JP2008056591A - Medicinal composition for treatment or prevention of inflammatory intestinal disease - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a medicinal composition excellent in treating or preventing effect against inflammatory intestinal diseases and having less adverse effects. <P>SOLUTION: This medicinal composition for the treatment or prevention of the inflammatory intestinal diseases is characterized by comprising at least any one of a compound expressed by general formula (1) [wherein, R is any one of H and a water soluble group] and its medicinally acceptable salt. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a pharmaceutical composition for the treatment or prevention of inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a general term for diseases of unknown cause that cause chronic inflammation or ulceration in the mucosa of the large intestine and small intestine, and is mainly represented by ulcerative colitis, Crohn's disease, and intestinal Behcet's disease Is done.
The cause of the onset of inflammatory bowel disease is still unknown, but it is speculated that one of the causes may be abnormal activation of the immune mechanism against a specific antigen. By exposure to specific antigens, inflammatory cytokines such as interleukin (IL) -1β, tumor necrosis factor (TNF) -α, IL-6, leukotriene (LT) B4, thromboxane (TX) A2, prosta Chemical mediators such as glandin (PG) E2 are released, and as a result of these series of reactions, inflammation occurs in the intestinal mucosa. Furthermore, it is considered that such inflammation of the intestinal mucosa persists and intestinal tissue damage occurs.
Ulcerative colitis, Crohn's disease, and Behcet's disease are all designated as specific diseases by the Ministry of Health, Labor and Welfare, and the number of patients tends to increase, but treatment methods that can fundamentally cure these inflammatory bowel diseases Has not yet been found. For this reason, the development of effective treatments for inflammatory bowel disease has become a major issue.

Current medical treatments for inflammatory bowel disease are often combined with nutritional therapy and drug therapy, among which 5-aminosalicylic acid preparations, steroids, immunosuppressants, etc. are used. (For example, refer nonpatent literature 1).
Examples of the 5-aminosalicylic acid preparation include salazosulfapyridine (product name: salazopyrine) and mesalazine (product name: pentasa). Among them, mesalazine removes sulfapyridine from salazosulfapyridine to give an active ingredient 5-amino It is extracted from salicylic acid and is said to have relatively few side effects. However, although the 5-aminosalicylic acid preparation can temporarily suppress inflammation, it does not actively promote the healing of inflammatory bowel disease, and it may develop again when it is stopped. There is a problem. In addition, the steroid agent and the immunosuppressive agent can effectively suppress inflammatory activity, but also have a problem of side effects due to long-term use (for example, see Non-Patent Documents 2 to 4).
Therefore, there is a strong demand for the development of a pharmaceutical composition that has excellent therapeutic or preventive effects on inflammatory bowel disease and has few side effects.

SANDS, B.M. E. Therapy of infrared bowel disease. Gastroenterology. 2000; 118 S68-S82. Schroder O, Stein J. et al. Low dose method in inframetric bow disease: current status and future directions. Am J Gastroenterol. 2003; 98: 530-37. Holtmann MH, Galle PR, Neuroth MF. Immunotherapeutic approaches to inflammatory bow diseases. Expert Opin Biol Ther. 2001; 1: 455-66. Rampton DS. Management of difference infrastructure bow disease: where are we now? World J Gastroenterol. 2000; 6: 315-23.

  An object of the present invention is to solve the conventional problems and achieve the following objects. That is, an object of the present invention is to provide a pharmaceutical composition having an excellent therapeutic or preventive effect on inflammatory bowel disease.

