JPH04210647A - Medicine and food or drink for preventing or treating ulcer - Google Patents

Abstract

PURPOSE:To obtain a medicine, food and drink, containing kappa-casein glycomacropeptide (GMP) or its enzymic hydrolyzate as an active ingredient, excellent in inhibitory effects on gastric acid secretion and utilizable also for preventing occurrence or recurrence of ulcer. CONSTITUTION:A medicine, food and drink containing a peptide selected from the group consisting of GMP obtained by using whey or a whey protein- containing solution such as a whey protein concentrate in producing cheese as a raw material, the GMP prepared by reducing the pH during the production process or treatment with an enzyme such as a sialidase and removing sialic acid residues in saccharide chains and the GMP obtained by hydrolysis with a proteolytic enzyme such as pepsin or trypsin as a gastric acid secretion inhibitory ingredient. The GMP is used as an oral antiulcer agent such as a sugar- coated tablet, a tablet or a capsule or as an antiulcer food by addition to various foods and drinks.

Description

[Detailed description of the invention]

[00011

[Industrial Field of Application] The present invention relates to pharmaceuticals and food and drink products for the prevention or treatment of gastric ulcers containing casein glycomacropeptide or its enzymatically decomposed product as an active ingredient. [0002] Anti-ulcer agents include antacids that suppress the digestive action of gastric juice, anticholinergic agents that suppress gastric juice secretion itself, anti-gastrin agents, and histamine receptor antagonists. However, antacids such as sodium bicarbonate have a quick effect but have a short duration of action, and long-term administration of large amounts can induce alkalosis, while calcium carbonate preparations can cause hypercalcemia, which can cause urinary stones. , Magnesium preparations have the disadvantage of being more likely to cause diarrhea. Furthermore, anti-conon drugs also have side effects such as dry mouth, constipation, and heart palpitation, so they cannot necessarily be said to be satisfactory anti-ulcer agents. Furthermore, peptide preparations, which are the mainstay of antigastrin drugs, like urogastrone and secretin, must be purified from animal urine and organs, resulting in high manufacturing costs and limited production quantities. [0003]Although histamine receptor antagonists have recently been developed, they have the problem that ulcers tend to recur when administration is discontinued. Particularly in today's stressful society, the lifetime morbidity rate of gastric ulcers is said to be 20%, and the probability of recurrence is extremely high, at over 80%, and in the event of recurrence, it is necessary to start administering anti-ulcer drugs again. In other words, patients suffering from stomach ulcers must continue to take pharmaceutical anti-ulcer drugs on a regular basis, and even if drugs with few side effects are used, it cannot be said that they have no effect on the human body. [0004] Under these circumstances, anti-ulcer agents that are highly effective in suppressing the secretion of gastric juice, do not involve risks such as side effects, and can be manufactured at a relatively low cost, or prevent the onset and recurrence of ulcers, which can be considered chronic diseases, are needed. There is a strong need to provide food materials with the functionality of [0005]

[Problems to be Solved by the Invention] The present invention solves the problems seen in conventional anti-ulcer agents as described above, and
This was done in consideration of the characteristics of ulcers as a chronic disease. In other words, it is obtained from relatively inexpensive raw materials, has a good gastric juice secretion suppressing effect, and can be used not only as a medicine to treat ulcers, but also as a functional food or pathological food to prevent the onset and recurrence of ulcers. The challenge is to provide materials that can be used. [0006] Chernikov and 5tan (XXI
InternationalDairy Congr
ess, Moscow, vo 1.1. Book2. p
p. 161.1982) conducted an experiment in which a pepsin-degraded product of casein was administered into the blood of dogs, and suggested that some substances in this degraded product suppressed gastric juice secretion, while others promoted it. The report does not mention any specific experimental data. After that, there were no related reports for a while, but in 1987 Guilloteau
et al (Reprod, Nutr, Develop lop
, 27.287-288.1987) reported that there was no change in the amount of gastric juice secretion even when casein macropeptide was administered intravenously to calves. Thus, at present, no clear conclusion has yet been drawn regarding the effect of suppressing gastric juice secretion on peptides obtained by enzymatically decomposing milk proteins. [00071 Against this background, the present inventors
Whey produced during cheese production, whey protein concentrate,
After intensive studies using rats on the gastric secretion suppressing effect of κ-casein glycomacropeptide (hereinafter abbreviated as GMP) obtained from whey protein-containing solutions such as protein-free cheese whey, GMP was administered intravenously. The present inventors have discovered that they exhibit remarkable gastric juice secretion suppressing effects and anti-ulcer effects not only when administered orally, but also when administered orally, and have thus arrived at the present invention. [0008]

