JP2004107302A - Therapeutic agent for hypersensitive bowel syndrome - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a therapeutic agent for hypersensitive bowel syndrome, particularly Crohn's disease and ulcerative colitis by enhancing innate immune ability in intestinal tissue in an organism. <P>SOLUTION: This therapeutic agent for hypersensitive bowel syndrome comprises isoleucine as an active ingredient. The hypersensitive bowel syndrome includes Crohn's disease or ulcerative colitis. The therapeutic agent can combinedly be used together with yogurt of Lactobacillus lactis. A method for enhancing the innate immune ability comprises secreting an antimicrobial peptide from Paneth's cell in the intestinal tissue epithelium by administering isoleucine and suppressing abnormal immunity of the intestinal tissue in order to treat the hypersensitive bowel syndrome. <P>COPYRIGHT: (C)2004,JPO

Description

【００３７】
イソロイシン投与前およびイソロイシン投与後のＬｏｇ　ＣＦＵの変動を図１０に示した。図中に示した結果からも判明するように、常在腸内細菌である乳酸杆菌（Ｌａｃｔｏｂａｃｉｌｌｉ）の増加の傾向が認められた。
以上の事実から、イソロイシンと共に乳酸桿菌ヨーグルトを併用すると、より有効な治療が得られる事実が判明する。
【００３８】
製剤例：顆粒剤
組成：
イソロイシン　　　　　　　　　　　　　　　　　　　３００ｇ
乳糖　　　　　　　　　　　　　　　　　　　　　　　１３４ｇ
結晶セルロース　　　　　　　　　　　　　　　　　　　２０ｇ
トウモロコシ澱粉　　　　　　　　　　　　　　　　　　２０ｇ
３％ヒドロキシプロピルメチルセルロース水溶液　　　１００ｍｌ
ステアリン酸マグネシウム　　　　　　　　　　　　　　　３ｇ
【００３９】
製法：
イソロイシンに乳糖、結晶セルロースおよびトウモロコシ澱粉を６０メッシュのふるいで篩化し、均一に混合した後、練合機に入れ、３％ヒドロキシプロピルメチルセルロース水溶液を注加して、さらに練合した。次いで１６メッシュのふるいで篩化し、造粒を行い、５０℃で通風乾燥した。乾燥後、造粒をおこない、顆粒在を得た。
【００４０】
【発明の効果】
以上記載のように、本発明は、生体における腸管組織に先天性免疫能を増強させることによる、過敏性腸症候群、特にクローン病ならびに潰瘍性大腸炎の治療剤が提供される。
特に本発明の有効成分であるイソロイシンは、クローン病の主症状である水様状態の下痢症状の回数を抑えることができ、難病であるクローン病を有効に治療することができ、その医療上の価値は多大なものである。
【図面の簡単な説明】
【図１】本発明の試験例における評価１の結果である、全試験対象者における大便の１日平均頻度の推移を示す図である。
【図２】本発明の試験例における評価１の結果である、過敏性腸症候群患者［クローン病患者（ＣＤ）および潰瘍性大腸炎患者（ＵＣ）］における大便の１日平均頻度の推移を示す図である。
【図３】本発明の試験例における評価２の結果である、全試験対象者における水様／泥状下痢／１日の平均発生回数の推移を示す図である。
【図４】本発明の試験例における評価２の結果である、過敏性腸症候群患者［クローン病患者（ＣＤ）および潰瘍性大腸炎患者（ＵＣ）］における水様／泥状下痢／１日の平均発生回数の推移を示す図である。
【図５】本発明の試験例における評価３の結果である、全試験対象者における腹部の疼痛スコアの推移を示す図である。
【図６】本発明の試験例における評価３の結果である、過敏性腸症候群患者［クローン病患者（ＣＤ）および潰瘍性大腸炎患者（ＵＣ）］における腹部の疼痛スコアの推移を示す図である。
【図７】本発明の試験例における評価４の結果である、全試験対象者における一般症状のスコアの推移を示す図である。
【図８】本発明の試験例における評価４の結果である、過敏性腸症候群患者［クローン病患者（ＣＤ）および潰瘍性大腸炎患者（ＵＣ）］における一般症状のスコアの推移を示す図である。
【図９】本発明の試験例における評価５の、クローン病患者におけるイソロイシン投与によるＣＤＡＩの変動を示す図である。
【図１０】本発明の試験例における評価６の、イソロイシン投与前およびイソロイシン投与後の乳酸杆菌（Ｌａｃｔｏｂａｃｉｌｌｉ）について、Ｌｏｇ　ＣＦＵの変動を示した図である。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a therapeutic agent for irritable bowel syndrome (IBD), particularly Crohn's disease and Ulcerative colitis.
