US 20030125349A1 (19) United States (12) Patent Application Publication (10) Pub. N0.: US 2003/0125349 A1 Cautreels et al. (43) Pub. Date: Jul. 3, 2003

(54) MEDICAMENT CONTAINING (22) Filed: Jan. 22, 2003 CILANSETRON FOR THE TREATMENT OF NON-OBSTIPATIVE MALE IRRITABLE Related US. Application Data BOWEL SYNDROME PATIENTS (62) Division of application No. 09/908,735, ?led on Jul. (75) Inventors: Werner L. M. Cautreels, Weesp (NL); 20, 2001. Claus Rudolf Steinborn, SeelZe (DE); Heinz Guenter Krause, Burgdorf (DE); (60) Provisional application No. 60/220,848, ?led on Jul. Steven David Caras, Marietta, GA 26, 2000. (US); Egbertus Hendrikus Evert Biesheuvel, Weesp (NL); Albertus (30) Foreign Application Priority Data Hermannus Dirk Plekkenpol, Hilversurn (NL) Jul. 26, 2000 (DE) ...... 100 36 645.7 May 14, 2001 (DE) ...... 101 23 447.3 Correspondence Address: CROWELL & MORING LLP Publication Classi?cation INTELLECTUAL PROPERTY GROUP (51) Int. Cl? ...... A61K 31/4745 PO. BOX 14300 (52) Us. 01...... 514/285 WASHINGTON, DC 20044-4300 (US) (73) Assignee: Solvay Pharmaceuticals GmbH, Han (57) ABSTRACT nover (DE) The present invention relates to the use of cilansetron for the (21) Appl. No.: 10/347,707 treatment of non-obstipative rnale IBS patients. US 2003/0125349 A1 Jul. 3, 2003

MEDICAMENT CONTAINING CILANSETRON and altered intestinal activity, such as diarrhea, obstipation FOR THE TREATMENT OF NON-OBSTIPATIVE (=constipation), or alternately diarrhea and obstipation. MALE IRRITABLE BOWEL SYNDROME Since it has hitherto not been possible to give any clearly PATIENTS tangible physiological or other organic results as a cause of IBS, medical diagnosis of this illness is usually based on the CROSS REFERENCE TO RELATED absence or presence of a number of symptoms, Which are APPLICATIONS generally regarded as typical of IBS and are recorded for [0001] This application claims priority of US. Provisional eXample in the “Rome Criteria” (cf. W. G. Thompson et al., Patent Application No. 60/220,848, ?led Jul. 26, 2000. Gastroent. Int. 2 (1989) 92-95; W. G. Thompson et al., Gut Convention priority is also claimed based on Federal Repub 45/II (1999) II 43-II 47; W. G. Thompson, Lancet 341 (1993) lic of Germany Patent Application Nos. DE 100 36 645.7, 1569-1572). ?led Jul. 26, 2001 and DE 101 23 447.3, ?led May 14, 2001. [0009] According to the invention, cilansetron may pref erably be used in the form of cilansetron hydrochloride. BACKGROUND OF THE INVENTION Usually, cilansetron hydrochloride monohydrate is used. [0002] The present invention relates to a novel medicinal Further pharmacologically acceptable acid addition salts of use of cilansetron or the acid addition salts thereof. cilansetron are knoWn from EP 0 297 651 B1. [0003] Cilansetron is a 5HT3-receptor antagonist Which [0010] Clinical test data prove the surprising suitability of falls Within the scope of European Patent No. EP 297,651 B1 cilansetron for the treatment of non-obstipative IBS patients and has the chemical name (R)-(—)-4,5,6,8,9,10-heXahydro of both the male and the female seX. 10-[(2-methyl-1H-imidaZol-1-yl)methyl]-11H-pyrido-[3,2, 1-jk]-carbaZol-11-one. [0011] The effect of cilansetron on non-obstipative IBS patients of both sexes Was investigated in a 12-week pla [0004] The use of, inter alia, cilansetron for the production cebo-controlled clinical double-blind study With randomiZed of pharmaceutical preparations for the treatment of func selection and parallel test groups. Within the scope of the tional disturbances in the loWer intestinal tract in larger study, those IBS patients Were regarded as non-obstipative mammals and humans Which involve increased sensitivity to patients Whose symptoms met the “Rome Criteria” (see pain and/or abnormally accelerated stool passage in the above) and the nature and frequency of Whose stools met the colon region is already knoWn from European Patent No. EP folloWing criteria: 601,345 B1. The functional disturbances Which can be treated, inter alia, by cilansetron also include, for eXample, [0012] i)<25% IBS events adversely affected by “irritable boWel syndrome” (=IBS), in particular in conjunc obstipation. tion With abnormally accelerated passage of the stool through the colon. [0013] ii) Characterised as non-obstipative in accor dance With the “Rome Criteria” (see above, people [0005] In International Patent Application Publication No. Who did not have <3 boWel movements per Week WO 99/17755, 5HT3-receptor antagonists are described and/or Whose stools Were not hard/lumpy in nature). Which are particularly Well-suited for the treatment of non obstipative (=diarrhea-predominant IBS patient group; in [0014] iii) <4 days (in succession or not in succes contrast to the obstipation-predominant IBS patient group) sion) Without boWel movement over a tWo-Week female IBS patients. Alosetron is cited as an eXample in WO observation period (=“run-in period”). 