JP3512553B2 - Constipation inhibitor and composition containing it - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a constipation suppressor suitable for preventing or ameliorating constipation and a composition containing the same.

[0002]

2. Description of the Related Art Changes in eating habits are remarkable in the modern era, and together with the tendency of aging, various new diseases have become a big problem. Such diseases include excretion abnormal diseases such as constipation resulting from an increase in intake of high-energy foods such as lipids and a decrease in intake of crude fiber-containing foods. It is said that such diseases also cause rectal cancer and the like, as can be seen from the large number of patients with rectal cancer in Europe and the United States, for example, and early measures are important. From such a point of view, health foods containing plant fibers and the like have been put on the market. Also, sales of laxatives containing components such as senna are strong, which reflects this situation. However, the action on constipation of plant fibers and the like is weak, and it is difficult to say that it is practical. Since the laxatives on the market have too strong action, it cannot be denied that their use is difficult.

[0003]

SUMMARY OF THE INVENTION The present invention has been made under such circumstances, and has mild side effects.
Moreover, it is an object to provide a compound which can surely improve bowel movements.

[0004]

[Means for Solving the Problems] In view of such a situation,
The present inventors have earnestly researched for a compound having few side effects, mildly, and surely improving bowel movements, and as a result,
The inventors have found such an action in the compound represented by the general formula (I), that is, oligogalacturonic acid and / or a physiologically acceptable salt thereof, and completed the invention. Hereinafter, the present invention will be described in detail.

[0005]

[Chemical 2] General formula (I) (However, in the formula, n represents an integer of 0 to 20.)

(1) Constipation suppressant of the present invention The constipation suppressor of the present invention comprises the compound represented by the general formula (I) and / or a physiologically acceptable salt thereof.
Such a compound can be easily obtained by hydrolyzing pectin with an enzyme such as pectinase or by acid hydrolysis. In addition, n can be divided into a single product by purifying these hydrolyzates by ultrafiltration or gel filtration. In the present invention, even if n is single,
An unpurified product having a distribution can be used, but a single product or a product having a narrow distribution width is preferably used. Here, n is preferably 0 to 20, more preferably 1 to 15, and further preferably 1 to 8. The salt can be used without particular limitation as long as it is physiologically acceptable, for example, alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, ammonium salts, Examples thereof include organic amine salts, basic amino acid salts, and transition metal salts such as manganese and iron. Among these, the most preferable ones are transition metal salts having a high effect, and among them, iron salts are most preferable. This salt is more preferable than the free form because it is more effective than the free form.
Here, the salt as used in the present invention means not only a salt having a chemical equivalent of 1: 1 but also a complex having a quantitative ratio different from the chemical equivalent. The salt of the compound represented by the general formula (I) can be produced by mixing the compound represented by the general formula (I) and the corresponding base with water or the like as a medium.

As shown in the Examples below, the constipation suppressive agent of the present invention is excellent in safety and has a mild and surely improving effect on bowel movements. The daily dose of 10 to 100,000 mg may be administered once or in several divided doses. Examples of the administration route include oral administration, intravenous, arterial, portal vein, abdominal cavity, subcutaneous, etc. injection or drip injection. The most preferred of these is oral administration. This is because the constipation suppressive agent of the present invention exhibits excellent durability upon oral administration. Furthermore, oral administration is preferable in terms of ease of administration. Although the constipation suppressive agent of the present invention is certain, it does not rapidly induce urgency like conventional laxatives, and therefore administration of the constipation suppressor of the present invention may affect social life. Is very few.

(2) Composition of the present invention The composition of the present invention is one or two selected from the compounds represented by the general formula (I) and physiologically acceptable salts thereof.
It is characterized by containing at least one species. The composition of the present invention is preferably used as a medicine or food and drink. This is because the constipation suppressive agent of the present invention has a mild and reliable constipation suppressing action and high safety. For the formulation of the composition of the present invention, in addition to one or more selected from the compounds represented by the general formula (I) and physiologically acceptable salts, the composition is usually used in these medicines and foods and drinks. Can be included. Examples of such optional components include excipients, binders, coating agents, lubricants, sugar coating agents, disintegrating agents, bulking agents, flavoring agents, emulsifying / solubilizing / dispersing agents in pharmaceutical compositions. , Stabilizers, pH adjusters, isotonic agents, and the like. In food and drink, sweeteners, confectionery bases,
Examples thereof include flavoring agents, polysaccharides, emulsion stabilizers and thickeners. These compositions can be manufactured according to a conventional method. For example, it may be emulsified and mixed in a vacuum pot, or granulated by a granulator.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION Embodiments of the present invention will be described in detail below with reference to examples, but it goes without saying that the present invention is not limited to these examples.