In order to solve the above-mentioned problems, the present inventors have made extensive studies and as a result, obtained the following findings. That is, a pharmaceutical composition containing at least one of a compound represented by the general formula (1) described below and a pharmaceutically acceptable salt thereof has an excellent therapeutic or preventive effect on inflammatory bowel disease model mice. This is the knowledge.
Conventionally, EG-626 (phthalazinol), which is a kind of a compound represented by the general formula (1), in which R in the general formula (1) is a hydrogen atom, has an arteriosclerosis-preventing action and platelet aggregation inhibition. It has been known to have an action and the like, and is expected to be used for the treatment or prevention of arteriosclerotic diseases, thrombotic diseases and the like (for example, Japanese Patent Laid-Open Nos. 50-70378 and 50-70380). No. publication).
However, at least one of the compound represented by the general formula (1) and a pharmaceutically acceptable salt thereof is excellent in therapeutic or preventive effect on inflammatory bowel disease, and therefore, an excellent pharmaceutical for inflammatory bowel disease. It has not been known at all that it can be used as a composition, which is a new finding of the present inventors.

Therefore, this invention is based on the said knowledge by the present inventors, and as means for solving the said subject, it is as follows. That is,
<1> A pharmaceutical composition for treatment or prevention of inflammatory bowel disease, comprising at least one of a compound represented by the following general formula (1) and a pharmaceutically acceptable salt thereof: A pharmaceutical composition characterized.
However, in said general formula (1), R represents either a hydrogen atom or a water-soluble group.
<2> The pharmaceutical composition according to <1>, wherein in general formula (1), R represents a water-soluble group.
<3> The pharmaceutical composition according to <2>, wherein the water-soluble group contains at least one of proline and a pharmaceutically acceptable salt thereof.

  ADVANTAGE OF THE INVENTION According to this invention, the conventional problems can be solved and the pharmaceutical composition excellent in the treatment or prevention effect with respect to an inflammatory bowel disease can be provided.

(Pharmaceutical composition)
The pharmaceutical composition of the present invention is a pharmaceutical composition for the treatment or prevention of inflammatory bowel disease, and is at least one of a compound represented by the following general formula (1) and a pharmaceutically acceptable salt thereof ( A compound represented by the general formula (1) and / or a pharmaceutically acceptable salt thereof), and further contains other components as necessary.

<Compound>
In the general formula (1), R represents either a hydrogen atom or a water-soluble group. Among these, R is preferably a water-soluble group. When R is a water-soluble group, the solubility of the compound in water is improved, and the blood concentration can be easily increased when administered to a living body. It is advantageous in that it can be suitably used as an agent.
The water-soluble group is not particularly limited as long as it can impart water solubility to the compound, and can be appropriately selected according to the purpose. For example, amino acids such as proline, lysine, glycine, and alanine, Examples include sugars. Among them, as the water-soluble group, proline and lysine are preferable, and proline is particularly preferable in terms of excellent stability in an aqueous solution. Further, the water-soluble group may be a pharmaceutically acceptable salt of the various water-soluble groups described above.

<Salt>
The pharmaceutically acceptable salt is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include any of inorganic salts and organic salts. More specifically, hydrochlorides, Examples thereof include hydrobromide, sulfate, phosphate, acetate, oxalate, tartrate, citrate, maleate, and fumarate.

<Specific example>
In addition, specific examples of the compound represented by the general formula (1) and / or a pharmaceutically acceptable salt thereof include a compound represented by the following structural formula (2) (R: proline, hydrochloride). Is particularly preferred.

The compound represented by the structural formula (2) is also referred to as SHI-219. SHI-219 has high solubility in water, and its blood concentration easily rises when administered to a living body. Therefore, oral absorption is good, and it is preferably used as an injection or suppository. It is excellent in that it can. The SHI-219 is also excellent in stability in an aqueous solution.
The SHI-219 has an effect of treating or preventing inflammatory bowel disease by being converted into a compound represented by the following structural formula (3) (EG-626: phthalazinol) in vivo. it is conceivable that. That is, it can be said that SHI-219 is a prodrug of a compound (EG-626: phthalazinol) represented by the following structural formula (3).

  The compound represented by the structural formula (3) is a compound in which R in the general formula (1) is a hydrogen atom, and the compound is also referred to as EG-626 (phthalazinol). The structure of EG-626 is considered to be the active ingredient of the pharmaceutical composition.

