JP2008179569A - Medicine and method for applying the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a medicine and method for applying the same for patients of inflammatory large intestinal disorder by noticing the pharmacological effect of carbon monoxide (CO), and completed as a result of examination of the applying method of the same, since conventionally, in 10 to 30% of the patients, medicinal treatments are not effective and surgical treatments are applied in such the case to perform the excision of diseased part, but the burden to the patients is large. <P>SOLUTION: This medicine is for the treatment of digestive tract inflammation such as gastric ulcer, inflammatory intestinal disorder, etc., and is an aqueous solution dissolved with carbon monoxide. The medicine described in the claim 1 is locally administered to the diseased part by administering it to the digestive tract directly and locally, taking it orally or administering it by using a tube inserted into the intestine. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a drug and a method for applying the drug.

  Various pharmacotherapeutic agents have been used for inflammatory bowel disease (intestinal bowl disease, IBD), but the cause is unknown and radical treatment cannot be expected. Even if it is paid, there are many problems such as accompanying side effects, and it is difficult to use.

  Inflammatory bowel disease usually refers to ulcerative colitis (UC) and Crohn disease (CD), which are persistent inflammatory bowel diseases in the narrow sense, but in a broad sense, pathogenic microorganisms, drugs, It is understood as a concept that includes diseases caused by blood circulation disorders, radiation, chemical and physical factors.

  In particular, the cause of UC and CD is not clear. Chronic nonspecific inflammation is present in the intestinal mucosa, clinically refractory, recurrent, relapsed, and there is no radical treatment. , Exhibit extremely diverse pathologies. In addition, it occurs more frequently in young people and must be treated in consideration of many social factors such as advancement, employment, marriage, etc. The Ministry of Health, Labor and Welfare has organized a specialized research team for clinical diagnosis. It is also a big issue.

  As a treatment method, in addition to general therapy (medical and psychological rest, intestinal tract rest, diet therapy and improvement of general condition) as medical treatment, detailed therapy according to individual cases is required. As pharmacotherapy, 5-aminosalicylic acid (mesalazine, pensata (registered trademark)), 5-aminosalicylic acid (mesalazine, pensata (registered trademark)), which is mainly an adrenocortical steroid hormone agent, salazosulfapyridine salazopyrin (registered trademark), SASP, immunosuppressant, etc. ASA) is also used.

  Crohn's disease (CD) is a lesion that occurs in the entire digestive tract from the oral cavity to the anus, mainly in young adults. Pathologically, it shows non-specific granulomatous lesions that are clinically relapsed and relapsed. It is an intractable bowel disease whose cause is unknown. Treatment is based on medical treatment mainly consisting of nutritional therapy and drug therapy, but it is indicated by surgery for bowel obstruction, perforation, massive bleeding, etc. For pharmacotherapy, biologics such as steroids, 5-aminosalicylic acid (5-ASA), immunosuppressants, and TNF-α antibodies are used, but effective drugs with few side effects such as application of drug delivery system. Development has become an issue.

  Furthermore, the treatment of gastric / duodenal ulcer has been dramatically effective due to the emergence of acid secretion inhibitors, and the involvement of Helicobacter pylori infection has been pointed out as one of the causes. Treatment is also recommended. However, there are a number of cases that are difficult to treat, such as cases where relapse continues and cases where drug treatment is not effective. In addition, the long-term administration of an acid secretion inhibitor does not clear the suspicion of safety, and the development of a better therapeutic agent is desired.

  In patients with this inflammatory bowel disease, drug therapy is considered to be ineffective in 10 to 30%, in which case surgical treatment is applied and the affected area is excised. In addition, since relapses easily when steroids and other drugs are withdrawn, the result is long-term administration of the drug, which may cause severe side effects (diabetes, necrosis of the femoral head, etc.). ) Is required to improve and develop.

  In view of such a current situation, the present inventor has completed the drug of the present invention and a method for applying the drug as a result of earnest research, and the features of the drug include gastric ulcer, inflammatory bowel disease, etc. A drug for treating inflammation of the gastrointestinal tract, which is an aqueous solution in which carbon monoxide is dissolved, and is used by being locally administered directly to a digestive system organ. It is in the point which administers the chemical | medical agent of Claim 1 to an affected part directly from the pipe | tube inserted in the intestine.

  The present invention has been completed as a result of studying the administration method by paying attention to the pharmacological action of carbon monoxide (CO) described later by the present inventor. Simple and short-time operation by tube administration. In addition, the treatment after administration is completely unnecessary, and it has an excellent characteristic that cannot be considered by a conventional therapeutic agent that there is no side effect due to CO.

