KR20180037408A - Pharmaceutical composition for improving Irritable Bowel Syndrome comprising Lactitol - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for preventing and treating novel syndrome, in which the prevention and treatment effect is improved and side effects are alleviated by mixing an existing medicine for preventing and treating irritable bowel syndrome and lactitol, and preferably, provides a pharmaceutical composition for alleviating and treating the irritable bowel syndrome, which comprises: 1) any one selected from a group consisting of ramosetron, a pharmaceutically acceptable salt of ramosetron, alosetrone, a pharmaceutically acceptable salt of alosetrone, rifaximin, a pharmaceutically acceptable salt of rifaximin, eluxadoline, a pharmaceutically acceptable salt of eluxadoline, octylonium and a pharmaceutically acceptable salt of octylonium; and 2) any one selected from a group consisting of lactitol, lactitol hydrate, and a pharmaceutically acceptable salt of lactitol.

Description

[0001] The present invention relates to a pharmaceutical composition for preventing and treating irritable bowel syndrome comprising lactitol, and a pharmaceutical composition for improving Irritable Bowel Syndrome comprising Lactitol,

The present invention relates to a pharmaceutical composition for the prevention and treatment of irritable bowel syndrome. The present invention relates to a pharmaceutical composition for the prevention and treatment of a novel syndrome in which prophylactic and therapeutic effects of a conventional drug for the prevention and treatment of irritable bowel syndrome are combined with lactitol, ≪ / RTI >

Irritable Bowel Syndrome (IBS) is one of the common diseases of the intestines and is estimated to cause 15% of people in the United States.

Other names for Irritable Bowel Syndrome include, but are not limited to, spastic colon, spastic colitis, and mucous colitis.

Irritable bowel syndrome is caused by the abnormal function of the nerves that regulate the muscles or organs of the organs of the gastrointestinal tract. The abnormal function of the nervous system in IBS may occur in the muscular organ, spinal cord or brain of the stomach. Normal activities, such as stretching of the small intestine by food, cause abnormal sensory signals to the spinal cord and brain that they perceive as pain. Abnormal commands through the motor nerves may also produce painful spasm (contraction) of the muscles. Thus, irritable bowel syndrome can be due to both sensory dysfunction, motor dysfunction, or sensory and motor neuron dysfunction.

Irritable bowel syndrome usually causes cramping, abdominal pain, bloating, constipation, and diarrhea. Irritable bowel syndrome does not cause more severe symptoms in most patients, but it is the source of chronic pain, fatigue and other symptoms. This may increase the cost of medical care for the patient and contribute to absenteeism. Along with increased costs, the high prevalence of IBS can also produce diseases with high social costs. It may also be assessed as a chronic disease and may dramatically affect the quality of life of sufferers.

Therefore, there is a need for effective and stable treatment of irritable bowel syndrome.

1. International patent application WO 99/17755

The present invention provides a novel pharmaceutical composition which is useful for the prevention and treatment of irritable bowel syndrome and which alleviates side effects.

According to an aspect of the present invention,

1) a medicament for alleviating and treating irritable bowel syndrome or a pharmaceutically acceptable salt of said medicament; And

2) any one selected from the group consisting of lactitol, lactitol hydrate, and pharmaceutically acceptable salts of lactitol; To

The present invention provides a pharmaceutical composition for alleviating and treating irritable bowel syndrome.

According to another aspect of the present invention,

1) a pharmaceutically acceptable salt of ramosetron, a ramosetron, a pharmaceutically acceptable salt of Alosetorn, a pharmaceutically acceptable salt of alocetrone, rifaximin, rifaximin, Acceptable salt, eluxadoline, a pharmaceutically acceptable salt of eluxurazine, octylonium and a pharmaceutically acceptable salt of octylronium, and

2) any one selected from the group consisting of lactitol, lactitol hydrate, and pharmaceutically acceptable salts of lactitol; To

The present invention provides a pharmaceutical composition for alleviating and treating irritable bowel syndrome.

The composition according to the present invention as described above is superior to conventional lamosaetron, alocetrone, rifaximin, eloxadolin or octylonium in mitigating irritable bowel syndrome and its therapeutic effect, Is high.