[Means for Solving the Problems] The present invention relates to pharmaceuticals and food/beverage products for preventing or treating gastric ulcers, which contain as an active ingredient GMP or a peptide obtained by decomposing GMP, which has the effect of suppressing gastric juice secretion. [0009] It has been known for a long time that GMP is liberated in whey during cheese production, and GMP is used as a raw material in cheese whey, whey protein concentrate produced by ultrafiltration of cheese whey, or when heated, etc. Cheese whey from which whey proteins have been precipitated and removed by the method described above or lactose mother liquor can be used. In order to industrially produce GMP, the method disclosed in Japanese Patent Publication No. 59-27358 can be used, but this method
I can't get P. [0010] In order to obtain GMP with high purity, the method disclosed in Japanese Patent Application Laid-Open No. 1-276542 or Japanese Patent Application No. 2-9
The method described in Japanese Patent No. 5686 may be used. Furthermore, GMP can also be obtained from the liquid remaining after producing rennet casein curd by the method disclosed in JP-A-61284199. Although the GMP thus obtained may be used as an antiulcer agent in the form of a solution, it is usually dried by spray drying or freeze drying and used in the form of a powder. Incidentally, since GMP is stable against heat, it is further desirable to include a sterilization step before the drying step. [00111 GMP obtained in this way can be processed by lowering the pH during the manufacturing process, by removing sialic acid in sugar chains by treating with enzymes such as sialidase, or by treating with pepsin, trypsin, or actinase. It may be treated with enzymes such as When using these enzymes, GMP is dissolved in a buffer solution having a pH near the optimum pH of the enzyme, and enzyme treatment is carried out at an optimum temperature for a required period of time. The resulting enzyme-treated GMP is heated with boiling water or the like to inactivate the enzyme, and used as enzyme-treated GMP. Alternatively, this enzyme-treated GMP may be further purified by chromatography or the like before use. [0012] The GMP obtained as described above can be used as an oral anti-ulcer agent such as sugar-coated tablets, tablets, or capsules. It can also be used as an anti-ulcer food by adding it to various foods and drinks, such as soft drinks, fruit juice drinks, fermented drinks, jelly, and ice cream. Furthermore, it can be added to sweets such as gum and candy. [0013] Furthermore, GMP, which is a component of the present anti-ulcer substance,
is a peptide derived from milk components, and when ingested orally, there is no adverse effect on the human body, and there are no particular restrictions on the amount of ingestion. However, when actually ingested orally as an anti-ulcer agent or as a food for treating or preventing ulcers, the appropriate amount is 0.1 to 1000 .mu./Kg body weight/day, preferably 1 to 100 .mu./Kg body weight/day. That is, no effect is observed at doses below 1 mg/Kg body weight/day, and although there are no side effects, no significant increase in efficacy is observed even when doses of 1,000 μg or more are administered. The present invention is characterized in that the peptide can be administered in large amounts and continuously over a long period of time. [0014] Furthermore, the GMP obtained as described above can be further purified using an anion exchange resin to obtain highly purified GMP, which can then be used as a pharmaceutical product such as an injection solution or a preparation. Although GMP is a milk-derived peptide, it is said to have almost no antigenicity and is less likely to cause allergic symptoms. /day, preferably 0.1
Approximately 10 cm/kg body weight/day is appropriate. That is,
There is no effect below 0.01 mg/Kg body weight/day, and 10
At doses of 0 mg/Kg body weight/day or more, no side effects are observed and there are no problems, but no particular increase in effectiveness is observed. [0015] In the case of oral administration or administration by injection, the drug may be administered once a day, or may be administered in several divided doses. [0016]

Effects of the Invention The effects of the antiulcer agent according to the present invention are summarized as follows. (1) Since it is a milk-derived peptide that is commonly ingested as food, there is no need to worry about side effects when administered. (2) Because it is made from milk, which is a food product, the manufacturing cost is much lower than that of conventional anti-ulcer agents. (3) Compared to conventional anti-ulcer drugs, it can be prepared in large quantities;
It can be widely used not only as a medicine but also as a food material. [0017] The present invention will be specifically described below based on Examples. [0018]

[Example 1] This example shows the effect of suppressing gastric juice secretion in an intravenous administration test of the anti-ulcer substance according to the present invention. [Test Method] Wistar rats (male, 7 months old, 8 rats in each group) were fasted for 16 hours and water was restricted for 2 hours. 01. 0.
1゜1.10, 100 mg/Kg body weight, β-lactoglobulin at 1■/Kg body weight, or physiological saline alone was intravenously injected, and the pylorus of the stomach was immediately ligated. After 4 hours, the pylorus of the stomach was also ligated, the stomach was removed, and the gastric juice accumulated in the stomach was collected and its volume was measured, as well as its acidity was measured by titration. As shown in the attached Table 1, GMP was 0. 1mg/Kg
In the group administered at or above body weight, gastric acid secretion decreased significantly. [0019]