[0002]
[Prior art]
There are Crohn's disease and ulcerative colitis as irritable bowel syndrome, which is a chronic inflammatory disease resulting from ulcers in the digestive tract of the small intestine and large intestine, or rarely in the stomach and oral tissues. Both are due to differences in ulcer depth, and Crohn's disease based on deep ulcer formation causes complications such as stenosis, fistula, perforation, and adhesion from the small intestine to the large intestine tissue, diarrhea and cecal region from the terminal ileum Abdominal pain is the main symptom, and it is a disease that is difficult to cure by repeated remission, recurrence, and relapse.
[0003]
On the other hand, inflammation caused by shallow ulceration that specifically occurs from the colon to the entire large intestine is distinguished from Crohn's disease as ulcerative colitis, but it is a chronic inflammatory disease that arises from ulcers like Crohn's disease. It is a disease with rectal bleeding, mucous crypt abscess, inflammatory pseudopolyp, abdominal pain, diarrhea.
[0004]
Among them, Crohn's disease is a disease that has been designated as an intractable disease by the Ministry of Health, Labor and Welfare because its etiology cannot be identified and is difficult to cure. Until now, the pathogenesis of Crohn's disease has been estimated to include genetic predisposition, infection with bacteria and viruses, and microcirculatory factors (chemical substances) in the intestinal tract. The idea of being there has become mainstream.
[0005]
In other words, in the intestinal tract tissue in patients with Crohn's disease, abnormal immunity has occurred for some reason, and a phenomenon that a large amount of harmful foreign substances such as bacteria and viruses that should not be absorbed is taken in from the intestinal tract. ing. As a result, a large amount of immune cells such as macrophages are produced. These macrophages produce TNF-α (tumor necrosis factor-α: tumor necrosis factor), and the produced TNF-α is in the intestinal mucosa. Inflammation is caused by binding to a receptor, and it is believed that ulcers gradually develop when such inflammatory symptoms persist.
[0006]
Therefore, substances that can suppress the occurrence of abnormal immunity in the intestinal tissue are considered to be able to effectively cope with the treatment of Crohn's disease. Nothing has been done actively. For the treatment of Crohn's disease so far, steroidal agents such as prednisolone and betamethasone, 5-ASA preparations such as mesalazine and salazisulfapyridine, antibiotics or immunosuppressants, anti-inflammatory agents, etc. The current situation is that administration is performed alone or in combination.
[0007]
By the way, the monolayer epithelium of the human intestinal tract tissue is formed continuously from stem cells present in the crypts (Crypts), and lesions in the intestinal mucosa (ie, a decrease in immunity) are caused by bacteria, viruses Therefore, the living body has an innate immunity reaction mechanism. In the intestinal tract tissue, a healthy epithelium is maintained by its innate immune response, maintaining the survival of stem cells and suppressing the occurrence of ulcers due to inflammation.
[0008]
As one of the innate immune reactions in the living body, secretion of an antimicrobial peptide derived from the living body is mentioned. That is, when there is a risk of infection in a living body such as bacteria or viruses, some types of antibacterial peptides such as β-defensins are produced in epithelial cells and are congenital to those that can be pathogens. It is known to act as an immune effector.
