KR20030019951A - Medicaments containing cilansetron for treating non-obstipated male ibs patients - Google Patents

Abstract

The present invention relates to the use of silanesetron for the treatment of constipated male irritable bowel syndrome patients.

Description

MEDICAMENTS CONTAINING CILANSETRON FOR TREATING NON-OBSTIPATED MALE IBS PATIENTS for the Treatment of Men's Irritable Bowel Syndrome Without Constipation

Silanesetron is a 5HT ₃ -receptor antagonist which belongs to the scope of European Patent EP 0 297 651 B1, and (R)-(-)-4,5,6,8,9,10-hexahydro-10-[(2 -Methyl-1H-imidazol-1-yl) methyl] -11H-pyrido- [3,2,1-jk] -carbazol-11-one.

In particular, the use of silanesetron for the production of pharmaceuticals intended to increase the sensitivity to pain and / or to produce macrophages with abnormally fast stool movement in the vicinity of the colon or to treat functional disorders of the lower intestinal tract in humans. Is already well known from European patent EP 0 601 345 B1. In particular, functional disorders that can be treated with silanesetron include, for example, "irritable bowel syndrome (IBS)" including abnormally rapid movement of feces through the colon.

In International Patent Application Publication No. WO 99/17755, 5HT ₃ -receptor antagonists treat female irritable bowel syndrome patients without constipation (= group of patients with irritable bowel syndrome with severe diarrhea; as opposed to the group with patients with severe constipation with irritable bowel syndrome). Particularly suitable for. Allosetron is cited by way of example in WO 99/17755; In this clinical trial, alosetron has significantly superior efficacy to female irritable bowel syndrome patients compared to the effectiveness of male irritable bowel syndrome patients. In male trials treated with allosetron, no noticeable improvement was observed in this medical trial compared to the group treated with placebo. In one embodiment of WO 99/17755, in particular silanesetron is mentioned within the scope of the publication.

The present invention relates to novel medicinal uses of cilansetron or acid addition salts thereof.

Surprisingly, silanesetron has been found to be equally suitable for the treatment of unconstipated male and female patients suffering from irritable bowel syndrome (= IBS).

Accordingly, the subject of the present invention is a silanesetron or a pharmaceutically acceptable acid addition salt and / or solvent thereof for the preparation of a pharmaceutical preparation for the treatment and / or prevention of irritable bowel syndrome in male patients without constipation. It relates to the use of the compound.

Irritable bowel syndrome presents a series of signs that involve pain and / or discomfort in the lower abdomen and diarrhea, constipation, or altered bowel activity that alternates with diarrhea and constipation. The medical diagnosis for this disease is largely considered to be a typical symptom of irritable bowel syndrome, since until now no clear physiological or other organic consequences could be clearly identified as a 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). It was based on the absence or presence of various symptoms described by way of example.

According to the invention, the silanesetron is preferably used in the form of silanesetron hydrochloride. Generally, cilansetron hydrochloride monohydrate is used. Further pharmacologically acceptable acid addition salts of silanesetron are known from EP 0 297 651 B1.

Clinical trial data demonstrate the surprising suitability of silanesetron for the treatment of constipated male and female irritable bowel syndrome patients.

The effect of silanesetron on both constipation-free patients with irritable bowel syndrome was evaluated using a 12-week clinical double-blind study with placebo in a randomly selected group of parallel tests. It was investigated through. In this study, the patients with irritable bowel syndrome were patients without symptoms of constipation whose symptoms were according to the "Roman Diagnostics Criteria" (see above) and whose stool characteristics and frequency were according to the following criteria:

i) Less than 25% of irritable bowel syndrome conditions adversely affected by constipation.

ii) Characterized by non-constipation in accordance with the "Roman Diagnostics Criteria" (see above, persons who have less than 3 days of no bowel movements per week and / or are not hard / lumpy in nature).

iii) 4 days or less (continuous or discontinuous) on days without bowel movement during the 2-week observation period (= "run-in period").

iv) The average characteristic of the stool during the two-week observation period is 4 or more (according to the Bristol stool scale).

Similarly, a person who answers "no" to only 50% or less of the question about whether they felt pain or discomfort in the lower abdomen, or pain or discomfort in the lower abdomen is judged "self-limited" during the 2-week observation period. Patients with less than 2 times are included in this experiment.

Silanesetron is used in dosages of 1, 2, 8 and 16 mg. Patients were checked weekly to see if their signs of irritable bowel syndrome (stomach pain, such as abdominal pain, abnormal bowel activity) were "moderately relieved (primary efficacy variable)". Stomach pain, such as pain in the abdomen, stool characteristics and frequency of stool (secondary efficacy variable) were measured daily in patients.

In the transient results of the double blind trial, data from a total of 454 patients (297 female and 157 male patients) were measured and listed in the table below. Corresponding to the criteria on which clinical double blind trials are based, the indication of "adequate alleviation" of the symptoms of irritable bowel syndrome in two patient subgroups of male and female irritable bowel syndrome patients. The success rate is shown in the table below.

table

Success rate [%] Silanesetron (mg TID) Placebo One 2 8 16 Male patient 30.0 51.3 63.0 56.3 58.6 Female patient 41.8 69.6 60.3 56.9 61.4

The "primary effectiveness parameter" relates to the success rate for the question (= "responder rate"), which asks patients weekly for signs of irritable bowel syndrome during the course of the last week (lower abdomen). Pain / discomfort, abnormal bowel activity) in the "appropriate relief". A "responder" is "yes" to the question of whether he / she has been treated for at least 4 weeks and "moderately relieved" of his / her irritable bowel syndrome symptoms during at least half of his / her treatment period. It is the patient who answers.