Hereinafter, the present invention will be described in detail.

It has surprisingly been found that the combination of an agent for the relief and treatment of irritable bowel syndrome and lactitol, preferably ramosetron, alocetrone, rifaximin, eluxurdin or octylronium and lactitol, The present invention has been accomplished on the basis of the finding that the therapeutic effect is remarkably improved by overcoming the range predicted by those of ordinary skill in the art to which the present invention belongs. A pharmaceutical composition for treatment.

The pharmaceutical composition for relieving and treating irritable bowel syndrome according to the present invention comprises

1) a pharmaceutically acceptable salt of ramosetron, ramosetron, a pharmaceutically acceptable salt of alocetrone, a pharmaceutically acceptable salt of alocetron, a rifaximin, a pharmaceutically acceptable salt of rifaximin, A pharmaceutically acceptable salt of ruxeraldehyde, a pharmaceutically acceptable salt of ruxeraldehyde, a pharmaceutically acceptable salt of ruxeraldehyde, a pharmaceutically acceptable salt of ruxaldoline, a pharmaceutically acceptable salt of octylonium and octylonium, and

2) any one selected from the group consisting of lactitol, lactitol hydrate, and pharmaceutically acceptable salts of lactitol; To

.

The ramosetron is a receptor antagonist of serotonin, a neurotransmitter that regulates the senses and motility of the intestine. It is administered orally 5 μg as ramosetron hydrochloride once a day, and its amount can be controlled according to the symptoms. 2.5 μg, up to 10 μg.

The alosetron is a potent and selective inhibitor of the serotonin 5-HT3 receptor and is orally administered twice a day in 1 mg increments and should be discontinued if severe constipation is present.

It is known that rifaximin can be administered up to 4 times a day depending on the symptoms, with 600 mg once a day as an antibiotic acting on the gastrointestinal tract.

The above-mentioned ELUXARDOLIN has a remarkable effect of reducing diarrhea and abdominal pain caused by irritable bowel syndrome, and it is known that it can be administered to 75 mg to 100 mg per day.

The above-mentioned octylonium acts directly on the smooth muscle of the gastrointestinal tract and inhibits intracellular influx of calcium ions, and shows gentle action. It can be administered 20 to 40 mg once orally twice or three times a day and appropriately alleviated according to the symptoms It is known.

The lactitol is a water-soluble disaccharide which acts on the lower part of the gastrointestinal tract to proliferate intestinal lactic acid bacteria, produce organic acids and lower intestinal acidity to normalize the physiological rhythm of the large intestine and improve the likelihood of diarrhea. The dose is about 10 to 20 g per day .

The hydrates and pharmaceutically acceptable salts of ramosetron, allocitron, octylonium and lactitol used in the present invention are well known in the art to which the present invention belongs and can be used without any particular limitation, Lomosetron, alocetron hydrochloride, octylonium bromide, and lactitol monohydrate.

The composition ratio of the pharmaceutical composition for relieving and treating irritable bowel syndrome according to the present invention may be as follows.

1) a pharmaceutically acceptable salt of ramititol and ramosetron or ramosetron, a pharmaceutically acceptable salt of ramosetron or ramosetron when it is lactitol 1 in a weight ratio of from 0.000000125 to 0.000002 .

2) a pharmaceutically acceptable salt of alocetrone or alocetron when in the ratio of ticitol 1 in terms of weight ratio, 0.00005-0.0005.

3) a pharmaceutically acceptable salt of rifaximin or rifaximin when it contains ticitol 1 in a weight ratio of from 0.05 to 0.1, if it comprises lactitol and a pharmaceutically acceptable salt of rifaximin or rifaximin.

4) a pharmaceutically acceptable salt of elixarthroline or elixarthroline when it contains ticitol 1 in a weight ratio of from 0.00016 to 0.002.

5) a pharmaceutically acceptable salt of octylonium or octylonium, and a pharmaceutically acceptable salt of octylonium or octylonium, when lactitol 1, in a weight ratio of from 0.0008 to 0.001

When such a weight ratio is administered in combination with a daily dose as a medicine, prevention and treatment effects of irritable bowel syndrome are increased, and administration of ramosetron, alocetrone, rixacumin, elulsaturin, octylonium And the amount of side effects such as constipation and the like can be increased by decreasing the dose. The amount of the drug can be selectively determined in accordance with the symptom according to the weight ratio. Anyone with ordinary knowledge of the field can do so without difficulty.