[0009]
According to previous studies, in the small intestine, it has been reported that α-defensins (cryptodines) are abundant in granules secreted from Paneth cells of the small intestine crypt (Crypts). [J. Biol. Chem. 267: 23216-23225 (1992); Infect. Immun. 62: 5040-5047 (1994); Cell Biol. 118: 926-936 (1992); Infect. Immun. 60: 3556-3565 (1992); Infect. Immun. 65: 2389-2395 (1997)].
[0010]
The bactericidal action of α-defensins present in the granules secreted from the Paneth cells is extremely strong. For example, according to immunohistological examination of Paneth cells, in the small intestine, anti-microbial peptides α-defensins are present only in granules secreted from Paneth cells, and these granules are intestinal crypts. It is known that the cells are secreted from the basal part of the Paneth cells toward the tip of the crypt lumen. From this fact, granule-secreting cells (panate cells) in the body, especially in the intestinal epithelium, respond to mucosal immunity positively by sensing bacteria or viruses and releasing bactericidal peptides at their effective concentrations, It is believed to play a functional role in the host's defense response to bacterial or viral infection (ie, enhanced innate immunity).
[0011]
Therefore, if a substance capable of deliberately inducing secretion of a bioantibacterial peptide (bactericidal peptide) into the intestinal epithelium is found and administered to the living body, it becomes a therapeutic agent for various diseases by enhancing the innate immune function of the living body. You can get it. In particular, the pathogenesis of irritable bowel diseases such as Crohn's disease and ulcerative colitis is due to a decrease in innate immunity due to abnormal immunity in the intestinal tissue. The potentiating substance is a highly effective treatment for irritable bowel syndrome. In addition, if such a substance is not toxic to the living body and can be safely administered, it is a therapeutic agent that is extremely effective clinically.
[0012]
By the way, it is known that secretion of such a bioantibacterial peptide is promoted by administering leucine, isoleucine or valine, which are essential amino acids having a branched chain among amino acids.
[0013]
Therefore, the present inventors examined the therapeutic effect on irritable bowel symptoms caused by such an essential amino acid having a branched chain, and isoleucine is extremely effective among irritable bowel syndrome among the branched chain essential amino acids, that is, Crohn's disease. As a result, the present invention has been found to be effective in the treatment of ulcerative colitis, and the present invention has been completed.
[0014]
Furthermore, according to the study by the present inventors, the combined use of lactic acid bacteria products, especially lactobacilli yogurt, with isoleucine significantly reduces the number of watery diarrhea that plagues patients with Crohn's disease and is extremely effective. As a result, the present invention has been completed.
[0015]
[Problems to be solved by the invention]
Accordingly, the present invention has been completed based on the results of such studies, and provides a therapeutic agent for irritable bowel syndrome by enhancing innate immunity in the intestinal tissue in the living body, that is, in particular, Crohn's disease and It is an object to provide a therapeutic agent for ulcerative colitis.
[0016]
[Means for Solving the Problems]
Therefore, the invention according to claim 1, which is a basic aspect of the present invention, is a therapeutic drug for irritable bowel syndrome containing isoleucine as an active ingredient.
[0017]
The invention according to claim 2 is a therapeutic agent for irritable bowel syndrome comprising isoleucine used in combination with lactobacillus yogurt as an active ingredient.
[0018]
Irritable bowel syndrome effectively treated with the therapeutic agent provided by the present invention includes Crohn's disease and ulcerative colitis. Therefore, the invention according to claim 3 is the therapeutic agent according to claim 1 or 2, wherein the irritable bowel syndrome is Crohn's disease, and the invention according to claim 4 is characterized in that the irritable bowel syndrome is ulcerative. The therapeutic agent according to claim 1 or 2, which is colitis.
[0019]
Moreover, in order to treat irritable bowel syndrome, the invention according to claim 5 as another aspect of the present invention administers isoleucine to secrete antibacterial peptides from panate cells in the intestinal tissue epithelium. This method suppresses abnormal immunity of tissues and enhances innate immunity.