Example 1. Production Example 1. Pectin 1Kg, pectinase 50g and water 5
1 was stirred at 35 ° C. for 1 hour, ultrafiltered and freeze-dried to obtain 123 g of a pectin hydrolyzate (constipation inhibitor 1). Furthermore, this product was produced by gel filtration and concentrated to give 30 g of galacturonic acid (n = 0, constipation suppressor 2), 11 g of dimer (n = 1, constipation suppressor 3), and trimer (n = 2, constipation suppressor 4) 8 g, tetramer (n = 3, constipation increase suppressor 5) 5 g, pentamer (n = 4, constipation suppressor 6) 7 g, hexamer (n = 5, constipation suppressant) Agent 7) 5 g, 7-mer (n = 6, constipation suppressor 8) 4 g, 8-mer (n = 7, constipation suppressor 9) 3
g was obtained.

Example 2. Production Example 2 1 g of the constipation inhibitors 2 to 9 and 1 g of ferrous chloride were added to water 2
It was dissolved in 00 ml, stirred at room temperature for 2 hours, purified by ultrafiltration, and lyophilized for 48 hours. Then, each complex was treated with galacturonic acid complex (constipation inhibitor 1
0) 0.1 g, dimer complex (constipation inhibitor 1
1) 0.4 g, trimer complex (constipation inhibitor 1
2) 0.5 g, tetramer complex (constipation suppressant 1
3) 0.8 g, pentamer complex (constipation inhibitor 1
4) 1.3 g, hexamer complex (constipation inhibitor 1
5) 1.2g, 7-mer complex (constipation suppressant 16)
1.6g, octamer complex (constipation inhibitor 17)
1.1 g was obtained.

Example 3. Example of compounding into candy The following component (A) is heated and melted at 150 ° C, cooled to 120 ° C, then the component (B) is added, stirred and molded into a uniform product, and cooled to obtain a candy. It was

Example 4. Example of compounding into candy The following component (A) is heated and melted at 150 ° C, cooled to 120 ° C, then the component (B) is added, stirred and molded into a uniform product, and cooled to obtain a candy. It was

Example 5. Example of compounding into gummy The following component (A) is melted by heating at 110 ° C., component (B) separately swollen and dissolved is added, and then component (C) is further added and poured into a mold and left for one day and night. I took it off and got a gummy.

Example 6. Example of compounding into gummy The following component (A) is melted by heating at 110 ° C., component (B) separately swollen and dissolved is added, and then component (C) is further added and poured into a mold and left for one day and night. I took it off and got a gummy.

Example 7. Capsule The following (A) component is mixed and stirred uniformly, and (B) is added to it.
The ingredients were added and thoroughly kneaded with a kneader. This was encapsulated with a capsule filling machine to prepare a capsule. (A) Squalene 15 Triglyceride linolenic acid 15 Wheat germ oil 10 Refined sardine oil 20 α-d tocopherol 0.2 (B) Defatted soybean powder 39.8 Constipation suppressor 5 10

Example 8. Tablets The following ingredients are uniformly mixed and granulated by a fluidized bed granulation method,
Dried. This was tableted with a tableting machine to obtain tablets.

Example 9. Granules The following component (A) is placed in a glad granulator, and a 5% aqueous solution of component (B) is added dropwise to granulate, followed by drying at 40 ° C.
The particles were sized to obtain granules. (A) Lactose 67.5 Corn starch 10 Constipation suppressant 7 20 (B) Hydroxypropyl cellulose 2.5

Example 10. Granules The following component (A) is placed in a glad granulator, and a 5% aqueous solution of component (B) is added dropwise to granulate, followed by drying at 40 ° C.
The particles were sized to obtain granules. (A) Lactose 67.5 Corn starch 10 Constipation suppressant 8 20 (B) Hydroxypropyl cellulose 2.5

Example 11. Example of compounding into candy The following component (A) is heated and melted at 150 ° C, cooled to 120 ° C, then the component (B) is added, stirred and molded into a uniform product, and cooled to obtain a candy. It was

Example 12. Example of compounding into candy The following component (A) is heated and melted at 150 ° C, cooled to 120 ° C, then the component (B) is added, stirred and molded into a uniform product, and cooled to obtain a candy. It was

Example 13. Example of compounding into gummy The following component (A) is melted by heating at 110 ° C., component (B) separately swollen and dissolved is added, and then component (C) is further added and poured into a mold and left for one day and night. I took it off and got a gummy.

Example 14. Example of compounding into gummy The following component (A) is melted by heating at 110 ° C., component (B) separately swollen and dissolved is added, and then component (C) is further added and poured into a mold and left for one day and night. I took it off and got a gummy.

