US 2011 O15893 OA1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0158930 A1 Hirata et al. (43) Pub. Date: Jun. 30, 2011 (54) METHOD FOR TREATMENT OF RRTABLE Related U.S. Application Data BOWEL, SYNDROME (60) Provisional application No. 61/190.559, filed on Aug. 28, 2008. (75) Inventors: Takuya Hirata, Tokyo (JP); Toshiyuki Funatsu, Tokyo (JP); Publication Classification Yoshihiro Keto, Tokyo (JP); (51) Int. Cl. Shinobu Akuzawa, Tokyo (JP) A63L/78 (2006.01) C07D 403/06 (2006.01) (73) Assignee: ASTELLAS PHARMA INC., A6IPI/00 (2006.01) Tokyo (JP) A6IPL/T2 (2006.01) (52) U.S. Cl. ................................... 424/78.01: 548/302.7 (21) Appl. No.: 13/061,384 (57) ABSTRACT A method for treatment of a patient suffering from irritable (22) PCT Fled: Aug. 27, 2009 bowel syndrome with diarrhea or mixed irritable bowel syn drome, which comprises administering to the patient a thera (86) PCT NO.: PCT/UP2009/064904 peutically effective amount of ramosetron or a pharmaceuti cally acceptable salt thereof in combination with a S371 (c)(1), therapeutically effective amount of polycarbophil or a phar (2), (4) Date: Feb. 28, 2011 maceutically acceptable salt thereof. Patent Application Publication Jun. 30, 2011 Sheet 1 of 2 US 2011/O1589.30 A1 Fig.1 s 120 aw *e 100 aS$ 100 80 isd 80 v s 60 se sk sk 60 40 6 40 se g 20 20 - a k es O -- - - - , , , g- O W 0. 0.3 1 100 300 000 0.3 g/kg 300 mg/kg 0.3 g/kg + s S. 300 mg/kg Ramosetron Polycarbophi s Š w gkg) (mg/kg) s? s S s cSSk 2 s SS ; SS {r q'sS. & Fig.2 A B it; 120 s 100 s s OO 80 80 - 60 60 3 40 ce: 40 20 is 20 ra r 0 8.- 2 0 OW 1. 3. 100 100 300 OO W 30 g/kg 300 mg/kg 30 g/kg + r--------------------- KY S. 300 mg/kg Ramosetron Polycarbophil s S gkg) (mg/kg) ass g s S. c S. k q'ss & Fig. 3 6 250 5 200 g sk ss 150 - 3 100 – 50 H O OW 10 30 OO 100 30 OOO Ramosetron Polycarbophil (ug/kg) (mg/kg) Patent Application Publication Jun. 30, 2011 Sheet 2 of 2 US 2011/O1589.30 A1 Fig.4 250 2OO 150 1OO 50 O ---- DW 3OO 1000 DW 300 1000 Polycarbophil Polycarbophil (mg/kg) (mg/kg) Ramosetron 100 g/kg Fig.5 250 200 - 150 100 50 OW 3OO 1000 DW 3OO 1000 Polycarbophil Polycarbophil (mg/kg) (mg/kg) Ramosetron 100 uglkg US 2011/0158930 A1 Jun. 30, 2011 METHOD FOR TREATMENT OF RRTABLE 0007 Patent Reference 3: U.S. Pat. No. 3,297,664 BOWEL, SYNDROME 0008 Patent Reference 4: WO 2004/062623 TECHNICAL FIELD 0009 Patent Reference 5: WO 2008/096777 0001. The present invention relates to a treatment method of using ramosetron or a pharmaceutically acceptable salt Non-Patent References thereof in combination with polycarbophil or a pharmaceuti (0010. Non-Patent Reference 1: Gastroenterology, 2006; cally acceptable salt thereof for treatment of a patient suffer 130: p. 1480-1491 ing from irritable bowel syndrome with diarrhea or mixed 0011 Non-Patent Reference 2: Japanese Journal of Phar irritable bowel syndrome. macology, 2002; 89: p. 133-141 BACKGROUND ART 0012 Non-Patent Reference 3: Neurogastroenterology 0002 Irritable bowel syndrome (IBS) is a functional gas and Motility, 2008; 20(5): p. 557-565 trointestinal disorder with which the patient experiences chronic disturbance of bowel habit (constipation or diarrhea) DISCLOSURE OF THE INVENTION and abdominal pain/discomfort without any organic disease 0013 The present inventors have assiduously studied for in the gastrointestinal tract. According to the diagnostic cri the purpose of creating a more excellent treatment method for teria for IBS (Rome III Criteria) published in 2006, IBS is patients suffering from IBS with diarrhea or mixed IBS. categorized as IBS with constipation, IBS with diarrhea, 0014. As a result, the inventors have confirmed an excel mixed IBS or unclassified IBS (for example, see Non-Patent lent synergistic effect of ramosetron in combined administra Reference 1). It is reported that the prevalence of IBS to the tion with polycarbophil both in the pharmacological efficacy total population reaches 10% to 20% and IBS patients and the side effect thereof, and have completed the present account for about 20 to 40% of outpatients in gastrointestinal invention. medicine department, and it is considered that IBS is a gas 0015 Using a restraint stress induced rat diarrheal model trointestinal disorder recognized at high frequency. Further, and a 5-HT induced mouse diarrheal model, the inventors the IBS symptom greatly worsens the quality of life and the investigated the Synergistic effect of ramosetron and polycar work productivity of the patient, which is being a serious bophiland have found that the combined use of the two drugs Social problem. At present, for the pharmacological treatment significantly enhances the respective inhibitory effects for of