99/17755. In clinical tests, alosetron exhibited signi?cantly better effectiveness on female IBS patients, compared With [0015] iv) Average nature of stools >4 (corresponding the effectiveness on male IBS patients. On male test subjects to the “Bristol stool scale”) over a tWo-Week obser treated With alosetron, no signi?cant improvement in con vation period. dition compared With the placebo group Was noted in these [0016] Likewise, those patients Were included in the study clinical tests. In one embodiment of said application no. WO Who responded “No” to the question about pain/feeling of 99/17755, cilansetron also is mentioned among other sub unWellness in the loWer abdomen only in 250% of the cases stances as coming Within the scope of the disclosure. or Who judged their pain/feeling of unWellness in the loWer abdomen as “restrictive” for <2 times over a tWo-Week SUMMARY OF THE INVENTION observation period. [0006] It has noW surprisingly been discovered that [0017] Cilansetron Was used in doses of 1, 2, 8 and 16 mg. cilansetron is equally suitable for the treatment of non The patients Were checked Weekly for “adequate alleviation” obstipative male and female patients suffering from irritable (=primary effectiveness parameter) of their IBS symptoms boWel syndrome (=IBS). (stomach pains such as pains in the abdomen, abnormal [0007] The invention therefore relates to the use of boWel activity). Stomach pains such as pains in the abdo cilansetron or the pharmacologically acceptable acid addi men, nature of the stools and stool frequency Were rated tion salts and/or solvates thereof for the production of daily by the patients (=secondary effectiveness parameter). pharmaceutical preparations for the treatment and/or pro phylaXis of irritable boWel syndrome (IBS) in non-obstipa [0018] In a provisional result of the double-blind study, the tive male patients. data of a total of 454 patients (297 female patients and 157 male patients) Were evaluated and plotted in the table beloW. [0008] IBS designates a group of symptoms, accompanied Corresponding to the criteria on Which the clinical double by pain and/or a feeling of unWellness in the loWer abdomen blind study Was based, in both patient subgroups of male US 2003/0125349 A1 Jul. 3, 2003

IBS patients and female IBS patients the success rates [0024] In accordance With the invention, cilansetron or a relating to the “adequate alleviation” of the IBS symptoms pharmacologically acceptable acid addition salt of as set forth in the table below Were noted: cilansetron may be contained as a therapeutic agent, together With conventional pharmaceutical auxiliaries and/or carri TABLE ers, in solid or liquid pharmaceutical preparations. Examples of solid preparations are preparations Which can be admin Cilansetron (mg TID) istered orally, such as tablets, coated tablets, capsules, Success rate [%] Placebo 1 2 8 16 poWders or granules, or alternatively suppositories. These preparations may contain conventional pharmaceutical inor Male patients 30.0 51.3 63.0 56.3 58.6 ganic and/or organic carriers, such as talcum, lactose or Female patients 41.8 69.6 60.3 56.9 61.4 starch, in addition to conventional pharmaceutical auxilia ries, for example lubricants or tablet disintegrating agents. Liquid preparations such as suspensions or emulsions of [0019] The “primary effectiveness parameter” corre cilansetron may contain the usual diluents such as Water, oils sponds to the success rate (=“responder rate”) to the ques and/or suspension agents such as polyethylene glycols and tion, Which Was put Weekly to the patients, as to Whether they had experienced “adequate alleviation” of their IBS the like. Other auxiliaries may additionally be added, such as preservatives, taste correctives and the like. symptoms (pain/feeling of unWellness in the loWer abdo men, abnormal boWel activity) during the course of the [0025] Cilansetron or a pharmacologically acceptable acid previous Week. A “responder” is regarded as a patient Who addition salt of cilansetron can be mixed and formulated Was treated for at least four Weeks and Who responded “Yes” With the pharmaceutical auxiliaries and/or carriers in a to the question posed of Whether “adequate alleviation” of knoWn manner. For the production of solid medicament his/her IBS symptoms had occurred for at least half of forms, cilansetron or an acid addition salt can for example his/her treatment period. be mixed With the auxiliaries and/or carriers in a conven tional manner and can be Wet or dry granulated. The [0020] At the end of the double-blind study, the data of a granules or poWder can be poured directly into capsules or total of 471 patients (308 female patients and 163 male be pressed into tablet cores in a conventional manner. These patients) Were evaluated. The ?nal success rates Were 40% can be coated in a knoWn manner if desired. for the placebo group, 62% for the dose 1 mg cilansetron (TID), 53% for the dose 2 mg cilansetron (TID), 55% for the [0026] The folloWing example is intended to explain the dose 8 mg cilansetron (TID) and 63% for the dose 16 