Example 15. Capsule The following (A) component is mixed and stirred uniformly, and (B) is added to it.
The ingredients were added and thoroughly kneaded with a kneader. This was encapsulated with a capsule filling machine to prepare a capsule. (A) Squalene 15 Triglyceride Linolenic Acid 15 Wheat Germ Oil 10 Refined Sardine Oil 20 α-d Tocopherol 0.2 (B) Defatted Soybean Powder 39.8 Constipation Depressant 13 10

Example 16. Tablets The following ingredients are uniformly mixed and granulated by a fluidized bed granulation method,
Dried. This was tableted with a tableting machine to obtain tablets. Dextrin 15 Lactose 5 Palatinose 15 Potato starch 40 Magnesium stearate 5 Constipation suppressant 14 20

Example 17. Granules The following component (A) is placed in a glad granulator, and a 5% aqueous solution of component (B) is added dropwise to granulate, followed by drying at 40 ° C.
The particles were sized to obtain granules. (A) Lactose 67.5 Corn starch 10 Constipation suppressant 15 20 (B) Hydroxypropyl cellulose 2.5

Example 18. Granules The following component (A) is placed in a glad granulator, and a 5% aqueous solution of component (B) is added dropwise to granulate, followed by drying at 40 ° C.
The particles were sized to obtain granules. (A) Lactose 67.5 Corn starch 10 Constipation suppressant 16 20 (B) Hydroxypropyl cellulose 2.5

Example 19. Granules The following component (A) is placed in a glad granulator, and a 5% aqueous solution of component (B) is added dropwise to granulate, followed by drying at 40 ° C.
The particles were sized to obtain granules. (A) Lactose 67.5 Corn starch 10 Constipation suppressant 17 20 (B) Hydroxypropyl cellulose 2.5

[0029]

【Example】

Example 1. Acute toxicity and toxicity test An acute toxicity test by oral administration was carried out using 1 group of 10 ddy mice each having a body weight of 15 to 25 g. The samples used were constipation inhibitors 1 to 17 of Examples 1 and 2. 30% for each sample
A physiological saline solution or dispersion was used, and 12 g / Kg was orally administered, and life or death was determined 72 hours later. No deaths were observed in any of the groups. From this, it is clear that the constipation inhibitor of the present invention is highly safe.

Example 2. Gastric Retention Test A gastric retention test was carried out using 10 ICR mice (male, 25 to 30 g) per group. That is, after fasting mice for 24 hours, 1 g / Kg of sucrose and 2 g / Kg of specimen
And bromothymol blue sodium (BTB) 0.3%
350 μl of saline solution was administered. The animals were sacrificed 30 minutes after the administration, the stomach and intestinal tract were removed, and BTB was extracted and quantified from the stomach, intestine, and feces with ethanol to determine the gastric retention rate.
Samples are constipation inhibitors 1-17 and dried leaves of senna (control 1)
And wheat bran (control 2), in which physiological saline was administered instead of the test substance. The results are shown in Table 1. From this, it can be seen that the constipation inhibitor of the present invention promotes gastric excretion more surely than that of the usual crude fiber, Fuma, and does not exert a more rapid action than Senna. It is also found that among the constipation suppressive agents of the present invention, the transition metal salts are superior in action.

[0031]

[Table 1]

Example 3 Atropine-administered ICR mice (male, 25 g to 30 g) in groups of 5 were used.
The constipation-suppressing effect in an atropine-administered constipation model was examined.
That is, atropine (0.5 mg / Kg) was intradermally administered immediately after feeding and 3 hours after feeding to obtain an experimental constipation model. As a sample, 2 g / Kg was administered at the time of feeding. At this time, BTB was also administered as in Example 2. Feces were collected over time up to 6 hours after administration, and the weight of feces and the amount of excreted BTB were measured. Constipation suppressants 9 and 17 were used as samples, wheat bran was used as control 1, and dried leaves of senna were used as control 2. The results are shown in Table 2.
In addition, no treatment is a group to which neither atropine nor a sample is administered.
From this, it can be seen that the constipation inhibitor of the present invention restored constipation to a state close to normal. Furthermore, it is also found that excretion is not abnormally promoted unlike senna.

[0033]

[Table 2]

[0034]

EFFECTS OF THE INVENTION According to the present invention, it is possible to provide a compound which can mildly improve bowel movements with few side effects.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI C07H 7/033 C07H 7/033 C08B 37/06 C08B 37/06 // A23L 1/06 A23L 1/06 (58) Fields investigated (Int.Cl. ⁷ , DB name) C07H 7/033 C08B 37/06 CA (STN) REGISTRY (STN)

Claims (6)

(57) [Claims] 1. A constipation inhibitor comprising a compound represented by the following general formula (I) and / or a physiologically acceptable salt thereof. General formula (I) (However, in the formula, n represents an integer of 0 to 20.) 2. The constipation suppressor according to claim 1, wherein n is 1 to 8 in the general formula (I). 3. The constipation suppressor according to claim 1, wherein the salt of the compound represented by the general formula (I) is a transition metal salt. 4. A composition for preventing or ameliorating constipation, which comprises the constipation suppressor according to any one of claims 1 to 3. 5. A food containing the composition according to claim 4. 6. A pharmaceutical containing the composition according to claim 4.