In the present invention, the CO solution is stored in a sealed container. At this time, the gas phase portion in the container may be CO alone or a mixture with other gases. Since the solubility is proportional to the concentration in the mixed gas according to Henry's law, it is generally considered that a method having a high CO concentration in the gas phase portion has a large effect.
Although CO is generally known as a gas that is hardly soluble in water, the inventors have measured the following solubility. This is proportional to the gas concentration (partial pressure) based on Henry's law unless the aqueous solution contains a metal component (for example, heme) having the same solubility as that in the chemical handbook and having CO binding properties.
CO concentration in gas phase Detected concentration 50% 532ppm
5% 52ppm
1% 11.5ppm
0.1% 1.8ppm

  CO has a binding force with hemoglobin in blood that is 250 times greater than that of oxygen (O2). For this reason, CO poisoning accidents frequently occur, and CO is regarded as a toxic gas. However, recent studies have shown that CO has physiological activity in vivo.

  The fact that CO, which is said to be harmful in nature, was produced in vivo in almost 100 years, even though it was already known in the blood of healthy humans and animals at the end of the 19th century. It was not the subject of research. However, in the early 1990s, heme oxygenase (HO) research became rapidly active among medical and biochemical researchers worldwide, and various actions of CO in vivo were known. As a result, it has gained a lot of attention in clinical practice.

  CO is produced in vivo by cleavage of heme. This heme is present in a large amount in red blood cells and the like as hemoglobin. For example, red blood cells are destroyed with a life of 120 days. At this time, HO works to break down the heme nucleus. The CO produced from heme by the enzymatic action of this HO binds to red blood cells Hb to form carbon monoxide hemoglobin (Carboxylhemoglobin: COHb), circulates in the body on the blood, and replaces O2 in the lung as free CO. It is excreted during expiration. This is exhaled CO, and everybody emits about 1-2 ppm.

  Since CO is a very stable gas molecule and has no loss in the living body, the CO concentration is linked to the amount of CO generated in the living body, whether in blood or exhaled. That is, the amount of CO generated is proportional to the increase in HO. Among them, inducible HO-1 is induced by a stress response, so it is considered that the degree of stress can be known by monitoring this CO.

  On the other hand, CO has been known to have various physiological functions from recent studies. As described in the previous section, the expression of HO-1 and the production of CO are correlated, but the produced CO itself has anti-inflammatory action, anti-apoptotic action, anti-proliferative action and other anti-stress actions, and cell tissue homeostasis. It has become known that there is an effect. Not only does this HO constantly work on heme degradation, but HO-1, which increases against stress, is a biological factor (enzyme) that plays a very important role in maintaining the homeostasis and maintaining a healthy state. It is. For example, humans and mice deficient in HO-1 have been found to be difficult to survive because they are affected by lesions such as severe infections. As you can see, HO-1 protects the body from various stresses and is essential for our survival.

  In addition, it is known that if HO-1 is increased intentionally, symptoms are reduced in various inflammatory diseases, and HO-1 increases in proportion to the severity of symptoms.

  Furthermore, there is an increasing expectation for clinical application in which CO is directly applied to a patient and the therapeutic effect and the protective effect of a transplanted organ are utilized.

  Conventionally, the CO exposure method has been a gas exposure method by living in a gas chamber. However, this is a small-scale and simple operation at the level of animal experiments, but further ingenuity is required in consideration of the operation with the practical application to the human body in mind. Therefore, the method obtained by the inventors through various studies is the administration method according to the present invention.

  This is a simple operation of storing an aqueous CO solution in a septum-equipped container, collecting the required amount with a syringe, and administering it to the affected area via a tube. Regarding the safety of CO, even if the necessary dose is administered directly to the affected area, the digestive tract is considered to be a closed system and there is no leakage to the outside, and even if the dose is absorbed by the living body There is no problem because the amount can be adjusted without harm. Furthermore, since this gas enters the blood after the intended intended action is expressed, it is excreted from the exhaled air relatively quickly, so that it is considered that no side effects or the like occur at all.

In the present invention, transanal administration of a CO solution suppresses the formation of ulcers and reduces intestinal wet weight. As one of the mechanisms, suppression of mucosal lipid peroxidation and suppression of mucosal neutrophil infiltration In addition, a remarkable effect of promoting healing of enteritis was observed. Moreover, a remarkable gastric ulcer healing promotion effect was recognized, and it was confirmed that healing of ulcer was significantly promoted. The present invention having such an effect is an ideal condition as a therapeutic agent that a device suitable for a clinical environment is compact, is extremely easy to operate, is a safe method, and has no side effects on the living body. It is the biggest feature to have.
In short, the drug of the present invention and the method for applying the drug have the following great effects.
(1) Since the medicine is an aqueous solution, the production is simple.
(2) Application to the affected area is also simple.
(3) It has a great effect on the treatment of inflammatory gastrointestinal diseases.

  Hereinafter, the present invention will be described in more detail with reference to examples.