Irritable bowel syndrome refers to a series of symptoms involving pain and / or uncomfortable feeling in the lower abdomen and diarrhea, constipation, or changes in bowel activity where diarrhea and constipation alternate. The medical diagnosis of this disease is generally regarded as a typical symptom of irritable bowel syndrome, as it has not been possible to clearly present substantive physiological or other organic results as the cause of irritable bowel syndrome. Rome Criteria "(WG Thompson et al., Gastroent, Int. 2 (1989) 92-95; WG Thompson et al., Gut. 45 / II (1999) II43-II47; WG Thompson, Lancet 341 (1993) 1569-1572) Based on the absence or presence of various symptoms described as examples.

The clinical trial data according to the invention demonstrate the remarkable suitability for the treatment of male and female irritable bowel syndrome patients.

The effect of the composition according to the invention on patients with irritable bowel syndrome was investigated through a clinical 12-week double-blind study in which placebo was administered to a randomly selected group of parallel tests .

In this study, patients with irritable bowel syndrome were patients whose symptoms were according to the "Rome Diagnostic Criteria" (see above) and whose characteristics and frequency of stool complied with the following criteria:

i) 25% or less of the irritable bowel syndrome that is adversely affected by constipation.

ii) characterized by non-constipation according to the "Rome Diagnostic Criteria" (see above, a person who does not have bowel movement less than three times a week and / or whose stool is of a hard / lumpy nature).

iii) No bowel movement days for up to 4 days (continuous or discontinuous) during a 2-week observation period (= "run-in period").

iv) The average characteristic of the stools during the 2-week observation period is 4 or more (= "Bristol stool scale").

Likewise, a person who answered "no" only if the lower abdomen felt a pain / uncomfortable feeling in only 50% or less of the question, or the pain / uncomfortable feeling of the abdomen under his / her own judgment during the two- Patients with less than 2 events were included in this study.

The composition according to the present invention was orally administered at a total dose of 15 g twice a day in 7.5 g portions. The contents of other components in the composition except lactitol are shown in Table 1. The daily dose of 15 g was determined to be a median of 10 to 20 g of the daily dose of lactitol occupied by most of the ingredients. The other ingredients were used in a small amount compared to lactitol. I did.

The components used in this test were ramosetron hydrochloride, alocetron hydrochloride, octylonium bromide, and lactitol monohydrate. As a comparative example, there was no lactitol but pure ramosetron hydrochloride, alosetron hydrochloride, Citrus, El Rusadolin, and bromyl octylonium alone were administered. In Comparative Example 1, 5 g of ramosetron hydrochloride was orally administered once a day, in Comparative Example 2, 1 mg of alosetron hydrochloride was administered orally twice a day, In Comparative Example 3, 30 mg of octyl bromide was orally administered twice per day, in Comparative Example 4, 600 mg of rifaximin was orally administered twice a day, and in Comparative Example 4, oral olanzapathilone 30 mg was administered orally twice a day .

Ramosetron Alosetron Octylonium Rifaak citizen El Rusadarin Example 1 2.5 g Example 2 5 g Example 3 10 g Example 4 1 mg Example 5 2 mg Example 6 3 mg Example 7 10 mg Example 8 30 mg Example 9 60 mg Example 10 500 mg Example 11 25 mg

Patients were checked weekly for signs of irritable bowel syndrome (stomach pain such as abdominal pain, abnormal bowel activity) as "moderately relieved (the first efficacy variable)". Stomach pain such as abdominal pain, stool characteristics and stool frequency (secondary efficacy variables) were measured daily in patients.

Data for a total of 45 patients (33 female patients and 12 male patients) were measured and reported in Table 2 below.

Table 2 shows that in the two patient subgroups of patients with male and female irritable bowel syndrome, the indications of irritable bowel syndrome were "alleviation" in response to the criteria on which the clinical double- Is the success rate of being.