<Manufacturing>
The method for producing the compound represented by the general formula (1) and / or a pharmaceutically acceptable salt thereof is not particularly limited and may be appropriately produced according to the purpose. It can be produced by referring to the descriptions in JP-A-70378, JP-A-50-70380, and JP-A-58-116471.
More specifically, for example, the compound (SHI-219) represented by the structural formula (2) is converted from the compound (EG-626) represented by the structural formula (3) with a catalytic amount of dimethylaminopyridine. It can be obtained by condensation with Nt-Boc-L-proline with dicyclohexylcarbodiimide (DCC) in the presence of (DMAP) and then removing the protecting group.

In the pharmaceutical composition, the content of the compound represented by the general formula (1) and / or a pharmaceutically acceptable salt thereof is not particularly limited. For example, the dosage form of the pharmaceutical composition described later is used. Or it can select suitably according to the grade of a desired effect, etc.
The pharmaceutical composition may be the compound represented by the general formula (1) and / or a pharmaceutically acceptable salt thereof.

<Other ingredients>
There is no restriction | limiting in particular as said other component, In the range which does not impair the effect of this invention, it can select suitably according to the objective, For example, a pharmacologically acceptable carrier etc. are mentioned. There is no restriction | limiting in particular as said carrier, For example, it can select suitably according to the dosage form etc. of the said pharmaceutical composition mentioned later. Moreover, there is no restriction | limiting in particular as content of the said other component in the said pharmaceutical composition, According to the objective, it can select suitably.

<Dosage form>
There is no restriction | limiting in particular as a dosage form of the said pharmaceutical composition, According to the desired administration method as mentioned later, it can select suitably, for example, an oral solid agent (a tablet, a coated tablet, a granule, a powder, a capsule) Agents), oral liquids (internal liquids, syrups, elixirs, etc.), injections (solutions, suspensions, solid agents for dissolution), suppositories, and the like.

Examples of the oral solid preparation include, for example, the compound represented by the general formula (1) and / or a pharmaceutically acceptable salt thereof, an excipient, and, if necessary, a binder, a disintegrant, a lubricant. Additives such as a thickener, a coloring agent, and a flavoring and flavoring agent can be added to produce the product by a conventional method.
Examples of the excipient include lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, and silicic acid. Examples of the binder include water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl starch, methylcellulose, ethylcellulose, shellac, calcium phosphate, polyvinylpyrrolidone and the like. It is done. Examples of the disintegrant include dry starch, sodium alginate, agar powder, sodium hydrogen carbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, and lactose. Examples of the lubricant include purified talc, stearate, borax, and polyethylene glycol. Examples of the colorant include titanium oxide and iron oxide. Examples of the flavoring / flavoring agent include sucrose, orange peel, citric acid, tartaric acid and the like.

As the oral solution, for example, to the compound represented by the general formula (1) and / or a pharmaceutically acceptable salt thereof, additives such as a flavoring / flavoring agent, a buffer, a stabilizer, It can be produced by a conventional method.
Examples of the flavoring / flavoring agent include sucrose, orange peel, citric acid, tartaric acid and the like. Examples of the buffer include sodium citrate. Examples of the stabilizer include tragacanth, gum arabic, and gelatin.

Examples of the injection include a compound represented by the general formula (1) and / or a pharmaceutically acceptable salt thereof, a pH adjuster, a buffer, a stabilizer, an isotonic agent, a local anesthetic. An agent for injection, etc. can be produced by a conventional method, for subcutaneous use, intramuscular use, intravenous use and the like.
Examples of the pH adjusting agent and the buffering agent include sodium citrate, sodium acetate, sodium phosphate and the like. Examples of the stabilizer include sodium pyrosulfite, EDTA, thioglycolic acid, thiolactic acid, and the like. Examples of the isotonic agent include sodium chloride and glucose. Examples of the local anesthetic include procaine hydrochloride and lidocaine hydrochloride.