The method of using the CO solution and its effectiveness are described below.
Examination in rat enteritis model Inhibition of acute enteritis with CO solution 7-week-old male Wistar rat was laparotomized at the midline of the abdomen, exposing the distal colon, trinitrobenzene sulfonic acid (TNBS), 0.1M-100μl (35% ETOH) was injected into the colon lumen according to the previous report to produce TNBS enteritis. Immediately after preparation of TNBS enteritis, 1 ml of CO solution was administered transanally twice a day, and lesions were evaluated on the third day after preparation of TNBS enteritis. As evaluation items, ulcer area, intestinal wet weight, colonic mucosa lipid peroxidation, and colonic mucosal neutrophil infiltration were evaluated. Colorectal mucosal lipid peroxidation was evaluated by TBARS, and neutrophil infiltration was evaluated by MPO activity.
Moreover, the same thing was administered also to the rat which does not produce an ulcer as a blank, and the result was seen.

The results of the evaluation are as follows.
Ulcer area (ulcer rat)
Blank 68.5 ± 3.7mm ²
Example 31.3 ± 7.9 mm ²
Ulcer area (healthy rats)
Blank 0.4 ± 0.4mm ²

Example 0.67 ± 0.67 mm ²

Intestinal wet weight (ulcer rat)
Blank 611.8 ± 24.6mg
Example 514.2 ± 12.5 mg
Intestinal wet weight (healthy rats)
Blank 336.4 ± 11.6mg
Example 331 ± 11.9 mg

Large intestine lipid peroxidation (ulcer rat)
Blank 4.04 ± 0.13 nmol / mg prt.
Example 2.38 ± 0.45 nmol / mg prt.
Large intestine lipid peroxidation (normal rats)
Blank 1.39 ± 0.36 nmol / mg prt.
Example 1.27 ± 0.27 nmol / mg prt.

Intestinal mucosal neutrophil infiltration (ulcer rat)
Blank 2.34 ± 1.12 mU / mg prt.
Example 0.66 ± 0.40 mU / mg prt.
Intestinal mucosal neutrophil infiltration (healthy rats)
Blank 0.078 ± 0.018 mU / mg prt.
Example 0.095 ± 0.031 mU / mg prt.

  From the above, transanal administration of CO solution suppresses the formation of ulcers, reduces intestinal wet weight, and as one of the mechanisms, suppression of mucosal lipid peroxidation and suppression of mucosal neutrophil infiltration were observed. It was.

Intestinal inflammation healing effect by CO solution In the above model, it has been found that colon ulcer lesions are sufficiently lesioned on the second day after TNBS injection. The anal ulcer was administered twice a day, and the ulcer area was evaluated 7 days after the preparation of TNBS enteritis, and the healing effect of the lesion was examined. As shown below, a remarkable effect of promoting enteritis healing was observed.

Ulcer area First day 0 ± 0
2nd day 69.8 ± 17.7mm ²
Day 4 Blank 60.9 ± 12.3mm ²
Example 61.5 ± 14.3 mm ²
Day 7 Blank 69.3 ± 14.3mm ²
Example 26.0 ± 13.1 mm ²

Ulcer healing promotion effect in mouse acetic acid gastric ulcer model 7 weeks old male Using C57BL / 6 mice, laparotomy was performed at the midline of the abdomen under Nembutal anesthesia and 40% acetic acid was applied to the anterior wall of the posterior stomach. (30 seconds) Acetic acid ulcer was prepared by the pressing method. One week after the creation of acetic acid ulcer, the ulcer area of the lesion was measured and evaluated. In this model, it was found that lesions formed and reached a peak 3 days after the production of acetic acid ulcer, and 0.2 ml of CO solution was orally administered twice a day from the same day, and the healing promotion effect was determined.

Intestinal wet weight First day 410.5 ± 23.6mg
Day 2 789.8 ± 79.3 mg
Day 4 Blank 809.6 ± 41.7mg
Example 754.8 ± 70.7 mg
Day 7 Blank 852.2 ± 49.7mg
Example 674.8 ± 56.6 mg

Ulcer area First day 0 ± 0
3rd day 19.88 ± 1.99mm ²
Day 7 Blank 11.32 ± 2.04mm ²
Example 4.53 ± 0.60 mm ²
As described above, a remarkable gastric ulcer healing promotion effect was recognized by administration of the CO solution.

Claims (3)

  A drug for treating gastrointestinal inflammation such as gastric ulcer and inflammatory bowel disease, which is an aqueous solution in which carbon monoxide is dissolved, and is used by being locally administered directly to the gastrointestinal tract. The drug according to claim 1, wherein the aqueous solution contains one or more of components having a heme nucleus (hemoglobin, hemin, etc.) Co, Mg, Zn. A method of applying a drug, wherein the drug according to claim 1 is locally administered directly to the affected area by oral ingestion or using a tube inserted into the intestine.