[Table 1] sample Gastric acid secretion (mEmJhr) GMP (0,0-1 integral movement 0.281f: 0.105 (0.11Ig/Xg body weight) 0.108±o,oss (Button 1 integrated o, o96±o, o52 (10mg/Xg body■ 0.086fO,092 α shout 1 body button 0.058±0.049 β-lactoglobulin (-1 monoweight) 0.291±0.070 saline 0.327±0.089 (Standard deviation above mean value (n=8)) (Standard deviation above mean value (n=8)) [00203

Example 21 This shows the gastric juice secretion suppressing effects of desialylated GMP prepared by treating GMP with sialidase and hydrolyzed GMP prepared by treating GMP with trypsin in an intravenous administration test. [00213 (Enzyme treatment of GMP)] For desialylated GMP, dissolve GMP25■ in 2.5 ml of 0.1 M acetic acid solution (pH 5), and add sialidase 1.2
5■ was added and incubated at 30°C for 30 minutes. The enzyme was inactivated by heating in boiling water for 10 minutes, and then diluted to a predetermined concentration. The sialic acid removal rate was calculated by measuring the amount of free sialic acid and the amount of bound sialic acid using a Far East sialic acid measurement kit. For trypsinization of GMP, GMP60■ was mixed with 0.1M Tris buffer (p
H8) was dissolved in 6 ml, 0.6 μl of trypsin was added, and the mixture was incubated at 37° C. for 30 minutes. 1 in boiling water
After heating for 0 minutes to inactivate the enzyme, it was diluted to a predetermined concentration. Trinibusin degradation rate was determined by NOVO Enzyme I
nformation (November AF
95/1-GB, 1970), the average number of residues was measured and calculated. [0022] [Test Method] Wistar rats (male, 7 months old, 8 rats in each group) were fasted for 16 hours and water was restricted for 2 hours. GMP (sialic acid removal rate 95%) was intravenously injected at 1 kg/kg body weight or trypsin-hydrolyzed GMP 1 kg/kg body weight, and the pylorus of the stomach was immediately ligated. The hydrolysis rates of GMP were 41% and 68%. After 4 hours, the gastric cardia was also ligated, the stomach was removed, and the gastric juice accumulated in the stomach was collected and the volume was measured, as well as the acidity was measured by titration. As shown in Table 2,
In the desialylated GMP group or the hydrolyzed GMP group, a decrease in gastric acid secretion equivalent to that in the untreated GMP group was observed. [0023] [Table 2] Sample gastric acid secretion (!IBQ/Senr) Desialylated GMP 0.091±0.067 Hydrolyzed GMP CMpI! -41%) 0. n=8)) [0024]

[Example 3] This example shows the effect of suppressing gastric juice secretion in an oral administration test of the anti-ulcer substance of the present invention. [Test method] Wistar rats (male, 7 months old, 8 rats in each group) were fasted for 16 hours and water was restricted for 2 hours. 2ml
GMP according to the present invention dissolved in water of 0. 1. 1.
10. 100.1000 .mu./Kg body weight or water alone was orally administered, and 1 hour later, the pylorus of the stomach was ligated. 4
After a period of time, the gastric cardia was also ligated, the stomach was removed, and the gastric juice accumulated in the stomach was collected and the volume was measured, and the acidity was also measured by titration. As shown in Table 3, the amount of gastric acid secretion was significantly reduced in the group to which GMP was administered at 1 kg/kg body weight or more. [0025]

[Table 3] sump le Gastric acid secretion (mE & 4hr) GMP (0, lxg1Kg body movement 0.278±0.106 (-1 one ■ 0.132±0.096 (1 Gaga V Hetai 1 0.106±0.081 (1aDIIg1Kg body■ 0.071±0. Alpha, <1000*g/lcg body movement 0.089±0.054 water 0.287±0.094 (Standard deviation above mean value (n=8)) (Standard deviation above mean value (n=8)) [0026]

[Example 4] This example shows the effect of treating gastric ulcer in an intravenous administration test of the anti-ulcer substance according to the present invention. [Test method] Wistar rats (male, 8 weeks old, 6 in each group) that had been fasted for 16 hours were injected with 0.0% 70% ethanol. GMP according to the invention administered orally in 5 ml and immediately dissolved in physiological saline.
1■/Kg body weight, β-lactoglobulin 1■/Kg
Body weight or saline alone was administered intravenously. After 5 hours, the stomach was removed, the large incision was made, and the mucosal surface was washed with physiological saline, and the degree of ulceration was observed. The degree of ulceration was divided into 6 levels depending on the degree of mucosal bleeding foci. As shown in Table 4, a clear reduction in ulcers was observed in the GMP-administered group. [0027]