  Examples of the suppository include known compounds for suppositories such as polyethylene glycol, lanolin, cocoa butter, fatty acid triglyceride, etc., to the compound represented by the general formula (1) and / or a pharmaceutically acceptable salt thereof. After adding a carrier and a surfactant such as TWEEN (registered trademark) if necessary, it can be produced by a conventional method.

<Target disease>
Examples of the inflammatory bowel disease to be treated or prevented by the pharmaceutical composition include ulcerative colitis, Crohn's disease, intestinal Behcet's disease and the like. Among these, the pharmaceutical composition is particularly suitable for ulcerative colitis and Crohn's disease.

<Administration>
The said pharmaceutical composition can be used by administering to the patient of the said inflammatory bowel disease, for example.
The animal to which the pharmaceutical composition is administered is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include humans, mice, rats, cows, pigs, monkeys and the like.
The method for administering the pharmaceutical composition is not particularly limited, and can be appropriately selected according to the dosage form of the pharmaceutical composition, and examples thereof include oral administration, administration by injection, and rectal administration. .
The dosage of the pharmaceutical composition is not particularly limited and can be appropriately selected according to the age, weight, desired degree of effect, etc. of the patient to be administered. The amount of the compound represented by the general formula (1) and / or a pharmaceutically acceptable salt thereof per day is preferably 10 to 500 mg / kg body weight, more preferably 20 to 100 mg / kg body weight. .
Moreover, there is no restriction | limiting in particular also as the administration time of the said pharmaceutical composition, According to the objective, it can select suitably.

<Effect>
Since the pharmaceutical composition is excellent in the treatment or prevention of inflammatory bowel disease, it is suitable for application to patients with various inflammatory bowel diseases such as ulcerative colitis, Crohn's disease, and intestinal Behcet's disease. It is particularly suitable for application to patients with ulcerative colitis and Crohn's disease. In addition, from the results of existing basic research and clinical trials regarding other diseases (arteriosclerotic diseases, thrombotic diseases) of the EG-626, the compound represented by the general formula (1) may have side effects. Therefore, it is considered that the pharmaceutical composition is advantageous in terms of high safety.
In addition, the fact that the pharmaceutical composition is excellent in the treatment or prevention effect of inflammatory bowel disease, for example, using a mouse model of inflammatory bowel disease and the like, the degree of alleviation of each symptom by administration of the pharmaceutical composition It can be confirmed by biochemical examination.

  Examples of the present invention will be described below, but the present invention is not limited to these examples.

(Example 1: Improvement of symptoms in inflammatory bowel disease model mice by administration of SHI-219)
-Production of inflammatory bowel disease model mice and drug administration-
6-week-old BALB / c mice (Nippon SLC Co., Ltd.) with an average weight of 20 g were used in each group of 5 mice. Under normal consumption, distilled water was allowed to drink freely for 7 days in the normal group. The -219 administration group was allowed to drink a 5% by weight aqueous dextran sulfate sodium (DSS) solution for 7 days. Furthermore, SHI-219 (2 mg or 0.5 mg / 0.3 ml distilled water / mouse) was injected intraperitoneally once a day for 7 consecutive days into the SHI-219 administration group. The following items were evaluated for each mouse.

[Hematology]
On day 7 after the start of administration, blood was collected from the heart under anesthesia immediately before sacrifice, and the white blood cell count and hemoglobin concentration were measured according to the usual method of hematological examination.

[Symptom Activity Index (DAI)]
For the symptom activity index, the state of the mice on the seventh day after the start of administration was classified into each score according to the following criteria, and the average value of the mice in each group was determined. The results are shown in Table 1.
[Score classification criteria]
Score 0: No weight loss, normal stool condition (pellet), no occult blood or bleeding.
Score: There is a weight loss of 1 to 5% by mass, the state of the stool is normal (pellet shape), and there is no occult blood or bleeding.
Score 2: Weight loss of 5-10% by weight, stool is loose and pasty but not attached to the anus.
Score 3: 11-15% by weight weight loss, stool is loose and pasty but not attached to the anus.
Score 4: There is a weight loss exceeding 15% by mass, the stool is diarrhea, and there is bleeding that can be confirmed with the naked eye.