[0020]
Even in this case, such innate immunity can be more effectively enhanced by using lactic acid bacteria product, that is, lactobacilli yogurt, together with isoleucine.
Further, irritable bowel syndrome treated by enhancing innate immunity includes Crohn's disease and ulcerative colitis.
[0021]
DETAILED DESCRIPTION OF THE INVENTION
As described above, the present invention improves immunity abnormalities in the intestinal tract tissue, induces secretion of antibacterial peptides that exert innate immunity in the living body, and enhances innate immunity to enhance irritable bowel syndrome. It is a therapeutic agent for treating Crohn's disease or ulcerative colitis.
[0022]
In the therapeutic agent provided by the present invention, isoleucine, which is an active ingredient, is administered orally or parenterally to effectively treat Crohn's disease, which is irritable bowel syndrome, or ulcerative colitis. Can do.
[0023]
The amount to be used is not particularly limited, and is sufficient to treat Crohn's disease, which is an irritable bowel syndrome, or ulcerative colitis by enhancing the innate immune response by administration to a living body. An amount may be administered. For example, for adults, diarrhea is effectively reduced by orally administering an amount of about 3 to 6 g / day, preferably about 4 g / day (2 g / 2 times / day) every day. Abdominal pain was reduced in the cecum from the end.
In addition, isoleucine, which is an active ingredient of the preventive agent provided by the present invention, is a kind of essential amino acid, and its safety has been sufficiently confirmed. is not.
[0024]
For example, in the case of oral administration, isoleucine is used as a powder or granule as it is, and other excipients as appropriate, for example, excipients such as starch, lactose, sucrose, crystalline cellulose, calcium hydrogen phosphate, etc. Binders such as acacia, hydroxypropylcellulose, alginic acid, gelatin, polyvinylpyrrolidone; lubricants such as stearic acid, magnesium stearate, calcium stearate, talc; disintegrating agents such as modified starch, calcium carboxymethylcellulose, hydroxypropylcellulose; Along with carboxyvinyl polymer and the like, it can be formulated into tablets, granules, capsules, powders, etc., which are orally administered preparations that are widely used pharmaceutically.
[0025]
On the other hand, in the present invention, it has been found that Crohn's disease, which is an irritable bowel syndrome, or ulcerative colitis is more effectively treated by using a lactic acid bacteria product together with isoleucine. Examples of such lactic acid bacteria preparations include products such as lactobacilli yogurt. This Lactobacillus yogurt product is produced by the enhancement of innate immune function by administration of isoleucine, for example, after the deep ulcer in the intestinal tract, which is a pathological symptom of Crohn's disease, is cured, It is considered that more effective treatment could be achieved by the protective action of the intestinal mucosa.
[0026]
【Example】
The actual therapeutic effects of Irritable Bowel Syndrome (IBD) caused by isoleucine, which is an active ingredient, provided by the present invention will be described below for Crohn's disease patients and Ulcerative colitis patients. The present invention will be described in more detail by explaining the results of tests conducted on the subject.
In the test, informed consent from the subject was obtained in advance.
[0027]
Test example: Effect of isoleucine administration on patients with irritable bowel syndrome Target patients The following subjects were used as subjects (19 subjects) as hypersensitive syndrome patients and healthy volunteers.
Crohn's disease patients: 12 ulcerative colitis patients: 5 healthy volunteers: 2
2. Isoleucine administration protocol and test evaluation Isoleucine (2 g × 2 times / day: 4 g / day in total) was orally administered.
From 2 weeks before administration, record the test subject's symptoms (fecal habits; number of diarrhea; abdominal pain; general condition), and for Crohn's disease patients (12 patients), from 1 week before administration CDAI (Chron's disease activity index) was measured until the end of administration.
Isoleucine was orally administered every day for 4 weeks (28 days) after the start of administration of isoleucine.
