[0012]

[Means for Solving the Problems] Carbohydrate ingested as food is digested and absorbed from the small intestine. Therefore, it is considered that the absorption amount of sugar can be reduced by inhibiting the absorption field from the small intestine.

The carbohydrate absorption inhibitor of the present invention is characterized in that it contains a conjugate of sugar and amino acid as a main component and is water-soluble. As the amino acid used in the present invention,
Aspartic acid, glutamic acid, lysine, arginine,
Examples thereof include histidine, serine, threonine, asparagine, glutamine, aminobutyric acid, aminohydroxybutyric acid, aminopimelic acid, diaminopimelic acid, amikihexanoic acid, aminovaleric acid, etc., but are not particularly limited thereto.

Glucose and galactose are used as monosaccharides and sucrose, maltose and lactose are used as disaccharides in the sugar used in the present invention. Considering the affinity with the carrier, glucose is preferably used.

The sugar absorption inhibitor of the present invention is required to be water-soluble because it can freely diffuse in the small intestine and bind to the sugar carrier. When it becomes water-insoluble, it is considered that the affinity of the sugar for the carrier decreases.

The reaction for binding sugar and amino acid is as follows:
Method of activating the hydroxyl group of sugar with cyanogen bromide and reacting with primary amino group in amino acid, method of activating hydroxyl group of sugar using epichlorohydrin and reacting with primary amino group in amino acid, periodate sugar A general reaction such as a method of oxidizing with an acid to form a Schiff's base with a primary amino group in an amino acid and reducing the Schiff's base with sodium borohydride can be used. It is not limited.

The sugar absorption inhibitor of the present invention is used orally. For formulation, capsules, tablets, granules, and powdered sugar can be prepared by a technique well known in the technical field of pharmacy. It may be administered as a formulation in which one or more additives physically and chemically compatible with the sugar intestinal absorption inhibitor are mixed. As additives that can be used, gum arabic, polyvinyl alcohol,
Polyvinylpyrrolidone, calcium carbonate, kaolin, calcium stearate, magnesium stearate, talc, polyethylene glycol, agar, hydrogenated oil and the like can be used. Moreover, you may use a coloring agent, a flavoring agent, a flavoring agent, a stabilizer etc. as needed.

The sugar intestinal absorption inhibitor of the present invention may be a liquid preparation. For such liquid preparations, water based or water based pharmaceutically acceptable carriers such as ethanol, propylene glycol, polyethylene glycol or glycerol or dilute aqueous solutions of sorbitol are preferred. Such formulations may contain preservatives, flavoring agents and sweeteners.

Among the additives used, sugars such as starch, sucrose and fructose are substances which are intended to inhibit the absorption by the use of sugar absorption inhibitors, so they should be avoided or minimally used. To

The preparation obtained as described above is used as a medicine for treating obesity and diabetes, and as a functional food (prevention of obesity), for example, juice, cake,
It can also be added to bread, cookies, chocolate, candy, etc.

The dose of the carbohydrate absorption inhibitor of the present invention may vary depending on the malignancy of the disease, the age of the patient, the condition and general condition of the patient, the progress of the disease, etc., but is 0.1 per adult. ~ 100g, usually taken before meals.

[0022]

The sugar absorption inhibitor of the present invention is a substance having an affinity for a carrier that actively transports sugar, and binds to this carrier to antagonistically absorb the sugar from the intestinal tract. Acts to suppress. In the present invention, the conjugate of a sugar and an amino acid is provided with the ability to specifically bind to a carrier of a carbohydrate existing in the intestine. Furthermore, since the amino acid is bound to the sugar, the hydrophilicity of the conjugate itself is enhanced. Therefore, it is considered that the rate of uptake into the cells of the conjugate bound to the carrier is remarkably reduced, and as a result, the ability of transporting the entire carbohydrate into the body is reduced and the absorption amount of the carbohydrate is reduced.

[0023]

EFFECTS OF THE INVENTION Therefore, the carbohydrate absorption inhibitor of the present invention can markedly reduce the amount of carbohydrate absorbed from the intestinal tract, so that obesity and the like can be prevented or treated without causing pain. .

[0024]

EXAMPLES The present invention will be described below with reference to examples. Example 1 10 g of D-glucose was added to 2 M sodium carbonate buffer (p
H = 11) 50 ml was added and stirred with a stirrer. To this, 5.9 g of ground cyanogen bromide was added and stirred for about 10 minutes to cause a reaction. During the reaction, 5M sodium hydroxide and ice were added to control pH to 11 and temperature to 20 ° C.
Immediately after completion of the reaction, 7.4 g of L-aspartic acid was added, and the mixture was stirred at 4 ° C. for 24 hours for reaction. The reaction product was put into hexane and crystallized to obtain a D-glucose-L-aspartic acid conjugate.