[Pathological examination: Colon length and histological disorder score]
Seven days after the start of administration, the length of the large intestine immediately after slaughtering under anesthesia was measured with a ruler. The excised large intestine is incised along the vertical axis, and half (the other half is used in Example 2 and later) is fixed with 10% formalin neutral buffer for histological evaluation of the degree of damage. 4 mm square sections were stained with hematoxylin and eosin and assayed under a 100-fold microscope. 15 fields were selected for each section, and each field was graded by a third party according to the following criteria, and the average value was obtained. The results are shown in Table 1.
[Grade classification criteria]
Grade 0: Normal intestinal mucosa.
Grade 1: About 1/3 of the crypt disappeared.
Grade 2: About 2/3 crypts disappeared.
Grade 3: The lamina propria is covered with a single layer of epithelium and there is a slight infiltration of inflammatory cells.
Grade 4: There is erosion and significant inflammatory cell infiltration.

From the results of Table 1, it can be seen that each symptom of the SHI-219 administration group is remarkably improved as compared to the control group (DSS administration group).
Specifically, in the symptom activity index (DAI), which is an indicator of living conditions, diarrheal stool mixed with fresh blood, weight loss, and anemia were observed in all of the control groups, whereas the SHI-219 administration group There was no fresh bloody stool, stool formation was improved, and weight loss was mild. In addition, white blood cell count and anemia status were examined as hematological indicators. When inflammation occurs, the white blood cell count is expected to increase, but the white blood count in the SHI-219 administration group was lower than that in the control group. Since hemorrhage caused by diarrhea causes anemia, the hemoglobin concentration of the control group was reduced to about 65% of the normal group, but the SHI-219 administration group was about 73% of the normal group and higher than the control group. . Pathologically, the length of the large intestine during inflammation tends to be shortened. Although the length of the large intestine was remarkably shortened in the control group, it can be seen that the length of the large intestine in the SHI-219 administration group was significantly longer than that in the control group although it was shorter than that in the normal group. It can also be seen that the histological disorder score is significantly lower in the SHI-219 administration group than in the control group.
From the above results, it was shown that SHI-219 is effective in improving the symptoms of inflammatory bowel disease in mice.

(Example 2: Change in myeloperoxidase (MPO) activity in colonic mucosa by administration of SHI-219)
The tissue of the proximal part of the large intestine collected from 5 mice in each group on the 7th day after the start of administration in Example 1 was homogenized, and tetramethylbenzidine (TMBZ) and hydrogen peroxide solution were added and incubated at room temperature for 15 minutes. The absorbance at 630 nm was measured. At the same time, the protein content of the tissue homogenate was measured with a commercially available protein assay kit (Bio-Rad), and the resulting absorbance (A) at 630 nm was quantified based on the protein content.
At the time of the first measurement, human MPO was examined by the guaiacol method and used as a standard value. Based on the standard value, the measured absorbance (A) was converted to MPO activity (mU / mg protein) by the following formula. The results are shown in FIG.
[formula]
MPO activity = [A / protein concentration (mg / ml)] × 1.6

  From the results of FIG. 1, in the control group (DSS administration group), the MPO activity (0.671 ± 0.089 mU / mg) was clearly increased to nearly twice that of the normal group, whereas in the SHI-219 administration group ( It can be seen that MPO activity did not increase at 2 mg or 0.5 mg. Therefore, from this result, it was shown that SHI-219 has an action of significantly suppressing inflammation caused by leukocytes.