Further, until 2 weeks after the end of the administration, the test subject's symptoms (fecal habits; number of diarrhea; abdominal pain; general symptoms) were recorded.
[0029]
Evaluation 1: Average daily frequency of stool The transition of daily average frequency of stool among all the test subjects is shown in FIG. 1, and patients with irritable bowel syndrome [Crohn's disease patient (CD) and ulcerative colitis patient (UC)] The transition of the average daily frequency of stool in is shown in FIG.
No change due to isoleucine administration was observed in the average daily frequency of stool.
[0030]
Evaluation 2: Evaluation of occurrence of watery / mud diarrhea The changes in the average number of watery / mud diarrhea / daily occurrence in all test subjects are shown in FIG. 3 and patients with irritable bowel syndrome [Crohn's disease patient (CD) 4 and FIG. 4 shows changes in watery / mud diarrhea / average number of occurrences per day in patients with ulcerative colitis (UC).
As can be seen from the results shown in FIG. 3, the average frequency of watery / mud diarrhea / daily decreased significantly by administration of isoleucine, and the pathological condition in patients with irritable bowel syndrome caused by administration of isoleucine. It is understood that the occurrence of diarrhea can be suppressed.
[0031]
Evaluation 3: Evaluation of abdominal pain The degree of abdominal pain was evaluated according to the following score.
0: No abdominal pain 1: Slight abdominal pain 2: Recognized pain in the abdomen 3: Severe pain in the abdomen Based on the results, the transition of the abdominal pain score in all test subjects is shown in FIG. The transition of the abdominal pain score in patients with irritable bowel syndrome [Crohn's disease patient (CD) and ulcerative colitis patient (UC)] is shown in FIG.
A change in the abdominal pain score was observed after the administration of isoleucine, but this was not a significant change.
[0032]
Evaluation 4: Evaluation of general symptoms The degree of general symptoms was evaluated according to the following score.
0: Good 1: Slightly unhealthy 2: Poor physical condition 3: Very poor physical condition 4: Based on the result of requiring medical assistance, the transition of general symptom scores in all test subjects is shown in FIG. FIG. 8 shows changes in scores of general symptoms in patients with irritable bowel syndrome [Crohn's disease patient (CD) and ulcerative colitis patient (UC)].
In the evaluation of general symptoms, no significant change was observed with isoleucine administration.
[0033]
Evaluation 5: Change in CDAI (Chron's disease activity index) by isoleucine administration in patients with Crohn's disease (CD) In 9 patients with Crohn's disease (CD), CDAI before isoleucine administration and during administration of isoleucine over 4 weeks CDAI variation was assessed.
The results are shown in FIG.
As can be seen from the results shown in the figure, CDAI before administration of isoleucine is significantly reduced during the period of administration of isoleucine, and it is understood that isoleucine is effective in the treatment of Crohn's disease.
[0034]
Evaluation 6: Effect of isoleucine on the number of lactobacilli in feces in patients with Crohn's disease (CD) Isoleucine (2 g × 2 times / day: total 4 g / day) was administered to 6 patients with Crohn's disease. Orally administered for 1 week.
The stool of the patient before isoleucine administration and the stool of the patient on the 7th day after isoleucine administration for 1 week were collected, and the number of lactobacilli in the stool was evaluated.
LBS (Lactobacillus Selective agar) agar medium (manufactured by Becton & Dexon) was used as the medium, and cultured at 37 ° C. for 72 hours under aerobic conditions. The number of colonies found on the medium was indicated as CFU (colony forming unit).
[0035]
Results The results are shown in Table 1.
[0036]
[Table 1]
Table 1

[0037]
The change of Log CFU before and after isoleucine administration is shown in FIG. As can be seen from the results shown in the figure, an increasing tendency of Lactobacilli, which is a resident intestinal bacterium, was observed.
From the above facts, it can be seen that more effective treatment can be obtained by using Lactobacillus yogurt together with isoleucine.