[Table 4] Sample ulcer degree GMP 1.57±130 β-lactoglobulin 3.11±1.48 Physiological saline 3.67±138 GMP-containing milk drink 1.0±121 Milk drink 2° ±145 GMP-containing Jelly 1.87±1.54 Jelly 3.01±L55 Ulcer degree: 0 = No ulcer observed on the gastric mucosa. 1 = Redness only. 2 = 1 bleeding sore. 3 = 2-5 bleeding sores. 4 = 6-9 bleeding sores. 5 = 10 or more bleeding sores. (Standard deviation above mean value (n=6)) [0028]

Example 5 This example shows the use of the anti-ulcer substance of the present invention in a food product for preventing ulcers. (1) Production of milk drink for preventing ulcers A milk drink for preventing ulcers was prepared using GMP according to the following formulation. [0029]

[Table 5] Ingredient blending amount (vt%) Skim milk powder 7.7 Glucose 6.0 Safflower oil 2.0 Sugar ester 0.1 Vitamins 0.02 Yogurt flavor 0.18 GMP 1.0 Mizumugi, 0 [ 00301 Based on the above formulation, 23.1 g of skim milk, 15 g of glucose, 0.06 g of vitamins, and 0.0 g of yogurt flavor. 54g of safflower oil and 3g of GMP dissolved in 100ml of warm water heated to 60℃, add 6g of safflower oil.
g and sugar ester (product name DKF160) 0.3g
The mixture was gradually added dropwise to emulsify the mixture at 60° C. while stirring with a TK homomixer. After heat sterilizing this at 90°C for 5 minutes, it was cooled to 10°C to obtain a product. In addition, a milk beverage except for excluding GMP from the above recipe was also produced in the same manner. Next, these milk drinks were given to rats to examine their anti-ulcer effects. [00311 [Test method] At the same time as the start of fasting, milk drinks containing the above GMP or G
Wistar rats (A, 8 weeks old, 6 rats in each group) were given a milk drink prepared without EMP ad libitum, and after 16 hours, 70% alcohol was given at 0.00%. 5 ml was administered. After a further 5 hours, the stomach was removed, a large groove incision was made, and the mucosal surface was washed with physiological saline, and the degree of ulceration was observed. As shown in Table 4, a clear reduction in ulcers was observed in the group administered the milk drink containing GMP. [0032] (2) Production of jelly for preventing gastric ulcers A jelly for preventing ulcers was produced using GMP according to the formulation shown in Table 6 below. [0033]

[Table 6] Ingredient blending amount (vt%) Sugar positive, 0 Prune extract 4.0 Gelatin 0.5 GMP 5.0 Water 75.5 [0034] According to the table above, sugar, gelatin, GMP
was added to 50 ml of water, heated at 80°C to dissolve, and after adding prune extract and stirring, the mixture was transferred to a container and cooled. In addition, a GMP-free jelly was also produced in the same manner. [0035] Next, give these jellies to rats,
We investigated its effectiveness in preventing gastric ulcers. [Test method] Wistar rats (male, 8 weeks old, 6 in each group) fasted for 16 hours were given the above GMP-containing jelly or GM.
2 g each of P-free jelly was administered. 1 hour later 70
% alcohol to 0. After 5 ml of administration, the stomach was removed, a large groove incision was made, and the mucosal surface was washed with physiological saline, and the degree of ulceration was observed. As shown in Table 4, GMP
A clear reduction in ulcers was seen in the group receiving the jelly containing . Continuation of the front page (51) Int, C1,5 A 61 K 37/'16 // C07K 15/14 Identification code CL Internal reference number 8317-4C 7731-4H I Technical display location

Claims (3)

[Claims] Claim 1: Selected from the group consisting of κ-casein glycomacropeptide, κ-casein glycomacropeptide with sialic acid residues removed from sugar chains, and κ-casein glycomacropeptide hydrolyzed with a protease. 1. A preventive or therapeutic agent for gastric ulcer, which contains one or more peptides as a gastric acid secretion suppressing ingredient. 2. The agent for preventing or treating gastric ulcer according to claim 1, which is in an oral dosage form. Claim 3: A κ-casein glycomacropeptide selected from the group consisting of κ-casein glycomacropeptide, κ-casein glycomacropeptide from which sialic acid residues in sugar chains have been removed, and κ-casein glycomacropeptide hydrolyzed with a protease. A functional food/beverage product having a preventive or therapeutic effect on gastric ulcer, characterized by containing one or more peptides as a gastric acid secretion suppressing ingredient.