mg production of pharmaceutical preparations containing cilansetron (TID). The success rates Were very similar for cilansetron hydrochloride. the male and female patient groups. The greatest differences Were observed for the dose of 1 mg cilansetron (TID). EXAMPLE 1 [0021] It can be seen from the data given above that the Tablets non-obstipative IBS patients of both sexes respond to the treatment With cilansetron in all the dosages investigated. [0027] [0022] It is particularly surprising that cilansetron is effec tive, as proved by the above results of the investigations, in the treatment of non-obstipative (=diarrhea-predominant) Composition: male IBS patients, since the person skilled in the art had to Cilansetron hydrochloride monohydrate 4 parts conclude from the contents of W0 99/ 17755 that Corn starch 30 parts Lactose 70 parts cilansetron, just like alosetron, Was preferentially suited only Kollidon 25 TM 5 parts for the treatment of non-obstipative female IBS patients. Magnesium stearate 2 parts [0023] Previously-knoWn 5HT3-receptor antagonists are Talcum 3 parts usually administered tWice a day for treatment of IBS Total: 114 parts (=“BID dosage”). HoWever, it has proved more advanta geous for treating IBS patients of both sexes instead to administer 5HT3-receptor antagonists three times a day [0028] Preparation Procedure: (=“TID dosage”), for example in doses of 1 mg to 16 mg [0029] The active substance Was mixed With corn starch each time to IBS patients of both sexes. It is particularly preferred to spread the thrice daily administration of 5HT3 and ?nely-poWdered lactose in a mixer. The resulting mix antagonists across the day and in particular to prescribe them ture Was moistened thoroughly With a 20% solution of after main meals (morning, mid-day and evening). Examples polyvinylpyrrolidone (Kollidon 25 TM by BASE) in deminer aliZed Water. If necessary, further demineraliZed Water Was of 5HT3-receptor antagonists Which can be more advanta geously administered in three daily doses include alosetron, added. The moist granules Were passed through a 2 mm aZasetron, dolasetron, granisetron, indisetron, itasetron, sieve, dried on trays at 40° C. and then passed through a 1 lerisetron, ondansetron, ramosetron, tropisetron and (R) mm sieve (FreWitt machine). After mixing the granules With Zacopride. It has proved particularly advantageous for treat magnesium stearate and talcum, tablets of a Weight of 114 mg Were pressed therefrom, so that each tablet contained 4 ing IBS patients of both sexes to administer cilansetron or the pharmacologically acceptable acid addition salts and/or mg of active substance. solvates thereof to the patients three times a day, for example [0030] LikeWise, other pharmaceutical preparations of each time in doses of betWeen 1 mg and 16 mg per cilansetron, for example those knoWn from EP 895,782 A2, administered dose. may be used. US 2003/0125349 A1 Jul. 3, 2003

[0031] The foregoing description and examples have been administering a pharmaceutical composition comprising at set forth merely to illustrate the invention and are not least one 5HT3-receptor antagonist to said patient three intended to be limiting. Since modi?cations of the disclosed times a day. embodiments incorporating the spirit and substance of the 5. A method according to claim 4, Wherein said at least invention may occur to persons skilled in the art, the invention should be construed broadly to include all varia one 5HT3-receptor antagonist is administered in a dose of tions falling Within the scope of the appended claims and from 1 mg to 16 mg. equivalents thereof. 6. Amethod according to claim 4, Wherein the three times What is claimed is: daily administration of said pharmaceutical composition 1. A method of inhibiting preparations for the treatment takes place after morning, mid-day and evening meals, and/or prophylaxis of irritable boWel syndrome (=IBS) in a respectively. non-obstipative male patient, said method comprising 7. A method according to claim 4, Wherein said 5HT3 administering to said patient a pharmaceutical composition receptor antagonist comprises at least one active substance comprising an effective IBS inhibiting amount of cilansetron selected from the group consisting of alosetron, aZasetron, or a pharmacologically acceptable acid addition salt thereof dolasetron, granisetron, indisetron, itasetron, lerisetron, or a solvate thereof. ondansetron, ramosetron, tropisetron, and (R)-Zacopride. 2. A method according to claim 1, Wherein said pharma ceutical composition comprises cilansetron hydrochloride. 8. A method according to claim 4, Wherein said 5HT3 3. A method according to claim 1, Wherein said pharma receptor antagonist comprises cilansetron or a pharmaco ceutical composition comprises cilansetron hydrochloride logically acceptable acid addition salt thereof or a solvates monohydrate. thereof. 4. A method of treating a human patient suffering from irritable boWel syndrome (=IBS), said method comprising