IBS, mainly used is an antispastic drug Such as anticholin diarrhea. Further, the inventors have found that the repeated ergic drug, an antidiarrheal drug such as opioid receptorago combined administration of ramosetron and polycarbophil nist, or a bulking-agent or a probiotics for regulating the attenuates the inhibitory effect of ramosetron on spontaneous enteric environment. defecation in mice. On the other hand, it is reported that a 0003 Ramosetron is a serotonin (5-HT) receptor antago high-molecular polymer Such as colestimide or sevelamer nist having a chemical name of (-)-(R)-5-(1-methyl-1H hydrochloride adsorbs the other low-molecular compound indol-3-yl)carbonyl-4,5,6,7-tetrahydro-1H-benzimidazole administered simultaneously therewith and attenuates the (for example, see Patent Reference 1). Heretofore, ramo absorption and the effect of the compound (Kayset al., Am. J. setron has been prescribed for an adult patient with the gas Kidney Dis. 2003:42: 1253-1259;Yamada et al., Pharmacol trointestinal symptom Such as vomiting caused by antine ogy and Therapy, 2001; 29: 37–44). However, oral adminis oplastic agents, in a mode of oral administration at a dose of tration of a prepared mixed solution of ramosetron and poly 0.1 mg once a day or intravenous injection at a dose of 0.3 mg carbophil has been confirmed to possess the antidiarrheal once a day. Recently, it has been confirmed that ramosetron effect, but on the contrary, rather provides significant effect hydrochloride at an extremely low daily dose of 0.001 to 0.05 enhancement; and therefore, it is considered that the possi mg is also effective for treatment of IBS with diarrhea (for bility that polycarbophil may adsorb ramosetron to attenuate example, see Patent Reference 2). At present, there are only a the effect thereof would be low. few reports showing the efficacy of the combined use of 5-HT, receptor antagonist with any other agent for IBS, such SUMMARY OF THE INVENTION as a noradrenaline reuptake inhibitor and a mast-cell degranu lation inhibitor (for example, see Patent References 4 and 5), 0016 Specifically, the invention relates to the following: while it is still unclear whether the concomitant administra 0017 (1) A method for treatment of a patient suffering tion of ramosetron with the existing agents for IBS described from irritable bowel syndrome with diarrhea or mixed irri above show the beneficial synergistic effect. table bowel syndrome, which comprises administering to the 0004. On the other hand, polycarbophil is a polyacrylic patient a therapeutically effective amount of ramosetron or a acid crosslinked with divinylglycol, and is a high-molecular pharmaceutically acceptable salt thereof in combination with polymer having high water absorbability (for example, see atherapeutically effective amount of polycarbophil or a phar Patent Reference 3). Polycarbophil is used as an antidiarrheal maceutically acceptable salt thereof; drug or for treatment of altered bowel habit in IBS. Specifi 0018 (2 The method of 1 comprising administering to cally, it is considered that, owing to its water absorbing effect, the patient 0.001 to 0.05 mg of ramosetron hydrochloride as polycarbophil could absorb water in an intestinal lumen a daily dose or an equivalent molar amount of ramosetron or increased by stress or the like, therefore normalizing the stool other pharmaceutically acceptable salt thereof, and condition to prevent diarrhea (for example, see Non-Patent 0019. 3. The method of 1 or 2 comprising administer References 2 and 3). ing to the patient 1.0 to 5.0 g of polycarbophil calcium as a daily dose or an equivalent molar amount of polycarbophil or PRIOR ART REFERENCES other pharmaceutically acceptable salt thereof. Patent References 0020. The invention also relates to the following: 0005 Patent Reference 1: EP 381422 0021 4Use of ramosetron or a pharmaceutically accept 0006 Patent Reference 2: US 2005/0192329 able salt thereof for the manufacture of a medicament for the US 2011/0158930 A1 Jun. 30, 2011 treatment of irritable bowel syndrome with diarrhea or mixed each group with n=12, in which *P<0.05/3, **P<0.01/3 to irritable bowel syndrome in combination with polycarbophil distilled water administration group (Fisher's exact test). B or a pharmaceutically acceptable salt thereof, and shows the incidence of diarrhea in each group with n=24, in 0022 5. Use of ramosetron hydrochloride in a daily dose which *P<0.05, **P<0.01 to distilled water administration of 0.001 to 0.05 mg, or an equivalent molar amount of ramo group, #P-0.05, #P-0.01 to ramosetron or polycarbophil setron or other pharmaceutically acceptable salt thereof, for administration group (Fisher's exact test).