Example 2 D-Glucose-L was prepared in the same manner as in Example 1 except that 8.1 g of L-lysine was used instead of L-aspartic acid.
-A lysine conjugate was obtained.

<Intestinal absorption inhibition test> Wi as an experimental animal
An 8-week-old male male rat (average body weight: 180 g) was used. The rats were given water only for 16 to 18 hours to be fasted, then killed by decapitation under ether anesthesia, and laparotomized after blood removal. About 12 cm of the small intestine is cut and about 10 ml of Tyrode's solution (NaCl: 8 g, KCl: 0.2 g, C in 1 liter)
aCl ₂ : 0.2 g, MgCl ₂ : 0.1 g, NaH ₂
PO ₄ : 0.05 g, NaHCO ₃ : 1 g, Gluco
The intestinal tract was washed three times with 1 g of se (containing 1 g, pH = 8.0). A stainless rod (diameter: 3 mm) was inserted into the cut small intestine, ligated with a thread, traced with a Kimwipe moistened with Tyrode's solution, the intestinal tract was inverted, and the inverted one end was ligated. A 26 G injection needle was inserted, and the inside of the everted intestine was filled with Tyrode's solution. Furthermore, ligate with a thread, and
Three cm of inverted intestinal Sac (Glucose concentration of internal Tyrode solution was 100 mg / dl) were prepared.

10 ml of Tyrode's solution alone (Comparative Example 1) and 10 ml of Tyrode's solution containing 50 mg of the sugar absorption inhibitors of Examples 1 and 2 were added to a 15 ml plastic centrifuge tube. Each inverted intestine Sac was immersed in a centrifuge tube and incubated at 37 ° C. for 120 minutes while blowing a mixed gas containing 95 vol% O ₂ and 5 vol% CO ₂ . After incubation, the liquid in the inverted intestine Sac was taken out, and the glucose concentration in the liquid was measured by an automatic glucose measuring device (Kyoto Daiichi Kagaku Co., glucose auto and stat GA1120).
It was measured at. The results are shown in Table 1.

[0028]

[Table 1]

From Table 1, when the carbohydrate absorption inhibitor was not added (Comparative Example 1), glucose was transported into the inverted intestine Sac by active transport against the concentration gradient, and the initial value (10
The concentration of glucose in inverted intestine Sac when the carbohydrate absorption inhibitor is added (Examples 1 and 2) is almost unchanged from the initial value, while the concentration is increased to about 5 times that of 0 mg / dl). From this, it can be seen that the active transport of glucose is inhibited.

<Glucose tolerance test> Wista as an experimental animal
Using 8-week-old r-type male rats (average weight of about 160 g),
From the day before the experiment, water was given overnight and fasted, and then glucose 2 g / rat 1 kg and the conjugate 50 obtained in Examples 1 and 2 were used.
0.8 ml of a solution prepared by dissolving mg in 5 ml of physiological saline to a concentration of 10 mg / ml was forcibly administered using a sonde. Before administration, 15 minutes after administration and 45 minutes after administration, 0.2 ml of blood was collected from the jugular vein and immediately centrifuged to collect plasma.

The glucose concentration of this plasma was measured using an automatic glucose measuring device (Glucose Auto and Stat GA 1120 manufactured by Kyoto Daiichi Kagaku Co., Ltd.). In this test, 5 rats were used, and the difference in glucose concentration before and after administration was taken as the blood glucose elevation value.

As a control, 0.8 ml of physiological saline was administered instead of the sample and the same operation was performed. The results are shown in Table 2 below.

[0033]

[Table 2]

When the blood glucose elevation value 15 minutes after administration was examined, the average value in the control group was 117 mg / dl, whereas the average value in the administration group of Example 1 was 54 mg / dl, and the administration group of Example 2 was The average value was 63 mg / dl, which was a significantly low value. Further, 45 minutes after the administration, the control group had 79 mg / dl, whereas the Example 1 administration group had 43 mg / dl and the Example 2 administration group had 48 mg / dl, indicating that the glucose absorption inhibitory effect was observed. It was

Claims (1)

[Claims] 1. A main component is a conjugate of sugar and amino acid,
A sugar absorption inhibitor characterized by being water-soluble.