[0038]
Formulation example: Granule composition:
300g isoleucine
Lactose 134g
Crystalline cellulose 20g
Corn starch 20g
3% hydroxypropyl methylcellulose aqueous solution 100ml
Magnesium stearate 3g
[0039]
Manufacturing method:
Lactose, crystalline cellulose, and corn starch were sieved to isoleucine with a 60 mesh sieve and mixed uniformly, then placed in a kneader and poured into a 3% hydroxypropylmethylcellulose aqueous solution, and further kneaded. Next, it was sieved with a 16-mesh sieve, granulated, and air-dried at 50 ° C. After drying, granulation was performed to obtain granules.
[0040]
【The invention's effect】
As described above, the present invention provides a therapeutic agent for irritable bowel syndrome, particularly Crohn's disease and ulcerative colitis, by enhancing innate immunity in intestinal tissue in a living body.
In particular, isoleucine, which is an active ingredient of the present invention, can reduce the number of watery diarrhea symptoms, which are the main symptoms of Crohn's disease, and can effectively treat Crohn's disease, which is an intractable disease. The value is tremendous.
[Brief description of the drawings]
FIG. 1 is a graph showing the transition of daily average frequency of stool in all test subjects, which is the result of evaluation 1 in a test example of the present invention.
FIG. 2 shows changes in the average daily frequency of stool in patients with irritable bowel syndrome [Crohn's disease patient (CD) and ulcerative colitis patient (UC)], which is the result of evaluation 1 in the test example of the present invention. FIG.
FIG. 3 is a diagram showing the transition of the average number of occurrences of watery / mud diarrhea / day in all test subjects, which is the result of evaluation 2 in the test example of the present invention.
FIG. 4 shows water / mud diarrhea / day in irritable bowel syndrome patients [Crohn's disease patient (CD) and ulcerative colitis patient (UC)], which is the result of evaluation 2 in the test example of the present invention. It is a figure which shows transition of the average frequency | count of occurrence.
FIG. 5 is a diagram showing the transition of the abdominal pain score in all test subjects, which is the result of evaluation 3 in the test example of the present invention.
FIG. 6 is a diagram showing the transition of the abdominal pain score in patients with irritable bowel syndrome [Crohn's disease patient (CD) and ulcerative colitis patient (UC)], which is the result of evaluation 3 in the test example of the present invention. is there.
FIG. 7 is a graph showing changes in scores of general symptoms in all test subjects, which is the result of evaluation 4 in the test example of the present invention.
FIG. 8 is a graph showing changes in scores of general symptoms in patients with irritable bowel syndrome [Crohn's disease patient (CD) and ulcerative colitis patient (UC)], which is the result of evaluation 4 in the test example of the present invention. is there.
FIG. 9 is a graph showing changes in CDAI by isoleucine administration in patients with Crohn's disease, evaluated 5 in the test example of the present invention.
FIG. 10 is a graph showing changes in Log CFU of Lactobacillus before and after isoleucine administration in Evaluation 6 in the test example of the present invention.

Claims (8)

A therapeutic agent for irritable bowel syndrome (IBD) characterized by containing isoleucine as an active ingredient. A therapeutic agent for irritable bowel syndrome containing isoleucine as an active ingredient in combination with lactobacilli yogurt. The therapeutic agent according to claim 1 or 2, wherein the irritable bowel syndrome is Crohn's disease. The therapeutic agent according to claim 1 or 2, wherein the irritable bowel syndrome is ulcerative colitis. A method of enhancing innate immunity by administering isoleucine to secrete antibacterial peptides from panate cells in the intestinal tissue epithelium to suppress abnormal immunity of the intestinal tissue in order to treat irritable bowel syndrome. The method for enhancing innate immunity according to claim 5, wherein Lactobacillus yogurt is used in combination with isoleucine. The method for enhancing innate immunity according to claim 5 or 6, wherein the irritable bowel syndrome is Crohn's disease. The method for enhancing innate immunity according to claim 5 or 6, wherein the irritable bowel syndrome is ulcerative colitis.

Images