(Example 3: Change in inflammatory cytokine amount in colonic mucosa by administration of SHI-219)
The concentration of IL-1β, IL-6, and TNF-α in rectal tissue collected from each group of mice on day 7 after the start of administration in Example 1 was determined according to the product handling procedure (manufactur's protocol: R & D). Measurement was performed by ELISA according to Systems, Minneapolis, USA). Briefly, a biotin-treated antibody reagent was dispensed into a 96-well plate, and the homogenized supernatant of rectal tissue was added thereto and incubated at 37 ° C. for 2 hours in a 5% carbon dioxide atmosphere. After washing with bovine serum, a streptavidin peroxidase (HRP) solution was added, and the mixture was further incubated at room temperature for 30 minutes, and then the absorbance at 590 nm was measured with a microplate reader. The total protein concentration was determined by the Lowry method, and the absorbance was converted to mg unit amount of protein. The results are shown in Table 2.

  From the results of Table 2, in the control group (DSS administration group), the inflammatory cytokine concentration in the mucosa was remarkably increased compared to the normal group (non-administration group), whereas SHI-219 administration (2 mg or 0.5 mg). ) Shows that the increase in local cytokine concentration was significantly suppressed. Therefore, this result showed that SHI-219 has an anti-inflammatory effect.

(Example 4: Change in arachidonic acid metabolite level in colonic mucosa by administration of SHI-219)
The tissue of the proximal part of the large intestine of each group of 5 mice on the 7th day after the start of administration in Example 1 was collected, and the supernatant was collected after homogenization in ethyl acetate, and the TXB2 was collected using a commercially available specific ELISA kit. (Stable metabolite of TXA2), LTB4, and PGE2 levels were measured according to the product handling procedure and converted to mg units of tissue. The results are shown in FIGS.

  From the results of FIGS. 2A to C, in the control group (DSS administration group), the level of TXB2, which is a stable metabolite of inflammatory factors derived from arachidonic acid, PGE2, LTB4, and TXA2, is about twice as high as that in the normal group. However, it was confirmed that the increase in the level of PGE2 was moderated and the increase in the levels of LTB4 and TXB2 was remarkably suppressed by administration of SHI-219.

(Example 5: Confirmation of COX-2 expression in colonic mucosa by administration of SHI-219)
Seven days after the start of administration in Example 1, the mice were sacrificed, and the rectal tissue specimens were stained with anti-mouse COX-2 polyclonal antibody. Briefly, sections were fixed overnight by immersion in a 3.3% formalin bovine serum solution at 4 ° C. and embedded in the OCT compound. The buried sample was snap frozen with liquid nitrogen to make 4 micron serial sections. Samples dried in air were fixed with acetone for 15 minutes and treated with 0.3% hydrogen peroxide in 50% methanol for 15 minutes at room temperature to inhibit endogenous peroxidase. Non-specific binding was prevented by treatment with 2% bovine serum albumin, and the tissue was incubated overnight with 20 mg / ml biotin-treated anti-mouse COX-2 monoclonal antibody at 4 ° C. and then avidin-biotin over 20 minutes at room temperature. The oxidase complex was incubated. After washing with bovine serum, the tissue was incubated in 0.3% 3,3-diaminobenzidine tetrahydrochloride containing 0.003% hydrogen peroxide. All sections were counterstained with Mayer's hematoxylin. The result of 400 times magnification under a microscope is shown in FIG.

  From the results of FIG. 3, COX-2 was not expressed at all in the normal group (FIG. 3a), but inflammation was observed in the control group (DSS administration group) (FIG. 3b) and the SHI-219 administration group (FIG. 3c). It was confirmed that COX-2 was expressed around the obtained cells. This confirmed that SHI-219 does not inhibit the expression of COX-2, suggesting that SHI-219 has an anti-inflammatory action mechanism different from that of steroids and COX inhibitors.