At the end of the double-blind experiment, a total of 471 patients (308 female and 163 male patients) were measured. Final success rates were 40% for the placebo group, 62% for the 1 mg silanesetron administration (TID), 53% for the 2 mg silanesetron administration (TID), 55% and 16 mg for the 8 mg silanesetron administration (TID) 63% for silanesetron administration (TID). The success rate was very similar for the male and female patient groups. The largest difference was observed for the administration of 1 mg silanesetron (TID).

The data given above showed that patients with irritable bowel syndrome without bilateral constipation responded to silanesetron at all doses studied.

The constipation demonstrated by the results is natural, as the skilled person would conclude from the disclosure in WO 99/17755 that silanesetron is differentially suitable for the treatment of female irritable bowel syndrome patients without constipation, like allosetron. The effectiveness of silanesetron in the treatment of patients with no irritable bowel syndrome was surprising.

Previously known 5HT ₃ -receptor antagonists have been prescribed twice daily (= "BID administration") for the treatment of irritable bowel syndrome. However, for example, administration of 5HT ₃ -receptor antagonist three times per day (= "TID administration") to bilateral irritable bowel syndrome patients every time 1-16 mg is more effective in treating patients with both types of irritable bowel syndrome. It turned out. It is preferred to administer the 5HT ₃ -antagonist _three times a day, and also to prescribe after stock (morning, lunch and dinner). Three times a day, examples of 5HT ₃ -receptor antagonists that may be administered more advantageously are allosetronone, azasetron, dolasetron, granisetrone, indiesetron, itasetron, lerisetron, ondansetron, Lamosetrone, trocetolone and (R)-jacobride. When treating patients with both types of irritable bowel syndrome, it was found to be best to administer silanesetron or its pharmaceutically acceptable acid addition salts and / or solvates to patients three times a day, 1 to 16 mg at a time. .

As therapeutic agents, silanesetron or pharmaceutically acceptable acid addition salts of silanesetron can be included in the pharmaceutical formulations of solid or liquid together with traditional pharmaceutical auxiliaries and / or carriers, according to the invention. . Examples of solid preparations are orally administrable tablets, coated tablets, capsules, powders or granules, or optionally suppositories. Such formulations may include conventional pharmaceutical inorganic and / or organic carriers such as talc, lactose or starch, and may also include conventional pharmaceutical adjuvants such as lubricants, tablet disintegrating agents. have. Liquid formulations such as silanesetron suspensions or emulsions may generally comprise diluents such as suspending agents such as water, oils and / or polyethylene glycols. Other adjuvants may be optionally added, such as preservatives, taste correctives, and the like.

Acid addition salts of silanesetron or pharmacologically acceptable silanesetron may be formulated by mixing with a pharmaceutical adjuvant and / or carrier in a known manner. For the preparation in solid pharmaceutical form, the silanesetron or acid addition salt can be mixed with, for example, an adjuvant and / or a carrier in a conventional manner and can be dry or wet granulated. The granules or powders are encapsulated or compressed into tablets directly in a conventional manner. These can be coated if necessary.

The following examples are intended to illustrate the preparation of pharmaceutical formulations comprising silanesetron hydrochloride.

Example 1: Tablet

Configuration

4 parts of silanesetron hydrochloride monohydrate

30 parts corn starch

Lactose, Part 70

Collidone 25 ^R part 5

Magnesium Stearate 2 parts

Talc Part 3

114 total

Manufacturing process

The actives were mixed in a mixer with corn starch and finely powdered lactose. The resulting mixture was completely wetted with a 20% solution of polyvinylpyrrolidone (Kollidon 25 ^R , manufactured by BASF) in deionized water. More deionized water was added as needed. The moist granules were passed through a 2 mm sieve, dried in a tray at 40 ° C., and then passed through a 1 mm sieve (the frying machine). The granules were once mixed with magnesiumstearate and talc, from which 114 mg of weight tablets were compressed and each tablet obtained contained 4 mg of active substance.

In addition, other pharmaceutical formulations of silanesetron can be used examples known from EP 0 895 782 A2.

Claims (8)

Use of silanesetron or a pharmacologically acceptable acid addition salt thereof and / or solvate thereof for the manufacture of a pharmaceutical formulation for the treatment and / or prevention of constipation-free male irritable bowel syndrome patients. Use according to claim 1, characterized in that the silanesetron is silanesetron hydrochloride. Use according to claim 1, characterized in that the silanesetron is a silanesetron hydrochloride monohydrate. Use of at least one 5HT ₃ -receptor antagonist for the preparation of said pharmaceutical formulation for treating patients with both sexes with 3 times a day. 5. Use according to claim 4, wherein the at least one 5HT ₃ -receptor antagonist is used in a dosage of 1-16 mg. Use according to claim 4, characterized in that three administrations per day are made after breakfast, lunch and dinner which are staple foods. 5. The method according to claim 4, wherein the 5HT ₃ -receptor antagonist is acerosetron, azasetron, dorasetron, granistron, indysetron, itacetron, lerisetron, ondansetron, lamosetron, trocetolone And / or (R) -jacobopride is used. 5. Use according to claim 4, characterized in that silanesetron or a pharmacologically acceptable acid addition salt and / or solvate thereof is used as the 5HT ₃ -receptor antagonist.