Success rate (%) Male patient Female patient Placebo 25.8 27.5 Example 1 68.2 69.3 Example 2 72.3 73.1 Example 3 71.2 71.3 Example 4 68.5 68.9 Example 5 73.1 73.9 Example 6 70.2 71.2 Example 7 65.2 65.4 Example 8 67.2 67.8 Example 9 64.1 66.4 Example 10 67.3 67.9 Example 11 68.0 67.2 Comparative Example 1 48.9 55.1 Comparative Example 2 52.4 58.2 Comparative Example 3 42.3 44.8 Comparative Example 4 54.3 59.7 Comparative Example 5 54.1 59.8

The primary efficacy parameter is related to the success rate of the question [the "responder rate"], which is given to patients every week during their previous week's course of their irritable bowel syndrome (in the lower abdomen Pain / discomfort, abnormal bowel activity) experienced "relieved ". A "responder" is said to be "yes " for a question about whether it has been" cured "for his / her irritable bowel syndrome symptoms that have been treated for at least 4 weeks and have been seen during at least half of the treatment period for him / .

The success rate of Table 2 is much higher than that of the placebo group in the case of the composition according to the present invention and is higher than that of Comparative Examples 1, 2 and 3 which are conventionally known therapeutic ingredients and can be improved by containing lactitol It is judged that the effect is sufficiently proven.

The compositions according to the present invention may be included in solid or liquid pharmaceutical preparations together with conventional pharmaceutical auxiliaries and / or carriers.

Examples of solid formulations are those that can be administered orally, such as tablets, coated tablets, capsules, powders or granules, or optionally suppository. Such preparations may contain conventional pharmaceutical inorganic and / or organic carriers such as talcum, lactose or starch, and may additionally contain conventional pharmaceutical adjuvants such as lubricants, tablet disintegrants, have.

Liquid preparations such as suspensions or emulsions may generally contain diluents, such as suspensions, such as water, oils and / or polyethylene glycols. Other adjuvants such as preservative, taste corrective and the like may optionally be added.

The composition according to the present invention can be formulated to be mixed with pharmaceutical adjuvants and / or carriers by known methods. May be mixed with, for example, adjuvants and / or carriers, and may be dry or wet granulated, in a conventional manner, for preparation in solid pharmaceutical form. The granules or powders are put into the capsule directly or compressed into tablets in a conventional manner. These can be coated if necessary.

Claims (6)

1) a medicament for alleviating and treating irritable bowel syndrome or a pharmaceutically acceptable salt of said medicament; And
2) any one selected from the group consisting of lactitol, lactitol hydrate, and pharmaceutically acceptable salts of lactitol; To
A pharmaceutical composition for alleviating and treating irritable bowel syndrome,
The use according to claim 1, wherein the medicament for relieving and treating irritable bowel syndrome or a pharmaceutically acceptable salt of the medicament is a pharmaceutically acceptable salt of ramosetron or ramosetron, for the relief and treatment of irritable bowel syndrome A pharmaceutical composition.
The use according to claim 1, wherein the medicament for relieving and treating irritable bowel syndrome or a pharmaceutically acceptable salt thereof is a pharmaceutically acceptable salt of alocetrone or alocetrone, for the relief and treatment of irritable bowel syndrome A pharmaceutical composition.
The pharmaceutical composition for the relief and treatment of irritable bowel syndrome according to claim 1, wherein the medicament for relieving and treating irritable bowel syndrome or a pharmaceutically acceptable salt thereof is a pharmaceutically acceptable salt of rifaximin or rifaximin. Composition.
The use according to claim 1, wherein said medicament for relieving and treating irritable bowel syndrome or a pharmaceutically acceptable salt of said medicament is a pharmaceutically acceptable salt of eloxadolin or eloxadolin for the relief and treatment of irritable bowel syndrome A pharmaceutical composition.
The use of a medicament for relieving and treating irritable bowel syndrome or a pharmaceutically acceptable salt of the medicament according to claim 1 for the treatment and relief of irritable bowel syndrome characterized by being a pharmaceutically acceptable salt of octylonium or octylonium A pharmaceutical composition.