(Reference Example 1: Confirmation of blood concentration of EG-626 after administration of SHI-219 and EG-626)
In Reference Example 1, the difference in the blood concentration of EG-626 that appears in blood after administration of SHI-219 or EG-626, which is the compound represented by the general formula (1), into the duodenum was confirmed. did.
Rabbits weighing 3.7 to 4.3 kg under anesthesia with a physiological saline solution of SHI-219 at a dose of 74.6 mg / kg / 5 ml (3 animals) or 14.9 mg / kg / 5 ml (3 animals) Alternatively, a carboxymethylcellulose (CMC) suspension of EG-626 is administered into the duodenum at a dose of 50 mg / kg / 5 ml to rabbits (4 animals) weighing 2.3 to 3.5 kg. About 2 ml of blood was collected from the unilateral carotid artery. After centrifugation, the serum was divided into two 0.5 ml samples A and B. 2 μg / 20 μl of an ethyl acetate solution of an internal standard for quantification represented by the following structural formula (4) was added to each. The serum was extracted 3 times with 1 ml of ethyl acetate, and the ethyl acetate layer was collected and washed with 0.5 ml of water, and then the ethyl acetate layer was concentrated. Five minutes before the measurement, 20 μl of methanol was added at a time, and the absorbance at 294 nm of the component separated by the eluent of 60% methanol / water was determined by high performance liquid chromatography equipped with a μC18 bonder pack column. FIG. 4 shows the result of quantifying the content of EG-626 in 1 ml of serum by adding the quantitative value.

SHI-219 is a condensate of EG-626 and natural L-proline, and the ratio of EG-626 in the SHI-219 molecule corresponds to 67% by mass. The solubility of EG-626 in water at 20 ° C. is 0.02%, while the solubility of SHI-219 in water at 20 ° C. exceeds 50%.
From the results shown in FIG. 4, SHI-219 had a dose of 74.6 mg / kg, and its blood concentration increased dramatically immediately after administration, whereas EG-626 had a dose of 50 mg / kg (in SHI-219). Even when administered, an increase in blood concentration is low, and SHI-219 is administered at 14.9 mg / kg (an amount equivalent to 1/5 equivalent of EG-626). It was confirmed that the blood concentration reached almost the same level. Therefore, SHI-219 is excellent in that it has good gastrointestinal absorption and easily increases in blood concentration, and SHI-219, which is stable in water, is quickly converted to EG-626 in blood. As a result, it was shown that, for example, not only oral preparations and suppositories but also injections are more suitable compounds for the pharmaceutical composition of the present invention.

  Since the pharmaceutical composition of the present invention is excellent in the treatment or prevention effect of inflammatory bowel disease, it is suitable for application to patients with various inflammatory bowel diseases such as ulcerative colitis, Crohn's disease, and intestinal Behcet's disease. It is particularly suitable for application to patients with ulcerative colitis and Crohn's disease.

FIG. 1 is a graph showing changes in myeloperoxidase (MPO) activity in colonic mucosa by administration of SHI-219. FIG. 2A is a graph showing changes in TXB2 level (pg / mg) in the colonic mucosa by administration of SHI-219. FIG. 2B is a graph showing changes in LTB4 levels (pg / mg) in the colonic mucosa by administration of SHI-219. FIG. 2C is a graph showing changes in PGE2 levels (pg / mg) in the colonic mucosa by administration of SHI-219. FIG. 3 is a tissue staining image showing the presence or absence of changes in COX-2 expression in the colonic mucosa by administration of SHI-219. FIG. 4 is a graph showing the difference in blood concentration between SHI-219 and EG-626.

Claims (3)

A pharmaceutical composition for the treatment or prevention of inflammatory bowel disease, comprising at least one of a compound represented by the following general formula (1) and a pharmaceutically acceptable salt thereof: Pharmaceutical composition.
However, in said general formula (1), R represents either a hydrogen atom or a water-soluble group.   The pharmaceutical composition according to claim 1, wherein R in the general formula (1) represents a water-soluble group. The pharmaceutical composition according to claim 2, wherein the water-soluble group contains at least one of proline and a pharmaceutically acceptable salt thereof.